GB2487366A - Use of inhibitors of ATP-sensitive potassium channels for the treament of hearing loss - Google Patents
Use of inhibitors of ATP-sensitive potassium channels for the treament of hearing loss Download PDFInfo
- Publication number
- GB2487366A GB2487366A GB1100783.8A GB201100783A GB2487366A GB 2487366 A GB2487366 A GB 2487366A GB 201100783 A GB201100783 A GB 201100783A GB 2487366 A GB2487366 A GB 2487366A
- Authority
- GB
- United Kingdom
- Prior art keywords
- atp
- inhibitor
- sensitive potassium
- potassium channel
- hearing loss
- 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.)
- Withdrawn
Links
- 206010011878 Deafness Diseases 0.000 title claims abstract description 48
- 230000010370 hearing loss Effects 0.000 title claims abstract description 47
- 231100000888 hearing loss Toxicity 0.000 title claims abstract description 47
- 208000016354 hearing loss disease Diseases 0.000 title claims abstract description 47
- 108010053914 KATP Channels Proteins 0.000 title claims abstract description 39
- 102000016924 KATP Channels Human genes 0.000 title claims abstract description 39
- 239000003112 inhibitor Substances 0.000 title claims abstract description 39
- 229960004580 glibenclamide Drugs 0.000 claims abstract description 34
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims abstract description 34
- 206010036626 Presbyacusis Diseases 0.000 claims abstract description 22
- 229940100389 Sulfonylurea Drugs 0.000 claims abstract description 10
- 208000009800 presbycusis Diseases 0.000 claims abstract description 10
- 238000007920 subcutaneous administration Methods 0.000 claims abstract description 4
- 239000007924 injection Substances 0.000 claims abstract description 3
- 238000002347 injection Methods 0.000 claims abstract description 3
- 239000008188 pellet Substances 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 15
- 230000037396 body weight Effects 0.000 claims description 8
- -1 sulfonylurea compound Chemical class 0.000 claims description 5
- 102100024645 ATP-binding cassette sub-family C member 8 Human genes 0.000 claims description 4
- 101000760570 Homo sapiens ATP-binding cassette sub-family C member 8 Proteins 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 2
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 claims description 2
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 claims description 2
- HNSCCNJWTJUGNQ-UHFFFAOYSA-N Glyclopyramide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)NC(=O)NN1CCCC1 HNSCCNJWTJUGNQ-UHFFFAOYSA-N 0.000 claims description 2
- 108010091821 Sulfonylurea Receptors Proteins 0.000 claims description 2
- 102000018692 Sulfonylurea Receptors Human genes 0.000 claims description 2
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 claims description 2
- 229960001466 acetohexamide Drugs 0.000 claims description 2
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 210000000170 cell membrane Anatomy 0.000 claims description 2
- 229960001761 chlorpropamide Drugs 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000006196 drop Substances 0.000 claims description 2
- 239000003221 ear drop Substances 0.000 claims description 2
- 229940047652 ear drops Drugs 0.000 claims description 2
- 229960000346 gliclazide Drugs 0.000 claims description 2
- 229960004346 glimepiride Drugs 0.000 claims description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 claims description 2
- 229960001381 glipizide Drugs 0.000 claims description 2
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims description 2
- 229960003468 gliquidone Drugs 0.000 claims description 2
- 229950002888 glyclopyramide Drugs 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 229960002277 tolazamide Drugs 0.000 claims description 2
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 claims description 2
- 229960005371 tolbutamide Drugs 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims 1
- 230000009885 systemic effect Effects 0.000 abstract description 9
- 230000001681 protective effect Effects 0.000 abstract description 6
- 230000002829 reductive effect Effects 0.000 abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 abstract description 6
- 230000003449 preventive effect Effects 0.000 abstract description 4
- 230000000699 topical effect Effects 0.000 abstract 1
- 241000699670 Mus sp. Species 0.000 description 24
- 102100021177 ATP-sensitive inward rectifier potassium channel 11 Human genes 0.000 description 17
- 101000614701 Homo sapiens ATP-sensitive inward rectifier potassium channel 11 Proteins 0.000 description 17
- 108091006146 Channels Proteins 0.000 description 13
- 230000010372 presbyacusis Effects 0.000 description 12
- 229940068196 placebo Drugs 0.000 description 11
- 239000000902 placebo Substances 0.000 description 11
- 238000011740 C57BL/6 mouse Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 7
- 230000002068 genetic effect Effects 0.000 description 7
- 238000011813 knockout mouse model Methods 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000010172 mouse model Methods 0.000 description 6
- 102000004257 Potassium Channel Human genes 0.000 description 5
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 5
- 210000002768 hair cell Anatomy 0.000 description 5
- 108020001213 potassium channel Proteins 0.000 description 5
- 230000024883 vasodilation Effects 0.000 description 5
- 230000032683 aging Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002513 implantation Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 241000282412 Homo Species 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 210000003027 ear inner Anatomy 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 238000001134 F-test Methods 0.000 description 2
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 2
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 2
- 208000000258 High-Frequency Hearing Loss Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010028632 Myokymia Diseases 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 208000009966 Sensorineural Hearing Loss Diseases 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 208000032257 benign familial neonatal 1 seizures Diseases 0.000 description 2
- 210000000133 brain stem Anatomy 0.000 description 2
- 230000006727 cell loss Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 231100000885 high-frequency hearing loss Toxicity 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000013707 sensory perception of sound Effects 0.000 description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 1
- TUMUOLDYJYUKOV-UHFFFAOYSA-N 1-(4-imidazol-1-ylbenzoyl)-n-methylcyclobutane-1-carbothioamide Chemical compound C=1C=C(N2C=NC=C2)C=CC=1C(=O)C1(C(=S)NC)CCC1 TUMUOLDYJYUKOV-UHFFFAOYSA-N 0.000 description 1
- UNKNNJPCQUDLMW-UHFFFAOYSA-N 2-[1-(3-chlorophenyl)cyclobutyl]-1-cyano-3-pyridin-3-ylguanidine Chemical compound ClC1=CC=CC(C2(CCC2)N\C(NC=2C=NC=CC=2)=N\C#N)=C1 UNKNNJPCQUDLMW-UHFFFAOYSA-N 0.000 description 1
- TYZQFNOLWJGHRZ-UHFFFAOYSA-N 2-[2-(4,5-dihydro-1h-imidazol-2-yl)-1-phenylethyl]pyridine Chemical compound N=1CCNC=1CC(C=1N=CC=CC=1)C1=CC=CC=C1 TYZQFNOLWJGHRZ-UHFFFAOYSA-N 0.000 description 1
- ZTGKHKPZSMMHNM-UHFFFAOYSA-N 3-(2-phenylethenyl)benzene-1,2-disulfonic acid Chemical class OS(=O)(=O)C1=CC=CC(C=CC=2C=CC=CC=2)=C1S(O)(=O)=O ZTGKHKPZSMMHNM-UHFFFAOYSA-N 0.000 description 1
- YJCCSLGGODRWKK-NSCUHMNNSA-N 4-Acetamido-4'-isothiocyanostilbene-2,2'-disulphonic acid Chemical compound OS(=O)(=O)C1=CC(NC(=O)C)=CC=C1\C=C\C1=CC=C(N=C=S)C=C1S(O)(=O)=O YJCCSLGGODRWKK-NSCUHMNNSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 208000012904 Bartter disease Diseases 0.000 description 1
- 208000010062 Bartter syndrome Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 102000014468 Calcitonin Gene-Related Peptide Receptors Human genes 0.000 description 1
- 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 description 1
- 208000025103 Congenital isolated hyperinsulinism Diseases 0.000 description 1
- 208000011897 Deaf-Blind disease Diseases 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000016621 Hearing disease Diseases 0.000 description 1
- 208000027601 Inner ear disease Diseases 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 108020005196 Mitochondrial DNA Proteins 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 102100035593 POU domain, class 2, transcription factor 1 Human genes 0.000 description 1
- 101710084414 POU domain, class 2, transcription factor 1 Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 1
- 206010061373 Sudden Hearing Loss Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 210000003030 auditory receptor cell Anatomy 0.000 description 1
- WNRBERXEBGAUGT-UHFFFAOYSA-N benzo[c]quinolizin-11-ium Chemical class C1=CC=[N+]2C3=CC=CC=C3C=CC2=C1 WNRBERXEBGAUGT-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- VKQDZNZTPGLGFD-UHFFFAOYSA-N ciclazindol Chemical compound C12=NCCCN2C2=CC=CC=C2C1(O)C1=CC=CC(Cl)=C1 VKQDZNZTPGLGFD-UHFFFAOYSA-N 0.000 description 1
- 229950009468 ciclazindol Drugs 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229950002375 englitazone Drugs 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 201000004403 episodic ataxia Diseases 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000012254 genetic linkage analysis Methods 0.000 description 1
- 229960001764 glibornuride Drugs 0.000 description 1
- RMTYNAPTNBJHQI-LLDVTBCESA-N glibornuride Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)N[C@H]1[C@H](C2(C)C)CC[C@@]2(C)[C@H]1O RMTYNAPTNBJHQI-LLDVTBCESA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000009569 green tea Nutrition 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 208000014612 hereditary episodic ataxia Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- VDNVVLOBNHIMQA-UHFFFAOYSA-N iberiotoxin Chemical compound C1SSCC(C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(O)=O)NC(=O)C(CCCNC(N)=N)NC(=O)C1NC(=O)C(CCCCN)NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCCNC(N)=N)NC(=O)C(CC(O)=O)NC(=O)C(C(C)C)NC(=O)CNC(=O)C(CC=1C=CC=CC=1)NC(=O)C(CC(C)C)NC(=O)C(CC(O)=O)NC(=O)C(CCCCN)NC1=O)CSSCC1NC(=O)C(C(C)C)NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(NC(=O)C(CCC(O)=O)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(CO)NC1=O)CSSCC1NC(=O)C(CC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(O)=O)NC(=O)C(C(C)O)NC(=O)C(NC(=O)C1NC(=O)CC1)CC1=CC=CC=C1 VDNVVLOBNHIMQA-UHFFFAOYSA-N 0.000 description 1
- 108010068927 iberiotoxin Proteins 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 208000004731 long QT syndrome Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960001962 mefloquine Drugs 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229950001332 midaglizole Drugs 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 229960003365 mitiglinide Drugs 0.000 description 1
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 230000012769 potassium ion homeostasis Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- QHGVXILFMXYDRS-UHFFFAOYSA-N pyraclofos Chemical compound C1=C(OP(=O)(OCC)SCCC)C=NN1C1=CC=C(Cl)C=C1 QHGVXILFMXYDRS-UHFFFAOYSA-N 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- XLOMZPUITCYLMJ-UHFFFAOYSA-N thiamylal Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=S)NC1=O XLOMZPUITCYLMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001166 thiamylal Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 230000009495 transient activation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 208000027491 vestibular disease Diseases 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The use of inhibitors of ATP-sensitive potassium channels for the protective (including preventive) therapy or the reduced progression of hearing loss, in particular age-related hearing loss (presbycusis). Preferred is the systemic or local administraÂtion of clinically established sulfonylureas, such as, for example, glibenclamide. The administration may be oral, topical, subcutaneous or by injection.
Description
Use of inhibitors of ATP-sensitive potassium channels for the treatment of hearing loss The present invention relates to the use of inhibitors of ATP-sensitive potassium channels for the protective (including preventive) therapy or the reduced progression of hearing loss, in particular age-related hearing loss (presbycusis). Preferred is the systemic or local administra-tion of clinically established sulfonylureas, such as, for example, glibenclamide.
Presbyacusis is a major form of sensorineural age-related hearing loss that involves the de- generation and irreversible loss of hair cells in the mammalian inner ear. It affects about 70- 80% of the elderly (> 65 years) and currently no protective or curative therapy exists. The pathomechanisms of presbyaeusis are not well understood, but ischemia, oxidative stress and mutations of mitochondrial DNA might, among others, contribute to hair cell loss.
Glibenciamide is an example for the group of suifonylureas and is used as an oral antidiabetic, GlibencIamide blocks ATP-sensitive potassium channels in -eeiis of the pancreas, which facilitates insulin release.
Herzog et al. (in: Herzog M, Scherer EQ, Albrecht B, Rorabaugh B, Scofield MA, Wange-mann P. CGRP receptors in the gerbil spiral modiolar artery mediate a sustained vasodilation via a transient cAMP-mediated Ca2+-decrease. J Membr Biol. 2002 Oct 1;189(3):225-36) describe the alteration of eochlear blood flow as may be involved in the etiology of inner ear disorders like sudden hearing loss, fluctuating hearing loss and tinnitus. The K+-channel blockers iberiotoxin and glibenclamide partially prevented CGRP-or forskolin-induced vaso- dilations but failed to reverse these vasodilations. The publication suggests that the vasodila-tion, amongst others, is mediated by a transient activation of glibenclamide-sensitive KATP channels. Glibenclamide can prevent vasodilation, but not reverse it. Furthermore, a connec-tion with presbycusis is not mentioned.
Wu and Marcus (in: Wu T, Marcus DC. Age-related changes in cochlear endolymphatic po-tassium and potential in CD-l and CBAICaJ mice. J Assoc Res Otolaryngol. 2003 Sep;4(3):353-62) describe the CD-i mouse strain as known to have early onset of hearing loss that is progressive with aging, and thus examined whether a disturbance of K+ homeostasis and pathological changes in the cochlear lateral wall were involved in the age-related hearing loss (AHL) of CD-i as compared to the CBAICaJ strain which has minimal AHL. Old CD-i mice displayed a significantly reduced endolymphatic K+ concentration by 30% in both basal and apical turns.
WO 2005/025293 describes fused ring heterocycles as potassium channel modulators, in par- ticular in the treatment of diseases through the modulation of potassium ion flux through volt-age-dependent potassium channels, such as central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearing and vision loss, Alzheimer's disease, age-related memory loss, learning deficiencies, anxiety and motor neuron diseases, maintaining bladder control or treating urinary incontinence). WO 2005/025293 relates to the modulation of "voltage-dependent" potassium-channels, and there-fore channels different in molecular composition, functional and pharmaceutical properties from those in the present invention.
Tn view of the above, an ongoing demand exists for the development of new and effective treatments for the protective (including preventive) therapy or the reduced progression of hearing loss, in particular age-related hearing loss presbycusis).
In a first aspect of the present invention, this object of the present invention is solved by an inhibitor of an ATP-sensitive potassium channel for use in the treatment of hearing loss, pref-erably age-related hearing loss (presbycusis). Further preferred is the use of glihenclamide for the production of a medicament for the treatment of hearing loss, preferably age-related hear- ing loss (presbycusis). Another aspect of the present invention relates to a method for treat- ment of hearing loss, preferably age-related hearing loss (presbycusis), comprising adminis-tering to a patient in need thereof a therapeutically effective amount of an inhibitor of an ATP-sensitive potassium channel.
In the context of the present invention, treatment shall include both cell-protective (including preventive) therapy or the reduced progression and/or actual treatment of the disease symp-toms of hearing loss, preferably, age-related hearing loss as described herein, which can be alleviated and/or even completely abolished using said treatment.
Preferred is an inhibitor of an ATP-sensitive potassium channel according to the present in- vention, wherein said ATP-sensitive potassium channel is selected from ATP-sensitive potas-sium channels of the plasma membrane that comprise Kjr6. 1 and/or Kir6.2type subunits as well as sulfonylurea receptors (SUR1/SUR2a/b), and combinations thereof More preferred is the inhibitor of an ATP-sensitive potassium channel according to the present invention, wherein said ATP-sensitive potassium channel is selected from ATP-sensitive potassium channels comprising an Kjr6.2-type subunit, as well as a SUR1 subunit.
Furthermore, additional suitable potassium channels can be identified by the person of skill based on channels based on methods as described in the literature, such as, for example in Shieh et al. (Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M Potassium channels: mo- lecular defects, diseases, and therapeutic opportunities Pharmacol Rev. 2000 Dec;52(4):557- 94). Over 50 human genes encoding various K(+) channel subunits have been cloned during the past decades, and precise biophysical properties, subunit stoichiometry, channel assembly, and modulation by second messenger and ligands have been elucidated to a large extent. Re-cent advances in genetic linkage analysis have greatly facilitated the identification of many disease-producing loci, and naturally occurring mutations in various K(+) channels have been identified in diseases such as long-QT syndromes, episodic ataxia/myokymia, familial con- vulsions, hearing and vestibular diseases, Bartter's syndrome, and familial persistent hyperin-sulinemic hypoglycemia of infancy. Shieh et al. aim to 1) provide an understanding of K(+) channel function at the molecular level in the context of disease processes and 2) discuss the progress, hurdles, challenges, and opportunities in the exploitation of K(+) channels as thera-peutic targets by pharmacological and emerging genetic approaches.
The present invention is based on the surprising finding that the application of sulfonylureas, such as, for example, glibenclamide in a mouse model showed a clearly protective effect on hearing of aging animals. A similar effect is expected in the human patient, whereby an irre-versible loss of the inner and outer hair cells shall be prevented. Nevertheless, the detailed mechanisms for the effect of inhibitors of ATP-sensitive potassium channels are currently not known.
In mouse models of Parkinson Disease, where aging is also the main risk factor, the genetic inactivation of the ATP-sensitive potassium channel (K-ATP) subunit Kirô.2 completely res-cued vulnerable dopamine neurons from degeneration (Liss et al. 2005, Nature Neuroscience).
Thus, the inventors investigated whether the early age of onset and rapid progression of pres- byacusis present in the C57BL/6 mouse genetic background could be prevented by systemi-cally blocking Kir6.2-containing K-ATP channels with the specific inhibitor glibenclamide (sulfonylurea).
hi general, any suitable inhibitor of an ATP-sensitive potassium channel according to the pre- sent invention can be used in order to provide a treatment. In addition to the inhibitors as de-scribed herein, such as the sulfonylureas, the person of skill can identify new inhibitors through screening potential inhibitors using known ATP-sensitive potassium channels, such as, for example ATP-sensitive potassium channels comprising SUR1/Kjr6.2-type subunits.
Preferred is the inhibitor of an ATP-sensitive potassium channel according to the present in-vention, wherein said inhibitor is selected from a sulfonylurea compound containing a central S-phenyl sulfonylurea structure, for example with at least one p-substitution on the phenyl ring, and various groups terminating the urea N' end group, such as acetohexamide, chlor- propamide, tolbutamide, tolazamide, glipizide, gliclazide, glibenclamide (glyburide), gliqui- done, glyclopyramide, glibornuride, and glimepiride. All sulfonylureas contain a central 5- phenyl sulfonylurea structure with p-substitution on the phenyl ring and various groups termi- nating the urea N' end group. Further preferred are a 1. generation or 2. generation sulfony-lurea, glinides, and other drugs established to inhibit beta-cell-like ATP-sensitive potassium channels, such as glinides, such as, for example, nateglinide, repaglinide, mitiglinide, megliti-nide, gliptins, such as, for example, sitagliptin, vildagliptin, thiazolidinedione derivatives, such as troglitazone, englitazone, ciclazindol, neomycin, (-)-epigallocatechin-3-gallate (EGCG), a major polyphenolic substance found in green tea, haloperidol, taurine, propofol, thiamylal, phenformin, metformin, benzo[c]quinolizinium compounds MPB-9 1, cyanogua-nidine PNU-99963, midaglizole, LY397364, LY389382, stilbene disulphonates D1DS and SITS, mefloquine, and MCC-134 (1 -[4-(l H-imidazol-1-yl)benzoyl] -N-methyl-cyclobutanecarbothioamide).
In general, the inhibitor according to the invention can be provided to the patient in any suit-able and effective manner, such as orally, topically, subcutaneously, systemically, rectally or by injection. Preferred is systemically or locally. Furthermore, the inhibitor according to the invention can be provided to the patient in any suitable and effective pharmaceutically accept- able form, such as in the form of a tablet, eardrops, subcutaneous pellet, drops, droplets, cap- sule, dragée, powder, suppository and/or gel. Most preferred is the systemic or local admini-stration of already clinically validated and established sulfonylureas, such as, for example glibenclamide. Particularly preferred is the local intracochlear administration, for example via an implanted device, such as, for example, a respectively modified drug eluting electrode, drug reservoir electrode, an electrode coated with a drug-releasing polymer, or the intrascalar application via implantable miero-fluidics technology systems (see, for example, Fiering J, et al., Local drug delivery with a self-contained, programmable, microfluidic system. Biomed Microdevices. 2009 Jun;1 1(3):571-8).
In general, the inhibitor according to the invention can be provided to the patient in any suit- able and effective amount or dosage, such as in an amount of between 0.1 mg to 10 mg, pref- erably 0.2 mg to 5 mg, and more preferably between 0.5 mg to 2 mg per dosage as adminis-tered. Further preferably, said inhibitor according to the invention is provided in a dosage of between 0.2 mg/kg of body weight to 5 mg/kg of body weight per day, preferably between 0.1 mg/kg of body weight to 2 mg/kg of body weight per day. Furthermore, the inhibitor accord-ing to the invention can be provided to the patient over any suitable period of time in one or more dosages per day, preferably said inhibitor is administered over a period of between 4 weeks to 12 months to the patient.
The patient preferably can be a mammalian patient, such as, for example, a human patient, more preferably a patient having an age of more than 50 years, or 55 years. Nevertheless, the invention also includes younger patients with risk factors, such as, for example, soldiers, mu-sicians or hunters.
Another aspect of the present invention relates to a method for treating hearing loss, prefera-bly age-related hearing loss (presbycusis), comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of an ATP-sensitive potassium channel as described herein.
Yet another aspect of the present invention then relates to a method for reducing the fre- quency, occurrence, and/or severity of hearing loss, preferably age-related hearing loss (pres-bycusis), comprising administering to a patient in need thereof a therapeutically effective amount of an inhibitor of an ATP-sensitive potassium channel as described herein.
Systemic application of glibenclamide significantly reduces the progression of age-related hearing loss in a mouse model of presbyacusis. The inventors' results indicate that glibencla-mide, a licensed drug in human therapy of diabetes mellitus, promises to have a therapeutic potential against age-related hearing loss also in humans. The inventors expect an even larger efficiency combined with smaller systemic side effects by local glibenclamide treatment of the inner ear, for example, by the use of established intratympanic drug delivery systems (see also above).
The present invention will now he explained in the following examples with reference to the accompanying figures, without being limited thereto. For the purposes of the present inveiF tion, all references as cited herein are incorporated by reference in their entireties.
Figure 1 shows the mean ABR thresholds of wildtype mice at the age of 4 weeks (dashed line, n=7) and age-matched Kir6.2 knockout mice (continuous line, n=1 1).
Figure 2 shows the mean ABR thresholds of wildtype mice at the age of 12 weeks (dashed line, n=7) and age-matched Kir6.2 knockout mice (continuous line, n1 1).
Figure 3 shows the mean ABR thresholds of wildtype mice at the age of 24 weeks (dashed line, n=7) and age-matched Kir6.2 knockout mice (continuous line, n=1 1).
Figure 4 shows the mean ABR thresholds of 52 week old wildtype mice (n14; dashed line) and 96 week old Kir6.2 knockout mice (n=5; continuous line).
Figure 5 shows the time course of mean ABR thresholds of Kir6.2 knockout mice from 4 weeks up to 52 weeks of age (left panel) and wildtype mice (right panel) from 4 weeks up to 96 weeks of age.
Figure 6 shows the mean ABR-thresholds of 13 C57BL/6 mice treated with Placebo pellets (dashed line) and 13 CS7BL/6 mice treated with glibenclamide pellets (continuous line) be-fore treatment on day one (P0).
Figure 7 shows the mean ABR-thresholds of 12 CS7BL/6 mice treated with Placebo pellets (dashed line) and 10 C57BL/6 mice treated with glibenclamide pellets (continuous line) 13 weeks after pellet implantation (P13W).
Figure 8 shows the mean ABR-thresholds of 13 C57BL/6 mice treated with Placebo pellets (dashed line) and 13 C57BL/6 mice treated with glibenclamide pellets (continuous line) 26 weeks after pellet implantation (P26W).
Figure 9 shows the time course of mean ABR thresholds of the glibenclamide treated mice (left panel) and the placebo group (right panel) from experimental day one (P0) up to 26 weeks after pellet implantation (P26W).
Examples
Example 1 -K-ATP channel knockout mice are protected against presbyacusis To compare the onset and progression of age-related hearing loss (presbyacusis) in mice with a genetic inactivation of the ATP-sensitive potassium channel (K-ATP) subunit Kir6.2 (Kir6.2K0) in comparison to genetic background controls (C57B16), the inventors determined threshold audiograms from auditory brainstem evoked responses (ABR) to tone-pips (2-45 kHz) from an age of 4 up to 96 weeks. Results are plotted as mean + SEM. Fishers F-test and Student's t-test were used to assess statistical differences of mean ABR thresholds at a sig-nificance level of 0.05 (*) or 0.01 (**).
Wildtype mice of C57BL/6 genetic background developed early-onset presbyacusis with in-creased thresholds in the high frequency range. In contrast, Kir6.2 knockout (KO) mice showed a statistically significant slowing and reduction of the age-dependent high-frequency hearing loss by about 50 dB at one year of age. At 4 weeks of age ABR thresholds of Kir6.2 KO mice and CS7BL/6 mice were similar. However, at higher frequencies (32 and 45.2 kHz) Kir6.2 KO mice showed significantly lower thresholds (Fig. 1).
Typically, age-related hearing loss proceeds from high to low frequencies. In the wildtype mice, it has reached 16 kHz at 12 week of age (Fig. 2). However, a moderate hearing loss also occurs at the lower frequencies (2.8 and 4 kHz). Tn contrast, there was no significant hearing loss at any frequency in the Kir6.2 KO mice: At the age of 24 weeks C57BL/6 mice developed a severe hearing loss both at the higher and lower frequencies compared to the Kirô.2K0 mice (Fig. 3).
At 96 weeks of age wildtype mice are virtually deaf (dashed line in Fig. 4). The C57BL/6 audiogram at 52 weeks of age showed significant frequency dependent threshold losses be-tween 20 to 45 dB (Fig 4).
In contrast to wildtype mice, which developed early-onset presbyacusis with increased thresholds in the high frequency range, Kir6.2 knockout mice showed a significant slowing of age-dependent hearing loss and reduction of the age-dependent high-frequency hearing loss by about 50 dB at one year of age (Fig. 5). The inventors verified by histological analysis that presbyacusis was associated with hair cell loss. Global genetic inactivation of K-ATP chan- nels containing the Kir6.2 subunit significantly reduces the progression and severity of age-related hearing loss in a mouse model of presbyacusis. As the inventors also detected mRNA and functional expression of Kir6.2-mediated K-ATP channels in cochlear hair cells, the data show that Kir6.2-containing K-ATP channels in hair cells might control the vulnerability for age-related hearing loss. Given the global and unconditional nature of the Kir6.2 knockout model, more indirect and systemic effects cannot be excluded. However, the main systemic effect in the Kir6.2 KO mouse is a diabetic metabolic state with reduced glucose tolerance, which is expected to accelerate presbyacusis. In conclusion, our aging study establishes K-ATP channels as novel and promising drug targets to treat age-related hearing loss.
Example 2 -Pharmacological inhibition of ATP-sensitive potassium channels reduces age-related hearing loss in a mouse model of presbyacusis Methods Wild-type CS7BL/6 mice (8 week old males, obtained from Charles River WIGA GmbH, Germany) were implanted with subcutaneous pellets, releasing glibenclamide (glyburide) at a concentration of 27.8 jig per day over a period of up to 7 months. An age matched control group was implanted with placebo pellets (pellets without glibenclamide). Pellets were ob-tained from Innovative Research of America (Sarasota, FL). The occurrence and progression rates of age-related hearing loss were monitored by recording auditory brainstem response (ABR) thresholds. All data are plotted as mean + SEM. Fishers F-test and Student's t-test were used to assess statistical differences of mean ABR thresholds at a significance level of 0.05 (*) or 0.01 (**) Results Male C57BL/6 mice implanted at 8 weeks of age with glibenclamide pellets for chronic ap-plication over a period of up to 7 months showed a delayed onset of and significantly (p<0.05) less age-related hearing loss compared to placebo-treated controls.
Before treatment at 8 weeks, no statistically significant differences in ABR thresholds were detected between the experimental and placebo groups (Fig. 6).
Thirteen weeks after pellet implantation mice treated with glibenclamide showed less age-related hearing loss compared to the placebo group. Note the lower ABR thresholds in the glibenclamide-treated group compared to the placebo-treated group, especially at the higher frequencies (p<O.OS). For instance, at 22.6 kHz the threshold of the glibenclamide-treated group was about 15 dB below that of the placebo-treated control group (Fig. 7).
Another 13 weeks later (P26W) the age-related hearing loss at 22.6 kflz in the glibenclamide-treated group was 23 dB less than in the control group (Fig. 8). Age-related hearing loss in humans and rodents typically progresses from high to low frequencies and has reached 16 kHz at this age in the control group.
The progression of age-related hearing loss was delayed and of smaller amplitude in gliben-clamide-treated mice compared to placebo-treated animals (Fig. 9). At 32 kHz the age-related threshold elevation in both the glibenclamide treated and control group was substantial, but significantly (p> 0.05) smaller in the glibenclamide-treated group. At 22.6 kHz and 16 kHz the protective effect of glibenclamide was obvious.
Systemic application of glibenclamide significantly reduces the progression of age-related hearing loss in a mouse model of presbyacusis. The inventors' results indicate that glibencla-mide, a licensed drug in human therapy of diabetes mellitus, promises to have a therapeutic potential against age-related hearing loss also in humans. The inventors expect an even larger efficiency combined with smaller systemic side effects by local glibenclamide treatment of -10 - the inner ear, for example by the use of already established intratympanic drug delivery sys-tems or the ones as described above. -11 -
Claims (10)
- Claims 1. An inhibitor of an ATP-sensitive potassium channel for use in the treatment of hearing loss.
- 2. The inhibitor of an ATP-sensitive potassium channel according to claim I, wherein said hearing loss is age-related hearing loss (presbycusis).
- 3. The inhibitor of an ATP-sensitive potassium channel according to claim 1 or 2, wherein said ATP-sensitive potassium channel is selected from ATP-sensitive potassium channels of the plasma membrane that comprise Kjró. 1 and/or K116.2-type subunits as well as sulfonylurea receptors (SUR1/SUR2a/b), and combinations thereof
- 4. The inhibitor of an ATP-sensitive potassium channel according to claim 3, wherein said ATP-sensitive potassium channel is selected from ATP-sensitive potassium channels com-prising an K16.2-type subunit.
- 5. The inhibitor of an ATP-sensitive potassium channel according to any of claims 1 to 4, wherein said inhibitor is selected from a sulfonylurea compound containing a central S-phenyl sulfonylurea structure, for example with at least one p-substitution on the phenyl ring, and various groups terminating the urea N' end group, such as acetohexamide, chlorpropamide, tolbutamide, tolazamide, glipizide, gliclazide, glibenclamide (glyburide), gliquidone, gly-clopyramide, and glimepiride.
- 6. The inhibitor of an ATP-sensitive potassium channel according to any of claims 1 to 5, wherein said inhibitor is provided locally, e.g. by local intracochlear administration, orally, topically, subcutaneously, systemically, rectally or by injection.
- 7. The inhibitor of an ATP-sensitive potassium channel according to any of claims 1 to 6, wherein said inhibitor is provided in form of a tablet, eardrops, subcutaneous pellet, drops, droplets, capsule, dragée, powder, suppository or gel.-12 -
- 8. The inhibitor of an ATP-sensitive potassium channel according to any of claims 1 to 7, wherein said inhibitor is provided in an amount of between 0.1 mg to 10 mg, preferably 0.2 mg to 5 mg, and more preferably between 0.5 mg to 2 mg per dosage.
- 9. The inhibitor of an ATP-sensitive potassium channel according to any of claims 1 to 8, wherein said iniibitor is provided in a dosage of between 0.2 mg/kg of body weight to 5 mg/kg of body weight per day, preferably between 0.1 mg/kg of body weight to 2 mg/kg of body weight per day.
- 10. The inhibitor of an ATP-sensitive potassium channel according to any of claims 1 to 9, wherein said inhibitor is administered over a period of at least between 4 weeks to 12 months or longer, such as, for example, continuously.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1100783.8A GB2487366A (en) | 2011-01-18 | 2011-01-18 | Use of inhibitors of ATP-sensitive potassium channels for the treament of hearing loss |
| PCT/EP2012/050683 WO2012098143A1 (en) | 2011-01-18 | 2012-01-18 | Use of inhibitors of atp-sensitive potassium channels for the treatment of hearing loss |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1100783.8A GB2487366A (en) | 2011-01-18 | 2011-01-18 | Use of inhibitors of ATP-sensitive potassium channels for the treament of hearing loss |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB201100783D0 GB201100783D0 (en) | 2011-03-02 |
| GB2487366A true GB2487366A (en) | 2012-07-25 |
Family
ID=43736567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1100783.8A Withdrawn GB2487366A (en) | 2011-01-18 | 2011-01-18 | Use of inhibitors of ATP-sensitive potassium channels for the treament of hearing loss |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2487366A (en) |
| WO (1) | WO2012098143A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10183972B2 (en) | 2016-07-14 | 2019-01-22 | University Of South Florida | BK channel-modulating peptides and their use |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050129783A1 (en) * | 2001-04-19 | 2005-06-16 | Mccleary Edward L. | Composition and method for treatment of neurophysiological conditions and maintenance of neurophysiological health |
| US20070248690A1 (en) * | 2006-04-24 | 2007-10-25 | Trager Seymour F | Composition and methods for alleviating symptoms of neurotoxicity |
| WO2010042728A1 (en) * | 2008-10-08 | 2010-04-15 | Cornell University | Small molecule modulators of prongf uptake |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005025293A2 (en) | 2003-09-10 | 2005-03-24 | Icagen, Inc. | Fused ring heterocycles as potassium channel modulators |
-
2011
- 2011-01-18 GB GB1100783.8A patent/GB2487366A/en not_active Withdrawn
-
2012
- 2012-01-18 WO PCT/EP2012/050683 patent/WO2012098143A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050129783A1 (en) * | 2001-04-19 | 2005-06-16 | Mccleary Edward L. | Composition and method for treatment of neurophysiological conditions and maintenance of neurophysiological health |
| US20070248690A1 (en) * | 2006-04-24 | 2007-10-25 | Trager Seymour F | Composition and methods for alleviating symptoms of neurotoxicity |
| WO2010042728A1 (en) * | 2008-10-08 | 2010-04-15 | Cornell University | Small molecule modulators of prongf uptake |
Non-Patent Citations (1)
| Title |
|---|
| KOCHER, "Presbycusis: Reversible with anesthesia drugs?", Medical Hypotheses, 72, 2009, 157-159 * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB201100783D0 (en) | 2011-03-02 |
| WO2012098143A1 (en) | 2012-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kanzaki et al. | Glial cell line‐derived neurotrophic factor and chronic electrical stimulation prevent VIII cranial nerve degeneration following denervation | |
| KR101733247B1 (en) | Tetrahydroquinoline derivatives for treating post-traumatic stress disorders | |
| US20180235934A1 (en) | Noradrenergic drug treatment of obstructive sleep apnea | |
| US11291671B2 (en) | Solid drug implants for intracochlear delivery of therapeutics for the treatment of Otic disorders | |
| US20100173874A1 (en) | Delivery of modulators of glutamate-mediated neurotransmission to the inner ear | |
| JP2009520801A (en) | Treatment of type 2 diabetes with a combination of DPIV inhibitor and metformin or thiazolidinedione | |
| WO2004022069A1 (en) | Delivery of modulators of glutamate-mediated neurotransmission to the inner ear | |
| Rattka et al. | Do proconvulsants modify or halt epileptogenesis? Pentylenetetrazole is ineffective in two rat models of temporal lobe epilepsy | |
| CA3133912A1 (en) | Cgrp antagonists for the treatment of medication overuse headache, post-traumatic headache, post-concussion syndrome and vertigo | |
| US20220387367A1 (en) | D-Serine Inhibits Neuroinflammation Due To A Brain Injury | |
| Emmett et al. | Treatment of tinnitus with tocainide hydrochloride | |
| Pitha et al. | Sustained Dorzolamide Release Prevents Axonal and Retinal Ganglion Cell Loss in a Rat Model of IOP–Glaucoma | |
| Montiel et al. | Modulation of the autophagy‐lysosomal pathway and endoplasmic reticulum stress by ketone bodies in experimental models of stroke | |
| Assimakopoulos et al. | Treatment of Meniere’s disease by intratympanic gentamicin application | |
| GB2487366A (en) | Use of inhibitors of ATP-sensitive potassium channels for the treament of hearing loss | |
| Wolters | Deep brain stimulation and continuous dopaminergic stimulation in advanced Parkinson's disease | |
| Thumann et al. | Tolbutamide eye drops increase aqueous humor outflow and lower intraocular pressure: a proof of concept for glaucoma treatment | |
| ES2356244T3 (en) | PREPARATION OF FLUPIRTINE FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES OF THE VISUAL SYSTEM AND DIATEBES MELLITUS. | |
| US11911376B2 (en) | Methods for preventing and treating retinal damage | |
| WO2005070437A1 (en) | Drug for treating pain | |
| CN118121599A (en) | Use of PHA-543613 in preparing medicine for treating epilepsy | |
| EP2437740B1 (en) | Treatment of tinnitus and associated auditory dysfunctions | |
| AU2004296566A1 (en) | Compounds for the treatment of ocular dryness caused by photorefractive surgery | |
| Raffaeli et al. | Intrathecal drug administration for the treatment of cancer and non-cancer chronic pain | |
| Mankekar et al. | History of intratympanic managements for inner ear disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |