TWI837197B - 胺基甲酸酯化合物於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的用途 - Google Patents
胺基甲酸酯化合物於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的用途 Download PDFInfo
- Publication number
- TWI837197B TWI837197B TW108137697A TW108137697A TWI837197B TW I837197 B TWI837197 B TW I837197B TW 108137697 A TW108137697 A TW 108137697A TW 108137697 A TW108137697 A TW 108137697A TW I837197 B TWI837197 B TW I837197B
- Authority
- TW
- Taiwan
- Prior art keywords
- peripheral neuropathy
- chemotherapy
- administration
- compound
- formula
- Prior art date
Links
- 208000032131 Diabetic Neuropathies Diseases 0.000 title claims abstract description 37
- 208000033808 peripheral neuropathy Diseases 0.000 title claims abstract description 34
- -1 carbamate compound Chemical class 0.000 title claims abstract description 32
- 238000002512 chemotherapy Methods 0.000 title claims abstract description 32
- 238000011282 treatment Methods 0.000 title description 16
- 230000002265 prevention Effects 0.000 title description 3
- 239000003814 drug Substances 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 3
- 229940123237 Taxane Drugs 0.000 claims description 3
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 125000006731 (C1-C8) thioalkoxy group Chemical group 0.000 claims description 2
- 206010012645 Diabetic autonomic neuropathy Diseases 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940127089 cytotoxic agent Drugs 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 14
- 150000001875 compounds Chemical class 0.000 description 50
- 238000012360 testing method Methods 0.000 description 44
- 208000004454 Hyperalgesia Diseases 0.000 description 38
- 206010053552 allodynia Diseases 0.000 description 26
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 22
- 238000005452 bending Methods 0.000 description 17
- 238000002474 experimental method Methods 0.000 description 17
- 208000002193 Pain Diseases 0.000 description 15
- 241000700159 Rattus Species 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 13
- 230000036407 pain Effects 0.000 description 13
- 230000006698 induction Effects 0.000 description 12
- 239000003981 vehicle Substances 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 229960002870 gabapentin Drugs 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000013641 positive control Substances 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- 201000010099 disease Diseases 0.000 description 10
- 239000013642 negative control Substances 0.000 description 10
- 230000004044 response Effects 0.000 description 8
- 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 8
- 229930012538 Paclitaxel Natural products 0.000 description 7
- 238000007912 intraperitoneal administration Methods 0.000 description 7
- 229960001592 paclitaxel Drugs 0.000 description 7
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 7
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 6
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 6
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 6
- 229960000836 amitriptyline Drugs 0.000 description 6
- 206010012601 diabetes mellitus Diseases 0.000 description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 229960001052 streptozocin Drugs 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 210000002683 foot Anatomy 0.000 description 5
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 238000004448 titration Methods 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 208000004044 Hypesthesia Diseases 0.000 description 4
