US20170035705A1 - Detrusor hyperactivity with impaired contractility ameliorating agent - Google Patents
Detrusor hyperactivity with impaired contractility ameliorating agent Download PDFInfo
- Publication number
- US20170035705A1 US20170035705A1 US14/817,318 US201514817318A US2017035705A1 US 20170035705 A1 US20170035705 A1 US 20170035705A1 US 201514817318 A US201514817318 A US 201514817318A US 2017035705 A1 US2017035705 A1 US 2017035705A1
- Authority
- US
- United States
- Prior art keywords
- detrusor
- acid
- dhic
- contractility
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 230000001771 impaired effect Effects 0.000 title claims description 25
- 208000013403 hyperactivity Diseases 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- FGMAOXGOTRUOKJ-UHFFFAOYSA-N 3-(15-hydroxypentadecyl)-2,4,4-trimethylcyclohex-2-en-1-one Chemical compound CC1=C(CCCCCCCCCCCCCCCO)C(C)(C)CCC1=O FGMAOXGOTRUOKJ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000012453 solvate Substances 0.000 claims abstract description 9
- 206010037211 Psychomotor hyperactivity Diseases 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- RBOXVHNMENFORY-KEMUOJQUSA-N dihydroisocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-KEMUOJQUSA-N 0.000 abstract description 32
- 208000004168 Underactive Urinary Bladder Diseases 0.000 description 23
- 230000000694 effects Effects 0.000 description 20
- 206010046555 Urinary retention Diseases 0.000 description 19
- 206010013990 dysuria Diseases 0.000 description 18
- 241000700159 Rattus Species 0.000 description 17
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 17
- 229940125904 compound 1 Drugs 0.000 description 17
- 229960002613 tamsulosin Drugs 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 206010020853 Hypertonic bladder Diseases 0.000 description 13
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 13
- 208000020629 overactive bladder Diseases 0.000 description 13
- 201000010099 disease Diseases 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 230000004064 dysfunction Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000027939 micturition Effects 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 5
- 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 5
- 150000001875 compounds Chemical class 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 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 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 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 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 230000036724 intravesical pressure Effects 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 238000012762 unpaired Student’s t-test Methods 0.000 description 4
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 101100154785 Mus musculus Tulp2 gene Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 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
- 244000299461 Theobroma cacao Species 0.000 description 3
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 3
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 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 3
- 239000000872 buffer Substances 0.000 description 3
- 235000014121 butter Nutrition 0.000 description 3
- 235000001046 cacaotero Nutrition 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- -1 fatty acid ester Chemical class 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 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 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 210000003708 urethra Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010021639 Incontinence Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229920001543 Laminarin Polymers 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohex-2-enone Chemical compound O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- DBTMGCOVALSLOR-VPNXCSTESA-N laminarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O[C@@H]1[C@@H](O)C(O[C@H]2[C@@H]([C@@H](CO)OC(O)[C@@H]2O)O)O[C@H](CO)[C@H]1O DBTMGCOVALSLOR-VPNXCSTESA-N 0.000 description 2
- 238000011418 maintenance treatment Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-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
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 0 CC(C)(CC1)C(*)=C(C)C1=O Chemical compound CC(C)(CC1)C(*)=C(C)C1=O 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 240000004542 Capparis mitchellii Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 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
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 235000004098 Prunus caroliniana Nutrition 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000020967 Sever disease Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 206010052901 Terminal dribbling Diseases 0.000 description 1
- 208000026723 Urinary tract disease Diseases 0.000 description 1
- 239000009975 Urodyn Substances 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N beta-monoglyceryl stearate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000000064 cholinergic agonist Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 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
- 239000007943 implant Substances 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 230000014511 neuron projection development Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
Definitions
- the present invention relates to a method for treating detrusor hyperactivity with impaired contractility (hereinafter referred to as “DHIC”), comprising the step of administering a therapeutically effective amount of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof.
- DHIC detrusor hyperactivity with impaired contractility
- Compound 1 of the present invention is a compound having a structure represented by Formula (1) below.
- Patent Document 1 discloses that a cyclohexenone long-chain alcohol comprising the compound represented by Formula (1) has an effect of promoting neurite growth, and thus is useful as a preventive and/or therapeutic agent for brain disorders such as dementia.
- Patent Document 2 discloses that a cyclohexenone long-chain alcohol comprising the compound represented by Formula (1) is useful as a therapeutic agent for treating dysuria.
- detrusor In normal micturition function, detrusor doesn't contract during storage phase (urine can be reserved in bladder), and contracts during only voiding phase. In storage dysfunction disease (overactive bladder), detrusor overactive occurs during storage phase, so, urine can't be reserved fully in bladder. Medicines, such as an anti-cholinergic agent and a ⁇ receptor agonist, are effective for storage dysfunction disease. While on the other hand, in urine-voiding dysfunction disease (underactive bladder), an increased residual urine volume is a problem. Medicines, such as a cholinesterase inhibitor and a cholinergic agonist, are used for urine-voiding dysfunction disease.
- Non-patent Document 1 Non-patent Document 2
- Non-patent Document 3 an effective agent for underactive bladder is invalidity or detrimental against overactive bladder
- DHIC is a disorder which presents both of detrusor overactive and detrusor impaired contractility in the body of the same individual (Non-patent Document 4, Non-patent Document 5). Because detrusor overactive occurs additionally with a residual urine volume increased by detrusor impaired contractility, it induces high-pressure during storage phase and incontinence. Further, if such condition is left unattended without appropriate care, it results in a sever disease such as urinary-tract infection, upper urinary tract disorder, or renal dysfunction.
- DHIC is clinically diagnosed by confirming coexistence of detrusor overactive during storage phase and detrusor impaired contractility during voiding phase using Pressure-Flow Study (nomogram analysis is useful for the diagnosis) (Non-patent Document 4, Non-patent Document 5).
- Non-patent Document 6 Non-patent Document 6
- overactive bladder is diagnosed by subjective symptom (urgency, incontinence, pollakiuria etc.)
- underactive bladder is diagnosed by subjective symptom (forceless urinary stream, terminal dribbling, retarded micturition, abdominal straining to urinate, a feeling of residual urine, urinary retention etc.), uroflowmetry, and measurement of residual urine volume etc.
- DHIC can be diagnosed by confirming coexistence of both the disorders.
- Non-patent Document 8 the therapeutic agent for DHIC which presents both of detrusor overactivity and detrusor impaired contractility in the body of the same individual. It was recently reported that an ⁇ 1-blocker such as Tamsulosin etc., which was effective on urine-voiding dysfunction (underactive bladder), was also effective on overactive bladder (Non-patent Document 8).
- An object of the present invention is to provide a method for treating DHIC by improving both of detrusor overactivity and detrusor impaired contractility.
- the present invention provides a method for treating a disorder that presents both detrusor overactivity and detrusor impaired contractility, comprising the step of administering a therapeutically effective amount of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof.
- the present invention provides a method for treating DHIC, comprising the step of administering a therapeutically effective amount of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof, to a patient with DHIC.
- the present invention provides a method of ameliorating a disease that presents both of detrusor underactivity and detrusor hyperactivity, using 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof, to a patient that presents both of detrusor underactivity and detrusor hyperactivity.
- the present invention enables effective treatments of DHIC.
- FIG. 1 shows representative cystometry charts of rat dysuria model that presents DHIC.
- FIG. 2 shows the effects of Compound 1 of the present and ⁇ 1-blocker (Tamsulosin) on detrusor contractility in rat dysuria model that presents DHIC.
- Compound 1 of the present invention is a known compound, and is produced by, for example, the method disclosed in International Publication WO1999/008987.
- treatment means maintenance treatment for alleviating the symptoms and preventing the recurrence by improving a disease that presents both of detrusor overactivity and detrusor underactivity, especially, maintenance treatment for alleviating the symptoms and preventing the recurrence by ameliorating DHIC.
- a treatment of DHIC means a method of ameliorating a disease that presents both of detrusor overactivity during storage phase and detrusor impaired contractility during voiding phase.
- Compound 1 of the present invention may be formed acid adduct salt, or base adduct salt.
- the present include the present invention to the extent that the salt is a pharmaceutically acceptable salt thereof.
- the salt includes an acid adduct salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid etc.; an acid adduct salt with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methansulfonic acid, p-toluenesulfonic acid, or glutamic acid etc.; salt with an inorganic base such as sodium, potassium, magnesium, calcium, or aluminum etc.; salt with an organic base such as methylamine, ethylamine, meglumine,
- Examples of the solvent of the solvate of Compound 1 of the present invention include water, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, hexane, acetone, methyl ethyl ketone, and methyl isobutyl ketone etc.
- 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof of the present invention can be prepared into various dosage forms by using known preparation methods using a pharmaceutically acceptable carrier.
- the dosage form is not particularly limited, and examples thereof include oral agents such as tablets, coated tablets, pills, powdered drugs, granules, capsules, liquids, suspensions, or emulsions; and parenteral agents such as injections or suppositories.
- examples of carrier include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid; binders such as water, ethanol, propanol, cornstarch, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium phosphate, or polyvinyl pyrrolidone; disintegrants such as dry starch, sodium alginate, powdered agar, powdered laminaran, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, or lactose; disintegration inhibitors such as sucrose, stearic acid, cacao butter, or hydrogenated oils; absorbefacients such as quaternary ammonium salts or sodium la
- examples of the carrier include excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, or talc; binders such as gum arabic powder, tragacanth powder, gelatin, or ethanol; and disintegrators such as laminaran or agar.
- Capsules are usually prepared in a standard method by blending the drug with one or more carriers as exemplified above, and encapsulating the mixture into hard gelatin capsules, soft capsules, etc.
- an internal liquid medicine, a syrup, an elixir, or the like may be prepared by a standard method using sweetening/flavoring agent, buffer, stabilizer, etc.
- sweetening/flavoring agents include sucrose, wild orange peel, citric acid, and tartaric acid
- buffers include sodium citrate
- stabilizers include tragacanth, gum arabic, and gelatin.
- examples of usable carriers include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides.
- the liquids, emulsions, and suspensions are preferably sterilized and rendered isotonic to the blood.
- diluents for preparing such dosage forms include water, aqueous lactic acid solution, ethanol, propylene glycol, macrogols, ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid ester.
- sodium chloride, glucose, or glycerin in an amount sufficient to prepare an isotonic solution may be added to the pharmaceutical formulation.
- general solubilizers, buffers, anesthetics, and the like may also be added to the pharmaceutical formulation.
- coloring agents, preservatives, aromatics, flavors, sweetening agents, or other medicinal products may be incorporated, if necessary, into the pharmaceutical formulations.
- the method for administering the DHIC ameliorating agent of the present invention is not particularly limited, and is suitably selected according to the dosage form thereof, the age, gender, and other conditions of the patient, the severity of the symptoms of the patient, and the like.
- tablets, pills, powdered drugs, granules, capsules, liquids, suspensions, and emulsions are orally administered.
- the injections are intravenously administered singly, or as a mixture with a general infusion liquid such as liquid glucose or an amino acid liquid. Further, as necessary, the injections are singly administered intra-arterially, intramuscularly, intradermally, subcutaneously, or intraperitoneally.
- the suppositories are intrarectally administered.
- the amount of the compound of the present invention or a salt thereof to be incorporated into each of the above dosage unit form depends on the symptoms of the target patient, or depends on the drug form; however, the amount per dosage unit form is generally preferably about 0.005 to 1,000 mg, more preferably 1 to 800 mg, further preferably 5 to 500 mg for oral agents; about 0.001 to 500 mg, more preferably 0.02 to 400 mg, further preferably 1 to 250 mg for injections; and about 0.01 to 1,000 mg, more preferably 1 to 800 mg, further preferably 5 to 500 mg for suppositories.
- the daily dose for an adult of the drug to be administered with the above dosage form is generally about 0.005 to 5,000 mg, preferably 0.01 to 2,000 mg, more preferably 10 to 1600 mg, further preferably 20 to 800 mg, although such doses depend on the symptom, body weight, age, gender, etc., of the patient.
- the daily dose is preferably taken at one time, or divided into two to four administrations.
- the models were produced by partial ligation ( ⁇ 1.57 mm) of urethra in rats (9 weeks, female, Sprague-Dawley). Six weeks after preparation of the model, the rats were released the ligation. The next day, the intravesical pressure and the voided volume were measured under awake condition. And the detrusor contractility during voiding phase was evaluated by nomogram analysis using Qmax and Pdet. Additionally, the detrusor overactivity, as index of overactive bladder, and the increase of residual urine volume, as index of underactive bladder, were evaluated.
- FIG. 1 shows representative cystometry charts.
- the dysuria model rat control
- sham rat there is the characteristics of detrusor hyperactivity with impaired contractility that are characterized by remarkable overactivity and increased residual urine volume (Table 1).
- Non-patent Document 9 Urol Clin North Am, 17, p 553-566 (1990)
- the plot of control group is positioned in a position relatively close to the origin compared to it of sham group (the distance from the origin: Sham group 24.75 ⁇ 3.14, control group 4.24 ⁇ 0.53, p ⁇ 0.05)
- the distance from the origin: Sham group 24.75 ⁇ 3.14, control group 4.24 ⁇ 0.53, p ⁇ 0.05 it is judged that reduction of detrusor contractility occurs in the rat dysuria model ( FIG. 2 ).
- the dysuria models in this example were prepared in the same manner as in Test Example 1.
- the test drugs (vehicle: 6% Gelucire, Compound 1 of the present invention 10 mg/kg) were orally administered to each group after two weeks from the preparation of the models twice a day for four weeks. On the day of the final administration, the rats were released the ligation of urethra. The next day, the intravesical pressure and the voided volume were measured using cystometry under conscious condition. The detrusor overactivity, as an index of overactive bladder, and the increase of residual urine volume, as an index of underactive bladder, were evaluated. Additionally, the detrusor contractility during voiding phase was evaluated by nomogram analysis using Qmax and Pdet.
- the rats were released the ligation of urethra at six weeks after the preparation of the model.
- the next day the intravesical pressure and the voided volume were measured using cystometry under conscious condition.
- the detrusor contractility during voiding phase was evaluated by nomogram analysis using Qmax and Pdet. Tamsulosin (3 ⁇ g/kg) was administered intravenously to the dysuria rat at the evaluation (six weeks after preparation of the model).
- ⁇ 1 blocker Tropsulosin
- the dysuria models in the present example were prepared by treating 10-week-old female Wistar rats with streptozotocin (65 mg/kg, i.p.). From four weeks after the preparation of the models, Tamsulosin (1 ⁇ g/kg/hr) was administered subcutaneously using osmotic pump. Four weeks after the implant of osmotic pump, the intravesical pressure and the voided volume were measured using cystometry under urethane anesthesia condition. And the residual urine volume, as an index of underactive bladder, was evaluated.
- Table 2 shows the results. In comparison with the Sham group, significant increase of the residual urine volume, which is an index of underactive bladder, was observed in the control group (eight weeks after the development of the disease in the models). Tamsulosin showed significant reduction on the increase of residual urine volume which was observed in the control group.
- Compound 1 of the present invention shows effect for ameliorating both dysfunctions in DHIC that detrusor overactivity and detrusor impaired contractility coexist (Test Example 2). Therefore, it is suggested that Compound 1 of the present invention is a useful therapeutic agent for DHIC (Test Example 2).
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)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
- The present invention relates to a method for treating detrusor hyperactivity with impaired contractility (hereinafter referred to as “DHIC”), comprising the step of administering a therapeutically effective amount of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof.
- 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one (hereinafter referred to as “
Compound 1 of the present invention”) is a compound having a structure represented by Formula (1) below. -
Patent Document 1 discloses that a cyclohexenone long-chain alcohol comprising the compound represented by Formula (1) has an effect of promoting neurite growth, and thus is useful as a preventive and/or therapeutic agent for brain disorders such as dementia. Patent Document 2 discloses that a cyclohexenone long-chain alcohol comprising the compound represented by Formula (1) is useful as a therapeutic agent for treating dysuria. - However, the effect as a therapeutic agent for treating dysuria shown in Patent Document 2 was confirmed only against dysuria with depressed bladder function (the effect was confirmed by the improvement in maximum voided volume, bladder capacity, and micturition efficiency). More specifically, the effect of ameliorating detrusor hyperactivity with impaired contractility of
Compound 1 of the present invention has been completely unknown. - In normal micturition function, detrusor doesn't contract during storage phase (urine can be reserved in bladder), and contracts during only voiding phase. In storage dysfunction disease (overactive bladder), detrusor overactive occurs during storage phase, so, urine can't be reserved fully in bladder. Medicines, such as an anti-cholinergic agent and a β receptor agonist, are effective for storage dysfunction disease. While on the other hand, in urine-voiding dysfunction disease (underactive bladder), an increased residual urine volume is a problem. Medicines, such as a cholinesterase inhibitor and a cholinergic agonist, are used for urine-voiding dysfunction disease. However, it is generally known that an effective agent for overactive bladder does not work or is even detrimental against underactive bladder (Non-patent
Document 1, Non-patent Document 2). Also, it is known that an effective agent for underactive bladder is invalidity or detrimental against overactive bladder (Non-patent Document 3). In these ways, although there are some therapeutic approaches against an individual disease of overactive bladder or underactive bladder, there is merely agent to be expected effective against both overactive bladder and underactive bladder. - DHIC is a disorder which presents both of detrusor overactive and detrusor impaired contractility in the body of the same individual (Non-patent Document 4, Non-patent Document 5). Because detrusor overactive occurs additionally with a residual urine volume increased by detrusor impaired contractility, it induces high-pressure during storage phase and incontinence. Further, if such condition is left unattended without appropriate care, it results in a sever disease such as urinary-tract infection, upper urinary tract disorder, or renal dysfunction.
- DHIC is clinically diagnosed by confirming coexistence of detrusor overactive during storage phase and detrusor impaired contractility during voiding phase using Pressure-Flow Study (nomogram analysis is useful for the diagnosis) (Non-patent Document 4, Non-patent Document 5).
- Also, because DHIC is disorder which presents both of detrusor overactive and detrusor impaired contractility, the diagnosis of overactive bladder and underactive bladder can be available for diagnosis of DHIC (Non-patent Document 6, Non-patent Document 7). Those are, overactive bladder is diagnosed by subjective symptom (urgency, incontinence, pollakiuria etc.), and underactive bladder is diagnosed by subjective symptom (forceless urinary stream, terminal dribbling, retarded micturition, abdominal straining to urinate, a feeling of residual urine, urinary retention etc.), uroflowmetry, and measurement of residual urine volume etc. Then DHIC can be diagnosed by confirming coexistence of both the disorders.
- In therapeutic strategy for DHIC, because conflicting dysfunctions of detrusor overactive and detrusor impaired contractility coexist in the body of the same individual, it is therapeutic high-difficult dysuria. As described above, generally, the ameliorating agent with only either of overactive bladder or underactive bladder was clinically insufficient effect against patients with DHIC.
- Considering this situation, we need the therapeutic agent for DHIC which presents both of detrusor overactivity and detrusor impaired contractility in the body of the same individual. It was recently reported that an α1-blocker such as Tamsulosin etc., which was effective on urine-voiding dysfunction (underactive bladder), was also effective on overactive bladder (Non-patent Document 8).
-
- Patent Document 1: International Publication WO1999/008987
- Patent Document 2: International Publication WO2002/066024
-
- Non-patent Document 1: J Smooth muscle Res 48, p 115-124 (2012)
- Non-patent Document 2: Br J Urol 82, p 272-277 (1998)
- Non-patent Document 3: J Urol 174, p 1137-1141 (2005)
- Non-patent Document 4: JAMA, 257, p 3076-3081 (1987)
- Non-patent Document 5: Rev Hosp Clin Fac Med Sao Paulo, 59, p 206-215 (2004)
- Non-patent Document 6: Neurourol Urodyn, 29, p 4-20 (2010)
- Non-patent Document 7: Eur Urol, 65, p 389-398 (2014)
- Non-patent Document 8: JAMA 296, p 2319-2328 (2006)
- An object of the present invention is to provide a method for treating DHIC by improving both of detrusor overactivity and detrusor impaired contractility.
- The inventors of the present invention carried out extensive research to attain the above object, and found that 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one represented by Formula (1) below ameliorates both of detrusor overactivity and detrusor impaired contractility, and thus is useful as a therapeutic agent for treating a disorder based on DHIC.
- More specifically, the present invention provides a method for treating a disorder that presents both detrusor overactivity and detrusor impaired contractility, comprising the step of administering a therapeutically effective amount of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof.
- Further, the present invention provides a method for treating DHIC, comprising the step of administering a therapeutically effective amount of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof, to a patient with DHIC.
- Further, the present invention provides a method of ameliorating a disease that presents both of detrusor underactivity and detrusor hyperactivity, using 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof, to a patient that presents both of detrusor underactivity and detrusor hyperactivity.
- The present invention enables effective treatments of DHIC.
-
FIG. 1 shows representative cystometry charts of rat dysuria model that presents DHIC. -
FIG. 2 shows the effects ofCompound 1 of the present and α1-blocker (Tamsulosin) on detrusor contractility in rat dysuria model that presents DHIC. - Sham: n=11, Control (6% Gelucire): n=19,
Compound 1 of the present invention (10 mg/kg×2/day p.o.): n=8, Tamsulosin (0.3 mg/kg, i.v.): n=6 -
Compound 1 of the present invention is a known compound, and is produced by, for example, the method disclosed in International Publication WO1999/008987. - The term “treatment” in the present invention means maintenance treatment for alleviating the symptoms and preventing the recurrence by improving a disease that presents both of detrusor overactivity and detrusor underactivity, especially, maintenance treatment for alleviating the symptoms and preventing the recurrence by ameliorating DHIC.
- In the present specification, the phrase “a treatment of DHIC” means a method of ameliorating a disease that presents both of detrusor overactivity during storage phase and detrusor impaired contractility during voiding phase.
-
Compound 1 of the present invention may be formed acid adduct salt, or base adduct salt. And the present include the present invention to the extent that the salt is a pharmaceutically acceptable salt thereof. Specifically, it includes an acid adduct salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid etc.; an acid adduct salt with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methansulfonic acid, p-toluenesulfonic acid, or glutamic acid etc.; salt with an inorganic base such as sodium, potassium, magnesium, calcium, or aluminum etc.; salt with an organic base such as methylamine, ethylamine, meglumine, or ethanolamine etc.; salt with basic amino acid such as lysine, arginine, or ornithine; ammonium salt etc. - Examples of the solvent of the solvate of
Compound 1 of the present invention include water, methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, ethyl acetate, toluene, hexane, acetone, methyl ethyl ketone, and methyl isobutyl ketone etc. - 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one, a salt thereof, or a solvate thereof of the present invention can be prepared into various dosage forms by using known preparation methods using a pharmaceutically acceptable carrier. The dosage form is not particularly limited, and examples thereof include oral agents such as tablets, coated tablets, pills, powdered drugs, granules, capsules, liquids, suspensions, or emulsions; and parenteral agents such as injections or suppositories.
- In preparing tablets, examples of carrier include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid; binders such as water, ethanol, propanol, cornstarch, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium phosphate, or polyvinyl pyrrolidone; disintegrants such as dry starch, sodium alginate, powdered agar, powdered laminaran, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, or lactose; disintegration inhibitors such as sucrose, stearic acid, cacao butter, or hydrogenated oils; absorbefacients such as quaternary ammonium salts or sodium lauryl sulfate; moisturizers such as glycerin or starch; adsorbents such as starch, lactose, kaolin, bentonite, or colloidal silicic acid; and lubricants such as purified talc, stearate, boric acid powder, or polyethylene glycol. Further, the tablets may be generally coated tablets such as sugar-coated tables, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-coated tablets, or multi-coated tablets.
- In preparing pills, examples of the carrier include excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, or talc; binders such as gum arabic powder, tragacanth powder, gelatin, or ethanol; and disintegrators such as laminaran or agar. Capsules are usually prepared in a standard method by blending the drug with one or more carriers as exemplified above, and encapsulating the mixture into hard gelatin capsules, soft capsules, etc.
- In preparing oral liquid formulations, an internal liquid medicine, a syrup, an elixir, or the like, may be prepared by a standard method using sweetening/flavoring agent, buffer, stabilizer, etc. In this case, examples of sweetening/flavoring agents include sucrose, wild orange peel, citric acid, and tartaric acid; examples of buffers include sodium citrate; and examples of stabilizers include tragacanth, gum arabic, and gelatin.
- In preparing suppositories, examples of usable carriers include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides.
- In preparing injections, the liquids, emulsions, and suspensions are preferably sterilized and rendered isotonic to the blood. Examples of diluents for preparing such dosage forms include water, aqueous lactic acid solution, ethanol, propylene glycol, macrogols, ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid ester.
- In this case, sodium chloride, glucose, or glycerin in an amount sufficient to prepare an isotonic solution may be added to the pharmaceutical formulation. Further, general solubilizers, buffers, anesthetics, and the like, may also be added to the pharmaceutical formulation. Additionally, coloring agents, preservatives, aromatics, flavors, sweetening agents, or other medicinal products may be incorporated, if necessary, into the pharmaceutical formulations.
- The method for administering the DHIC ameliorating agent of the present invention is not particularly limited, and is suitably selected according to the dosage form thereof, the age, gender, and other conditions of the patient, the severity of the symptoms of the patient, and the like. For example, tablets, pills, powdered drugs, granules, capsules, liquids, suspensions, and emulsions are orally administered. The injections are intravenously administered singly, or as a mixture with a general infusion liquid such as liquid glucose or an amino acid liquid. Further, as necessary, the injections are singly administered intra-arterially, intramuscularly, intradermally, subcutaneously, or intraperitoneally. The suppositories are intrarectally administered.
- The amount of the compound of the present invention or a salt thereof to be incorporated into each of the above dosage unit form depends on the symptoms of the target patient, or depends on the drug form; however, the amount per dosage unit form is generally preferably about 0.005 to 1,000 mg, more preferably 1 to 800 mg, further preferably 5 to 500 mg for oral agents; about 0.001 to 500 mg, more preferably 0.02 to 400 mg, further preferably 1 to 250 mg for injections; and about 0.01 to 1,000 mg, more preferably 1 to 800 mg, further preferably 5 to 500 mg for suppositories. Additionally, the daily dose for an adult of the drug to be administered with the above dosage form is generally about 0.005 to 5,000 mg, preferably 0.01 to 2,000 mg, more preferably 10 to 1600 mg, further preferably 20 to 800 mg, although such doses depend on the symptom, body weight, age, gender, etc., of the patient. For each day, the daily dose is preferably taken at one time, or divided into two to four administrations.
- The present invention is more specifically described below in reference to the Test Examples; however, the present invention is not limited to these examples.
- The models were produced by partial ligation (φ1.57 mm) of urethra in rats (9 weeks, female, Sprague-Dawley). Six weeks after preparation of the model, the rats were released the ligation. The next day, the intravesical pressure and the voided volume were measured under awake condition. And the detrusor contractility during voiding phase was evaluated by nomogram analysis using Qmax and Pdet. Additionally, the detrusor overactivity, as index of overactive bladder, and the increase of residual urine volume, as index of underactive bladder, were evaluated.
-
FIG. 1 shows representative cystometry charts. In the dysuria model rat (control) compared to sham rat, there is the characteristics of detrusor hyperactivity with impaired contractility that are characterized by remarkable overactivity and increased residual urine volume (Table 1). -
TABLE 1 The effects of Compound 1 of the present invention andα1-blocker (Tamsulosin) on detrusor overactivity and residual urine volume in rat dysuria model that presents DHIC. Detrusor Residual urine overactivity volume Group n (times/min) (mL) Sham 11 0.19 ± 0.09 0.10 ± 0.03 Control 19 1.73 ± 0.10# 0.57 ± 0.06 # Compound 1 of 8 0.63 ± 0.10* 0.28 ± 0.13* the present invention Tamsulosin 6 0.68 ± 0.33§ 0.64 ± 0.08 #p < 0.05 vs. Sham group (unpaired Student's t-test) *p < 0.05 vs. Control group (unpaired Student's t-test) §p < 0.05 vs. Control group (unpaired Student's t-test) - Through evaluation of detrusor contractility during voiding phase in refer to nomogram analysis which are used in clinical sites (Non-patent Document 9: Urol Clin North Am, 17, p 553-566 (1990)), because the plot of control group is positioned in a position relatively close to the origin compared to it of sham group (the distance from the origin: Sham group 24.75±3.14, control group 4.24±0.53, p<0.05), it is judged that reduction of detrusor contractility occurs in the rat dysuria model (
FIG. 2 ). - In the rat dysuria model from these findings, it is confirmed that the detrusor overactivity during storage phase and the reduction of detrusor contractility during voiding phase in nomogram analysis coexist in the body of the same individual which is clinical diagnostic index of DHIC. It is found that the rat dysuria model is able to be evaluated as model of DHIC.
- The effect of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-one (hereinafter referred to as “
Compound 1 of the present invention”) on DHIC was evaluated. - The dysuria models in this example were prepared in the same manner as in Test Example 1. The test drugs (vehicle: 6% Gelucire,
Compound 1 of thepresent invention 10 mg/kg) were orally administered to each group after two weeks from the preparation of the models twice a day for four weeks. On the day of the final administration, the rats were released the ligation of urethra. The next day, the intravesical pressure and the voided volume were measured using cystometry under conscious condition. The detrusor overactivity, as an index of overactive bladder, and the increase of residual urine volume, as an index of underactive bladder, were evaluated. Additionally, the detrusor contractility during voiding phase was evaluated by nomogram analysis using Qmax and Pdet. - In comparison with the detrusor overactivity (1.73±0.10 times/min) and the residual urine volume (0.57±0.06 mL) in control group receiving vehicle (6% Gelucire), detrusor overactivity (0.63±0.14 times/min) and residual urine volume (0.28±0.13 mL) in the
group receiving Compound 1 of the present invention were significantly improved (Table 1). Additionally, from the result of evaluation using nomogram analysis, because the plot ofCompound 1 of the present invention group is positioned in a position relatively distant from the origin compared to it of control group (the distance from the origin: 10.5±2.3, p<0.05), it is judged that detrusor contractility is improved inCompound 1 of the present invention group compared to control group (FIG. 2 ). - In DHIC model that detrusor overactivity and detrusor impaired contractility coexist, it is recognized that
Compound 1 of the present invention possesses effect for ameliorating both of detrusor overactivity and detrusor impaired contractility. - In the same manner as Test Example 1, the rats were released the ligation of urethra at six weeks after the preparation of the model. The next day, the intravesical pressure and the voided volume were measured using cystometry under conscious condition. The detrusor overactivity, as an index of overactive bladder, and the increase of residual urine volume, as an index of underactive bladder, were evaluated. Additionally, the detrusor contractility during voiding phase was evaluated by nomogram analysis using Qmax and Pdet. Tamsulosin (3 μg/kg) was administered intravenously to the dysuria rat at the evaluation (six weeks after preparation of the model).
- Detrusor overactivity was significantly improved in Tamsulosin (3 μg/kg) group (0.68±0.33 times/min) than control group (1.73±0.10 times/min) (Table 1). However, Tamsulosin (3 μg/kg) has no effect on residual urine volume (Table 1) and detrusor contractility in nomogram analysis (
FIG. 2 ). - The effects of α1 blocker (Tamsulosin) on underactive bladder were evaluated. The dysuria models in the present example were prepared by treating 10-week-old female Wistar rats with streptozotocin (65 mg/kg, i.p.). From four weeks after the preparation of the models, Tamsulosin (1 μg/kg/hr) was administered subcutaneously using osmotic pump. Four weeks after the implant of osmotic pump, the intravesical pressure and the voided volume were measured using cystometry under urethane anesthesia condition. And the residual urine volume, as an index of underactive bladder, was evaluated.
- Table 2 shows the results. In comparison with the Sham group, significant increase of the residual urine volume, which is an index of underactive bladder, was observed in the control group (eight weeks after the development of the disease in the models). Tamsulosin showed significant reduction on the increase of residual urine volume which was observed in the control group.
- The above results suggest that Tamsulosin improves underactive bladder, that is, detrusor impaired contractility.
-
TABLE 2 Effects of α1 blocker (Tamsulosin) on residual urine volume in rat underactive bladder model Residual urine volume Group n (mL) Control 10 1.11 ± 0.20 Tamsulosin 9 0.47 ± 0.11§ §p < 0.05 vs. Control group (unpaired Student's t-test) - Although an α1 blocker, which generally are used as dysuria-treating drug, has effect on underactive bladder (Comparative Example 2) and are also reported effect for improving overactive bladder (Non-patent Document 10: J Urol, 190, p 1116-1122 (2013)), the effect of Tamsulosin was not observed in dysuria (DHIC) that detrusor overactivity and detrusor impaired contractility coexist in the body of the same individual (Comparative Example 1).
- On the other hand,
Compound 1 of the present invention shows effect for ameliorating both dysfunctions in DHIC that detrusor overactivity and detrusor impaired contractility coexist (Test Example 2). Therefore, it is suggested thatCompound 1 of the present invention is a useful therapeutic agent for DHIC (Test Example 2).
Claims (2)
Priority Applications (20)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/817,318 US20170035705A1 (en) | 2015-08-04 | 2015-08-04 | Detrusor hyperactivity with impaired contractility ameliorating agent |
US15/155,526 US9687457B2 (en) | 2015-08-04 | 2016-05-16 | Detrusor hyperactivity with impaired contractility ameliorating agent |
AU2016301689A AU2016301689B2 (en) | 2015-08-04 | 2016-08-03 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
BR112017028381-6A BR112017028381A2 (en) | 2015-08-04 | 2016-08-03 | agent to improve detrusor muscle hyperactivity with impaired contractility |
TW105124867A TWI668005B (en) | 2015-08-04 | 2016-08-03 | Agent for improving detrusor hyperactivity with impaired contractility |
SG11201710583RA SG11201710583RA (en) | 2015-08-04 | 2016-08-03 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
EP16833066.0A EP3332779B1 (en) | 2015-08-04 | 2016-08-03 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
ES16833066T ES2836685T3 (en) | 2015-08-04 | 2016-08-03 | Agent to alleviate detrusor hyperactivity with impaired contractility |
CA2994648A CA2994648C (en) | 2015-08-04 | 2016-08-03 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
KR1020187006188A KR102076137B1 (en) | 2015-08-04 | 2016-08-03 | Decreased contractility accompanying concomitant detrusor muscle overactivity |
JP2017533103A JP6328856B2 (en) | 2015-08-04 | 2016-08-03 | Depressant detrusor overactivity improving agent with reduced contractile force |
MYPI2018700358A MY197287A (en) | 2015-08-04 | 2016-08-03 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
CN201680045566.3A CN107921011A (en) | 2015-08-04 | 2016-08-03 | The improver that overactive detrusor is damaged with contractile function |
PCT/JP2016/072753 WO2017022787A1 (en) | 2015-08-04 | 2016-08-03 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
RU2018107515A RU2714444C2 (en) | 2015-08-04 | 2016-08-03 | Agent reducing intensity of detrusor with impaired contractility |
MX2018001518A MX382014B (en) | 2015-08-04 | 2016-08-03 | ENHANCING AGENT FOR DETRUSOR OVERACTIVITY WITH IMPAIRED CONTRACTILITY. |
KR1020197034935A KR20190134825A (en) | 2015-08-04 | 2016-08-03 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
US15/599,890 US20170252307A1 (en) | 2015-08-04 | 2017-05-19 | Detrusor hyperactivity with impaired contractility ameliorating agent |
PH12018500176A PH12018500176A1 (en) | 2015-08-04 | 2018-01-23 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
HK18106741.9A HK1247106A1 (en) | 2015-08-04 | 2018-05-24 | Ameliorating agent for detrusor hyperactivity with impaired contractility |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/817,318 US20170035705A1 (en) | 2015-08-04 | 2015-08-04 | Detrusor hyperactivity with impaired contractility ameliorating agent |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/155,526 Continuation US9687457B2 (en) | 2015-08-04 | 2016-05-16 | Detrusor hyperactivity with impaired contractility ameliorating agent |
Publications (1)
Publication Number | Publication Date |
---|---|
US20170035705A1 true US20170035705A1 (en) | 2017-02-09 |
Family
ID=57943093
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/817,318 Abandoned US20170035705A1 (en) | 2015-08-04 | 2015-08-04 | Detrusor hyperactivity with impaired contractility ameliorating agent |
US15/155,526 Active 2035-08-05 US9687457B2 (en) | 2015-08-04 | 2016-05-16 | Detrusor hyperactivity with impaired contractility ameliorating agent |
US15/599,890 Abandoned US20170252307A1 (en) | 2015-08-04 | 2017-05-19 | Detrusor hyperactivity with impaired contractility ameliorating agent |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/155,526 Active 2035-08-05 US9687457B2 (en) | 2015-08-04 | 2016-05-16 | Detrusor hyperactivity with impaired contractility ameliorating agent |
US15/599,890 Abandoned US20170252307A1 (en) | 2015-08-04 | 2017-05-19 | Detrusor hyperactivity with impaired contractility ameliorating agent |
Country Status (17)
Country | Link |
---|---|
US (3) | US20170035705A1 (en) |
EP (1) | EP3332779B1 (en) |
JP (1) | JP6328856B2 (en) |
KR (2) | KR102076137B1 (en) |
CN (1) | CN107921011A (en) |
AU (1) | AU2016301689B2 (en) |
BR (1) | BR112017028381A2 (en) |
CA (1) | CA2994648C (en) |
ES (1) | ES2836685T3 (en) |
HK (1) | HK1247106A1 (en) |
MX (1) | MX382014B (en) |
MY (1) | MY197287A (en) |
PH (1) | PH12018500176A1 (en) |
RU (1) | RU2714444C2 (en) |
SG (1) | SG11201710583RA (en) |
TW (1) | TWI668005B (en) |
WO (1) | WO2017022787A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022013721A (en) * | 2020-07-03 | 2022-01-18 | 大鵬薬品工業株式会社 | Urination symptom treatment agent |
JP6894555B1 (en) * | 2020-07-03 | 2021-06-30 | 大鵬薬品工業株式会社 | Urinary symptom therapeutic agent |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1003706B1 (en) | 1997-08-13 | 2003-03-05 | Meiji Milk Products Company Limited | Cyclohexenone long-chain alcohol and medicament containing same |
JP3836684B2 (en) * | 2001-02-19 | 2006-10-25 | 明治乳業株式会社 | Treatment for dysuria |
RU2193401C1 (en) * | 2001-04-02 | 2002-11-27 | Аль-Шукри Салман Хасунович | Method for treating hyperactivity of urinary bladder |
WO2006004115A1 (en) * | 2004-07-05 | 2006-01-12 | Chugai Seiyaku Kabushiki Kaisha | Remedy for hyperactive bladder |
ES2345216T3 (en) * | 2005-01-18 | 2010-09-17 | Meiji Dairies Corporation | THERAPEUTIC AGENT FOR SENSORY DISORDERS. |
JP2009292797A (en) * | 2008-06-09 | 2009-12-17 | Kyoto Univ | Therapeutic agent for overactive bladder |
JP5566521B1 (en) | 2013-09-27 | 2014-08-06 | 大鵬薬品工業株式会社 | Bladder / urethral coordination disorder improving agent |
JP2015067565A (en) | 2013-09-27 | 2015-04-13 | 大鵬薬品工業株式会社 | Pharmaceutical composition containing 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexene-1-on or salt thereof |
-
2015
- 2015-08-04 US US14/817,318 patent/US20170035705A1/en not_active Abandoned
-
2016
- 2016-05-16 US US15/155,526 patent/US9687457B2/en active Active
- 2016-08-03 CN CN201680045566.3A patent/CN107921011A/en active Pending
- 2016-08-03 AU AU2016301689A patent/AU2016301689B2/en active Active
- 2016-08-03 JP JP2017533103A patent/JP6328856B2/en active Active
- 2016-08-03 CA CA2994648A patent/CA2994648C/en active Active
- 2016-08-03 KR KR1020187006188A patent/KR102076137B1/en active Active
- 2016-08-03 SG SG11201710583RA patent/SG11201710583RA/en unknown
- 2016-08-03 ES ES16833066T patent/ES2836685T3/en active Active
- 2016-08-03 MX MX2018001518A patent/MX382014B/en unknown
- 2016-08-03 BR BR112017028381-6A patent/BR112017028381A2/en not_active Application Discontinuation
- 2016-08-03 EP EP16833066.0A patent/EP3332779B1/en active Active
- 2016-08-03 KR KR1020197034935A patent/KR20190134825A/en not_active Withdrawn
- 2016-08-03 WO PCT/JP2016/072753 patent/WO2017022787A1/en active Application Filing
- 2016-08-03 RU RU2018107515A patent/RU2714444C2/en active
- 2016-08-03 TW TW105124867A patent/TWI668005B/en active
- 2016-08-03 MY MYPI2018700358A patent/MY197287A/en unknown
-
2017
- 2017-05-19 US US15/599,890 patent/US20170252307A1/en not_active Abandoned
-
2018
- 2018-01-23 PH PH12018500176A patent/PH12018500176A1/en unknown
- 2018-05-24 HK HK18106741.9A patent/HK1247106A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
ES2836685T3 (en) | 2021-06-28 |
US9687457B2 (en) | 2017-06-27 |
TW201717924A (en) | 2017-06-01 |
US20170252307A1 (en) | 2017-09-07 |
RU2018107515A3 (en) | 2019-09-05 |
CN107921011A (en) | 2018-04-17 |
EP3332779A1 (en) | 2018-06-13 |
CA2994648C (en) | 2020-04-07 |
PH12018500176A1 (en) | 2018-07-30 |
CA2994648A1 (en) | 2017-02-09 |
SG11201710583RA (en) | 2018-01-30 |
JPWO2017022787A1 (en) | 2018-04-26 |
TWI668005B (en) | 2019-08-11 |
MX2018001518A (en) | 2018-04-24 |
MX382014B (en) | 2025-03-13 |
AU2016301689B2 (en) | 2018-10-04 |
MY197287A (en) | 2023-06-09 |
RU2018107515A (en) | 2019-09-05 |
KR20190134825A (en) | 2019-12-04 |
EP3332779B1 (en) | 2020-10-28 |
RU2714444C2 (en) | 2020-02-17 |
EP3332779A4 (en) | 2019-03-13 |
KR102076137B1 (en) | 2020-02-11 |
WO2017022787A1 (en) | 2017-02-09 |
KR20180038003A (en) | 2018-04-13 |
JP6328856B2 (en) | 2018-05-23 |
AU2016301689A1 (en) | 2018-01-25 |
HK1247106A1 (en) | 2018-09-21 |
US20170035706A1 (en) | 2017-02-09 |
BR112017028381A2 (en) | 2018-08-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8642661B2 (en) | Pharmaceutical combinations of beta-3 adrenergic receptor agonists and muscarinic receptor antagonists | |
US20210330615A1 (en) | S-enantiomerically enriched compositions of beta blockers for treating amyotrophic lateral sclerosis | |
US9687457B2 (en) | Detrusor hyperactivity with impaired contractility ameliorating agent | |
JP2010501626A (en) | Bifeprunox dose to treat schizophrenia | |
US9271948B2 (en) | Agent for improving vesicourethral dyssynergia | |
US20100331361A1 (en) | Pharmaceutical composition containing alpha-adrenergic receptor antagonist and an anti-muscarinic agent and method of improving lower urinary tract symptoms associated with prostatic hypertrophy | |
US9603845B2 (en) | Prophylactic agent and/or therapeutic agent for stress urinary incontinence | |
US20240269133A1 (en) | Methods of treating interstitial cystitis/bladder pain syndrome | |
WO2024141073A1 (en) | Pharmaceutical combinations and compositions, and methods of use thereof | |
US12303474B2 (en) | S-enantiomerically enriched compositions of beta blockers for treating amyotrophic lateral sclerosis | |
CN112512526B (en) | Application of combination of compound A and compound B in preparation of medicine for treating gout or hyperuricemia | |
US20230255903A1 (en) | Urinary symptom therapeutic agent | |
JP2008513430A (en) | Pindolol for the treatment of premenstrual syndrome and premenstrual dysphoric disorder | |
CN101415425A (en) | Triglyceride-lowering agent and hyperinsulinism-ameliorating agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: TAHIO PHARMACETUICAL CO., LTD., JAPAN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HAYASHI, YUKIO;NOMA, TAKAHISA;REEL/FRAME:036829/0239 Effective date: 20150818 |
|
AS | Assignment |
Owner name: TAIHO PHARMACEUTICAL CO., LTD., JAPAN Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE CORRECT THE ASSIGNEE'S NAME PREVIOUSLY RECORDED ON REEL 036829 FRAME 0239. ASSIGNOR(S) HEREBY CONFIRMS THE TAHIO SHOULD BE CORRECTED TO TAIHO;ASSIGNORS:HAYASHI, YUKIO;NOMA, TAKAHISA;REEL/FRAME:037701/0132 Effective date: 20150818 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |