HRP20040102A2 - Combinations for the treatment of inflammatory disorders - Google Patents
Combinations for the treatment of inflammatory disorders Download PDFInfo
- Publication number
- HRP20040102A2 HRP20040102A2 HR20040102A HRP20040102A HRP20040102A2 HR P20040102 A2 HRP20040102 A2 HR P20040102A2 HR 20040102 A HR20040102 A HR 20040102A HR P20040102 A HRP20040102 A HR P20040102A HR P20040102 A2 HRP20040102 A2 HR P20040102A2
- Authority
- HR
- Croatia
- Prior art keywords
- prednisolone
- patient
- preparation
- corticosteroid
- amoxapine
- Prior art date
Links
- 208000027866 inflammatory disease Diseases 0.000 title claims description 27
- 238000011282 treatment Methods 0.000 title claims description 17
- 229960005205 prednisolone Drugs 0.000 claims description 62
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 62
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 claims description 61
- 229960002519 amoxapine Drugs 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 41
- 239000003246 corticosteroid Substances 0.000 claims description 40
- 229940123445 Tricyclic antidepressant Drugs 0.000 claims description 32
- 239000003029 tricyclic antidepressant agent Substances 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 22
- -1 7-hydrosciamoxapine Chemical compound 0.000 claims description 14
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 12
- 206010061218 Inflammation Diseases 0.000 claims description 10
- 230000004054 inflammatory process Effects 0.000 claims description 10
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- ZOCUOMKMBMEYQV-GSLJADNHSA-N 9alpha-Fluoro-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ZOCUOMKMBMEYQV-GSLJADNHSA-N 0.000 claims description 6
- HYRKAAMZBDSJFJ-LFDBJOOHSA-N Paramethasone acetate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]2(C)C[C@@H]1O HYRKAAMZBDSJFJ-LFDBJOOHSA-N 0.000 claims description 6
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 claims description 6
- 229960004544 cortisone Drugs 0.000 claims description 6
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 claims description 6
- 229960000890 hydrocortisone Drugs 0.000 claims description 6
- 238000001990 intravenous administration Methods 0.000 claims description 6
- YQZBAXDVDZTKEQ-UHFFFAOYSA-N loxapine succinate Chemical compound [H+].[H+].[O-]C(=O)CCC([O-])=O.C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 YQZBAXDVDZTKEQ-UHFFFAOYSA-N 0.000 claims description 6
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 claims description 5
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 claims description 5
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 claims description 5
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 claims description 5
- 229960003957 dexamethasone Drugs 0.000 claims description 5
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 5
- 229960004584 methylprednisolone Drugs 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- KAAZGXDPUNNEFN-UHFFFAOYSA-N Clotiapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2SC2=CC=C(Cl)C=C12 KAAZGXDPUNNEFN-UHFFFAOYSA-N 0.000 claims description 4
- PWRPUAKXMQAFCJ-UHFFFAOYSA-N Perlapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2CC2=CC=CC=C12 PWRPUAKXMQAFCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960002537 betamethasone Drugs 0.000 claims description 4
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 claims description 4
- 229960003864 clotiapine Drugs 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 238000007918 intramuscular administration Methods 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 229960005294 triamcinolone Drugs 0.000 claims description 4
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 claims description 4
- RVBSTEHLLHXILB-QODHSQIYSA-N (6r,8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-6,11,17-trihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one Chemical compound C1([C@H](O)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O RVBSTEHLLHXILB-QODHSQIYSA-N 0.000 claims description 3
- SHJZUHWENQCCJH-YQAXKJAASA-N (8s,9r,10s,11s,13s,14s)-9-fluoro-11-hydroxy-10,13-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 SHJZUHWENQCCJH-YQAXKJAASA-N 0.000 claims description 3
- BHDHELFREODRJK-XRYUJSLGSA-N (8s,9r,10s,13s,14s,17r)-9-fluoro-17-hydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-2,6,7,8,12,14,15,16-octahydro-1h-cyclopenta[a]phenanthrene-3,11-dione Chemical compound O=C1CC[C@]2(C)[C@@]3(F)C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 BHDHELFREODRJK-XRYUJSLGSA-N 0.000 claims description 3
- FTMJFHVKAXPFIY-UHFFFAOYSA-N 2,2-dichloro-N-[1,3-dihydroxy-1-(3-nitrophenyl)propan-2-yl]acetamide Chemical compound OCC(NC(=O)C(Cl)Cl)C(O)c1cccc(c1)[N+]([O-])=O FTMJFHVKAXPFIY-UHFFFAOYSA-N 0.000 claims description 3
- QTQGHKVYLQBJLO-UHFFFAOYSA-N 4-methylbenzenesulfonate;(4-methyl-1-oxo-1-phenylmethoxypentan-2-yl)azanium Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC(C)CC(N)C(=O)OCC1=CC=CC=C1 QTQGHKVYLQBJLO-UHFFFAOYSA-N 0.000 claims description 3
- MYYIMZRZXIQBGI-HVIRSNARSA-N 6alpha-Fluoroprednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3C[C@H](F)C2=C1 MYYIMZRZXIQBGI-HVIRSNARSA-N 0.000 claims description 3
- JSXBVMKACNEMKY-UHFFFAOYSA-N 8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine;hydron;chloride Chemical compound Cl.C1CN(C)CCN1C1=NC2=CC=CC=C2OC2=CC=C(Cl)C=C12 JSXBVMKACNEMKY-UHFFFAOYSA-N 0.000 claims description 3
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- YCISZOVUHXIOFY-HKXOFBAYSA-N Halopredone acetate Chemical compound C1([C@H](F)C2)=CC(=O)C(Br)=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@](OC(C)=O)(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O YCISZOVUHXIOFY-HKXOFBAYSA-N 0.000 claims description 3
- FOGXJPFPZOHSQS-AYVLZSQQSA-N Hydrocortisone butyrate propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O FOGXJPFPZOHSQS-AYVLZSQQSA-N 0.000 claims description 3
- DLVOSEUFIRPIRM-KAQKJVHQSA-N Hydrocortisone cypionate Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(CCC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCC1CCCC1 DLVOSEUFIRPIRM-KAQKJVHQSA-N 0.000 claims description 3
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 claims description 3
- HUMXXHTVHHLNRO-KAJVQRHHSA-N Prednisolone tebutate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CC(C)(C)C)(O)[C@@]1(C)C[C@@H]2O HUMXXHTVHHLNRO-KAJVQRHHSA-N 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 206010039710 Scleroderma Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 3
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 3
- XGMPVBXKDAHORN-RBWIMXSLSA-N Triamcinolone diacetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](OC(C)=O)[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O XGMPVBXKDAHORN-RBWIMXSLSA-N 0.000 claims description 3
- TZIZWYVVGLXXFV-FLRHRWPCSA-N Triamcinolone hexacetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)CC(C)(C)C)[C@@]1(C)C[C@@H]2O TZIZWYVVGLXXFV-FLRHRWPCSA-N 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- AKUJBENLRBOFTD-HIBZCRSPSA-N [2-[(9r,10s,11s,13s,16r,17r)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)C1C1C[C@@H](C)[C@@](C(=O)COC(C)=O)(O)[C@@]1(C)C[C@@H]2O AKUJBENLRBOFTD-HIBZCRSPSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 229960000836 amitriptyline Drugs 0.000 claims description 3
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 229950000210 beclometasone dipropionate Drugs 0.000 claims description 3
- 229940092705 beclomethasone Drugs 0.000 claims description 3
- 229940038482 beclomethasone dipropionate monohydrate Drugs 0.000 claims description 3
- SNHRLVCMMWUAJD-SUYDQAKGSA-N betamethasone valerate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O SNHRLVCMMWUAJD-SUYDQAKGSA-N 0.000 claims description 3
- 210000004958 brain cell Anatomy 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 claims description 3
- 230000030833 cell death Effects 0.000 claims description 3
- 229960002842 clobetasol Drugs 0.000 claims description 3
- 229960004703 clobetasol propionate Drugs 0.000 claims description 3
- 229960004299 clocortolone Drugs 0.000 claims description 3
- YMTMADLUXIRMGX-RFPWEZLHSA-N clocortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O YMTMADLUXIRMGX-RFPWEZLHSA-N 0.000 claims description 3
- 229960001357 clocortolone pivalate Drugs 0.000 claims description 3
- SXYZQZLHAIHKKY-GSTUPEFVSA-N clocortolone pivalate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(Cl)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)COC(=O)C(C)(C)C)[C@@]2(C)C[C@@H]1O SXYZQZLHAIHKKY-GSTUPEFVSA-N 0.000 claims description 3
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 claims description 3
- FZCHYNWYXKICIO-FZNHGJLXSA-N cortisol 17-valerate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O FZCHYNWYXKICIO-FZNHGJLXSA-N 0.000 claims description 3
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 claims description 3
- 229960003290 cortisone acetate Drugs 0.000 claims description 3
- NPUACKRELIJTFM-UHFFFAOYSA-N cr gas Chemical compound C1=NC2=CC=CC=C2OC2=CC=CC=C21 NPUACKRELIJTFM-UHFFFAOYSA-N 0.000 claims description 3
- 229960002593 desoximetasone Drugs 0.000 claims description 3
- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 claims description 3
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- 229960001401 hydrocortisone sodium succinate Drugs 0.000 claims description 3
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- PLBHSZGDDKCEHR-LFYFAGGJSA-N methylprednisolone acetate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(C)=O)CC[C@H]21 PLBHSZGDDKCEHR-LFYFAGGJSA-N 0.000 claims description 3
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- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
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Description
Dosadašnje spoznaje
Izum se odnosi na tretman upalnih poremećaja.
Do upale dolazi kada su tkiva ozlijeđena virusima, bakterijama, traumom, kemikalijama, toplinom, hladnoćom ili bilo kojom štetnom stimulacijom. Oslobađaju se kemikalije kao što su bradikinin, histamin, serotonin i ostale, koje privlače tkiva makrofaga i bijelih krvnih stanica na lokalizirane dijelove, a da bi nadvladali i uništili strane tvari. Tijekom tog procesa se oslobađaju medijatori kemikalija kao što je TNFα, povećavajući upalu. Upalni poremećaji su oni u kojima je upala akutna ili kronična. Jedan primjer upalnog poremećaja je osteoartritis.
Upalni poremećaji (npr. reumatoidni artritis, psorijaza, ulcerativni kolitis, Cronova bolest, smrt stanica mozga izazvana udarom, ankilozni spondilitis, fibromialgija i autoimune bolesti kao što je astma, multipla skleroza, dijabetes tipa I, sistemski eritematozni lupus, skleroderma, sistemska skleroza i Sjoerensov sindrom) su upalni poremećaju karakterizirani poremećenom regulacijom imunog sustava i neodgovarajućom mobilizacijom obrane tijela protiv vlastitog zdravog tkiva.
Jedan posto ljudi širom svijeta je pogođeno reumatoidnim artritisom, stalnom progresivnom bolesti koja uzrokuje ozbiljno naticanje, bol i konačno deformaciju i uništenje zglobova. Prema Fondaciji za artritis, reumatoidni artritis sada pogađa preko dva milijuna Amerikanaca od kojih su žene tri puta češće pogođene. Reumatoidni artritis je karakteriziran upalom zglobova i/ili ostalih internih organa, te prisutnošću povećanog broja limfocita i visoke razine proinflamatornih citokina.
Tretman reumatoidnog artritisa uključuje davanje sljedećih: (i) nesteroidni antiupalni lijekovi (NSAID, npr. detoprofen, diklorfenak, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indometacin, petoprofen, meklofenamea, mefanaminska kiselina, mekloksikam, nabumenon, naproksen natrij, oksaprozin, piroksikam, sulindak, tolmetin, celekoksib, rofekoksib, aspirin, kolin salicilat, salsalat i natrijev i magnezijev salicilat; (ii) steroidi (npr. kortizon, deksametazon, hidrokortizon, metilprednisolon, prednisolon, prenidizon, triamcinolon); (iii) DMARD tj. antireumatski lijekovi koji modificiraju bolest (npr. ciklosporin, azatioprin, metotreksat, leflunomid, ciklofosfamid, hidroksi-oksiklorokin, sulfalazin, D-penicilamin, minociklin i zlato); ili (iv) rekombinantni proteini (npr. ENBREL® (atanercept, topljivi TNF receptor) i REMICADE® (infliksimab) komerno monoklonalno anti-TNF tijelo).
Postoji potreba za razvitak novih lijekova za tretman reumatoidnog artritisa i ostalih upalnih poremećaja.
Sažetak izuma
Mi smo našli da kombinacija amoksapina (2-klor-11-(1-piperazinil)dibenz-[b,f]oksapin) i prednisolona (također poznat kao 1-dehidrokortizol; 1-dehidroksi-kortizon; 1,4-pregnadien-11β,17α,21-triol-3,20-dion; te 11β,17α,21-trihidroksi-1,4-pregnadien-3,2-dion) dovodi do značajnog smanjivanja razine TNFα koji je induciran u mononuklearnim stanicama perifernog krvotoka (PBMC).
Amoksapin je triciklički antidepresiv (TCA). Zasnovano na sposobnosti amoksapina da djeluje skupa s prednisolonom u inhibicijiu razine TNFα, stručnjak će repoznati da se ostali TCA također mogu koristiti u ovom izumu. Strukturni analozi amoksapina koji nisu triciklički antidepresivi se također mogu koristiti. Primjeri strukturnih analoga uključuju primjerice, klotiapin, perlapin, fluperlapin i dibenz(b,f)(1,4)oksazepin, 2-klor-11-(4-metil-1-piperazinil)-monohiroklorid.
Prednisolon je kortikosteroid. Na osnovu strukturne karakteristike i mehanizma djelovanja koji su karakteristika cijele obitelji kortikosteroida, stručnjak će prepoznati da se mogu koristiti ostali krotikosteroidi u kombinaciji s amoksapinom ili ostalim TCA za tretman upalnih poremećaja.
Prema ovome, karakteristika izuma je metoda tretmana pacijenata koji ima upalni poremećaj, a davanjem pacijentu (i) TCA (npr. amoksapin) i (ii) kortikosteroida (npr. prednisolon) istovremeno ili unutar 14 dana, u količinama koje su dozvoljene da smanje razinu TNFα toliko da se dobije terapijska korist kod pacijenta. U jednoj cjelini ta dva spoja jesu amoksapin i predinosol.
Izum je također karakteriziran metodom tretmana pacijenta koji ima upalni poremećaj, a davanjem pacijentu (i) klotiapina, perlapina, fluperlapina ili dibenz(b,f)(1,4)oksazepin, 2-klor-11-(4-metil-1-piperazinil)-monohidroklorida; te (ii) kortikosteroida (npr. prednisolon) istovremeno ili unutar 14 dana, u količinama koje su dovoljne da toliko smanje razinu TNFα da se dobije terapijska korist kod pacijenta.
Preferirano se dva spoja iz izuma daju unutar deset dana razmaka jedan od drugog, preferiranije unutar pet dana razmaka, a najpreferiranije unutar dvadeset četiri sata jedan razmaka ili istovremeno. Poremećaj koji se tretira prema izumu može primjerice biti: reumatoidni artirits, psorijaza, ulcerativni kolitis, Cronova bolest, smrt stanica mozga izazvana udarom, ankilozni spondilitis, fibromialgija i autioimune bolesti kao što je astma, multipla skleroza, dijabetes tipa I, sistemski eritematozni lupus, skleroderma, sistemska skleroza i Sjoerensov sindrom.
U gore opisanoj metodi tretmana oba spoja preferirano dolaze zajedno u farmaceutskom pripravku koji također uključuje farmaceutsko prihvatljivi nosač.
Izum je također karakteriziran farmaceutskim pripravkom koji uključuje (i) TCA (npr. amoksapin) te (ii) kortikosteroid (npr. prednisolon) skupa s farmaceutski prihvatljivim nosačem, razrjeđivačem i ekscipijensom.
Izum također prikazuje metode spojeva korisnih za tretman pacijenta koji ima upalni poremećaj. Metoda uključuje sljedeće korake: dovođenje u doticaj imunih stanica in vitro s (i) TCA ili kortikosteroidom, te (ii) sa spojem kandidatom, te određivanje je li je imuni odgovor relativno modificiran na (a) imune stanice koje su došle u doticaj s TCA ili krotikosteroidom ali nisu došle u dotican s spojem kandidatom, te (b) imune stanice koje su došle u doticaj sa spojem kandidatom ali ne s TCA ili kortikosteroidom. Spoj kandidat koji povećava imuni odgovor prema kontroli, a kad se spoji s TCA ili kortikosteroidom, može biti koristan za tretman pacijenta koji ima upalni poremećaj.
Spojevi korisni u izumu uključuju one ovdje opisane u bilo kojem farmaceutski prihvatljivom obliku, uključujući izomere kao što su dijastereomeri i enantiomeri, soli, solvati i njihovi polimorfi, kao i racemičćne smjese ovdje opisanih spojeva.
"Triciklički antiderpesiv" ili "TCA" znači spoj koji ima jednu od formula (I), (II) ili (III):
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pri čemu svaki X neovisno jeste H, Cl, F, Br, I, CH3, CF3, OH, OCH3, CH2CH3 ili OCH2CH3; Y jeste CH2, O, NH, S(O)0-2, (CH2)3, (CH2), CH2O, CH2NH, CHN ili CH2S; Z jeste C ili S; A je razgranati ili nerazgranat zasićeni ili jednostruko nezasićeni ugljikovodični lanac koji ima između 3 i 6 atoma ugljika, Svaki B neovisno jeste H, Cl, F, Br, I, CX3, CH2CH3, OCX3 ili OCX2CX3; te D jeste CH2, O, NH, S(O)0-2.
U preferiranom cjelinama svaki X neovisno jeste H, Cl ili F; Y jeste (CH2)2; Z jeste C; A jeste (CH2)3, te svaki B neovisnoj jeste H, Cl ili F.
Primjeri tricikličkih antidepresiva uključuju loksapin, loksapin sukcinat, loksapin hidroklorid, 7-hidroksiamoksapin, amitriptilin, klopramin, doksepin, imipramin, trimipramin, despramin, nortriptilin te protiptilin.
"Kortikosteroid" označuje prirodni ili sintetski steroidni hormon koji se može izvesti od kolesterola i karakteriziran je hidriranom ciklopentanperhidro-fenantrenskim sustavom prstena. Prirodni kortikosteroidi se općenito dobivaju iz adrenalnog korteksa. Sintetski kortikosteroidi se mogu halogenirati. Funkcionalne skupine potrebne za aktivnost uključuju dvostruku vezu Δ4 i C3 keton, te C20 keton. Kortikosteroidi mogu imati glukorotikoidnu i/ili mineralkortikoidnu aktivnost.
Primjeri kortikosteroida ukljulčuju primjerice deksametazon, betametazon, triamcinolon, triamcinolon acetonid, triamcinolon diacetat, triamcinolon heksacetonid, beklometazon dipropionat, beklometazon dipropionat monohidrat, flumetazon pivalat, diflorazon diacetat, fluocinolon acetonid, fluormetolon, fluormetolon acetat, klobetazol propionat, dezoksimetazon, fluoksimesteron, fluprednisolon, hidrokortizon, hidrokortizon acetat, hidrokortizon butirat, hidrokrotizon natrijv fosfat, hidrokortizon natrijev sukcinat, hidrokortizon cipionat, hidrokortizon probutat, hidrokortizon valerat, kortizon acetat, parametazon acetat, metilprednisolon, metilprednisolon acetat, metilprednisolon natrijev sukcinat, prednisolon, prednisolon acetat, prednisolon natrijev fosfat, prednisolon tebutat, klokortolon pivalat, flucinolon, deksametazon 21-acetat, betametazon 17-valerat, izoflupredon, 9-fluorokortizon, 6-hidroksideksametazon, diklorizon, meklorizon, fluprediden, doksibetazol, halopredon, halometazon, klobetazon, diflukortolon, izoflupredon acetat, fluorhidroksiandrostenedion, beklometazon, flumetzon, diflorazon, fluocinolon, klobetazol, kortizon, parametazon, klokortolon, prednisolon 21-hemisukcinat slobodne kiseline, prednisolon metasulfobenzoat, prednisolon terbutat, te triaminokolon acetonid 21-palmitat.
"Niska doza kortikosteroida" označuje dozu koja je niža od doze koja bi tipično bila dana pacijentu za tretman upale. Primjeri niskih doza kortikosteroida su sljedeći: kortizol, 12 mg/danu; kortizon, 15 mg/danu; prednison, 3 mg/danu; metilprednisolon, 2.5 mg/danu; triaminokolon, 2.5 mg/danu; betametazon, 250 μg/danu; deksametazon, 450 μg/danu; hidrokortizon, 9 mg/danu.
"Doza ekvivalentna dozi amoksapina" označuje dozu TCA koja u kombinaciji s danom dozom prednisolona daje isti antiupalni učinak kod pacijenta kao doza amoksapina u kombinaciji s dozom prednisolona.
"Doza ekvivalentna dozi prednisolona " označuje dozu kortikosteroida koja u kombinaciji s danom dozom amoksapina daje isti antiupalni učinak kod pacijenta kao doza prednisolona u kombinaciji s dozom amoksapinom.
Ostale karakteristike i prednosti izuma će biti očite iz sljedećeg detaljnog opisa u uz zahtjeva.
Detaljni opis
Mi smo našli da kombinacija amoksapina i prednisolona ima značajnu smanjuje TNFα na PBMC. Koncentracije koje su imale učinak u smanjivanje TNFα nisu neprihvatljivo toksične u normalnim stanicama. Stoga, kombinacije lijeka je korisna za tretman upalnih poremećaja.
Amoksapin
Amoksapin je triciklički antidepreseiv (TCA) tipa dibenzoksapina. On je strukturno sličan starijim TCA, a također je sličan fenotiazinima.
Točno djelovanje TCA nije potpuno razjašnjeno, ali se vjeruje da je jedan njihov važan efekt povećanje djelovanja norepinefrina i serotonina, a blokiranjem ponovnog prihvata različitih neurotransmitera u neuronskoj membrani. Amoksapin također ima sličnosti s antipsihotičkim lijekovima koji blokiraju receptore dopamina i mogu uzrokovati dikineziju. Amoksapin također blokira ponovni prihvat nenrepinefrina, što je slično djelovanju desipramina i maprotilina.
Na osnovi spsobnosti amoksapina da djeluje skupa s prednisolonom u inhibiciji razine TNFα, stručnjak će prepoznati da drugi TCA, kao što su strukturni u funkcionalni analozi amoksapina također mogu biti korišteni u kombinaciji s prednisolonom (ili drugim kortikosteroidom - vidi niže). Analozi amoksapina primjerice uključuju sljedeće: 8-hidroksiamoksapin, 7-hidroskiamoksapin, loksapin, loksapin sukcinat, loksapin hidroklorid, 8-hidroksiloksapin, klotiapin, perlapin, fluperlapin te dibenz(b,f)(1,4)oksazepin-2-klor-11-(4-metil-1-piperazinil)-mono-hidroklorid.
Prednisolon
Prednisolon je sintetski adrenalni kortikosteroid koji ima antiupalna svojstva i koristi se u širokom rasponu upalnih stanja. Poželjno je smanjiti količinu danog predisolona jer dugotrajna upotreba steroida može uzrokovati značajne nuzefekte.
Prednisolon je član kortikosteroida iz obitelji steroida. Kako dijeli strukturna svojstva i mehanizam djelovanja s kortikosteroidima iz iste obitelji, stručnjak će prepoznati da se mogu koristiti i drugi kortikosteroidi u kombinaciji s amoksapinom ili analogom amoksapina, a za tretmanu upalnih poremećaja. Kortikosteroidi uključuju primjerice deksametazon, betametazon, triamcinolon, triamcinolon acetonid, triamcinolon diacetat, triamcinolon heksacetonid, beklometazon dipropionat, beklometazon dipropionat monohidrat, flumetazon pivalat, diflorason diacetat, fluocinolon acetonid, fluormetolon, fluormetolon acetat, klobetazol propionat, dezoksimetazon, fluoksimesteron, fluprednisolon, hidrokortizon hidrokortizon acetat, hidrokortizon butirat, hidrokrotizon natrijev fosfat, hidrokortizon natrijev sukcinat, hidrokortizon cipionat, hidrokortizon probutat, hidrokortizon valerat, kortizon acetat, parametazon acetat, metilprednisolon, metilprednisolon acetat, metilprednisolon natrijev sukcinat, prednisolon, prednisolon acetat, prednisolon natrijev fosfat, prednisolon tebutat, klokortolon pivalat, flucinolon, deksametazon 21-acetat, betametazon 17-valerat, izoflupredon, 9-fluorokortizon, 6-hidroksideksametazon, diklorizon, meklorizon, fluprediden, doksibetazol, halopredon, halometazon, klobetazon, diflukortolon, izoflupredon acetat, fluorhidroksiandrostenedion, beklometazon, flumetzon, diflorazon, fluocinolon, klobetazol, kortizon, parametazon, klokortolon, prednisolon 21-hemisukcinat slobodna kiselina, prednisolon metasulfobenzoat, prednisolon terbutat, te triaminokolon acetonid 21-palmitat.
Terapija
Kombinacijska terapija se prema izumu može izvesti sama ili skupa s drugom terapijom i može se izvoditi doma, u ambulanti liječnika, u klinici te u bolnici. Tretman općenito počinje u bolnici tako da liječnik može iz blizine motriti terapijski učinak i po potrebi izvesti prilagodbe. Trajanje kombinacijske terapije ovisi o vrsti tretiranog upalnog poremećaja, starosti i stanju pacijenta, stupnju i tipu bolesti pacijenta te kako pacijent reagira na tretman. Uz to, osoba kod koje postoji veći rizik od razvitka upalnog poremećaja (npr. osoba koja ima genetsku predispoziciju na upalni poremećaj) može primiti profilaktički tretman za inhibiciju ili odgodu upalnog odgovora.
Doziranje, učestalost i način davanja svake komponente kombinacije se može neovisno kontrolirati. Primjerice, jedan spoj može biti dan oralno tri puta dnevno, dok se drugi spoj može davati intramuskularno jedanput dnevno. Kombinacijska terapija se također može formulirati zajedno tako da se spojevi isporuče jednim davanjem.
Formulacija farmaceutskih pripravaka
Pogodni načini davanja uklučuju oralno, rektalno, intravenozno, intramuskularno, subkutalno, inhalacijsko, topičko ili transdermalno, vaginalno i okularno davanje.
Kombinacija iz izuma također može biti u obliku komponenata farmaceutskog paketa. Dva lijeka se mogu formulirati zajedno ili odvojeno u pojedinim količinama doze.
Spojevi iz izuma također mogu biti korisni kada su formulirani kao soli. Primjerice, amitriptilin, drugi triciklički antidepresiv je formuliran kao hidroklorid, što ukazuje da se amoksapin može slično formulirati. Soli prednisolona uključuju primjerice prednisolon 21-hemisukcinat natrijevu soli i prednisolon 21-fosfat dinatrijevu sol.
Davanje svakog spoja iz kombinacije može biti na bilo koji pogodni način koji rezultira da ta koncentracija spoja u kombinaciji s drugim spojem ima antiupalni učinak. Svaki spoj se miješa s pogodnim nosačem i općenito je prisutan u količini od 1-95% po masi ukupne mase pripravka. Pripravak može biti u obliku doze koja je pogodna za oralno, parenteralno (npr. intravenzono, intramuskuparno, subkutalno), rektalno, transdermalno, nazalno, vaginalno, inhalacijsko ili okularno davanje. Stoga pripravak može biti u obliku npr. tableta, kapsula, pilula, prašaka, granula, suspenzija, emulzija, otopina, gelova uključujući hidrogelove, pasta, masti, krema, flastera, obloga, pogodnom za naprave za isporuku, supozitorija, klistira, implanta, sprejeva ili aerosola. Farmaceutski pripravci se mogu formulirati prema uobičajenoj farmaceutskoj praksi (vidi npr. Remington: Scince and Practice in Pharmacy, (19th izd.) izd. A. R. Gennaro, 1995, Mack Publishing Company, Easton, P. A. i Encyclopedia of Pharmaceutical Technology, izd. J. Swarbrick i J. C. Boylan, 1988-1999, Marcel Dekket, New York.
Farmaceutski pripravci prema izumu se mogu formulirati da oslobađaju spoj odmah nakon davanja ili u bilo kojem prethodno određenom periodu vremena nakon davanja, a upotrebom formulacije s kontroliranim oslobađanjem.
Davanje spojeva u formulaciji s kontroliranim oslobađanjem je korisno kada spoj sam ili u kombinaciji ima (i) uski terapijski indeks (npr. razlika između koncentracije u plazmi koja vodi štetnim nuzefektima ili toksičnoj reakciji i koncentracija u plazmi koja ima terapijski učinak je mala; općenito je terapijski indeks, TI, definiran kao omjer medijalne letalne doze (LD50) i medijalne efektivne doze (ED50); (ii) uski "prozor" apsorpcije u gastro-intestinalnom traktu; ili (iii) kratko biološko poluvrijeme, tako da je potrebno učestalo doziranje tijekom dana da se održi terapijska razina u plazmi.
Mogu se koristiti mnoge strategije da se dobije kontrolirano oslobađanje u kojem brzina oslobađanja nadvlada brzinu metabolizma terapijskog spoja. Primjerice, kontrolirano oslobađanje se može dobiti odgovarajućim odabirom parametara formulacije i sastojaka, uključujući npr. upotrebu odgovarajućih pripravaka s kontroliranim oslobađanjem i upotrebu presvlačenja. Primjeri uključuju jednostruke ili višestruke jedinične pripravke tableta ili kapsula, uljaste otopine, suspenzije, emulzije, mikrokapsule, mikrosfere, nanočestice, flastere i liposome.
Čvrsti oblici doze za oralnu upotrebu
Formulacije za oralnu upotrebu uključuju tablete koje sadrže aktivni sastojak(ke) u smjesi s netoksičinim farmaceutski privatljivim ekscipijensima. Ti ekscipijensi mogu biti primjerice inertni razrjeđivači ili punila (npr. magnezijev stearat, cinkov stearat, stearinska kiselina, silikati, hidrirana biljna ulja ili talk).
Dva spoja se mogu miješati zajedno u tableti ili drugom vezikulu ili mogu biti razdijeljeni. U jednom primjeru prvi spoj je sadržan unutar tablete, a drugi izvan, tako da se znatni dio drugog spoja oslobađa prije oslobađanja prvog spoja.
Formulacije za oralnu upotrebu mogu biti u obliku tableta za žvakanje ili tvrdih želatinskih kapsula, pri čemu je aktivna tvar miješana s inertnim čvrstim razrjeđivačem, ili u obliku mekih želatinskih kapsula, pri čemu je aktivna tvar miješana s vodenim ili uljni medijem.
Doziranja
Doziranje svakog spoja iz prijavljene kombinacije ovisi o nekoliko faktora, uključujući sljedeće: o metodi davanja, vrsti tretirane bolesti, ozbiljnosti bolesti, da li se radi o tretiranju ili prevenciji bolesti, starosti, težini i zdravlju tretirane osobe. Uz to, farmakogenomna (efekt genotipa na farmakokinetiku, farmakodinamiku ili učinkovitost terapijskog profila) informacija o određenom pacijentu može utjecati na korištenu dozu.
Kontinuirano dnevno doziranje s kombinacijom iz izuma ne mora biti neophodna. Terapijski tretman može zahtijevati cikluse tijekom kojih lijek nije davan, ili se terapija može nastaviti prema potrebi u periodu akutne upale.
Kao što je gore opisano, spoj se može davati oralno u obliku tableta, kapsula, eliksira ili sirupa ili rektalno u obliku supozitorija. Parenteralno davanje spoja je pogodno izvesti, primjerice u fiziološkoj otopini ili sa spojem ugrađenim u liposome. U slučajevima kad sam spoj nije dovoljno topljiv, može se koristiti solubilizator kao što je etanol.
Niže su zbog ilustrativnih razloga opisane doze amoksapina i prednisolona. Stručnjak će lako odrediti pogodno doziranje kortikosteroida koji nije TCA. Primjerice, TCA se može dozirati ekvivalentno kao niže prikazano doziranje amoksapina, a kortikosteroid može biti dan du dozama ekvivalentnim doziranju prednisolonu, što je niže prikazano. U jednoj cjelini kortikosteroid je nisko dozirani kortikosteroid.
Oralno davanje
Ukupna dnevna doza amoksapina prilagođenom za oralno davanje za sistemsku upotrebu je normalno oko 1-600 mg (0.01-8.5 mg/kg), preferirano oko 25-400 mg (0.35-5.7 mg/kg), preferiranije oko 100-300 mg (1.4-4.2 mg/kg). Davanje može biti tri puta dnevno od jednog dana do godinu dana, ili čak cijeli život pacijenta. Kronično dugotrajno davanje će biti indicirano u mnogim slučajevima. Dnevne doze do 600 mg mogu biti neophodne.
Ukupna dnevna doza prednisolona prilagođenog za oralno davanje za sistemsku upotrebu je normalno oko 0.05-200 mg (0.7-2800 mcg/kg), preferirano oko 0.1-60 mg (1-850 mcg/kg), preferiranije oko 0.1-5 mg (4-70 mcg/kg). Zbog povećanog efekta prednisolona utjecajem amoksapina, niske doze prednisolona (npr. 0.2, 0.4, 0.6, 0.8, 1, 2, ili 3 mg/danu) mogu biti učinkovite u tretmanu upale, a kad su u kombinaciji s TCA. Poželjno je davanje jednom do četiri puta dnevno. Kao i amoksapin, prednisilom može biti davan od jednog dana do godinu dana, ili čak cijeli život pacijenta. Doze do 200 mg mogu biti neophodne.
Rektalno davanje
Za pripravke prilagođene za rektalno upotrebu za prevenciju bolesti, obično je preferirana nešto veća doza spoja. Stoga je ukupna dnevna doza amoksapina normalno oko 1-600 mg (0.01-8.5 mg/kg). Amoksapin se normalno rektalno daje jedanput do tri puta dnevno. Ukupna dnevna doza prednisolona je normalno oko 0.1-100 mg (1-1420 mcg/kg). Prednisolon se normalno rektalno daje jedanput do četiri puta dnevno.
Intravenozno davanje
Ukupna dnevna doza amokspina za intravenozno davanje je oko 1-400 mg (0.014-5.7 mg/kg), preferirano oko 10-200 mg (0.14-2.8 mg/kg), a preferiranije oko 25-100 mg (0.35-1.4 mg/kg). Amoksapin se normalno intravenozno daje jedanput do četiri puta dnevno, ali može biti davan kontinuirano u infuziji.
Ukupna dnevna doza prednisolona za intravenozno davanje je oko 0.05-200 mg (0.0007-2.8 mg/kg), preferirano oko 0.1-60 mg (0.001-0.85 mg/kg), a preferiranije oko 0.1-5 mg (4-70 mg/kg). Gore opisane niske doze prednisolona su preferirane. Prednisolon se normalno intravenozno daje jedanput do četiri puta dnevno, ali kao i amoksapin može biti davan kontinuirano u infuziji.
Dodatni načini davanja
Za intramuskularno, subkutalno, inhalacijsko, topičko, vaginalno ili okularno davanje amoksapina, ukupna dnevna doza je oko 1-400 mg (0.014-5.7 mg/kg), preferirano oko 10-200 mg (0.14-2.8 mg/kg), a preferiranije oko 25-100 mg (0.35-1.4 mg/kg), a ukupno dnevna doza prednisolona je oko 0.1-100 mg (0.00014-1.42 mg/kg). Za svaki od ovih načina se amoksapin i prednisolon neovisno daju jedan do četiri puta dnevno.
Sljedeći primjeri ilustriraju izum. Nije mišljeno da ograničavaju izum na bilo koji način.
Primjer 1:
Priprava kombinacije para spojeva miješanjem serijski razrjeđenih matrica
Osnovna otopina amoksapina (16 mg/mL) (Sigma-Aldrich, St. Louis, MO, kataloški broj A129) i prednisolona (1.6 mg/mL) (Sigma-Aldrich, St. Louis, MO, kataloški broj P6004 su pripravljene u dimetilsulfoksidu (DMSO). Na amoksapinsku ploču od polipropilena s 384 jažica je dodano po 25 μL koncentrirane osnovne otopine kolonama 3, 9 i 15 (redovi C do N) kojima je prethodno dodano 75 μL bezvodnog DMSO. Koristeći TomTec Quadra Plus napravu za rukovanje tekućinom, amoksapinska osnovna otopina je serijski razrjeđivana dvostruko četiri puta u susjedne kolone (4-7, 10-13, 16-19). Šesta kolona (8, 14 i 20) nije primila nikakav spoj i služila je kao kontrola s vezikulom. Na prednisolonsku ploču od polipropilena s 384 jažica je dodano po 25 μL koncentrirane osnovne otopine u odgovarajuće jažice (red C, kolone 3-8, red C kolone 9-14, red C, kolone 15-20, red I, kolone 3-8, red I kolone 9-14, red I kolone 15-20). Ploči je prethodno dodano 75 μL bezvodnog DMSO. Koristeći TomTec Quadra Plus napravu za rukovanje tekućinom, 25 μ je serijski razrijeđeno dvostruko četiri puta u susjedne redove (redovi D-G i J-M). Šesti red (H i N) nije primio nikakav spoj i služila je kao kontrola s vezikulom. Ploče se zatvorene i čuvane na -20 °C do upotrebe.
Konačna amoksapin/prednisolonska kombinacijska ploča je generirana prijenosom 1 μL iz svake jažice s amoksapinske i prednisolonske ploče na ploču koja sadrži po 100 μL medija (RPMI; Gibco BRL, #11875-085), 10% serum goveđeg fetusa (Gibco BRL, #25140-097), 2% penicilin/streptomicin (Gibco BRL, #15140-122)), a upotrebom TomTec Quadra Plus napravu za rukovanje tekućinom. Ta ploča za razrjeđivanje je zatim miješana i 10 μL alikvota je prenešeno na konačnu ploču za testiranje, kojoj je prethodno dodan 40 μL/jažici PRMI medija koji sadrži odgovarajući stimulant za aktiviranje TNFα izlučivanja.
Primjer 2:
Test aktivnosti amoksapina i prednisolona u smanjivanju TNFα
Razrijeđena matrica spoja je testirana upotrebom TNFα ELISA metode. Ukratko, po 100 μL suspenzije razrijeđenih mononuklearnih stanica (PBMC) humane periferne krvi sadržanih u polistirenskoj ploči s 384 jažica (NagleNuc) su stimulirane da izlučuju TNFa djelovanjem forbol-12-miristat-13-acetata (Sigma) konačne koncetracije 10 ng/mL i 750 ng/�μL ionimicina (Sigma). Različite koncentracije svakog testiranog spoja su dodane u vrijeme stimulacije. Nakon 16-18 sati inkubacije pri 37 °C u vlažnom inkubatoru, ploča je centrifugirana i supernatant je prenešen u bijelu polistirensku ploču s 384 jažica (NagleNunc, Maxisorb) presvučenih s anti-TNF antirijelima (PharMingen, #18631D). Nakon dva sata inkubacije ploča je isprana (Tecan Power Washer 384) fiziološkom otopinom s fosfatnim puferom (PBS) koja sadrži 0.1% Tween 20 (polioksietilen-sorbitan-monolauerat) i inkubirano je još jedan sat s drugim anti-TNF antitijelom koji je bio obilježen biotinom (PharMingen, 18642D) i peroksidazom iz hrena (HRP) povezane na strepavidin (PharMingen, #13047E). Nako što je ploča isprana a 0.1% Twenn 20/PBS, HRP supstrat (koji sadrži luminol, vodikov peroksid i pojačivač kao što je para-jodfenol) je dodan u svaku jažicu i jakost svjetla je mjerena upotrebom LJL Analyse luminometer. Kontrolne jažice su sadržavale ciklosporin a (Sigma) konačne koncentracije 1 μg/mL.
Primjer 3:
Smanjivanje izlučivanja TNFα iz krvi na koju je djelovano s forbol-12-miristat-13-acetatom i jodomicinom uzrokovano kombinacijom amoksapina i prednisolona
Amoksapin i prednisolon su skupa smanjili TNFα u krvi induciran forbol-12-miristat-13-acetatom i jodomicinom. Kao što je prikazano na Tablicama 1 i 2, amoksapin može pojačati odgovor doze prednisolona skoro dva puta. Pri koncentraciji od 1.11 μM, sam prednisolon može inhibirati izlučivanje THFα za 28%. Dodatak 0.2 μM amoksapina povećava inhibiciju TNFα uzrokovanbu s 1.11 μM prednisolonom na 51%. To veliko povećanje aktivnosti od 82% dobiveno je relativno malim povećanjem od ukupnog broja čestica lijeka od samo 18%.
Tablica 1
Amoksapin [μM]
[image]
Tablica 2
Amoksapin [μM]
[image]
Povećanje aktivnosti prednisolona pomoću amoksapina je također opaženo pri sekundarnom probiranju. Inhibicija TNFα uzrokovana prednisolonom koncentracije 9 nM je povećana 2.9 puta do 40% u prisutnosti 400 nM amoksapina. TNFα inhibitorska aktivnost prednisolona i amoksapina samih pri tim koncentracijama je samo 14%, odnosno 16%. Štoviše, razina TNFα inhibicije postignuta pri 9 nM prednisolona u kombinaciji s 398 nM amoksapinom (40%) nije manja nego pri 1110 nM samom prednisolonu (35%). Ovo povećanje inhibicije TNFα čini predstavlja pomak povećanja aktivnosti od čak 100 puta za kombinaciju, a u usporedni sa samim prednisolonom.
Sposobnost amoksapina i prednisolona da inhibiraju izlučivanje TNFα iz LPS stimuliranie krvi je prikazano na Tablici 3.
Tablica 3
Amoksapin [μM]
[image]
Ostale cjeline
Sve gore spomenute publikacije i patentni u gornjim specifikacijama su ovdje ugrađeni citatom. Različite modifikacije i varijacije opisanih metoda i sustava iz izuma će biti očite stručnjacima, a bez skretanja od obujma i duha izuma. Mada je izum opisan u vezi sa specifičnim preferiranim cjelinama, treba razumjeti da izum, a kako je prijavljen, ne treba biti previše ograničen na tako specifične cjeline. Doista, različite modifikacije opisanih načina za izvođenje izuma su očite stručnjacima za molekularnu biologiju i slična polja i namjera je da budu unutar obujma izuma.
Claims (39)
1. Metoda tretmana pacijenta koji ima upalni poremećaj ili pacijenta koji je rizičan za razvitak upalnog poremećaja, naznačeno time da rečena metoda sadrži davanje rečenom pacijentu (i) triciklički antidepresiv, te (ii) kortikosteroid, a lijekovi (i) i (ii) su dani istovremeno ili razmaka do 14 dana, a u količinama dovoljnim da smanje ili inhibiraju upalu kod rečenog pacijenta.
2. Metoda iz patentnog zahtjeva 1, naznačeno time da triciklički antidepresiv jeste: amoksapin, 8-hidroksiamoksapin, 7-hidroskiamoksapin, loksapin, loksapin sukcinat, loksapin hidroklorid, 8-hidroksiloksapin, amitriptilin, klopramin, doksepin, imipramin, trimipramin, desipramin, nortriptilin ili protriptilin.
3. Metoda iz patentnog zahtjeva 2, naznačeno time da rečeni triciklički antidepresiv jeste amoksapin.
4. Metoda iz patentnog zahtjeva 1, naznačeno time da kortikosteroid jeste: deksametazon, betametazon, triamcinolon, triamcinolon acetonid, triamcinolon diacetat, triamcinolon heksacetonid, beklometazon dipropionat, beklometazon dipropionat monohidrat, flumetazon pivalat, diflorazon diacetat, fluocinolon acetonid, fluormetolon, fluormetolon acetat, klobetazol propionat, dezoksimetazon, fluoksimesteron, fluprednisolon, hidrokortizon, hidrokortizon acetat, hidrokortizon butirat, hidrokrotizon natrijev fosfat, hidrokortizon natrijev sukcinat, hidrokortizon cipionat, hidrokortizon probutat, hidrokortizon valerat, kortizon acetat, parametazon acetat, metilprednisolon, metilprednisolon acetat, metilprednisolon natrijev sukcinat, prednisolon, prednisolon acetat, prednisolon natrijev fosfat, prednisolon tebutat, klokortolon pivalat, flucinolon, deksametazon 21-acetat, betametazon 17-valerat, izoflupredon, 9-fluorokortizon, 6-hidroksideksametazon, diklorizon, meklorizon, fluprediden, doksibetazol, halopredon, halometazon, klobetazon, diflukortolon, izoflupredon acetat, fluorhidroksiandrostenedion, beklometazon, flumetzon, diflorazon, fluocinolon, klobetazol, kortizon, parametazon, klokortolon, prednisolon 21-hemisukcinat slobodne kiseline, prednisolon metasulfobenzoat, prednisolon terbutat, ili triaminokolon acetonid 21-palmitat.
5. Metoda iz patentnog zahtjeva 4, naznačeno time da rečeni kortikosteroid jeste prednisolon.
6. Metoda iz patentnog zahtjeva 1, naznačeno time da je rečeni triciklički antidepresiv dan u količini doze koja je ekvivalentna sa 1-600 miligrama amoksapina.
7. Metoda iz patentnog zahtjeva 6, naznačeno time da je rečeni triciklički antidepresiv dan u količini doze koja je ekvivalentna sa 100-300 miligrama amoksapina.
8. Metoda iz patentnog zahtjeva 1, naznačeno time da je rečeni kortikosteroid dan u količini doze koja je ekvivalentna sa 0.05-200 miligrama prednisolona.
9. Metoda iz patentnog zahtjeva 8, naznačeno time da je rečeni kortikosteroid dan u količini doze koja je ekvivalentna sa 0.05-5 miligrama prednisolona.
10. Metoda iz patentnog zahtjeva 9, naznačeno time da je rečeni kortikosteroid dan u količini doze koja je ekvivalentna sa 0.1-3 miligrama prednisolona.
11. Metoda iz patentnog zahtjeva 1, naznačeno time da su rečeni triciklički antidepresiv i rečeni kortikosteroid dani u razmaku unutar deset dana.
12. Metoda iz patentnog zahtjeva 11, naznačeno time da su rečeni triciklički antidepresiv i rečeni kortikosteroid dani u razmaku unutar pet dana.
13. Metoda iz patentnog zahtjeva 12, naznačeno time da su rečeni triciklički antidepresiv i rečeni kortikosteroid dani u razmaku unutar dvadeset četiri sata.
14. Metoda iz patentnog zahtjeva 13, naznačeno time da su rečeni triciklički antidepresiv i rečeni kortikosteroid dani istovremeno.
15. Metoda iz patentnog zahtjeva 1, naznačeno time da je rečeni upalni poremećaj imunoupalni poremećaj.
16. Metoda iz patentnog zahtjeva 15, naznačeno time da rečeni imunoupalni poremećaj jeste: reumatoidni artritis, psorijaza, ulcerativni kolitis, Cronova bolest, ili smrt stanica mozga izazvana udarom.
17. Metoda iz patentnog zahtjeva 16, naznačeno time da rečeni imunoupalni poremećaj jeste reumatoidni artritis.
18. Metoda iz patentnog zahtjeva 16, naznačeno time da rečeni upalni poremećaj jeste autoimuna bolest.
19. Metoda iz patentnog zahtjeva 18, naznačeno time da rečena autoimuna bolest jeste: astma, multipla skleroza, dijabetes tipa I, sistemski eritematozni lupus, skleroderma, sistemska skleroza i Sjoerensov sindrom.
20. Metoda iz patentnog zahtjeva 1, naznačeno time da su rečeni triciklički antidepresiv i rečeni kortikosteroid dani rečenom pacijentu na sljedeći način: oralno, rektalno, intravenozno, intramuskularno, subkutalno, inhalacijski, topički, vaginalno ili okularno.
21. Metoda za tretman pacijenta koji ima upalni poremećaj ili pacijenta koji je rizičan na razvitak upalnog poremećaja, naznačeno time da rečena metoda sadrži davanje rečenom pacijentu sljedećih lijekova: (i) klotiapin, perlapin, fluperlapin ili dibenz(b,f)(1,4)oksazepin, 2-klor-11-(4-metil-1-piperazinil)- monohiro-klorid; te (ii) kortikosteroid, pri čemu lijekovi (i) i (ii) jesu dani istovremeno ili u razmaku do 14 dana, a u količinama dovoljnim da smanje ili inhibiraju upalu kod rečenog pacijenta.
22. Metoda za tretman pacijenta koji ima upalni poremećaj ili pacijenta koji je rizičan na razvitak upalnog poremećaja, naznačeno time da rečena metoda sadrži davanje rečenom pacijentu farmaceutskog pripravka koji sadrži farmaceutski prihvatljiv nosač i sljedeće lijekove: (i) amoksapin te (ii) prednisolon, a u dozama da zajedno smanje ili inhibiraju upalu kod rečenog pacijenta.
23. Metoda iz patentnog zahtjeva 22, naznačeno time da je lijek (i) prisutan u rečenom pripravku u količini od 1-600 mg.
24. Metoda iz patentnog zahtjeva 23, naznačeno time da je lijek (i) prisutan u rečenom pripravku u količini od 100-300 mg.
25. Metoda iz patentnog zahtjeva 22, naznačeno time da je lijek (ii) prisutan u rečenom pripravku u količini od 0.05-200 mg.
26. Metoda iz patentnog zahtjeva 25, naznačeno time da je lijek (ii) prisutan u rečenom pripravku u količini od 0.05-5 mg.
27. Metoda iz patentnog zahtjeva 26, naznačeno time da je lijek (ii) prisutan u rečenom pripravku u količini od 0.1-3 mg.
28. Metoda iz patentnog zahtjeva 22, naznačeno time da je rečeni pripravak dan rečenom pacijentu oralno, rektalno, intravenozno, intramuskularno, subkutalno, inhalacijski, topički, vaginalno ili okularno.
29. Farmaceutski pripravak koji sadrži farmaceutski prihvatljiv nosač i sljedeće lijekove: (i) amoksapin te (ii) prednisolon, naznačeno time da su lijekovi (i) i (ii), a kad su dani zajedno pacijentu, prisutni u količinama koje nakon davanja inhibiraju ili smanjuju upalu.
30. Pripravak iz patentnog zahtjeva 29, naznačeno time da je lijek (i) prisutan u rečenom pripravku u količini od 1-600 mg.
31. Pripravak iz patentnog zahtjeva 30, naznačeno time da je lijek (i) prisutan u rečenom pripravku u količini od 100-300 mg.
32. Pripravak iz patentnog zahtjeva 29, naznačeno time da je lijek (ii) prisutan u rečenom pripravku u količini od 0.05-200 mg.
33. Pripravak iz patentnog zahtjeva 32, naznačeno time da je lijek (ii) prisutan u rečenom pripravku u količini od 0.05-5 mg.
34. Pripravak iz patentnog zahtjeva 33, naznačeno time da je lijek (ii) prisutan u rečenom pripravku u količini od 0.1-3 mg.
35. Pripravak iz patentnog zahtjeva 29, naznačeno time da je rečeni pripravak formuliran za oralno, rektalno, intravenozno, intramuskularno, subkutalno, inhalacijsko, topičko, vaginalno ili okularno davanje.
36. Farmaceutski paket, naznačeno time da sadrži lijekove (i) amoksapin i (ii) prednisolon.
37. Farmaceutski paket iz patentnog zahtjeva 36, naznačeno time da su lijekovi (i) amoksapin i (ii) prednisolon formulirani odvojeno u pojedinačnim količinama doze.
38. Farmaceutski paket iz patentnog zahtjeva 36, naznačeno time da su lijekovi (i) amoksapin i (ii) prednisolon formulirani zajedno u pojedinačnim količinama doze.
39. Metoda za identifikaciju kombinacija spojeva korisnih za tretman pacijenta koji ima upalni poremećaj, naznačeno time da rečena metoda sadrži sljedeće korake:
(a) dovođenje u in vitro doticaj stanica s (i) tricikličkim antiderpesantom ili kortikosteroidom, te (ii) sa spojem kandidatom, te
(b) određivanje je li kombinacija rečenog tricikličkim antiderpesanta ili kortikosteroida i rečenog spoja kandidata smanjuje razinu citokina u rečenim mononuklearnim stanicama periferne krvi relativno, a prema stanicama koje su dovedene u doticaj s tricikličkim antriderpesivom ili krotikosteroidom ali nisu došle u doticaj sa spojem kandidatom, ili su stanica došle u doticaj sa spojem kandidatom ali ne s rečenim tricikličkim antiderpesivom ili kortikosteroidom, pri čemu je smanjivanje rečene razine citokina upućuje na to da je rečena kombinacija kao kombinacija korisna za tretman pacijenta koji ima upalni poremećaj.
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| AU2002310511B8 (en) | 2003-01-29 |
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| US7335371B2 (en) | 2008-02-26 |
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| NZ530764A (en) | 2008-07-31 |
| KR20040026680A (ko) | 2004-03-31 |
| US20030078246A1 (en) | 2003-04-24 |
| DE60233414D1 (de) | 2009-10-01 |
| RU2300379C2 (ru) | 2007-06-10 |
| AU2002310511B2 (en) | 2007-12-06 |
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| IL159771A0 (en) | 2004-06-20 |
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| EP1414466B1 (en) | 2009-08-19 |
| ATE439844T1 (de) | 2009-09-15 |
| EP1414466A1 (en) | 2004-05-06 |
| NO20040097L (no) | 2004-03-01 |
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| RU2004103537A (ru) | 2005-02-27 |
| US20100173881A1 (en) | 2010-07-08 |
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