- 208000010428 Muscle Weakness Diseases 0.000 description 4
- 206010028372 Muscular weakness Diseases 0.000 description 4
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 208000034783 hypoesthesia Diseases 0.000 description 4
- 231100000862 numbness Toxicity 0.000 description 4
- 208000035824 paresthesia Diseases 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 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
- 230000002159 abnormal effect Effects 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 210000000548 hind-foot Anatomy 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 210000005036 nerve Anatomy 0.000 description 3
- 201000001119 neuropathy Diseases 0.000 description 3
- 230000007823 neuropathy Effects 0.000 description 3
- 229960001158 nortriptyline Drugs 0.000 description 3
- 229960005489 paracetamol Drugs 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229960001233 pregabalin Drugs 0.000 description 3
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 3
- 230000035807 sensation Effects 0.000 description 3
- 230000001953 sensory effect Effects 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 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 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229920002774 Maltodextrin Polymers 0.000 description 2
- 239000005913 Maltodextrin Substances 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 102000010909 Monoamine Oxidase Human genes 0.000 description 2
- 108010062431 Monoamine oxidase Proteins 0.000 description 2
- 208000007101 Muscle Cramp Diseases 0.000 description 2
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 229960000794 baclofen Drugs 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 229960002866 duloxetine Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 2
- 208000012866 low blood pressure Diseases 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940035034 maltodextrin Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229940005483 opioid analgesics Drugs 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 210000000578 peripheral nerve Anatomy 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000003775 serotonin noradrenalin reuptake inhibitor Substances 0.000 description 2
- 229910052814 silicon oxide Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000035900 sweating Effects 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000001225 therapeutic effect Effects 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
- 210000003462 vein Anatomy 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical class OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- IWQRJKGYECVOAA-UHFFFAOYSA-N 3-hexoxycarbonylbenzoic acid Chemical compound CCCCCCOC(=O)C1=CC=CC(C(O)=O)=C1 IWQRJKGYECVOAA-UHFFFAOYSA-N 0.000 description 1
- 208000000187 Abnormal Reflex Diseases 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000012219 Autonomic Nervous System disease Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- GEKAWPPUHLAZLH-UHFFFAOYSA-N C(C(O)C(O)C(=O)O)(=O)O.C(CCC(=O)O)(=O)O.C(=O)(O)C(O)C(O)C(=O)O Chemical compound C(C(O)C(O)C(=O)O)(=O)O.C(CCC(=O)O)(=O)O.C(=O)(O)C(O)C(O)C(=O)O GEKAWPPUHLAZLH-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000007379 Muscle Hypotonia Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 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
- 208000028389 Nerve injury Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 206010034620 Peripheral sensory neuropathy Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- YCXARMXCESBEDS-UHFFFAOYSA-N Promethazine teoclate Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC(Cl)=N2.C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 YCXARMXCESBEDS-UHFFFAOYSA-N 0.000 description 1
- 208000020764 Sensation disease Diseases 0.000 description 1
- 206010040030 Sensory loss Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 229940082992 antihypertensives mao inhibitors Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- MQRKKLAGBPVXCD-UHFFFAOYSA-L calcium;1,1-dioxo-1,2-benzothiazol-2-id-3-one;hydrate Chemical compound O.[Ca+2].C1=CC=C2C([O-])=NS(=O)(=O)C2=C1.C1=CC=C2C([O-])=NS(=O)(=O)C2=C1 MQRKKLAGBPVXCD-UHFFFAOYSA-L 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012829 chemotherapy agent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229950000206 estolate Drugs 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- SDXAEIYPSNMJQU-UHFFFAOYSA-N ethylamino carbamate Chemical compound CCNOC(N)=O SDXAEIYPSNMJQU-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical class OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000005165 hydroxybenzoic acids Chemical class 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 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
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 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
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 235000020938 metabolic status Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 210000003007 myelin sheath Anatomy 0.000 description 1
- VGKONPUVOVVNSU-UHFFFAOYSA-N naphthalen-1-yl acetate Chemical compound C1=CC=C2C(OC(=O)C)=CC=CC2=C1 VGKONPUVOVVNSU-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 208000005877 painful neuropathy Diseases 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 238000010149 post-hoc-test Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- HEKURBKACCBNEJ-UHFFFAOYSA-M potassium;1,1-dioxo-1,2-benzothiazol-2-id-3-one Chemical compound [K+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 HEKURBKACCBNEJ-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229950006030 promethazine teoclate Drugs 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229940043243 saccharin calcium Drugs 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 201000005572 sensory peripheral neuropathy Diseases 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium glycolate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- WRTMQOHKMFDUKX-UHFFFAOYSA-N triiodide Chemical compound I[I-]I WRTMQOHKMFDUKX-UHFFFAOYSA-N 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 231100000691 up-and-down procedure Toxicity 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本發明有關下式1的胺基甲酸酯化合物於藉由投予包括該胺基甲酸酯化合物的醫藥組成物於預防、緩解或治療糖尿病性周邊神經病變或化療誘發的周邊神經病變的用途之目的:
式中,
R1、R2、A1以及A2係如本文所定義。
周邊神經病變係指由運動、感覺和自律神經所組成的周圍神經的結構和功能性病症,並且根據該病症發生的神經類型而出現各種症狀。周邊神經病變可能是自身的疾病,也可能是由其他疾病(例如,局部缺血或糖尿病)引起的,或者可能是化療和放射療法的副作用引起的。症狀可能包括嗜睡、自律神經系統和感覺變化的各種組合。尤其是,感覺神經病會根據受到影響的神經和器官,而表現出正性症狀,包括感覺喪失、刺痛和疼痛。
在周邊神經病變中,最常見的是糖尿病併發症引起的神經病變,而約34%的糖尿病患者患有糖尿病周邊神經病變(DPN)。然而,已知50%的糖尿病周邊神經病變是無症狀的,這使疾病惡化。糖尿病周邊神經病變包括感覺異常和疼痛、異感痛、痛覺超敏、麻木、肌肉無力和痙攣。患者不會感覺到溫度或傷口的變化,也不會因感覺異常而感到麻木、刺痛、螫痛(sting)或灼痛,並且由於肌肉無力而具有下降的反射、平衡和協調能力。在伴有疼痛的糖尿病周邊神經病變的情況下,病理上加劇的疼痛是生活品質下降的主要原因,並且有時伴有抑鬱症。
為了從根本上預防或延遲糖尿病性周邊神經病變的發展,血糖控制對於防止周邊神經損傷至關重要。治療包含病因治療和對症治療。
通常使用低劑量的三環抗抑鬱藥(例如去甲替林(nortriptyline)或阿米替林(amitriptyline))、血清素-去甲腎上腺素再攝取抑制劑(SNRI)(例如,度洛西汀(duloxetine))以及抗驚厥療法(例如,加巴噴丁(gabapentin)或普瑞巴林(pregabalin))。另外,乙醯胺基酚或非類固
醇抗炎藥(NSAID)已被用作止痛藥。然而,目前的療法不足以顯示令人滿意的療效,因為它們在20至40%的患者中止痛效果低於30%(Lancet Neurol.2015;14:162-173)。
化療增加了許多癌症患者的存活率,但是引起各種副作用。其中,化療誘發的周邊神經病變(CIPN)的患病率為68%,在治療後數週至數月仍是一種症狀,並且是多年來遭受疼痛症候群的化療的代表性副作用。在化療劑中,已知鉑類藥物、紫杉烷類和長春花生物鹼可引起CIPN,且它們主要用於結直腸癌、胃癌、乳癌和血癌患者。CIPN係由於化療破壞神經軸突周圍的髓鞘而導致神經細胞變性引起的,主要症狀包括感覺障礙,諸如,疼痛、感覺異常、異感痛、痛覺超敏、麻木等。運動神經元疾病,諸如,肌肉無力、痙攣、肌張力低下等;以及自律神經疾病,諸如,低血壓、出汗、胃腸道異常等。
在化療中,劑量越高,投予的頻率越短,並且一起投予的藥物數目越多,發生的可能性越高。還已知在患者以前有其他神經病變的情況下發病率很高。
隨著CIPN的發展,已藉由國家綜合癌症網絡(National Comprehensive Cancer Network)指南進行各種嘗試,以中止化療或減少劑量以增加周圍神經的活力。在CIPN的治療中,適度推薦度洛西汀。此外,三環類抗抑鬱藥、加巴噴丁和類鴉片藥物的組合以及巴氯芬(baclofen)+阿米替林+氯胺酮的三聯組合已被建議作為可能的治療方法。此外,儘管尚未證明藥物療效,但是已經使用了各種藥物的組合,例如α-硫辛酸,胺磷汀(amifostine)、阿米替林、鈣和鎂等。
本發明旨在提供預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的方法。
本發明還旨在提供下式1的胺基甲酸酯化合物或其醫藥上可接受的鹽、溶劑化物或水合物於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的用途:
式中,
R1、R2、A1以及A2係如本文所定義。
本發明提供了用於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的藥劑,其包括治療有效量的下式1的胺基甲酸酯化合物或其醫藥上可接受的鹽、溶劑化物或水合物:
其中,R1和R2各自獨立地選自氫、鹵素、C1-C8烷基、鹵基-C1-C8烷基、C1-C8硫烷氧基和C1-C8烷氧基;以及A1和A2中的一者是CH,而另一者是N。
另外,本發明提供了用於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的醫藥組成物,其包括治療有效量的上式1的胺基甲酸酯化合物或其醫醫學上可接受的鹽、溶劑化物或水合物,以及另外一種或多種醫學上可接受的載體。
另外,本發明提供了用於預防、緩解或治療受試者的糖尿病周邊神經病變或化療誘發的周邊神經病變的方法,其包括向受試者投予治療有效量的上述式1的胺基甲酸酯化合物、或其醫藥上可接受的鹽、溶劑化物或水合物。
另外,本發明提供了上式1的胺基甲酸酯化合物或其醫藥上可接受的鹽、溶劑化物或水合物於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變或用於改善與之相關的症狀之用途。
根據本發明的一個具體例,在上式1中,R1和R2各自獨立地選自由氫、鹵素和C1-C8烷基所組成群組。
在本發明的一個具體例中,鹵基-C1-C8烷基是全氟烷基。
化合物合成領域的具有通常知識者可以使用已知的化合物或可以輕易地由其製備的化合物,而輕易地製備上式1和2的胺基甲酸酯化合物。具體地,用於製備上式1的化合物的方法在國際公開案第WO 2006/112685 A1、WO 2010/150946 A1和WO 2011/046380 A2號中有詳細描述,其揭露內容藉由引用方式併入本文。上式1的化合物可以藉由上述文獻中描述的任何方法化學合成,但是這些方法僅是例示性的,並且若需要,可以選擇性地改變單元操作的順序等。因此,上述方法無意於限制本發明的範疇。
第1圖顯示了在所有動物中測量的平均血糖水平(BGL),以確定在以鏈脲佐菌素在大鼠中誘發糖尿病。服用鏈脲佐菌素3天後,基線時的平均BGL為102.52±0.93mg/dl,但增加到385.33±7.28mg/dl。在整個試驗期間維持較高的BGL,在第14天的平均BGL為405.05±12.74mg/dl,以及在第23天的平均BGL為412.52±10.77mg/dl。從上述內容可證實已誘發糖尿病,並且在試驗期期間維持。
第2圖顯示了與其中僅投予載劑之陰性對照組相比之對機械性異感痛之預防和治療功效之結果,其係藉由以鏈脲佐菌素誘發之異感痛,且投予製備例中製備之胺基甲酸(R)-1-(2-氯苯基)-2-四唑-2-基)乙基酯
(後文稱為“測試化合物”)(2-胺基丁酸)和陽性對照化合物(加巴噴丁)之馮.弗雷(von Frey)試驗大鼠。
第3圖顯示了與其中僅投予載劑之陰性對照組相比之對機械性異感痛之預防功效之結果,其係藉由其中以紫杉醇誘發之機械性異感痛,且投予測試化合物和陽性對照化合物之馮.弗雷試驗大鼠。在第1、3、5、7和9天藉由以0.5ml/kg的劑量向大鼠腹膜內(IP)投予2mg/kg的紫杉醇而誘發的周邊神經病變。
上式1的胺基甲酸酯化合物可用於預防、緩解或治療糖尿病周邊神經病或化療誘發的周邊神經病變。
糖尿病周邊神經病變是一種慢性感覺運動神經病變,包括疼痛性糖尿病周邊神經病變或糖尿病自律神經病變。
為化療引起的周邊神經病變所苦有約40%的正在接受化療的患者,並且症狀根據所使用的化療劑而變化,例如,抗癌劑的機制和劑量以及持續時間。引起化療誘發的周邊神經病變的化療劑的主要類型包括鉑類藥物、紫杉烷類和長春花生物鹼。
用於預防、緩解或治療上述疾病的式1的胺基甲酸酯化合物的劑量通常可以根據受試者的疾病的嚴重程度、體重和代謝狀況而變化。對於個別患者的“治療有效量”是指足以實現上述藥理功效,即上述治療功效的活性化合物的量。基於游離形式和對人類每天一次的投予,本發明化合物的治療有效量為50至500mg、50至400mg、50至300mg、100至400
mg、100至300mg、50至200mg或100至200mg。治療有效量較佳為50至300mg,更佳為50至200mg。
本發明的化合物可以藉由用於投予治療劑的任何常規方法投予,例如口服、腸胃外、靜脈內、肌內、皮下或直腸投予。
治療有效量的上述式1的胺基甲酸酯化合物可以藉由適當的滴定方法而實現。根據本發明的一個具體例,該滴定方法可以包括(1)每天一次向患者投予12.5mg的式1化合物持續兩週的步驟;(2)然後是每天一次向患者投予25mg的式1化合物持續兩週的步驟;(3)然後每天一次向患者投予50mg的式1化合物持續兩週的步驟;以及(4)以兩週為間隔每天一次增加50mg或更少的式1化合物的量,直到獲得治療有效量的步驟。根據本發明的另一個具體例,滴定方法可包括(1)每天一次向患者投予50mg的式1化合物持續兩週的步驟;(2)以兩週為間隔每天一次增加50mg的式1化合物的量,直到每日投予一次200mg的式1化合物的步驟,其中式1化合物經投予6週,治療有效量為200mg/天。根據本發明的又一個具體例,滴定方法可包括(1)每天一次向患者投予50mg式1化合物的步驟,其中每週增加50mg的量直至劑量為100mg/天,並且在步驟(1)之後進一步(2)是每週增加50mg的量直到劑量為200mg/天的步驟;或(3)每週增加100mg的量,直到劑量為400mg/天的步驟,其中式1化合物可取決於治療有效量而投予2、4或6週(100mg/天、200mg/天或400mg/天)。
除了上述方法外,可以使用適當的滴定方法來完成治療有效量的式1化合物。
根據本發明的另一個具體例,提供了用於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的藥劑,包括治療有效
量的上述式1的胺基甲酸酯化合物、或其醫藥上可接受的鹽、溶劑化物或水合物。
糖尿病周邊神經病變或化療誘發的周邊神經病變的症狀實例包括,但不限於,感覺異常、痛覺超敏、異感痛、麻木、振動或位置感喪失、肌肉無力、痙攣、低血壓、出汗或胃腸道異常。
根據本發明的一個具體例的藥劑或醫藥組成物可以包括治療有效量的選自由本發明的胺基甲酸酯化合物、其醫藥上可接受的鹽、溶劑化物、水合物及其組合的化合物所組成群組。
上式1的胺基甲酸酯化合物的醫藥上可接受的鹽的實例獨立地包含乙酸鹽、苯磺酸鹽、苯甲酸鹽、酒石酸氫鹽、乙酸鈣、草酸鹽、碳酸鹽、檸檬酸鹽、乙二酸鹽、乙二磺酸鹽、月桂硫酸鹽(estolate)、乙磺酸鹽、富馬酸鹽、葡庚酸鹽(gluceptate)、葡萄糖酸鹽、麩胺酸鹽、胺基苯砒酸羥乙醯酯、己基間苯二酸鹽、羥胺(hydravamine)、氫溴酸鹽、鹽酸鹽、碳酸氫鹽、羥萘甲酸酯、碘化物、羥乙磺酸鹽、乳酸鹽、乳糖酸鹽、蘋果酸鹽、馬來酸鹽、扁桃酸鹽、甲磺酸鹽、甲基硝酸鹽、甲基硫酸鹽、黏酸鹽、萘磺酸鹽、亞硝酸鹽、雙羥萘酸鹽(pamoate(embonate(雙羥萘酸鹽))、萘乙酸泛酸鹽、磷酸鹽/二磷酸鹽、聚半乳醣醛酸鹽、水楊酸鹽、硬脂酸鹽、亞乙酸鹽、琥珀酸鹽或半琥珀酸鹽、硫酸鹽或半硫酸鹽、鞣酸鹽、酒石酸鹽、草酸鹽或半酒石酸鹽、異丙嗪茶氯酸鹽(teoclate)、三二基碘、芐星青(benzathine)、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、葡甲胺、普魯卡因(procaine)、鋁、銨、四甲基銨、鈣、鋰、鎂、鉀、鈉和鋅。
根據本發明的一個具體例的藥劑或醫藥組成物可以口服或
腸胃外投予。腸胃外投予可以包括靜脈內注射、皮下注射、肌內注射、腹膜內注射、內皮投予、局部投予、鼻內投予、陰道內投予、肺內投予、直腸投予等。在口服投予的情況下,根據本發明的一個具體例的醫藥組成物可以配製成平片劑(未包衣的片劑)或使活性劑被包衣或被保護免受胃中的降解。另外,可以藉由能夠將活性物質轉移至目標細胞的任何裝置來投予組成物。投予途徑可取決於欲治療的受試者的一般狀況和年齡、治療狀況的性質和所選活性成分而變化。
根據本發明的一個具體例的藥劑或醫藥組成物的合適劑量可以取決於諸如調配方法、投予方法、年齡、患者的體重和性別、病理狀況、飲食、投予時間、投予途徑、排泄速率和反應敏感性等因素而變化,以及具有通常知識的醫生可以輕易地證實並開出對所需治療或預防有效的劑量。根據一個具體例的醫藥組成物可以以一種或多種劑量,例如每天投予1至4次。根據一個具體例的醫藥組成物以游離形式為基準計,可以包含50至500mg、50至400mg、50至300mg、100至400mg、100至300mg、50至200mg或100至200mg,較佳為50至300mg,更佳為50至200mg的量。
根據本發明一個具體例的藥劑或醫藥組成物可以根據發明所屬技術領域中具有通常知識者可以輕易地進行的方法,使用醫學上可接受的載體及/或賦形劑配調配,藉此製備成單位劑量形式或裝在多劑量容器中。上述製劑可以是在油或水性介質中的溶液、懸浮液或乳劑(乳化溶液)、提取物、粉劑、粒劑、片劑或膠囊,並且可以進一步包含分散劑或安定劑。另外,醫藥組成物可以栓劑、噴霧劑、軟膏劑、乳膏劑、凝膠劑、吸入劑
或皮膚貼劑形式的投予。醫藥組成物也可以製備成用於投予哺乳動物,更佳為用於投予人類。
醫學上可接受的載體可以是固體或液體,並且可以選自填充劑、抗氧化劑、緩衝劑、抑菌劑、分散劑、吸附劑、界面活性劑、黏合劑、防腐劑、崩解劑、甜味劑、調味劑、助流劑、控釋劑、潤濕劑、安定劑、助懸劑和潤滑劑之一者或多者。另外,醫學上可接受的載體可以選自鹽水、無菌水、林格氏溶液、緩衝鹽水、右旋糖溶液、麥芽糊精溶液、甘油、乙醇及其混合物。
在一個具體例中,合適的填充劑包括,但不限於,糖(例如,右旋糖、蔗糖、麥芽糖和乳糖)、澱粉(例如,玉米澱粉)、糖醇(例如,甘露醇、山梨糖醇、麥芽糖醇、赤藻糖醇和木糖醇)、澱粉水解產物(例如,糊精和麥芽糊精)、纖維素或纖維素衍生物(例如,微晶纖維素)或其混合物。
在一個具體例中,合適的黏合劑包括,但不限於,聚維酮、共聚維酮、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、羥乙基纖維素、明膠、樹膠、蔗糖、澱粉或其混合物。
在一個具體例中,合適的防腐劑包括,但不限於,苯甲酸、苯甲酸鈉、芐醇、丁基羥基茴香醚、丁基羥基甲苯、氯丁醇、沒食子酸酯、羥基苯甲酸酯、EDTA或其混合物。
在一個具體例中,合適的崩解劑包括,但不限於,澱粉羥乙酸鈉、交聯的聚乙烯吡咯烷酮、交聯的羧甲基纖維素、澱粉、微晶纖維素或其混合物。
在一個具體例中,合適的甜味劑包括,但不限於,三氯蔗糖、
糖精、糖精鈉、糖精鉀、糖精鈣、乙醯磺胺酸鉀或環己基磺醯胺酸鈉、甘露醇、果糖、蔗糖、麥芽糖或其混合物。
在一個具體例中,合適的助流劑包括,但不限於,氧化矽、膠體氧化矽、滑石粉等。
在一個具體例中,合適的潤滑劑包括,但不限於,長鏈脂肪酸及其鹽,例如硬脂酸鎂和硬脂酸、滑石粉、甘油酯蠟或其混合物。
上式1的胺基甲酸酯化合物可與另外的藥物一起用於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變。
根據本發明的又一個具體例,提供了用於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的組合,其包括治療有效量的上述式1的胺基甲酸酯化合物以及此等另外的藥物。
根據本發明的另一個具體例,另外藥物的實例包括,但不限於,在糖尿病周邊神經病變的情況下,止痛藥(諸如,乙醯胺基酚或非類固醇抗炎藥(NSAID))、三環抗抑鬱藥(諸如,去甲替林或阿米替林)、抗抑鬱藥(諸如,單胺氧化酶(MAO)抑制劑)、抗驚厥藥(諸如,加巴噴丁或普瑞巴林)或巴氯芬+阿米替林+氯胺酮的組合;及在對於化療引起的周邊神經病變的情況下,止痛藥(諸如,乙醯胺基酚或NSAID)、三環類抗抑鬱藥(諸如,去甲替林或阿米替林)、抗抑鬱藥(諸如,MAO抑製劑)、抗驚厥藥(諸如,加巴噴丁或普瑞巴林、類鴉片藥物或辣椒素)。
在本發明的另一個具體例中,當根據本發明的藥劑或醫藥組成物是上述組合時,上述式1的胺基甲酸酯化合物[成分(a)]和另外藥物[成分(b)]的重量比(a:b)可落入1,000:1至1:1,000,或500:1至1:
500,或100:1至1:100,或50:1至1:50,或10:1至1:10之範疇,但不限於此。
如本文所用,術語“預防(prevent)”、“預防(preventing)”和“預防(prevention)”是指減少或消除疾病的可能性。
如本文所用,術語“緩解(alleviate)”、“緩解(alleviating)”和“緩解(alleviation)”是指完全或部分減輕疾病及/或其伴隨症狀。
如本文所用,術語“治療(treat)”、“治療(treating)”和“治療(treatment)”是指完全或部分消除疾病及/或其伴隨症狀。
如本文所用,術語“受試者”是指作為治療、觀察或實驗的對象的動物,較佳為哺乳動物(例如,靈長類動物(例如,人類)、牛、綿羊、山羊、馬、狗、貓、兔子、大鼠、小鼠等),最佳為人類。
如本文所用,術語“治療有效量”是指在系統、動物或人類中引起生物或醫學反應,包含緩解疾病或該疾病的症狀的活性化合物或醫藥調配物的量。治療,其中該量係由研究人員、獸醫、醫生(醫師)或其他臨床醫生決定。
如本文所用,術語“組成物”涵蓋含有指定量的特定成分的產品和直接或間接由指定量的特定成分的組合產生的任何產品。
本發明的藥劑及其組合可以有效預防、緩解和治療糖尿病周邊神經病變或化療引起的周邊神經病變。
後文中,將藉由工作實施例更詳細地解釋本發明。然而,
如下工作實施例僅旨在闡釋一個或多個具體例,而不旨在限制本發明的範疇。
製備例:胺基甲酸(R)-1-(2-氯苯基)-2-四唑-2-基-乙酯的合成
胺基甲酸(R)-1-(2-氯苯基)-2-四唑-2-基-乙酯(後文稱為“測試化合物”)係根據國際公開案第WO 2010/150946號的製備例50中記載的方法製備。
實施例1:糖尿病周邊神經病變模式試驗
實驗動物
購買了雄性大鼠(史-道二氏(Sprague-Dawley),160至180g,Harlan Laboratories,以色列),並在動物實驗室使其適應環境超過1週。將實驗動物維持在12小時的明暗循環,20至24℃的溫度,40%至60%的相對濕度,並且自由接觸水和食物的條件下。
機械性異感痛的測定(馮.弗雷試驗)
疼痛程度係藉由使用馮.弗雷細絲縮爪(withdraw)(迴避反應)而評估。機械刺激係藉由上下方法對右後爪而施加,及將顯示迴避反應的最低彎曲力定義為爪退縮閾值(J Neurosci Methods,1994;53(1):55-63)。首先,將大鼠置於丙烯酸盒(13×25×13cm3)中,該盒子位於距離地面約35cm的金屬絲網上,並穩定超過20分鐘。在具有各種彎曲力(0.008、0.02、0.04、0.07、0.16、0.4、0.6、1.0、1.4、2.0、4.0、6.0、8.0、10.0、15.0、26.0、60.0、100、180和300g)的馮.弗雷細絲中,從2.0g的細絲開始刺激。施加刺激以在垂直於足底表面的方向上稍微彎曲的程度,並且根據有無反應而用具有較低或較高彎曲力的細絲刺激大鼠。
誘發糖尿病周邊神經性疼痛
進行該實驗以研究兩種不同劑量(10mg/kg和30mg/kg)的化合物治療在鏈脲佐菌素(STZ)誘發的糖尿病周邊神經性疼痛模式中的鎮痛功效。
糖尿病係藉由將0.5ml鏈脲佐菌素(60mg/kg)溶於檸檬酸鹽緩衝液(pH=6)的注射液注射到大鼠的尾靜脈而誘發。注射前將動物置於紅燈下,並鎖定在約束裝置中進行投予。
在鏈脲佐菌素(STZ)誘發的糖尿病周邊神經性疼痛大鼠模式中,通過大鼠尾部血管注射STZ後14至24天之間,誘發糖尿病周邊神經病變。在測試的第3天,將所有動物的血糖水平(BGL)用於確定是否誘發了糖尿病;在第14天,通過馮.弗雷試驗顯示出機械性異感痛的動物在實驗的第14和23天進行了BGL測試(第1圖)。
從第14天到第24天每天投予測試化合物組、陽性對照組和陰性對照組(投予途徑:陰性對照組和測試化合物組-PO、陽性對照組-IP)。在陰性對照組、測試化合物組和陽性對照組中,在投予前和投予後2小時,在實驗的第14天和第24天進行疼痛試驗。實驗後,將所有動物用二氧化碳安樂死。
結果
1)以10mg/kg和30mg/kg的待測化合物進行的馮.弗雷試驗結果:
與在第14天和第24天投予載劑的組相比,在基線時誘發陰性對照組動物的迴避反應所需的平均彎曲力為60.00±0.00g。在實驗的第14天,在投予藥物之前,由於機械性異感痛引起的縮足彎曲力顯著降低(18.55±2.47g),在實驗的第24天,在投予藥物之前,機械性異感痛仍然存在(23.00±5.35g)。
在實驗的第14天,陽性對照組(加巴噴丁,腹腔內投予劑量150mg/kg)的平均彎曲力為51.85±4.91g,相比於34.50±6.61g的載劑,無顯著的異感痛抑制功效。測試化合物(口服10mg/kg PO)的平均彎曲力為46.09±4.48g,與載劑的34.50±6.61g相比,也顯示出異感痛抑制功效的趨勢。投予30mg/kg PO的測試化合物也顯示出了異感痛抑制功效的趨勢(30mg/kg測試化合物為50.23±3.89g,而賦形劑為34.50±6.61g)。
在實驗的第24天,陽性對照組(加巴噴丁,腹腔內投予150mg/kg)的平均彎曲力為45.30±4.63g,與載劑的22.85±3.86g相比,顯示顯著的異感痛抑制功效。投予測試化合物(口服10mg/kg)的劑量為44.36±3.63g,與載劑的22.85±3.86g相比,也顯示顯著的異感痛抑制功效。測試化合物(口服30mg/kg)的投予量為46.91±4.46g,與載劑的22.85±3.86g相比,也顯示顯著的異感痛抑制功效(第2圖)。
2)在第14天和第24天以10mg/kg和30mg/kg的測試化合物進行馮.弗雷試驗的結果(治療前與治療後):
在實驗的第14天,投予加巴噴丁(腹腔內投予150mg/kg)後,陽性對照組的彎曲力從18.15±2.07g變成51.85±4.91g,表示異感痛的誘發經顯著抑制。投予測試化合物(口服10mg/kg)後,投予前的18.23±2.66g的彎曲力變成46.09±4.48g,表示異感痛的誘發經顯著抑制。在投予30mg/kg(口服)的測試化合物的情況下,投予前的彎曲力18.23±2.17g變成投予後的50.23±3.89g,也表示異感痛的誘發經顯著抑制。
在實驗的第24天,投予加巴噴丁(腹腔內投予150mg/kg)後,陽性對照組的投予前的彎曲力25.50±3.95g變成45.30±4.63g,表示異感痛的誘發經顯著抑制。投予前的彎曲力25.18±2.96g在投予測試化合物(口服10mg/kg)後成44.36±3.63g,表示異感痛的誘發經顯著抑制。在投予30mg/kg(口服)的測試化合物的情況下,從投予前的彎曲力23.55±2.52g變成投予後的46.91±4.46g,也表示異感痛的誘發經顯著抑制(第2圖)。
結論
根據本發明,在鏈脲佐菌素誘發的DPN大鼠模式中,與最高劑量(150mg/kg)的加巴噴丁(其係用於DPN治療異感痛的陽性對照)相比時,低劑量(10mg/kg)的測試化合物顯示與陰性對照組相比約75%的疼痛減輕,其為與150mg/kg的加巴噴丁相似的功效。從這樣的結果,證實了投予10mg/kg和30mg/kg的測試化合物有效地抑制了機械性異感痛。由此可知,投予測試化合物對糖尿病周邊神經病變有效。
實施例2:化療誘發的周邊神經病變模式測試
實驗動物
購買了雄性大鼠(史-道二氏,160至180g,Harlan Laboratories,以色列),並在動物實驗室使其適應環境超過1週。將實驗動物維持在12小時的明暗循環,20至24℃的溫度,40%至60%的相對濕度,並且自由接觸水和食物。
機械性異感痛的測定(馮.弗雷試驗)
使用馮.弗雷細絲縮爪(迴避反應)而評估疼痛程度。藉由上下方法對右後爪施加機械刺激,及將顯示迴避反應的最低彎曲力定義為爪退縮閾值(J Neurosci Methods,1994;53(1):55-63)。首先,將大鼠置於丙烯酸盒(13×25×13cm3)中,該盒子位於距離地面約35cm的金屬絲網上,並穩定超過20分鐘。在具有各種彎曲力(0.008、0.02、0.04、0.07、0.16、0.4、0.6、1.0、1.4、2.0、4.0、6.0、8.0、10.0、15.0、26.0、60.0、100、180和300g)的馮.弗雷細絲中,刺激從2.0g細絲開始。施加刺激以在垂直於足底表面的方向上稍微彎曲的程度,並且根據有無反應而用具有較低或較高彎曲力的細絲刺激大鼠。
紫杉醇誘發的疼痛性神經病變
為了誘發周邊神經病變,在第1、3、5、7以及9天以0.5ml/kg的劑量腹膜內(IP)投予2mg/kg的紫杉醇(其通常用於治療實性癌)。為了證實異感痛的誘發,使用了馮.弗雷試驗,並且在該研究中僅包含後爪平均疼痛閾值等於或小於43g的動物。
在實驗的第13天,僅選擇藉由馮.弗雷試驗而證實了異感痛的動物作為實驗組。在第13天和第14天進行疼痛測試之前2小時,口服投予測試化合物(10mg/kg和30mg/kg)和載劑作為陰性對照。在實驗第13天和第14天,在疼痛試驗30分鐘前,藉由腹膜內投予而投予嗎啡(5mg/kg)作為陽性對照。實驗後,將所有動物用二氧化碳安樂死。
結果
經由向大鼠投予紫杉醇而誘發的疼痛模式是化療誘發的周邊神經病變的眾所周知的模式。在藥物治療前藉由馮.弗雷試驗證實在第1、3、5、7和9天投予紫杉醇而誘發痛覺超敏,並從在第13天和第14天進行藥物治療後的陰性對照組(載劑投予)的數據證實了實驗期間的痛覺超敏維持。
在實驗的第13天,與載劑投予組相比,嗎啡投予(腹膜內投予5mg/kg)組顯示出對誘發異感痛的顯著抑制功效。測試化合物投予(10mg/kg)組相較於載劑投予組顯示抑制異感痛的傾向,並且測試化合物投予(30mg/kg)組相較於載劑投予組顯示對誘發異感痛的顯著抑制功效。
在實驗的第14天,與載劑投予組相比,嗎啡(腹腔內投予5mg/kg)投予組顯示對誘發異感痛的顯著抑制功效。測試化合物投予(10mg/kg)組相較於載劑投予組顯示抑制異感痛的傾向,並且測試化合物投予(30mg/kg)組相較於載劑投予組顯示對誘發異感痛的顯著抑制功效。
結論
考慮到在該研究條件下獲得的結果以及在生活方式數據中限制的結果,證實了以10mg/kg的劑量投予測試化合物顯示抑制周邊神經
病變的機械性異感痛模式的趨勢,並且以30mg/kg的劑量投予測試化合物在紫杉醇誘發的周邊神經病變模式中顯示顯著的機械異感痛抑制作用。由此可知,投予測試化合物對化療引起的周邊神經病變有效。
統計
各實驗組係藉由單因子變異數分析(ANOVA)和土耳其事後檢驗(Prism®GraphPad)而與陰性對照組進行比較。
Claims (7)
- 如申請專利範圍第1項所述之用途,其中,R1和R2各自獨立地選自由氫、鹵素和C1-C8烷基所組成群組。
- 如申請專利範圍第1至3項中任一項所述之用途,其中,該個體係哺乳動物。
- 如申請專利範圍第1至3項中任一項所述之用途,其中,該式1之胺基甲酸酯化合物以每日投予一次的游離形式為基準計,係使用50至500mg的量。
- 如申請專利範圍第1項所述之用途,其中,該糖尿病周邊神經病變為疼痛性糖尿病周邊神經病變、糖尿病自律神經病變或兩者皆是。
- 如申請專利範圍第1項所述之用途,其中,該化療誘發的周邊神經病變係選自由鉑類藥物、紫杉烷類和長春花生物鹼所組成群組中的一種或多種化學治療劑引起。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862747841P | 2018-10-19 | 2018-10-19 | |
US62/747,841 | 2018-10-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW202027744A TW202027744A (zh) | 2020-08-01 |
TWI837197B true TWI837197B (zh) | 2024-04-01 |
Family
ID=70284752
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW108137697A TWI837197B (zh) | 2018-10-19 | 2019-10-18 | 胺基甲酸酯化合物於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的用途 |
Country Status (12)
Country | Link |
---|---|
US (1) | US20210379018A1 (zh) |
EP (1) | EP3868375A4 (zh) |
JP (1) | JP7369185B2 (zh) |
KR (1) | KR20210062029A (zh) |
CN (1) | CN112912076B (zh) |
AU (1) | AU2019361856A1 (zh) |
BR (1) | BR112021006586A2 (zh) |
CA (1) | CA3116195A1 (zh) |
IL (1) | IL282287A (zh) |
MX (1) | MX2021004342A (zh) |
TW (1) | TWI837197B (zh) |
WO (1) | WO2020080866A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20230048032A (ko) * | 2020-08-06 | 2023-04-10 | 에스케이바이오팜 주식회사 | 카바메이트 화합물을 포함하는 경구용 고형 제제 및 이의 제조방법 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200722085A (en) * | 2005-04-22 | 2007-06-16 | Sk Corp | Neurotherapeutic azole compounds |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0811245B1 (pt) * | 2007-05-14 | 2021-05-25 | Sk Biopharmaceuticals Co., Ltd | Composto derivado de carbamoilóxi-aril-alcanoil-aril-piperazinas e seus usos |
JP5667885B2 (ja) * | 2008-03-14 | 2015-02-12 | バイオニューメリック・ファーマスーティカルズ・インコーポレイテッド | 化学的保護方法及び組成物 |
ES2541590T3 (es) | 2009-06-22 | 2015-07-22 | Sk Biopharmaceuticals Co., Ltd. | Método para la preparación de éster (R)-1-aril-2-tetrazolil-etílico de ácido carbámico |
US8404461B2 (en) | 2009-10-15 | 2013-03-26 | SK Biopharmaceutical Co. Ltd. | Method for preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester |
WO2015112902A2 (en) * | 2014-01-23 | 2015-07-30 | Sova Pharmaceuticals, Inc. | CYSTATHIONINE-(gamma)-LYASE (CSE) INHIBITORS FOR TREATING PAIN |
KR102421013B1 (ko) * | 2016-05-19 | 2022-07-14 | 에스케이바이오팜 주식회사 | 삼차신경통을 예방 또는 치료하기 위한 카바메이트 화합물의 용도 |
KR102489052B1 (ko) * | 2016-05-19 | 2023-01-16 | 에스케이바이오팜 주식회사 | 섬유근육통 또는 섬유근육통의 연관된 기능적 증후군을 예방 또는 치료하기 위한 카바메이트 화합물의 용도 |
US20210085646A1 (en) * | 2016-12-14 | 2021-03-25 | Sk Biopharmaceuticals Co., Ltd. | Orally Disintegrated Tablet Comprising Carbamate Compound |
KR20180068494A (ko) * | 2016-12-14 | 2018-06-22 | 에스케이바이오팜 주식회사 | 운동신경세포 질환의 예방, 경감 또는 치료를 위한 카바메이트 화합물의 용도 |
KR102635936B1 (ko) * | 2016-12-14 | 2024-02-13 | 에스케이바이오팜 주식회사 | 탈수초성 질환의 예방, 경감 또는 치료를 위한 카바메이트 화합물의 용도 |
KR20190054549A (ko) * | 2017-11-14 | 2019-05-22 | 에스케이바이오팜 주식회사 | 말초신경의 나트륨-채널병증을 예방 또는 치료하기 위한 카바메이트 화합물의 용도 |
-
2019
- 2019-10-18 US US17/286,529 patent/US20210379018A1/en active Pending
- 2019-10-18 CN CN201980068459.6A patent/CN112912076B/zh active Active
- 2019-10-18 JP JP2021521114A patent/JP7369185B2/ja active Active
- 2019-10-18 BR BR112021006586-5A patent/BR112021006586A2/pt unknown
- 2019-10-18 EP EP19873768.6A patent/EP3868375A4/en active Pending
- 2019-10-18 WO PCT/KR2019/013701 patent/WO2020080866A1/ko unknown
- 2019-10-18 TW TW108137697A patent/TWI837197B/zh active
- 2019-10-18 KR KR1020217010544A patent/KR20210062029A/ko unknown
- 2019-10-18 MX MX2021004342A patent/MX2021004342A/es unknown
- 2019-10-18 AU AU2019361856A patent/AU2019361856A1/en active Pending
- 2019-10-18 CA CA3116195A patent/CA3116195A1/en active Pending
-
2021
- 2021-04-13 IL IL282287A patent/IL282287A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW200722085A (en) * | 2005-04-22 | 2007-06-16 | Sk Corp | Neurotherapeutic azole compounds |
Non-Patent Citations (1)
Title |
---|
期刊 Christopher R. Cashman and Ahmet Höke Mechanisms of Distal Axonal Degeneration in Peripheral Neuropathies Neurosci Lett 2015 June 2; 596: HHS Public Access 2015 June 2 33-50 * |
Also Published As
Publication number | Publication date |
---|---|
CN112912076A (zh) | 2021-06-04 |
JP2022505172A (ja) | 2022-01-14 |
US20210379018A1 (en) | 2021-12-09 |
JP7369185B2 (ja) | 2023-10-25 |
IL282287A (en) | 2021-05-31 |
WO2020080866A1 (ko) | 2020-04-23 |
EP3868375A1 (en) | 2021-08-25 |
AU2019361856A1 (en) | 2021-05-06 |
TW202027744A (zh) | 2020-08-01 |
CA3116195A1 (en) | 2020-04-23 |
CN112912076B (zh) | 2024-07-16 |
EP3868375A4 (en) | 2022-06-29 |
MX2021004342A (es) | 2021-05-31 |
KR20210062029A (ko) | 2021-05-28 |
BR112021006586A2 (pt) | 2021-07-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1377278B1 (en) | Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase iv | |
BR112020001285A2 (pt) | s-enantiômeros de beta-hidroxibutirato e butanodiol e métodos para sua utilização | |
CN109475529B (zh) | 氨基甲酸酯化合物用于预防或治疗纤维肌痛或与纤维肌痛相关的功能综合征的用途 | |
JP5680412B2 (ja) | レオヌリンの使用およびその組成物 | |
TWI837197B (zh) | 胺基甲酸酯化合物於預防、緩解或治療糖尿病周邊神經病變或化療誘發的周邊神經病變的用途 | |
JPH0325407B2 (zh) | ||
CN110290788A (zh) | 氨基甲酸酯化合物用于预防、缓解或治疗双相障碍的用途 | |
JP6960415B2 (ja) | 三叉神経痛を予防又は治療する目的のためのカルバメート化合物の使用 | |
WO2023155837A1 (zh) | 具有镇痛和/或止痒功能的药物组合物及其用途 | |
KR20200136008A (ko) | 신경퇴행성 장애의 치료를 위한 약제학적 조성물의 연속 투여 | |
US12070448B2 (en) | Use of carbamate compound for prevention, alleviation or treatment of status epilepticus | |
RU2783733C1 (ru) | Применение соединения карбамата для предотвращения, облегчения или лечения диабетической периферической нейропатии или индуцированной химиотерапией периферической нейропатии | |
MX2014014316A (es) | Método de reducción de peso. | |
KR20190021180A (ko) | 퇴행성 신경질환 치료용 복합 제형 조성물 | |
US11666554B2 (en) | Use of a carbamate compound to prevent, alleviate or treat visceralgia or pain arising from visceral disease | |
EP3854391B1 (en) | Carbamate compound and use of formulation comprising same in preventing, alleviating, or treating acute stress disorder or post-traumatic stress disorder | |
JPWO2020023324A5 (zh) | ||
RU2664693C1 (ru) | Способ предоперационной подготовки пациентов к офтальмологическим операциям | |
US9284281B2 (en) | Indication of naphtho[2,3-F]quinoxaline-7,12-dione compound in alleviating pain | |
US20220362202A1 (en) | Drug For Treating And Preventing Dementia | |
Radhakrishnan | Adrenergic agonists | |
CN115715191A (zh) | 排尿症状治疗剂 | |
JPH02221222A (ja) | モノアミンオキシダーゼ阻害剤 | |
US20160022609A1 (en) | Methods for treating chronic pain using a combination of bupropion ((±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one) and phentermine (2-methyl-1-phenylpropan-2-amine) |