WO2020106337A1 - Methods for administering corticosteroids - Google Patents
Methods for administering corticosteroidsInfo
- Publication number
- WO2020106337A1 WO2020106337A1 PCT/US2019/046449 US2019046449W WO2020106337A1 WO 2020106337 A1 WO2020106337 A1 WO 2020106337A1 US 2019046449 W US2019046449 W US 2019046449W WO 2020106337 A1 WO2020106337 A1 WO 2020106337A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- corticosteroid
- dose
- urinary
- hsd1 inhibitor
- administered
- Prior art date
Links
- 239000003246 corticosteroid Substances 0.000 title claims abstract description 234
- 238000000034 method Methods 0.000 title claims abstract description 85
- 229960001334 corticosteroids Drugs 0.000 title claims description 22
- 101100451537 Caenorhabditis elegans hsd-1 gene Proteins 0.000 claims abstract description 257
- 239000003112 inhibitor Substances 0.000 claims abstract description 200
- 230000002485 urinary effect Effects 0.000 claims abstract description 131
- AODPIQQILQLWGS-UHFFFAOYSA-N (3alpa,5beta,11beta,17alphaOH)-form-3,11,17,21-Tetrahydroxypregnan-20-one, Natural products C1C(O)CCC2(C)C3C(O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC21 AODPIQQILQLWGS-UHFFFAOYSA-N 0.000 claims abstract description 107
- SYGWGHVTLUBCEM-UHFFFAOYSA-N (3alpha,5alpha,17alphaOH)-3,17,21-Trihydroxypregnane-11,20-dione Natural products C1C(O)CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC21 SYGWGHVTLUBCEM-UHFFFAOYSA-N 0.000 claims abstract description 56
- SYGWGHVTLUBCEM-ZIZPXRJBSA-N Urocortisone Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CC[C@@H]21 SYGWGHVTLUBCEM-ZIZPXRJBSA-N 0.000 claims abstract description 56
- AODPIQQILQLWGS-FDSHTENPSA-N 5a-Tetrahydrocortisol Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CC[C@H]21 AODPIQQILQLWGS-FDSHTENPSA-N 0.000 claims abstract description 55
- AODPIQQILQLWGS-GXBDJPPSSA-N tetrahydrocortisol Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CC[C@@H]21 AODPIQQILQLWGS-GXBDJPPSSA-N 0.000 claims abstract description 54
- 230000000694 effects Effects 0.000 claims abstract description 35
- 229940126062 Compound A Drugs 0.000 claims description 83
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 50
- 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 40
- 150000002148 esters Chemical class 0.000 claims description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
- 229960004618 prednisone Drugs 0.000 claims description 30
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 30
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 28
- 229940127557 pharmaceutical product Drugs 0.000 claims description 28
- 208000007465 Giant cell arteritis Diseases 0.000 claims description 22
- 206010043207 temporal arteritis Diseases 0.000 claims description 22
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- 229960000890 hydrocortisone Drugs 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 16
- 239000003826 tablet Substances 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- YXXKMTIGKAVJTA-UHFFFAOYSA-N ac1l3htk Chemical group C1C(C2)CC3[CH]C1CC2C3 YXXKMTIGKAVJTA-UHFFFAOYSA-N 0.000 claims description 12
- 230000001154 acute effect Effects 0.000 claims description 12
- 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 11
- 229960004584 methylprednisolone Drugs 0.000 claims description 11
- 238000007918 intramuscular administration Methods 0.000 claims description 10
- 229960005205 prednisolone Drugs 0.000 claims description 10
- 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 10
- 238000001990 intravenous administration Methods 0.000 claims description 9
- 229960003957 dexamethasone Drugs 0.000 claims description 8
- 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 8
- 206010047115 Vasculitis Diseases 0.000 claims description 6
- 230000000172 allergic effect Effects 0.000 claims description 6
- 208000010668 atopic eczema Diseases 0.000 claims description 6
- 230000004888 barrier function Effects 0.000 claims description 6
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 5
- 229960002537 betamethasone Drugs 0.000 claims description 5
- 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 5
- 229960004436 budesonide Drugs 0.000 claims description 5
- 229960001145 deflazacort Drugs 0.000 claims description 5
- FBHSPRKOSMHSIF-GRMWVWQJSA-N deflazacort Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)=N[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O FBHSPRKOSMHSIF-GRMWVWQJSA-N 0.000 claims description 5
- 208000002691 Choroiditis Diseases 0.000 claims description 4
- 208000017667 Chronic Disease Diseases 0.000 claims description 4
- 206010012455 Dermatitis exfoliative Diseases 0.000 claims description 4
- 208000032514 Leukocytoclastic vasculitis Diseases 0.000 claims description 4
- 208000004880 Polyuria Diseases 0.000 claims description 4
- 208000003971 Posterior uveitis Diseases 0.000 claims description 4
- 230000002365 anti-tubercular Effects 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 238000002512 chemotherapy Methods 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 239000011258 core-shell material Substances 0.000 claims description 4
- 201000001981 dermatomyositis Diseases 0.000 claims description 4
- 230000035619 diuresis Effects 0.000 claims description 4
- 230000005713 exacerbation Effects 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 206010025135 lupus erythematosus Diseases 0.000 claims description 4
- 239000008185 minitablet Substances 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 208000005987 polymyositis Diseases 0.000 claims description 4
- 201000001474 proteinuria Diseases 0.000 claims description 4
- 201000007529 rheumatic myocarditis Diseases 0.000 claims description 4
- 201000000306 sarcoidosis Diseases 0.000 claims description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 4
- 206010003230 arteritis Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 230000004968 inflammatory condition Effects 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
- 230000000699 topical effect Effects 0.000 claims description 3
- 208000030090 Acute Disease Diseases 0.000 claims description 2
- 206010000830 Acute leukaemia Diseases 0.000 claims description 2
- 208000026872 Addison Disease Diseases 0.000 claims description 2
- 208000005676 Adrenogenital syndrome Diseases 0.000 claims description 2
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 2
- 206010027654 Allergic conditions Diseases 0.000 claims description 2
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 claims description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
- 206010002921 Aortitis Diseases 0.000 claims description 2
- 206010002965 Aplasia pure red cell Diseases 0.000 claims description 2
- 208000032467 Aplastic anaemia Diseases 0.000 claims description 2
- 208000037157 Azotemia Diseases 0.000 claims description 2
- 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 2
- 208000009137 Behcet syndrome Diseases 0.000 claims description 2
- 206010004485 Berylliosis Diseases 0.000 claims description 2
- 208000019838 Blood disease Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010048962 Brain oedema Diseases 0.000 claims description 2
- 208000023355 Chronic beryllium disease Diseases 0.000 claims description 2
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 claims description 2
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 208000027932 Collagen disease Diseases 0.000 claims description 2
- 208000008448 Congenital adrenal hyperplasia Diseases 0.000 claims description 2
- 206010010356 Congenital anomaly Diseases 0.000 claims description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 2
- 206010012441 Dermatitis bullous Diseases 0.000 claims description 2
- 206010012442 Dermatitis contact Diseases 0.000 claims description 2
- WYQPLTPSGFELIB-JTQPXKBDSA-N Difluprednate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2CC[C@@](C(=O)COC(C)=O)(OC(=O)CCC)[C@@]2(C)C[C@@H]1O WYQPLTPSGFELIB-JTQPXKBDSA-N 0.000 claims description 2
- 206010013700 Drug hypersensitivity Diseases 0.000 claims description 2
- 208000017701 Endocrine disease Diseases 0.000 claims description 2
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 claims description 2
- 201000011275 Epicondylitis Diseases 0.000 claims description 2
- 206010015218 Erythema multiforme Diseases 0.000 claims description 2
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide 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)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 claims description 2
- POPFMWWJOGLOIF-XWCQMRHXSA-N Flurandrenolide Chemical compound C1([C@@H](F)C2)=CC(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O POPFMWWJOGLOIF-XWCQMRHXSA-N 0.000 claims description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 2
- 201000005569 Gout Diseases 0.000 claims description 2
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 2
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 2
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 claims description 2
- 208000003809 Herpes Zoster Ophthalmicus Diseases 0.000 claims description 2
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 2
- 206010021074 Hypoplastic anaemia Diseases 0.000 claims description 2
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 206010022941 Iridocyclitis Diseases 0.000 claims description 2
- 208000034624 Leukocytoclastic Cutaneous Vasculitis Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- GZENKSODFLBBHQ-ILSZZQPISA-N Medrysone 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@@H](C(C)=O)CC[C@H]21 GZENKSODFLBBHQ-ILSZZQPISA-N 0.000 claims description 2
- 206010027259 Meningitis tuberculous Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 2
- 206010030865 Ophthalmic herpes zoster Diseases 0.000 claims description 2
- 208000003435 Optic Neuritis Diseases 0.000 claims description 2
- MKPDWECBUAZOHP-AFYJWTTESA-N Paramethasone 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)CO)(O)[C@@]2(C)C[C@@H]1O MKPDWECBUAZOHP-AFYJWTTESA-N 0.000 claims description 2
- 241000721454 Pemphigus Species 0.000 claims description 2
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 2
- 206010035669 Pneumonia aspiration Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 208000003670 Pure Red-Cell Aplasia Diseases 0.000 claims description 2
- 208000025747 Rheumatic disease Diseases 0.000 claims description 2
- 206010039094 Rhinitis perennial Diseases 0.000 claims description 2
- 208000036284 Rhinitis seasonal Diseases 0.000 claims description 2
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 claims description 2
- 206010039807 Secondary adrenocortical insufficiency Diseases 0.000 claims description 2
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 claims description 2
- 231100000168 Stevens-Johnson syndrome Toxicity 0.000 claims description 2
- 206010042742 Sympathetic ophthalmia Diseases 0.000 claims description 2
- 208000004760 Tenosynovitis Diseases 0.000 claims description 2
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 2
- 208000003441 Transfusion reaction Diseases 0.000 claims description 2
- 206010044608 Trichiniasis Diseases 0.000 claims description 2
- 208000022971 Tuberculous meningitis Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 230000009798 acute exacerbation Effects 0.000 claims description 2
- 238000011360 adjunctive therapy Methods 0.000 claims description 2
- 229960000552 alclometasone Drugs 0.000 claims description 2
- FJXOGVLKCZQRDN-PHCHRAKRSA-N alclometasone Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O FJXOGVLKCZQRDN-PHCHRAKRSA-N 0.000 claims description 2
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 2
- 201000010105 allergic rhinitis Diseases 0.000 claims description 2
- 229960003099 amcinonide Drugs 0.000 claims description 2
- ILKJAFIWWBXGDU-MOGDOJJUSA-N amcinonide Chemical compound O([C@@]1([C@H](O2)C[C@@H]3[C@@]1(C[C@H](O)[C@]1(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]13)C)C(=O)COC(=O)C)C12CCCC1 ILKJAFIWWBXGDU-MOGDOJJUSA-N 0.000 claims description 2
- 208000007502 anemia Diseases 0.000 claims description 2
- 201000004612 anterior uveitis Diseases 0.000 claims description 2
- 201000009408 aspiration pneumonitis Diseases 0.000 claims description 2
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 2
- 201000008937 atopic dermatitis Diseases 0.000 claims description 2
- 230000001363 autoimmune Effects 0.000 claims description 2
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 2
- 229960004495 beclometasone Drugs 0.000 claims description 2
- 208000006752 brain edema Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 208000010353 central nervous system vasculitis Diseases 0.000 claims description 2
- 201000004709 chorioretinitis Diseases 0.000 claims description 2
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims description 2
- 229960003728 ciclesonide Drugs 0.000 claims description 2
- 229960002842 clobetasol Drugs 0.000 claims description 2
- 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 2
- 229960004299 clocortolone Drugs 0.000 claims description 2
- 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 2
- 229960002219 cloprednol Drugs 0.000 claims description 2
- YTJIBEDMAQUYSZ-FDNPDPBUSA-N cloprednol 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(Cl)C2=C1 YTJIBEDMAQUYSZ-FDNPDPBUSA-N 0.000 claims description 2
- 208000010247 contact dermatitis Diseases 0.000 claims description 2
- 229960003840 cortivazol Drugs 0.000 claims description 2
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 claims description 2
- 238000007428 craniotomy Methods 0.000 claims description 2
- 229960003662 desonide Drugs 0.000 claims description 2
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 claims description 2
- 229960002593 desoximetasone Drugs 0.000 claims description 2
- 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 2
- 229960004154 diflorasone Drugs 0.000 claims description 2
- WXURHACBFYSXBI-XHIJKXOTSA-N diflorasone 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](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-XHIJKXOTSA-N 0.000 claims description 2
- 229960004091 diflucortolone Drugs 0.000 claims description 2
- OGPWIDANBSLJPC-RFPWEZLHSA-N diflucortolone 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](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O OGPWIDANBSLJPC-RFPWEZLHSA-N 0.000 claims description 2
- 229960004875 difluprednate Drugs 0.000 claims description 2
- 230000002497 edematous effect Effects 0.000 claims description 2
- 230000000925 erythroid effect Effects 0.000 claims description 2
- 208000004526 exfoliative dermatitis Diseases 0.000 claims description 2
- 229960002011 fludrocortisone Drugs 0.000 claims description 2
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 claims description 2
- 229960004511 fludroxycortide Drugs 0.000 claims description 2
- 229960003469 flumetasone Drugs 0.000 claims description 2
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone 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](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 claims description 2
- 229960000676 flunisolide Drugs 0.000 claims description 2
- 229940043075 fluocinolone Drugs 0.000 claims description 2
- 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 2
- 229960000785 fluocinonide Drugs 0.000 claims description 2
- 229960005355 fluocortin Drugs 0.000 claims description 2
- XWTIDFOGTCVGQB-FHIVUSPVSA-N fluocortin butyl 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@H](C(=O)C(=O)OCCCC)[C@@]2(C)C[C@@H]1O XWTIDFOGTCVGQB-FHIVUSPVSA-N 0.000 claims description 2
- 229960003973 fluocortolone Drugs 0.000 claims description 2
- GAKMQHDJQHZUTJ-ULHLPKEOSA-N fluocortolone 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@H](C(=O)CO)[C@@]2(C)C[C@@H]1O GAKMQHDJQHZUTJ-ULHLPKEOSA-N 0.000 claims description 2
- 229960001048 fluorometholone Drugs 0.000 claims description 2
- FAOZLTXFLGPHNG-KNAQIMQKSA-N fluorometholone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@]2(F)[C@@H](O)C[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FAOZLTXFLGPHNG-KNAQIMQKSA-N 0.000 claims description 2
- 229960003590 fluperolone Drugs 0.000 claims description 2
- HHPZZKDXAFJLOH-QZIXMDIESA-N fluperolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)[C@@H](OC(C)=O)C)(O)[C@@]1(C)C[C@@H]2O HHPZZKDXAFJLOH-QZIXMDIESA-N 0.000 claims description 2
- 229960003238 fluprednidene Drugs 0.000 claims description 2
- YVHXHNGGPURVOS-SBTDHBFYSA-N fluprednidene Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](C(=C)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 YVHXHNGGPURVOS-SBTDHBFYSA-N 0.000 claims description 2
- 229960002714 fluticasone Drugs 0.000 claims description 2
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone 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](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims description 2
- 229960000671 formocortal Drugs 0.000 claims description 2
- QNXUUBBKHBYRFW-QWAPGEGQSA-N formocortal Chemical compound C1C(C=O)=C2C=C(OCCCl)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]1(C)C[C@@H]2O QNXUUBBKHBYRFW-QWAPGEGQSA-N 0.000 claims description 2
- 229960002383 halcinonide Drugs 0.000 claims description 2
- 229960002475 halometasone Drugs 0.000 claims description 2
- GGXMRPUKBWXVHE-MIHLVHIWSA-N halometasone Chemical compound C1([C@@H](F)C2)=CC(=O)C(Cl)=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 GGXMRPUKBWXVHE-MIHLVHIWSA-N 0.000 claims description 2
- 208000014951 hematologic disease Diseases 0.000 claims description 2
- 208000007475 hemolytic anemia Diseases 0.000 claims description 2
- 230000000148 hypercalcaemia Effects 0.000 claims description 2
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 2
- 201000006362 hypersensitivity vasculitis Diseases 0.000 claims description 2
- 208000018022 idiopathic eosinophilic pneumonia Diseases 0.000 claims description 2
- 208000016036 idiopathic nephrotic syndrome Diseases 0.000 claims description 2
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 2
- 201000004614 iritis Diseases 0.000 claims description 2
- 206010023332 keratitis Diseases 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 229960001798 loteprednol Drugs 0.000 claims description 2
- YPZVAYHNBBHPTO-MXRBDKCISA-N loteprednol Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)OCCl)[C@@H]4[C@@H]3CCC2=C1 YPZVAYHNBBHPTO-MXRBDKCISA-N 0.000 claims description 2
- 238000009115 maintenance therapy Methods 0.000 claims description 2
- 229960001011 medrysone Drugs 0.000 claims description 2
- 208000001223 meningeal tuberculosis Diseases 0.000 claims description 2
- 230000001394 metastastic effect Effects 0.000 claims description 2
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 2
- 206010063344 microscopic polyangiitis Diseases 0.000 claims description 2
- 229960001664 mometasone Drugs 0.000 claims description 2
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone 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)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 claims description 2
- 201000005962 mycosis fungoides Diseases 0.000 claims description 2
- 230000002107 myocardial effect Effects 0.000 claims description 2
- 230000001613 neoplastic effect Effects 0.000 claims description 2
- 210000000653 nervous system Anatomy 0.000 claims description 2
- 229960002858 paramethasone Drugs 0.000 claims description 2
- 208000022719 perennial allergic rhinitis Diseases 0.000 claims description 2
- 201000006292 polyarteritis nodosa Diseases 0.000 claims description 2
- 229960002794 prednicarbate Drugs 0.000 claims description 2
- FNPXMHRZILFCKX-KAJVQRHHSA-N prednicarbate 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)(OC(=O)OCC)[C@@]1(C)C[C@@H]2O FNPXMHRZILFCKX-KAJVQRHHSA-N 0.000 claims description 2
- 229960001917 prednylidene Drugs 0.000 claims description 2
- WSVOMANDJDYYEY-CWNVBEKCSA-N prednylidene Chemical group O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](C(=C)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 WSVOMANDJDYYEY-CWNVBEKCSA-N 0.000 claims description 2
- 208000008128 pulmonary tuberculosis Diseases 0.000 claims description 2
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 claims description 2
- 208000023504 respiratory system disease Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 206010048628 rheumatoid vasculitis Diseases 0.000 claims description 2
- 229960001487 rimexolone Drugs 0.000 claims description 2
- QTTRZHGPGKRAFB-OOKHYKNYSA-N rimexolone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CC)(C)[C@@]1(C)C[C@@H]2O QTTRZHGPGKRAFB-OOKHYKNYSA-N 0.000 claims description 2
- 208000017022 seasonal allergic rhinitis Diseases 0.000 claims description 2
- 230000001932 seasonal effect Effects 0.000 claims description 2
- 208000008742 seborrheic dermatitis Diseases 0.000 claims description 2
- 206010040400 serum sickness Diseases 0.000 claims description 2
- 208000023924 subacute bursitis Diseases 0.000 claims description 2
- 201000004595 synovitis Diseases 0.000 claims description 2
- 206010043554 thrombocytopenia Diseases 0.000 claims description 2
- 206010043778 thyroiditis Diseases 0.000 claims description 2
- 229960004631 tixocortol Drugs 0.000 claims description 2
- YWDBSCORAARPPF-VWUMJDOOSA-N tixocortol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CS)[C@@H]4[C@@H]3CCC2=C1 YWDBSCORAARPPF-VWUMJDOOSA-N 0.000 claims description 2
- 229960005294 triamcinolone Drugs 0.000 claims description 2
- 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 2
- 208000003982 trichinellosis Diseases 0.000 claims description 2
- 201000007588 trichinosis Diseases 0.000 claims description 2
- 229960002249 ulobetasol Drugs 0.000 claims description 2
- LEHFPXVYPMWYQD-XHIJKXOTSA-N ulobetasol 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](C)[C@@](C(=O)CCl)(O)[C@@]2(C)C[C@@H]1O LEHFPXVYPMWYQD-XHIJKXOTSA-N 0.000 claims description 2
- 208000009852 uremia Diseases 0.000 claims description 2
- 201000004331 Henoch-Schoenlein purpura Diseases 0.000 claims 1
- 206010019617 Henoch-Schonlein purpura Diseases 0.000 claims 1
- 208000031814 IgA Vasculitis Diseases 0.000 claims 1
- 201000009324 Loeffler syndrome Diseases 0.000 claims 1
- 208000015446 immunoglobulin a vasculitis Diseases 0.000 claims 1
- 101001078593 Caenorhabditis elegans 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4) isomerase 1 Proteins 0.000 description 23
- 101000618112 Homo sapiens Sperm-associated antigen 8 Proteins 0.000 description 23
- 102100021913 Sperm-associated antigen 8 Human genes 0.000 description 23
- 230000005764 inhibitory process Effects 0.000 description 23
- 239000002552 dosage form Substances 0.000 description 19
- 239000003814 drug Substances 0.000 description 12
- 238000012423 maintenance Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 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 description 10
- 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 description 10
- 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 description 10
- 229960004544 cortisone Drugs 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000000902 placebo Substances 0.000 description 10
- 229940068196 placebo Drugs 0.000 description 10
- 239000013543 active substance Substances 0.000 description 9
- 206010067484 Adverse reaction Diseases 0.000 description 8
- 230000002411 adverse Effects 0.000 description 8
- 230000006838 adverse reaction Effects 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 210000004556 brain Anatomy 0.000 description 7
- 230000003247 decreasing effect Effects 0.000 description 7
- 210000002700 urine Anatomy 0.000 description 7
- 238000002600 positron emission tomography Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 230000006399 behavior Effects 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 206010012601 diabetes mellitus Diseases 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 230000036470 plasma concentration Effects 0.000 description 5
- 208000008589 Obesity Diseases 0.000 description 4
- 208000001132 Osteoporosis Diseases 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 235000021152 breakfast Nutrition 0.000 description 4
- 229940000425 combination drug Drugs 0.000 description 4
- -1 for example Chemical class 0.000 description 4
- 235000020824 obesity Nutrition 0.000 description 4
- 239000007935 oral tablet Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000004088 simulation Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 208000010412 Glaucoma Diseases 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000010392 Bone Fractures Diseases 0.000 description 2
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 206010019233 Headaches Diseases 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 206010031264 Osteonecrosis Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000002641 glycemic effect Effects 0.000 description 2
- 201000001421 hyperglycemia Diseases 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 229940124624 oral corticosteroid Drugs 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- YCNCXQNUXCHRRX-ZHPDPMBESA-N (5s)-2-[[(1r,3s,4s)-3-bicyclo[2.2.1]heptanyl]amino]-5-methyl-5-propan-2-yl-1,3-thiazol-4-one Chemical group N([C@@H]1[C@@]2([H])CC[C@](C2)(C1)[H])C1=NC(=O)[C@](C)(C(C)C)S1 YCNCXQNUXCHRRX-ZHPDPMBESA-N 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 101100451536 Arabidopsis thaliana HSD2 gene Proteins 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010011655 Cushingoid Diseases 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010014476 Elevated cholesterol Diseases 0.000 description 1
- 206010014486 Elevated triglycerides Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010027940 Mood altered Diseases 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- HWZSMFYOTSVZIT-MDASCCDHSA-N N1N=CC(=C1)C=1SC=CC=1[C@@]12C[C@](C[C@@H](CC1)N2C=O)(C1=NC=CC=N1)O Chemical compound N1N=CC(=C1)C=1SC=CC=1[C@@]12C[C@](C[C@@H](CC1)N2C=O)(C1=NC=CC=N1)O HWZSMFYOTSVZIT-MDASCCDHSA-N 0.000 description 1
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
- 206010030043 Ocular hypertension Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 206010040799 Skin atrophy Diseases 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- 206010047112 Vasculitides Diseases 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- MMZFGTAMARVHAF-RTHVDDQRSA-N [(1S,5R)-3-hydroxy-3-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-8-yl]-[5-(1H-pyrazol-4-yl)thiophen-3-yl]methanone Chemical group OC1(C[C@@H]2CC[C@H](C1)N2C(=O)c1csc(c1)-c1cn[nH]c1)c1ncccn1 MMZFGTAMARVHAF-RTHVDDQRSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 201000004208 acquired thrombocytopenia Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000006400 anxiety behaviour Effects 0.000 description 1
- 230000037444 atrophy Effects 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
- 230000002146 bilateral effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000021824 exploration behavior Effects 0.000 description 1
- 238000011985 exploratory data analysis Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000013561 fixed dose combination tablet Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 108091005995 glycated hemoglobin Proteins 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000002989 hepatic vein Anatomy 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 229940124625 intravenous corticosteroids Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000015654 memory Effects 0.000 description 1
- 235000020938 metabolic status Nutrition 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000007510 mood change Effects 0.000 description 1
- 230000020763 muscle atrophy Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 210000003240 portal vein Anatomy 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 1
- 229960001233 pregabalin Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000019525 primary metabolic process Effects 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
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000012502 risk assessment Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000006403 short-term memory Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000000551 statistical hypothesis test Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/4196—1,2,4-Triazoles
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- HSDs Ib-hydroxy steroid dehydrogenases
- the HSD enzymes consist of two isoforms: the nicotinamide-adenine dinucleotide phosphate reduced-dependent type 1 (HSD1) in vivo generally converts inactive cortisone to active cortisol, and the nicotinamide-adenine dinucleotide dependent oxidative type 2 (HSD2) converts cortisol to cortisone.
- HSD1 nicotinamide-adenine dinucleotide phosphate reduced-dependent type 1
- HSD2 nicotinamide-adenine dinucleotide dependent oxidative type 2
- HSD1 selective inhibitor could potentially ameliorate side effects associated with corticosteroid administration, such as hyperglycemia, insulin resistance, obesity, hyperlipidemia, hypertension, and the like.
- PMR Polymyalgia rheumatica
- GCA giant cell arteritis
- PMR typically presents acutely with bilateral upper extremity pain.
- GCA typically presents with unilateral or bilateral headache, myalgias, fatigue, fever, weight loss, and sometimes acute vision loss.
- PMR and GCA represent either different manifestations of the same disease or overlapping conditions.
- GCA may present as classic cranial (temporal) arteritis, large-vessel vasculitis, or single-organ arteritis. From 40% to 60% of patients diagnosed with GCA also have PMR, and 16% to 21% of PMR patients have GCA.
- PMR occurs 3 to 10 times more frequently than GCA.
- GCA is the most frequent primary vasculitis with an incidence of 18 per 100 000.
- Oral corticosteroids (CS) have been the mainstay of PMR therapy for decades, and are the only medications indicated by FDA for PMR therapy. Clinical trials evidence for therapeutic efficacy in PMR (including for oral CS) is quite limited.
- FIG. 1 shows the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone for clinical trial subjects after a single dose of placebo or Compound A.
- placebo placebo
- Compound A 1 mg
- Compound A 3 mg
- Compound A 6 mg
- Compound A (e) 10 mg Compound A; (f) 30 mg Compound A; (g) 60 mg Compound A. (i) 0-24 hr; (ii); 24-48 hr; (iii) 0-last. A lower value indicates inhibition of liver HSD1.
- FIG. 2 shows the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone for clinical trial subjects prior to, and after single (on Day 1) and multiple (daily on Days 5 through 18) doses of Compound A.
- a lower value indicates inhibition of liver HSD1.
- the abscissa is labeled as Day, where -1 is prior to the first dose of study drug.
- FIG. 3 shows the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone for clinical trial subjects prior to, and after single (on Day 1) and multiple (daily on Days 2 through 14) doses of Compound A. (a) 0.4 mg and (b) 0.2 mg of Compound A. A lower value indicates inhibition of liver HSD1. The abscissa is labeled as Day, where -1 is prior to the first dose of study drug.
- FIG. 4 provides a schematic of the population pharmacokinetics model for Compound A, with 4-compartment transient absorption, saturable binding from the central compartment, and first-order elimination.
- FIG. 5 shows the relationship between plasma concentration and brain HSD1 enzyme occupancy for Compound A. Abscissa: logio(Compound A plasma concentration in ng / mL), ordinate: brain HSD1 enzyme occupancy (%). Intra-graph lines indicate plasma concentration ranges associated with daily doses of (a) 0.2 mg, (b) 0.4 mg, (c) 0.7 mg, and (d) 2.0 mg Compound A at steady state.
- FIG. 6 shows simulations of HSD1 inhibition for patients by Compound A. 3 mg first dose, then daily doses of (a) 1 mg QD; (b) 0.1 mg QD. The abscissa is labeled as days of dose administration.
- FIG. 7 shows simulations of HSD1 inhibition for patients by Compound A. 4 mg first dose, then daily doses of (a) 1 mg QD; (b) 0.1 mg QD. The abscissa is labeled as days of dose administration.
- FIG. 8 shows simulations of HSD1 inhibition for patients by Compound A. Three 1 mg daily doses, then daily doses of 0.1 mg QD. The abscissa is labeled as days of dose administration.
- FIG. 9 shows reversal of CS-induced tail biting behavior by Compound A.
- FIG. 10 shows restoration of CS-induced deficit of maze exploration behavior by Compound A.
- Vertical axis alternation rate (%). * P ⁇ 0.05; ** P ⁇ O.Olvs 0 dose (a) no CS; (b) - (1) CS; dosage of Compound A (mg / kg): (b) 0; (c) 0.01; (d) 0.03; (e) 1; (f) 3.
- a method for administering a corticosteroid to a patient in need thereof comprising:
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s ratio of urinary
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- a method for administering a corticosteroid to a patient in need thereof comprising:
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- Compound A refers to 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)- l-methylethyl]-4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide, which has the structure:
- co-administer and “co-administration” and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days).
- two or more active agents can be co-formulated as part of the same composition or administered as separate formulations. This also may be referred to herein as“concomitant” administration or variants thereof.
- administering to a patient refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.
- disorder is intended to be generally synonymous, and is used interchangeably with, the terms “disease,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms.
- a "dose” means the measured quantity of an active agent to be taken at one time by a patient.
- “dosing regimen” means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient. The additional doses of the active agent can be different from the dose taken at the first time.
- an agent, compound, drug, composition or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient).
- the precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.
- patient or “individual” or “ subject” means a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.
- pharmaceutically acceptable refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
- pharmaceutically acceptable refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug
- “Pharmacologically active” as in a “pharmacologically active” (or “active”) derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
- pharmaceutically acceptable salts include acid addition salts which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as
- risk means the probability or chance of adverse reaction, injury, or other undesirable outcome arising from a medical treatment.
- An "acceptable risk” means a measure of the risk of harm, injury, or disease arising from a medical treatment that will be tolerated by an individual or group. Whether a risk is “acceptable” will depend upon the advantages that the individual or group perceives to be obtainable in return for taking the risk, whether they accept whatever scientific and other advice is offered about the magnitude of the risk, and numerous other factors, both political and social.
- An "acceptable risk” of an adverse reaction means that an individual or a group in society is willing to take or be subjected to the risk that the adverse reaction might occur since the adverse reaction is one whose probability of occurrence is small, or whose consequences are so slight, or the benefits (perceived or real) of the active agent are so great.
- An "unacceptable risk” of an adverse reaction means that an individual or a group in society is unwilling to take or be subjected to the risk that the adverse reaction might occur upon weighing the probability of occurrence of the adverse reaction, the consequences of the adverse reaction, and the benefits (perceived or real) of the active agent.
- “At risk” means in a state or condition marked by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.
- safety means the incidence or severity of adverse events associated with administration of an active agent, including adverse effects associated with patient-related factors (e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medication).
- patient-related factors e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment
- active agent-related factors e.g., dose, plasma level, duration of exposure, or concomitant medication
- treating refers to therapeutic applications to slow or stop progression of a disorder, prophylactic application to prevent development of a disorder, or reversal of a disorder.
- Reversal of a disorder differs from a therapeutic application which slows or stops a disorder in that with a method of reversing, not only is progression of a disorder completely stopped, cellular behavior is moved to some degree, toward a normal state that would be observed in the absence of the disorder.
- a method for administering a corticosteroid to a patient in need thereof comprising:
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- a method for administering a corticosteroid to a patient in need thereof comprising:
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- a method for administering a corticosteroid to a patient in need thereof comprising:
- the corticosteroid is not prednisone
- the HSD1 inhibitor is 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)-l-methylethyl]- 4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]- a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazineacetamide (Compound B); and
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- the corticosteroid is not prednisone
- the HSD1 inhibitor is 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)-l-methylethyl]- 4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]- a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazineacetamide (Compound B); and
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- a method for administering a corticosteroid to a patient in need thereof comprising:
- the corticosteroid is not prednisone
- the HSD1 inhibitor is 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)-l-methylethyl]- 4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]- a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazineacetamide (Compound B); and
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- the corticosteroid is not prednisone
- the HSD1 inhibitor is 4- ⁇ 5-[l-(4-chloro-2,6-difluorophenoxy)-l-methylethyl]- 4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]- a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l-piperazineacetamide (Compound B); and
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s urinary ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- the HSD1 inhibitor is chosen from 4- ⁇ 5-[l-(4-chloro-2,6- difluorophenoxy)-l-methylethyl]-4-methyl-4H-l,2,4-triazol-3-yl-3-fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) and N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-a,a-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-l- piperazineacetamide (Compound B), or a pharmaceutically acceptable salt thereof.
- the HSD1 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof.
- the HSD1 inhibitor is Compound B, or a pharmaceutically acceptable salt thereof.
- the HSD1 inhibitor is AMG 221 ((5S)-2-[[(lR,3S,4S)-3- bicyclo[2.2.1]heptanyl]amino]-5-methyl-5-propan-2-yl-l,3-thiazol-4-one).
- the HSD1 inhibitor is Xanamem ((5-(lH-pyrazol-4- yl)thiophen-3-yl)((lR,3r,5S)-3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8- yl)methanone): [0050] In some embodiments, the HSD1 inhibitor is a compound as disclosed in
- the target threshold for the ratio of urinary is the target threshold for the ratio of urinary
- the target threshold is about 0.2 and the patient has an additional risk factor.
- the additional risk factor is chosen from diabetes, hypertension, elevated cholesterol, elevated triglycerides, nonalcoholic steatohepatitis, obesity, history of major adverse cardiovascular event, osteoporosis, osteonecrosis, ocular hypertension, or history of glaucoma.
- the additional risk factor is age.
- the additional risk factor is gender and the patient is female.
- the additional risk factor is prior cumulative corticosteroid exposure.
- the additional risk factor is a history of adverse events associated with corticosteroid administration.
- the target threshold for the ratio of urinary is the target threshold for the ratio of urinary
- the patient has been administered a corticosteroid for a period of time prior to being administered the HSD1 inhibitor.
- the patient is being administered the corticosteroid at a first dose for a first time period.
- the method further comprises administering a second dose of the corticosteroid to the patient.
- the second dose of the corticosteroid is a different amount than the first dose.
- the second dose of the corticosteroid is the same amount as the first dose.
- the corticosteroid is administered orally.
- the corticosteroid is administered intravenously or intramuscularly.
- the corticosteroid is administered intravenously. In some embodiments, the corticosteroid is administered intravenously and the HSD1 inhibitor is administered orally. In some embodiments, the corticosteroid is administered intravenously and the HSD1 inhibitor is administered orally at the same time as the intravenous
- the corticosteroid is administered intravenously and the HSD1 inhibitor is administered orally prior to the intravenous administration of the corticosteroid. In some embodiments, the corticosteroid is administered intravenously and the HSD1 inhibitor is administered orally in a manner sufficient to provide protection across multiple administrations of the corticosteroid, which may occur during a single day or more than one day. In some embodiments, the corticosteroid is administered intravenously and the HSD1 inhibitor is administered intravenously. In some embodiments, the corticosteroid and HSD1 inhibitor are co-formulated for intravenous administration. In some embodiments, the corticosteroid and HSD1 inhibitor are administered separately.
- the corticosteroid is administered intramuscularly. In some embodiments, the corticosteroid is administered intramuscularly at a frequency less than daily. In some embodiments, the corticosteroid is administered intramuscularly every other day. In some embodiments, the corticosteroid is administered intramuscularly twice a week. In some embodiments, the corticosteroid is administered intramuscularly once a week. In some embodiments, the corticosteroid is administered intramuscularly every other week. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered intramuscularly. In some embodiments, the corticosteroid and HSD1 inhibitor are co-formulated for intramuscular administration.
- the corticosteroid and HSD1 inhibitor are administered separately. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered orally. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered orally as a single loading dose. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered orally as a single loading dose followed by one or more maintenance doses. In some embodiments, the corticosteroid is administered intramuscularly and the HSD1 inhibitor is administered orally as a plurality of doses, each of which may be the same amount or differing amounts.
- the corticosteroid is chosen from alclometasone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clocortolone, cloprednol, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluticasone, fluprednidene, formocortal, halcinonide, halometasone,
- the corticosteroid is betamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.25 to about 20 mg. In some embodiments, the corticosteroid is betamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.6 to about 9 mg.
- the corticosteroid is prednisolone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.5 to about 200 mg. In some embodiments, the corticosteroid is prednisolone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.5 to 80 mg. In some embodiments, the corticosteroid is prednisolone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.5 to 60 mg. In some embodiments, the corticosteroid is prednisolone or a pharmaceutically acceptable salt or ester thereof, and the equivalent dosage of prednisolone is chosen from 1, 2.5, 5, 10, 20, and 30 mg.
- the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 40 mg. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 30 mg. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 20 mg. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 10 mg. In some embodiments, the corticosteroid is dexamethasone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.1 to about 9 mg.
- the corticosteroid is budesonide or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.25 mg to 9 mg. In some embodiments, the corticosteroid is budesonide or a pharmaceutically acceptable salt or ester thereof, and is administered at a dosage chosen from the following:
- the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 20 to about 800 mg. In some embodiments, the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 20 to about 240 mg orally. In some embodiments, the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 20 to about 500 mg every two hours (e.g., for anti-inflammatory). In some embodiments, the corticosteroid is hydrocortisone or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 20 to about 800 mg daily for the treatment of multiple sclerosis.
- the corticosteroid is deflazacort or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of from about 0.25 mg to about
- the corticosteroid is deflazacort or a pharmaceutically acceptable salt or ester thereof, and is administered at a dose of about 0.9 mg/kg/day.
- the corticosteroid is methylprednisolone or a
- the corticosteroid is methylprednisolone or a pharmaceutically acceptable salt or ester thereof, and is administered intravenously at a dose of from about 10 to about 40 mg.
- the corticosteroid is methylprednisolone or a
- the corticosteroid is administered at a dose equivalent to 1 mg prednisone. In some embodiments, the corticosteroid is administered at a dose equivalent to 2.5 mg prednisone. In some embodiments, the corticosteroid is administered at a dose equivalent to 5 mg prednisone. In some embodiments, the corticosteroid is administered at a dose equivalent to 10 mg prednisone. In some embodiments, the corticosteroid is
- the corticosteroid is administered at a dose equivalent to 30 mg prednisone.
- the side effects associated with corticosteroid are not limited to:
- administration are chosen from diabetes, fractures, obesity, Cushingoid appearance, hepatic steatosis, hypertension, hyperlipidemia, muscle weakness, dermal atrophy, impaired wound healing, osteoporosis/osteonecrosis, glaucoma, and mood/memory changes.
- the first dose of the HSD1 inhibitor is at least 0.7 mg. In some embodiments, the first dose of the HSD1 inhibitor is 0.7 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 1 mg. In some embodiments, the first dose of the HSD1 inhibitor is 1 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least
- the first dose of the HSD1 inhibitor is 2 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 2.5 mg. In some embodiments, the first dose of the HSD1 inhibitor is 2.5 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 3 mg. In some embodiments, the first dose of the HSD1 inhibitor is 3 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 4 mg. In some embodiments, the first dose of the HSD1 inhibitor is 4 mg. In some embodiments, the first dose of the HSD1 inhibitor is at least 5 mg. In some embodiments, the first dose of the HSD1 inhibitor is 5 mg. In some embodiments, the first dose of the HSD1 inhibitor is 6 mg.
- the first dose of the HSD1 inhibitor is sufficient to achieve the target threshold for the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone.
- the HSD1 inhibitor is administered at a single dose of 5 mg to achieve the target threshold. In some embodiments, the HSD1 inhibitor is administered at a dose of 6 mg to achieve the target threshold.
- multiple administrations are required to achieve the target threshold for the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone.
- the HSD1 inhibitor is administered at a dose of 2.5 mg for 2 days to achieve the target threshold. In some embodiments, the HSD1 inhibitor is administered at a dose of 2 mg for 3 days to achieve the target threshold. In some embodiments, the HSD1 inhibitor is administered at a dose of 1 mg for 5 days to achieve the target threshold. In some embodiments, the HSD1 inhibitor is administered at a dose of 0.7 mg for 7 days to achieve the target threshold.
- a second dose of the HSD1 inhibitor is not administered to the patient.
- the method further comprises administering a second dose of the HSD1 inhibitor. In some embodiments, prior to administering the second dose of the HSD1 inhibitor, the method further comprises measuring the ratio of urinary
- the method further comprising adjusting the dose of HSD1 inhibitor to maintain the patient’s ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone at a level below the target threshold.
- the second dose of the HSD1 inhibitor is the same as the first dose of the HSD1 inhibitor.
- the second dose of the HSD1 inhibitor is more than the first dose of the HSD1 inhibitor.
- the second dose of the HSD1 inhibitor is less than the first dose of the HSD1 inhibitor.
- the target threshold for the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone is about 0.2
- the first dose of the HSD1 inhibitor is the same amount as the second dose, i.e.., the dosing amount is constant.
- the first and second dose are 2 mg. In some embodiments, the first and second dose are 2.5 mg.
- the target threshold for the ratio of urinary is the target threshold for the ratio of urinary
- tetrahydrocortisol + allotetrahydrocortisol to urinary tetrahydrocortisone is about 0.2
- the second dose of the HSD1 inhibitor is less than the first dose of the HSD1 inhibitor, e.g., the first dose is a loading dose and the second dose is a maintenance dose.
- the first or loading dose is at least 3 mg, such as 3 mg. In some embodiments, the first or loading dose is at least 4 mg, such as 4 mg. In some embodiments, the first or loading dose is at least 5 mg, such as 5 mg. In some embodiments, the first or loading dose is at least 6 mg, such as 6 mg. In some embodiments, the second dose is 0.2 mg. In some embodiments, the second dose is 0.1 mg.
- the first or loading dose is at least 0.7 mg, such as 0.7 mg. In some embodiments, e.g., when the target threshold is 0.66, the first or loading dose is at least 1 mg, such as 1 mg. In some embodiments, the first or loading dose is at least 2 mg, such as 2 mg. In some embodiments, the first or loading dose is at least 3 mg, such as 3 mg. In some embodiments, the first or loading dose is at least 4 mg, such as 4 mg. In some embodiments, the first or loading dose is at least 5 mg, such as 5 mg. In some embodiments, the first or loading dose is at least 6 mg. In some embodiments, the second dose is 0.2 mg. In some embodiments, the second dose is 0.1 mg.
- the corticosteroid is administered at decreasing levels over a period of time, e.g., a 6-day course of methylprednisolone in which patients take 6, 5, 4, 3, 2, and finally 1 dosage form on successive days, and the HSD1 inhibitor is administered at a dose of at least 0.833 mg with each corticosteroid dosage form.
- the corticosteroid is methylprednisolone
- the dosage form is a tablet
- each tablet is 4 mg.
- the corticosteroid is formulated as a capsule.
- the HSD1 inhibitor is administered orally.
- the HSD1 inhibitor is provided in fixed dose combination (“FDC”) tablets with the corticosteroid.
- the FDC tablets are supplied for once daily dosage.
- a course of once daily dosages is provided.
- the HSD1 inhibitor is provided for a dosing regimen consistent with sub-chronic treatment with a corticosteroid.
- the subject will be instructed to take a decreasing count of tablets for a course of treatment.
- the subject will be instructed to take a 6, 5, 4, 3, 2, and 1 tablets for the first, second, third, fourth, fifth, and sixth day of a six day once daily course of treatment.
- the HSD1 inhibitor is provided for a dosing regimen consistent with chronic treatment with a corticosteroid.
- the subject will be instructed to take a single tablet for each day of a course of treatment.
- the subject will be instructed to take two tablets for each day of a course of treatment.
- the course of treatment is chosen from 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 6 months, and 1 year.
- the HSD1 inhibitor is administered intravenously.
- the HSD1 inhibitor is administered daily, optionally with divided doses. In some embodiments, the HSD1 inhibitor is administered every other day.
- the corticosteroid is administered to treat a chronic disease or disorder. In some embodiments, the corticosteroid is administered to treat an acute disease or disorder.
- the corticosteroid is administered to treat a disease or disorder chosen from:
- endocrine disorders such as primary or secondary adrenocortical insufficiency, congenital adrenal hyperplasia, nonsuppurative thyroiditis, and hypercalcemia associated with cancer;
- rheumatic disorders such as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, acute gouty arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, acute rheumatic carditis, dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus and epicondylitis;
- collagen diseases such as during an exacerbation or as maintenance therapy in selected cases of systemic lupus erythematosus, systemic dermatomyositis
- dermatologic diseases such as pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, exfoliative erythroderma, mycosis fungoides, severe psoriasis, and severe seborrheic dermatitis;
- allergic states such as control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment such as seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness, transfusion reactions, and drug hypersensitivity reactions;
- ophthalmic diseases such as severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as allergic comeal marginal ulcers, herpes zoster ophthalmicus, anterior segment inflammation, diffuse posterior uveitis and choroiditis, sympathetic ophthalmia, allergic conjunctivitis, keratitis,
- chorioretinitis chorioretinitis, optic neuritis, ulcerative colitis, and ocular inflammatory conditions unresponsive to topical corticosteroids, and iridocyclitis;
- respiratory diseases such as symptomatic sarcoidosis, Loefflef s syndrome not manageable by other means, berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis, and aspiration pneumonitis;
- hematologic disorders such as idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, erythroblastopenia (RBC anemia), pure red cell aplasia, and congenital (erythroid) hypoplastic anemia;
- neoplastic diseases such as for palliative management of leukemias and lymphomas in adults and acute leukemia of childhood;
- edematous states such as to induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus;
- gastrointestinal diseases such as to tide the patient over a critical period of the disease in: ulcerative colitis or regional enteritis;
- nervous system such as acute exacerbations of multiple sclerosis, cerebral edema associated with primary or metastatic brain tumor, or craniotomy;
- renal diseases such as to induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus; and other diseases or disorders such as tuberculous meningitis with subarachnoid block or. impending block when used concurrently with appropriate antituberculous chemotherapy, and trichinosis with neurologic or myocardial involvement.
- the corticosteroid is administered to treat vasculitis, e.g., Behcet’s disease, central nervous system vasculitis, cryogioblinerma Churg-Strauss syndrome, giant cell arteritis (GCA), granulomatosis with polyangiitis, Henoeh-Schonlein purpura, hypersensitivity vasculitis, aortitis, microscopic polyangiitis, polyarteritis nodosa, polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu’s arteritis, and urticarial vasculitis.
- vasculitis e.g., Behcet’s disease, central nervous system vasculitis, cryogioblinerma Churg-Strauss syndrome, giant cell arteritis (GCA), granulomatosis with polyangiitis, Henoeh-Schonlein purpura, hyper
- the vasculitis is chosen from GCA and PMR.
- the GCA is new-onset GCA.
- the GCA is ongoing GCA.
- the PMR is new-onset PMR.
- the PRM is ongoing PMR.
- coadministration of the HSD1 inhibitor and the corticosteroid is effective at alleviating adverse effects that arise from administration of corticosteroid.
- the adverse effects are chosen from one or more of the following: diabetes, impaired glucose tolerance, insulin resistance, weight gain, lipodystrophy, hepatic steatosis, elevated blood pressure, increased blood lipids, muscle atrophy, skin atrophy, impaired wound healing, bone fracture, osteoporosis, glaucoma, elevated intraocular pressure, memory deficits, mood changes, and hypothalamic-pituitary- adrenal (HP A) axis suppression.
- the foregoing has focused on methods for measuring HSD1 activity using the urinary metabolite ratio, i.e., the ratio of urinary (tetrahydrocortisol + allotetrahydrocortisol) to urinary tetrahydrocortisone for the patient.
- an alternative method is used to measure HSD1 activity.
- HSD1 activity is measured using a ratio of mass-labeled cortisol and cortisone in the blood, e.g., the plasma, or in the cerebrospinal fluid.
- the method as disclosed by Basu for measuring CS levels in the hepatic and portal veins is utilized. See Basu, et al. (2009) Diabetes 58: 39-45, which is incorporated herein by reference for all purposes.
- HSD1 activity is measured by a jugular mass-labeled cortisol: cortisone ratio.
- [9,11,12,12- 2 H4] cortisol (D4 cortisol) is used to characterize HSD1 inhibition as a precursor of the HSD1 substrate [9,12,12- 2 H3] cortisone (D3 cortisone) and the HSD1 product [9,12,12- 2 H3] cortisol (D3 cortisol).
- D4 cortisol is used to characterize HSD1 inhibition as a precursor of the HSD1 substrate [9,12,12- 2 H3] cortisone (D3 cortisone) and the HSD1 product [9,12,12- 2 H3] cortisol (D3 cortisol).
- HSD1 activity is measured using a ratio of active and inactive forms of a corticosteroid medication in the blood, e.g., the plasma, or in the cerebrospinal fluid.
- prednisone is used to characterize HSD1 inhibition as a precursor of the HSD1 product prednisolone.
- HSD1 activity is measured by conversion of a HSD1 substrate to a HSD1 product in a fat biopsy.
- the HSD1 substrate is mass labeled cortisone and the HSD1 product is mass labeled cortisol.
- the HSD1 substrate is [9,12,12- 2 H3] cortisone (D3 cortisone) and the HSD1 product is
- the HSD1 substrate is an 11-keto corticosteroid and that HSD1 product is an 11 -hydroxy corticosteroid.
- the HSD1 substrate is prednisone and the HSD1 product is prednisolone.
- HSD1 occupancy is measured rather than HSD1 activity or inhibition. Accordingly, also provided is a method for administering a corticosteroid to a patient in need thereof, comprising:
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s target HSD1 occupancy by HSD1 inhibitor at a level below the target threshold.
- the corticosteroid is not prednisone; and the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to maintain the patient’s target HSD1 occupancy by HSD1 inhibitor at a level below the target threshold.
- a method for administering a corticosteroid to a patient in need thereof comprising:
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s target HSD1 occupancy by HSD1 inhibitor at a level below the target threshold.
- the corticosteroid is not prednisone
- the HSD1 inhibitor is administered at a first dose for a first time period, such that the administration is effective to reduce the patient’s target HSD1 occupancy by HSD1 inhibitor at a level below the target threshold.
- the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 21 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 14 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 2-11 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 5-7 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 7 days.
- the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 3-4 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 4 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 3 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within 2 days. In some embodiments, the patient’s target HSD1 occupancy by HSD1 inhibitor is reduced to a level below the target threshold within a single day.
- the target HSD1 occupancy is 80%. In some embodiments, the target HSD1 occupancy is 90%. In some embodiments, the HSD1 occupancy is determined for the brain. In some embodiments, the HSD1 occupancy is determined for adipose tissue. In some embodiments, the HSD1 occupancy is determined for liver. In some embodiments, the HSD1 occupancy is determined for more than one tissue. In some embodiments, the HSD1 occupancy is determined from using an imaging method. In some embodiments, the imaging method is positron emission tomography (“PET”) following administration of a radiolabeled HSD1 ligand as a tracer.
- PET positron emission tomography
- the HSD1 ligand is [ n C] AS2471907 (3-(2-chlorophenyl)-4-(methyl- n C)-5-[2-[2,4,6- trifluorophenoxy]propan-2-yl]-4H-l, 2, 4-triazole).
- the imaging method is similar to the method disclosed in Gallezot, J.-D. J Nucl. Med. 2019, jnumed-118.
- the HSD1 occupancy in adipose tissue is determined from a biopsy of adipose tissue.
- a pharmaceutical product comprising a HSD1 inhibitor and a corticosteroid, wherein the corticosteroid is not prednisone; and the HSD1 inhibitor is 4- ⁇ 5- [ 1 -(4-chloro-2,6-difluorophenoxy)- 1 -methy lethy 1] -4-methy 1-4H- 1 ,2,4-triazol-3 -y 1-3- fluorobenzamide or a pharmaceutically acceptable salt thereof (Compound A) or N-[5- (aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-a,a-dimethyl-4-[5-(trifluoromethyl)-2- pyridinyl]-l-piperazineacetamide (Compound B).
- the pharmaceutical product is for intravenous or intramuscular administration.
- the pharmaceutical product is for oral administration.
- the pharmaceutical product comprises a combined preparation wherein the HSD1 inhibitor and the corticosteroid are co-formulated.
- the combined preparation is a tablet having two or more layers, wherein each of the HSD1 inhibitor and the corticosteroid are in different layers, optionally separated by a barrier layer.
- the combined preparation is a tablet having a core-shell configuration wherein the core comprises the HSD1 inhibitor and the shell comprises the corticosteroid, wherein the core and shell are optionally separated by a barrier layer.
- the combined preparation is a tablet having a core-shell configuration wherein the core comprises the corticosteroid and the shell comprises the HSD1 inhibitor, wherein the core and shell are optionally separated by a barrier layer.
- the combined preparation is a capsule containing the HSD1 inhibitor and the corticosteroid.
- the combined preparation is a combination of mini -tablets comprising the HSD1 inhibitor and mini -tablets comprising the corticosteroid.
- the pharmaceutical product comprises a combined preparation wherein the HSD1 inhibitor and the corticosteroid are co-packaged.
- the HSD1 inhibitor is formulated for oral administration and the corticosteroid is administered for intramuscular administration.
- the HSD1 inhibitor is Compound A, and is formulated for oral administration. In some embodiments, the HSD1 inhibitor is Compound B, and is formulated for oral administration.
- the HSD1 inhibitor is formulated as oral tablets. In some embodiments, the HSD1 inhibitor is formulated as oral tablets with a dosage of the HSD1 inhibitor chosen from 0.1, 0.2, 0.4, 0.7, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 and 6.0 mg. In some embodiments, the HSD1 inhibitor is formulated as oral tablets with Compound A. In some embodiments, the HSD1 inhibitor is formulated as oral tablets with Compound B.
- the pharmaceutical product comprises a twin pack.
- the pharmaceutical product comprises a kit comprising a first portion comprising the HSD1 inhibitor and a second portion comprising the
- the pharmaceutical product comprises a kit comprising a dosage form of HSD1 inhibitor at a loading dose and one or more dosage forms of the HSD1 inhibitor at a maintenance dose and one or more dosage forms of the corticosteroid.
- the pharmaceutical product comprises the following: (1) a loading dose of the HSD1 inhibitor together with six dosage forms comprising an amount of corticosteroid, which is to be administered on the first day; (2) a maintenance dose of the HSD1 inhibitor together with five dosage forms comprising the corticosteroid, which is to be administered on the second day; (3) a maintenance dose of the HSD1 inhibitor together with four dosage forms comprising the corticosteroid, which is to be administered on the third day; (4) a maintenance dose of the HSD1 inhibitor together with three dosage forms comprising the corticosteroid, which is to be administered on the fourth day; (5) a maintenance dose of the HSD1 inhibitor together with two dosage forms comprising the corticosteroid, which is to be administered on the fifth day; and (6) a maintenance dose of the HSD1 inhibitor together with one dosage form comprising the corticosteroid, which is to be administered on the sixth day.
- the loading dose of the HSD1 inhibitor is administered as six split doses wherein one of the split doses is administered with each of the dosage forms comprising the corticosteroid.
- the split dose is co-formulated with the dosage form comprising the corticosteroid.
- the maintenance dose of the HSD1 inhibitor is administered as split doses with each of the split doses co-formulated with the dosage forms comprising the corticosteroid. For example, on the third day, the maintenance dose of the HSD1 inhibitor is divided into four split doses, with each of the split doses being administered with a dosage form of the corticosteroid.
- the split maintenance dose of the HSD1 inhibitor is co-formulated with the corticosteroid.
- the pharmaceutical product further comprises one or more excipients.
- excipients such as binding agents, fillers, acceptable wetting agents, tabletting lubricants, and disintegrants can be used in tablets and capsules for oral administration.
- compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
- compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
- the compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
- the compositions for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
- the compositions for oral can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
- administration can be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants can be added.
- compositions for intravenous or intramuscular administration can be prepared by dissolving the compounds in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampoule. These are just a few examples of the many appropriate methods well known in the art for preparing compositions for oral, intravenous or intramuscular administration.
- tetrahydrocortisone was used as an indicator of HSD-1 activity.
- Compound A decreased the 5a-tetrahydrocortisol + 5p-tetrahydrocortisol to urinary tetrahydrocortisone ratio with increasing dose compared to placebo, resulting in approximately 80% inhibition at 6 mg. Increasing the dose above 6 mg did not substantially increase the level of inhibition.
- Compound A after a standard breakfast was administered on Day 1, followed by daily doses on Days 7 through 20 (2 mg and 0.7 mg cohorts, FIG. 2) or on Days 2 through 14 (0.4 and 0.2 mg cohorts, FIG. 3). Urine samples were collected on multiple days.
- Compound A significantly decreased HSD-1 activity.
- a population pharmacokinetics model (FIG. 4) was developed using a maximal dose of 20 mg.
- the selected model to describe the pharmacokinetics of Compound A was a two-compartment disposition model, with a 4-compartment transit absorption, saturable binding from the central compartment, and first-order elimination. Inter-individual variability was implemented on clearance (CL), volume of distribution (V2), absorption rate constant (kA), second order association constant (Kon), first order dissociation constant (Kofi), and total number of saturable binding receptors (R). This model had satisfactory goodness-of-fit and acceptable relative standard errors.
- CL, kA, R, Kon, and Koff are defined above.
- BAV is relative bioavailabibty
- kTR is a transit rate constant (equal to kA)
- k23 and k32 are transfer rate constants between central and peripheral compartments.
- the estimated total number of saturable binding receptors corresponds to 1.347 mg of Compound A.
- Example 3 Brain occupancy by Compound A
- Example 1 The population pharmacokinetic model of Example 1 was used to simulate brain HSD-1 occupancy following single and multiple doses of SPI-62. Results are shown in FIG.
- FIG. 6 (3 mg initial dose, then (a) 1 mg QD; (b) 0.1 mg QD), FIG. 7 (4 mg initial dose, then (a) 1 mg QD; (b) 0.1 mg QD), and FIG. 8 (3 x 1 mg initial doses, then 0.1 mg QD).
- mice typically prefer to explore the novel arm of a Y-maze, a behavior considered indicative of short-term memory.
- Corticosterone (CS) decreases the percentage of times mice enter the novel arm of a Y maze, and so is considered to have a negative cognitive effect.
- Single doses of 0.3 to 3 mg/kg Compound A (FIG. 10(d) - (1)) restored a more normal behavior pattern.
- Example 7 Dose scenarios in clinical practice
- an initial dose of more than 4 mg of Compound A e.g., 6 mg
- daily doses of more than 0.1 mg of Compound A e.g., 0.2 to 2 mg
- full HSD-1 inhibition throughout the course of treatment could be achieved by a fixed dose combination of a corticosteroid with an amount (N) of a HSD-1 inhibitor wherein 6N is sufficient to achieve full HSD-1 inhibition concurrently with the first corticosteroid dose.
- a fixed dose combination such that the amount of Compound A in six dosage forms is more than 4 mg (e.g., 0.7 to 1 mg) could be selected.
- an intramuscular dose of 40 to 240 mg methylprednisolone or an intralesional dose of 20 to 160 mg methylprednisolone can be expected to have substantial pharmacologic effect for at least 5 to 10 days.
- a single oral dose of more than 4 mg of Compound A (e.g., 6 mg) could be expected to rapidly achieve full HSD-1 inhibition and maintain substantial HSD-1 inhibition for at least 5 to 10 days.
- Example 8 Dosage Formulation for Tablets with 1 mg Compound A
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2021005801A MX2021005801A (en) | 2018-11-20 | 2019-08-14 | Methods for administering corticosteroids. |
BR112021009653-1A BR112021009653A2 (en) | 2018-11-20 | 2019-08-14 | method of administering a corticosteroid to a patient in need thereof, method of reducing or preventing side effects associated with administering corticosteroids to a patient in need thereof, and pharmaceutical product |
CN201980076112.6A CN113329754A (en) | 2018-11-20 | 2019-08-14 | Methods for administering corticosteroids |
AU2019384074A AU2019384074A1 (en) | 2018-11-20 | 2019-08-14 | Methods for administering corticosteroids |
CA3120339A CA3120339A1 (en) | 2018-11-20 | 2019-08-14 | Methods for administering corticosteroids |
EP19886299.7A EP3883578A4 (en) | 2018-11-20 | 2019-08-14 | Methods for administering corticosteroids |
US17/289,516 US20210393622A1 (en) | 2018-11-20 | 2019-08-14 | Methods for administering corticosteroids |
JP2021525303A JP7472122B2 (en) | 2018-11-20 | 2019-08-14 | How to Administer Corticosteroids |
IL283069A IL283069A (en) | 2018-11-20 | 2021-05-10 | Methods for administering corticosteroids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862769932P | 2018-11-20 | 2018-11-20 | |
US62/769,932 | 2018-11-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020106337A1 true WO2020106337A1 (en) | 2020-05-28 |
Family
ID=70774135
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2019/046449 WO2020106337A1 (en) | 2018-11-20 | 2019-08-14 | Methods for administering corticosteroids |
Country Status (10)
Country | Link |
---|---|
US (1) | US20210393622A1 (en) |
EP (1) | EP3883578A4 (en) |
JP (1) | JP7472122B2 (en) |
CN (1) | CN113329754A (en) |
AU (1) | AU2019384074A1 (en) |
BR (1) | BR112021009653A2 (en) |
CA (1) | CA3120339A1 (en) |
IL (1) | IL283069A (en) |
MX (1) | MX2021005801A (en) |
WO (1) | WO2020106337A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022076398A1 (en) * | 2020-10-07 | 2022-04-14 | Surface Ophthalmics, Inc. | Pharmaceutical kits and their use for treating dry eye disease |
US20230364060A1 (en) * | 2022-05-16 | 2023-11-16 | Sparrow Pharmaceuticals, Inc. | Methods and compositions for treating glucocorticoid excess |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR112021015481A2 (en) * | 2019-02-08 | 2021-12-07 | Sanofi Sa | Biotechnological optimization of microorganisms for the 1,2-dehydrogenation of steroids |
WO2023225507A1 (en) * | 2022-05-16 | 2023-11-23 | Sparrow Pharmaceuticals, Inc. | Methods and compositions for treating glucocorticoid excess |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040067222A1 (en) * | 2001-01-19 | 2004-04-08 | Walker Brian Robert | Regulation of glucocorticoid concentration |
US20060094699A1 (en) * | 2003-04-11 | 2006-05-04 | Kampen Gita Camilla T | Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy |
US20130022677A1 (en) * | 2010-03-05 | 2013-01-24 | University Of Strathclyde | Delayed prolonged drug delivery |
US20170327474A1 (en) * | 2010-09-07 | 2017-11-16 | Astellas Pharma Inc. | Therapeutic agent for pain |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0107383D0 (en) * | 2001-03-23 | 2001-05-16 | Univ Edinburgh | Lipid profile modulation |
US7880001B2 (en) * | 2004-04-29 | 2011-02-01 | Abbott Laboratories | Inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme |
US8415354B2 (en) | 2004-04-29 | 2013-04-09 | Abbott Laboratories | Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme |
MX2011000179A (en) * | 2008-07-03 | 2011-04-05 | Astellas Pharma Inc | Triazole derivative or salt thereof. |
EP2243494A1 (en) | 2009-04-22 | 2010-10-27 | OntoChem GmbH | Pharmaceutical composition, comprising a steroid-dehydrogenase-reductase inhibitor, and a mineralocorticoid receptor antagonist. |
WO2011068927A2 (en) * | 2009-12-04 | 2011-06-09 | Abbott Laboratories | 11-β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11B-HSD1) INHIBITORS AND USES THEREOF |
US20130245038A1 (en) * | 2012-03-13 | 2013-09-19 | Abbvie Inc. | Method For Selecting Or Identifying A Subject For V1B Antagonist Therapy |
CN114010641A (en) * | 2014-07-09 | 2022-02-08 | 爱普制药有限责任公司 | Methods for treating neurological disorders |
-
2019
- 2019-08-14 JP JP2021525303A patent/JP7472122B2/en active Active
- 2019-08-14 BR BR112021009653-1A patent/BR112021009653A2/en unknown
- 2019-08-14 AU AU2019384074A patent/AU2019384074A1/en active Pending
- 2019-08-14 MX MX2021005801A patent/MX2021005801A/en unknown
- 2019-08-14 US US17/289,516 patent/US20210393622A1/en active Pending
- 2019-08-14 CA CA3120339A patent/CA3120339A1/en active Pending
- 2019-08-14 EP EP19886299.7A patent/EP3883578A4/en active Pending
- 2019-08-14 WO PCT/US2019/046449 patent/WO2020106337A1/en active Application Filing
- 2019-08-14 CN CN201980076112.6A patent/CN113329754A/en active Pending
-
2021
- 2021-05-10 IL IL283069A patent/IL283069A/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040067222A1 (en) * | 2001-01-19 | 2004-04-08 | Walker Brian Robert | Regulation of glucocorticoid concentration |
US20060094699A1 (en) * | 2003-04-11 | 2006-05-04 | Kampen Gita Camilla T | Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy |
US20130022677A1 (en) * | 2010-03-05 | 2013-01-24 | University Of Strathclyde | Delayed prolonged drug delivery |
US20170327474A1 (en) * | 2010-09-07 | 2017-11-16 | Astellas Pharma Inc. | Therapeutic agent for pain |
Non-Patent Citations (2)
Title |
---|
ALLENDE ET AL.: "LC-MS/MS Method for the Simultaneous Determination of Free Urinary Steroids", CHROMATOGRAPHIA, vol. 77, 2014, pages 637 - 642, XP055710683, DOI: 10.1007/s10337-014-2638-4 * |
See also references of EP3883578A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022076398A1 (en) * | 2020-10-07 | 2022-04-14 | Surface Ophthalmics, Inc. | Pharmaceutical kits and their use for treating dry eye disease |
US20230364060A1 (en) * | 2022-05-16 | 2023-11-16 | Sparrow Pharmaceuticals, Inc. | Methods and compositions for treating glucocorticoid excess |
Also Published As
Publication number | Publication date |
---|---|
IL283069A (en) | 2021-06-30 |
CA3120339A1 (en) | 2020-05-28 |
JP2022507103A (en) | 2022-01-18 |
US20210393622A1 (en) | 2021-12-23 |
EP3883578A1 (en) | 2021-09-29 |
AU2019384074A1 (en) | 2021-06-03 |
JP7472122B2 (en) | 2024-04-22 |
MX2021005801A (en) | 2021-08-05 |
CN113329754A (en) | 2021-08-31 |
EP3883578A4 (en) | 2022-07-27 |
BR112021009653A2 (en) | 2021-08-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210393622A1 (en) | Methods for administering corticosteroids | |
Correll et al. | Pharmacokinetic characteristics of long-acting injectable antipsychotics for schizophrenia: an overview | |
US20200253985A1 (en) | Neuroactive steroids, compositions, and uses thereof | |
EP3706755A1 (en) | Ganaxolone for use in treating genetic epileptic disoders | |
US20210338692A1 (en) | A 19-nor c3,3-disubstituted c21-n-pyrazolyl steroid and methods of use thereof | |
US20200030304A1 (en) | Mitigation of cns disorders by combination therapy using neurosteroids, and ampa blockers | |
US20230018765A1 (en) | A 19-nor c3,3-disubstituted c21-n-pyrazolyl steroid and methods of use thereof | |
AU2017301735B2 (en) | Methods of medical treatment with SUR1-TRPM4 channel inhibitors | |
JP2022031479A (en) | Method of treating or preventing amyloid-related imaging abnormality associated with alzheimer's disease treatment | |
AU2016279000A1 (en) | Neuroactive steroid solutions and their methods of use | |
JP2019507786A (en) | Dosage regimen for the treatment of acute exacerbations of chronic obstructive pulmonary disease | |
JP2019507785A (en) | Dosage regimen for the treatment of acute exacerbations of inflammatory conditions | |
KR20100121601A (en) | Therapeutic regimens for the treatment of immunoinflammatory disorders | |
JP2009533413A (en) | Pharmaceutical composition comprising an analgesic and a vitamin | |
TW201726145A (en) | Corticosteroid formulations for maintaining corticosteroid synovial fluid concentrations | |
JP6420923B1 (en) | Medicine | |
Mehta et al. | Zuranolone. GABA-A receptor positive allosteric modulator, Treatment of major depressive disorder, Treatment of postpartum depression | |
Deepalakshmi et al. | A Comprehensive Review on Corticosteroids | |
JP2024501259A (en) | How to administer intravenous baclofen | |
RU2021113995A (en) | Methods of administering corticosteroids | |
JPWO2020106337A5 (en) | ||
Factor | Drug Monograph | |
Santosh et al. | STUDY OF PHENYTOIN DRUG RELATED WITH PHARMACOVIGILANCE | |
KR20230110793A (en) | Compositions comprising flumazenil and naltrexone and methods of use thereof | |
CN117580581A (en) | 19-norC 3, 3-disubstituted C21-N-pyrazolyl steroids for the treatment of major depressive disorder and postpartum depression |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 19886299 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2021525303 Country of ref document: JP Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 3120339 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112021009653 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2019384074 Country of ref document: AU Date of ref document: 20190814 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2021113995 Country of ref document: RU |
|
ENP | Entry into the national phase |
Ref document number: 2019886299 Country of ref document: EP Effective date: 20210621 |
|
ENP | Entry into the national phase |
Ref document number: 112021009653 Country of ref document: BR Kind code of ref document: A2 Effective date: 20210518 |