JPWO2021190641A5 - - Google Patents
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- JPWO2021190641A5 JPWO2021190641A5 JP2022558586A JP2022558586A JPWO2021190641A5 JP WO2021190641 A5 JPWO2021190641 A5 JP WO2021190641A5 JP 2022558586 A JP2022558586 A JP 2022558586A JP 2022558586 A JP2022558586 A JP 2022558586A JP WO2021190641 A5 JPWO2021190641 A5 JP WO2021190641A5
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- pharmaceutical product
- administered
- therapeutically effective
- effective amount
- pimozide
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- 238000000034 method Methods 0.000 claims description 33
- 206010052015 cytokine release syndrome Diseases 0.000 claims description 32
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 claims description 16
- 229960003634 pimozide Drugs 0.000 claims description 16
- 230000037396 body weight Effects 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical compound C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 claims description 8
- FAWLNURBQMTKEB-URDPEVQOSA-N 213546-53-3 Chemical compound N([C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N1[C@@H](CCC1)C(O)=O)C(C)C)C(C)C)C(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)N)C(C)C FAWLNURBQMTKEB-URDPEVQOSA-N 0.000 claims description 8
- 230000017128 negative regulation of NF-kappaB transcription factor activity Effects 0.000 claims description 8
- 108020003175 receptors Proteins 0.000 claims description 8
- 102000005962 receptors Human genes 0.000 claims description 8
- 208000025721 COVID-19 Diseases 0.000 claims description 6
- 238000002659 cell therapy Methods 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 5
- YZMHNNLDUWRZFW-UHFFFAOYSA-N (4-methoxyphenyl)-morpholin-4-yl-sulfanyl-sulfanylidene-$l^{5}-phosphane;morpholine Chemical compound C1COCC[NH2+]1.C1=CC(OC)=CC=C1P([S-])(=S)N1CCOCC1 YZMHNNLDUWRZFW-UHFFFAOYSA-N 0.000 claims description 4
- RNOAOAWBMHREKO-QFIPXVFZSA-N (7S)-2-(4-phenoxyphenyl)-7-(1-prop-2-enoylpiperidin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C(C=C)(=O)N1CCC(CC1)[C@@H]1CCNC=2N1N=C(C=2C(=O)N)C1=CC=C(C=C1)OC1=CC=CC=C1 RNOAOAWBMHREKO-QFIPXVFZSA-N 0.000 claims description 4
- DOEWDSDBFRHVAP-KRXBUXKQSA-N (E)-3-tosylacrylonitrile Chemical compound CC1=CC=C(S(=O)(=O)\C=C\C#N)C=C1 DOEWDSDBFRHVAP-KRXBUXKQSA-N 0.000 claims description 4
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 4
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 4
- SAYGKHKXGCPTLX-UHFFFAOYSA-N 2-(carbamoylamino)-5-(4-fluorophenyl)-3-thiophenecarboxamide Chemical group NC(=O)C1=C(NC(=O)N)SC(C=2C=CC(F)=CC=2)=C1 SAYGKHKXGCPTLX-UHFFFAOYSA-N 0.000 claims description 4
- BMUACLADCKCNKZ-UHFFFAOYSA-N 3-amino-5-(3-thiophenyl)-2-thiophenecarboxamide Chemical compound NC1=C(C(=O)N)SC(C2=CSC=C2)=C1 BMUACLADCKCNKZ-UHFFFAOYSA-N 0.000 claims description 4
- XFSSJIQCIPSBHJ-UHFFFAOYSA-N 6,6-dimethyl-2-phenylimino-5,7-dihydro-1,3-benzoxathiol-4-one Chemical compound S1C=2C(=O)CC(C)(C)CC=2OC1=NC1=CC=CC=C1 XFSSJIQCIPSBHJ-UHFFFAOYSA-N 0.000 claims description 4
- 108010028006 B-Cell Activating Factor Proteins 0.000 claims description 4
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 4
- 229940124291 BTK inhibitor Drugs 0.000 claims description 4
- 229940125814 BTK kinase inhibitor Drugs 0.000 claims description 4
- 102100021943 C-C motif chemokine 2 Human genes 0.000 claims description 4
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 claims description 4
- 102100025279 C-X-C motif chemokine 11 Human genes 0.000 claims description 4
- 102100036170 C-X-C motif chemokine 9 Human genes 0.000 claims description 4
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 claims description 4
- 208000001528 Coronaviridae Infections Diseases 0.000 claims description 4
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 claims description 4
- 102100023688 Eotaxin Human genes 0.000 claims description 4
- 208000035366 Familial hemophagocytic lymphohistiocytosis Diseases 0.000 claims description 4
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims description 4
- 208000036066 Hemophagocytic Lymphohistiocytosis Diseases 0.000 claims description 4
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 4
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 claims description 4
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 claims description 4
- 101000858060 Homo sapiens C-X-C motif chemokine 11 Proteins 0.000 claims description 4
- 101000947172 Homo sapiens C-X-C motif chemokine 9 Proteins 0.000 claims description 4
- 101000978392 Homo sapiens Eotaxin Proteins 0.000 claims description 4
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 claims description 4
- 101000959820 Homo sapiens Interferon alpha-1/13 Proteins 0.000 claims description 4
- 101001055222 Homo sapiens Interleukin-8 Proteins 0.000 claims description 4
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 claims description 4
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 4
- 102100040019 Interferon alpha-1/13 Human genes 0.000 claims description 4
- 108010065805 Interleukin-12 Proteins 0.000 claims description 4
- 108050003558 Interleukin-17 Proteins 0.000 claims description 4
- 108010002350 Interleukin-2 Proteins 0.000 claims description 4
- 102000000588 Interleukin-2 Human genes 0.000 claims description 4
- 108010065637 Interleukin-23 Proteins 0.000 claims description 4
- 108090001005 Interleukin-6 Proteins 0.000 claims description 4
- 102100026236 Interleukin-8 Human genes 0.000 claims description 4
- YMFNPBSZFWXMAD-UHFFFAOYSA-N JSH-23 Chemical compound NC1=CC(C)=CC=C1NCCCC1=CC=CC=C1 YMFNPBSZFWXMAD-UHFFFAOYSA-N 0.000 claims description 4
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 4
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 claims description 4
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 claims description 4
- CZQHHVNHHHRRDU-UHFFFAOYSA-N LY294002 Chemical compound C1=CC=C2C(=O)C=C(N3CCOCC3)OC2=C1C1=CC=CC=C1 CZQHHVNHHHRRDU-UHFFFAOYSA-N 0.000 claims description 4
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 claims description 4
- 208000004987 Macrophage activation syndrome Diseases 0.000 claims description 4
- 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 4
- 208000025370 Middle East respiratory syndrome Diseases 0.000 claims description 4
- PSPFQEBFYXJZEV-UHFFFAOYSA-N N'-(1,8-dimethyl-4-imidazo[1,2-a]quinoxalinyl)ethane-1,2-diamine Chemical compound C1=C(C)C=C2N3C(C)=CN=C3C(NCCN)=NC2=C1 PSPFQEBFYXJZEV-UHFFFAOYSA-N 0.000 claims description 4
- CHILCFMQWMQVAL-UHFFFAOYSA-N N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CHILCFMQWMQVAL-UHFFFAOYSA-N 0.000 claims description 4
- 241000526636 Nipah henipavirus Species 0.000 claims description 4
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 claims description 4
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 claims description 4
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 claims description 4
- 241000907316 Zika virus Species 0.000 claims description 4
- NMHKTASGTFXJPL-UHFFFAOYSA-N [2-methoxy-3-(octadecylcarbamoyloxy)propyl] 2-(1,3-thiazol-3-ium-3-yl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCNC(=O)OCC(OC)COP([O-])(=O)OCC[N+]=1C=CSC=1 NMHKTASGTFXJPL-UHFFFAOYSA-N 0.000 claims description 4
- WDENQIQQYWYTPO-IBGZPJMESA-N acalabrutinib Chemical compound CC#CC(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C(=O)NC=2N=CC=CC=2)=C2N1C=CN=C2N WDENQIQQYWYTPO-IBGZPJMESA-N 0.000 claims description 4
- 229950009821 acalabrutinib Drugs 0.000 claims description 4
- 229960004191 artemisinin Drugs 0.000 claims description 4
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 claims description 4
- 229930101531 artemisinin Natural products 0.000 claims description 4
- 229960003677 chloroquine Drugs 0.000 claims description 4
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 4
- ZCIGNRJZKPOIKD-CQXVEOKZSA-N cobicistat Chemical compound S1C(C(C)C)=NC(CN(C)C(=O)N[C@@H](CCN2CCOCC2)C(=O)N[C@H](CC[C@H](CC=2C=CC=CC=2)NC(=O)OCC=2SC=NC=2)CC=2C=CC=CC=2)=C1 ZCIGNRJZKPOIKD-CQXVEOKZSA-N 0.000 claims description 4
- 229960002402 cobicistat Drugs 0.000 claims description 4
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 claims description 4
- 229960005107 darunavir Drugs 0.000 claims description 4
- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 claims description 4
- 229950008454 favipiravir Drugs 0.000 claims description 4
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 claims description 4
- 229960000556 fingolimod Drugs 0.000 claims description 4
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960004171 hydroxychloroquine Drugs 0.000 claims description 4
- 229960001507 ibrutinib Drugs 0.000 claims description 4
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical group C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 claims description 4
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 4
- 229960004942 lenalidomide Drugs 0.000 claims description 4
- 229960004525 lopinavir Drugs 0.000 claims description 4
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 4
- 229960004963 mesalazine Drugs 0.000 claims description 4
- 229960004584 methylprednisolone Drugs 0.000 claims description 4
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 claims description 4
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 claims description 4
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 claims description 4
- 229960000311 ritonavir Drugs 0.000 claims description 4
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 4
- 230000009885 systemic effect Effects 0.000 claims description 4
- 229960003433 thalidomide Drugs 0.000 claims description 4
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 claims description 4
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 claims description 4
- 229950007153 zanubrutinib Drugs 0.000 claims description 4
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 3
- 208000001490 Dengue Diseases 0.000 claims description 2
- 206010012310 Dengue fever Diseases 0.000 claims description 2
- 208000004232 Enteritis Diseases 0.000 claims description 2
- 241000711549 Hepacivirus C Species 0.000 claims description 2
- 241000700721 Hepatitis B virus Species 0.000 claims description 2
- 241000709721 Hepatovirus A Species 0.000 claims description 2
- 208000032672 Histiocytosis haematophagic Diseases 0.000 claims description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 2
- 206010024641 Listeriosis Diseases 0.000 claims description 2
- 208000016604 Lyme disease Diseases 0.000 claims description 2
- 201000005505 Measles Diseases 0.000 claims description 2
- 201000009906 Meningitis Diseases 0.000 claims description 2
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- 206010037742 Rabies Diseases 0.000 claims description 2
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Description
他の実施形態は、以下の特許請求の範囲に記載されている。以下の項目［態様１］～［態様２８］に本発明の実施形態の例を列記する。
［態様１］
ピモジド及びアルテミシニン及びそれらの誘導体、又はそれらの薬学的に許容される塩、若しくはそれらの溶媒和物からなる群から選択される治療的有効量の化合物を、サイトカインストーム症候群（ＣＳＳ）の治療を必要とする対象に投与することを含む、前記治療を必要とする対象におけるサイトカインストーム症候群（ＣＳＳ）を治療する方法。
［態様２］
前記サイトカインストーム症候群（ＣＳＳ）が、サイトカイン放出症候群（ＣＲＳ）、家族性血球貪食性リンパ組織球症（ＦＨＬＨ）、エプスタイン－バーウイルス関連ＨＬＨ（ＥＢＶ－ＨＬＨ）、又は全身性若年性特発性関節炎関連マクロファージ活性化症候群（全身性ＪＩＡ－ＭＡＳ）と関連している、態様１に記載の方法。
［態様３］
前記サイトカインストーム症候群（ＣＳＳ）が、敗血症又は関連する細菌によって誘発される炎症と関連している、態様１に記載の方法。
［態様４］
前記サイトカインストーム症候群（ＣＳＳ）が、
（ａ）コロナウイルス感染症２０１９（ＣＯＶＩＤ－１９）
（ｂ）重症急性呼吸器症候群（ＳＡＲＳ）
（ｃ）中東呼吸器症候群（ＭＥＲＳ）
（ｄ）インフルエンザ
（ｅ）ヒト免疫不全ウイルス（ＨＩＶ）
（ｆ）マラリア
（ｇ）結核
（ｈ）デング熱
（ｉ）エボラウイルス病（ＥＶＤ）
（ｊ）Ａ型肝炎ウイルス、Ｂ型肝炎ウイルス又はＣ型肝炎ウイルス
（ｋ）ニパウイルス（ＮｉＶ）感染症
（ｌ）ペスト
（ｍ）肺炎
（ｎ）狂犬病
（ｏ）ブドウ球菌感染症
（ｐ）チフス熱
（ｑ）ジカウイルス（ＺＩＫＶ）
（ｒ）西ナイル熱
（ｓ）腸炎ビブリオ菌腸炎
（ｔ）各種脳炎
（ｕ）破傷風
（ｖ）リステリア症
（ｗ）ライム病
（ｘ）麻疹
（ｙ）髄膜炎
（ｚ）流行性耳下腺炎、及び
（ａａ）骨盤内炎症性疾患
から選択される感染症と関連している、態様１に記載の方法。
［態様５］
前記サイトカインストーム症候群（ＣＳＳ）が、キメラ抗原受容体（ＣＡＲ）Ｔ細胞療法又はＮＫ細胞療法から選択される細胞療法と関連している、又は抗体療法と関連している、態様１に記載の方法。
［態様６］
前記サイトカインストーム症候群（ＣＳＳ）が、ウイルス送達システムを含む遺伝子療法と関連している、態様１に記載の方法。
［態様７］
前記化合物が、ピモジド、又はその薬学的に許容される塩、若しくはその溶媒和物である、態様１～６のいずれか一態様に記載の方法。
［態様８］
前記化合物が、アルテミシニン又はその誘導体である、態様１～６のいずれか一態様に記載の方法。
［態様９］
ＩＬ－１α、ＩＬ－１β、ＩＬ－２、ＴＮＦα、ＩＦＮγ、ＩＬ－６、ＧＭＣＳＦ、Ｍ－ＣＳＦ、ＩＬ－１２、ＩＬ－１７、ＩＬ－２３、ＩＬ－２８、Ｉ型ＩＦＮ、ＣＣＬ２、ＣＸＣＬ８、ＣＸＣＬ９、ＣＸＣＬ１０、ＣＸＣＬ１１、ＣＣＬ１１、及びこれらのそれぞれの受容体に対する治療的有効量の抗体を投与することを更に含む、態様１～８のいずれか一態様に記載の方法。
［態様１０］
ＣＤ２０、ＣＤ４７、ＢＬｙＳ、ＡＰＲＩＬ、及びこれらのそれぞれの受容体に対する治療的有効量の抗体を投与することを更に含む、態様１～８のいずれか一態様に記載の方法。
［態様１１］
クロロキン、ヒドロキシクロロキン、レムデシビル、ファビピラビル、ロピナビル、リトナビル、フィンゴリモド、ダルナビル、コビシスタット、サリドマイド、レナリドミド、テトランドリン及びメチルプレドニゾロンから選択される治療的有効量の化合物を投与することを更に含む、態様１～８のいずれか一態様に記載の方法。
［態様１２］
治療的有効量のブルトン型チロシンキナーゼ（ＢＴＫ）阻害剤を投与することを更に含む、態様１～８のいずれか一態様に記載の方法。
［態様１３］
前記ＢＴＫ阻害剤が、イブルチニブ、ザヌブルチニブ、及びアカラブルチニブから選択される、態様１２に記載の方法。
［態様１４］
治療的有効量のＮＦ－κＢ阻害剤を投与することを更に含む、態様１～８のいずれか一態様に記載の方法。
［態様１５］
前記ＮＦ－κＢ阻害剤が、ＴＰＣＡ－１、ＢＯＴ－６４、ＢＭＳ ３４５５４１、ＳＣ－５１４、ＩＭＤ－０３５４、ＢＡＹ １１－７０８２、ＪＳＨ－２３、ＧＹＹ４１３７、ＣＶ－３９８８、ＬＹ２９４００２、ウォルトマンニン、及びメサラミンから選択される、態様１４に記載の方法。
［態様１６］
治療的有効量のピモジド、又はその薬学的に許容される塩、若しくはその溶媒和物を、サイトカインストーム症候群（ＣＳＳ）の治療を必要とする対象に投与することを含む、前記治療を必要とする対象におけるＣＯＶＩＤ－１９と関連するサイトカインストーム症候群（ＣＳＳ）を治療する方法。
［態様１７］
ピモジドが、１日当たり約０．１ｍｇ／ｋｇ体重～約０．５ｍｇ／ｋｇ体重の間の量で前記対象に投与される、態様１６に記載の方法。
［態様１８］
ピモジドが、１日当たり約０．１ｍｇ／ｋｇ体重～約０．３ｍｇ／ｋｇ体重の間の量で前記対象に投与される、態様１６に記載の方法。
［態様１９］
ピモジドが、１日当たり約０．３ｍｇ／ｋｇ体重以下の量で前記対象に投与される、態様１６に記載の方法。
［態様２０］
ピモジドが、前記対象に経口投与される、態様１６～１９のいずれか一態様に記載の方法。
［態様２１］
ピモジドが、非経口注射により前記対象に投与される、態様１６～１９のいずれか一態様に記載の方法。
［態様２２］
ＩＬ－１α、ＩＬ－１β、ＩＬ－２、ＴＮＦα、ＩＦＮγ、ＩＬ－６、ＧＭＣＳＦ、Ｍ－ＣＳＦ、ＩＬ－１２、ＩＬ－１７、ＩＬ－２３、ＩＬ－２８、Ｉ型ＩＦＮ、ＣＣＬ２、ＣＸＣＬ８、ＣＸＣＬ９、ＣＸＣＬ１０、ＣＸＣＬ１１、ＣＣＬ１１、及びこれらのそれぞれの受容体に対する治療的有効量の抗体を投与することを更に含む、態様１６～２１のいずれか一態様に記載の方法。
［態様２３］
ＣＤ２０、ＣＤ４７、ＢＬｙＳ、ＡＰＲＩＬ、及びこれらのそれぞれの受容体に対する治療的有効量の抗体を投与することを更に含む、態様１６～２１のいずれか一態様に記載の方法。
［態様２４］
クロロキン、ヒドロキシクロロキン、レムデシビル、ファビピラビル、ロピナビル、リトナビル、フィンゴリモド、ダルナビル、コビシスタット、サリドマイド、レナリドミド、テトランドリン及びメチルプレドニゾロンから選択される治療的有効量の化合物を投与することを更に含む、態様１６～２１のいずれか一態様に記載の方法。
［態様２５］
治療的有効量のブルトン型チロシンキナーゼ（ＢＴＫ）阻害剤を投与することを更に含む、態様１６～２１のいずれか一態様に記載の方法。
［態様２６］
前記ＢＴＫ阻害剤が、イブルチニブ、ザヌブルチニブ、及びアカラブルチニブから選択される、態様２５に記載の方法。
［態様２７］
治療的有効量のＮＦ－κＢ阻害剤を投与することを更に含む、態様１６～２１のいずれか一態様に記載の方法。
［態様２８］
前記ＮＦ－κＢ阻害剤が、ＴＰＣＡ－１、ＢＯＴ－６４、ＢＭＳ ３４５５４１、ＳＣ－５１４、ＩＭＤ－０３５４、ＢＡＹ １１－７０８２、ＪＳＨ－２３、ＧＹＹ４１３７、ＣＶ－３９８８、ＬＹ２９４００２、ウォルトマンニン、及びメサラミンから選択される、態様２７に記載の方法。
Other embodiments are described in the following claims. Examples of embodiments of the present invention are listed in the following items [Aspect 1] to [Aspect 28].
[Aspect 1]
A method for treating cytokine storm syndrome (CSS) in a subject in need of treatment, comprising administering to the subject in need of treatment a therapeutically effective amount of a compound selected from the group consisting of pimozide and artemisinin and their derivatives, or their pharma- ceutically acceptable salts, or their solvates.
[Aspect 2]
2. The method of aspect 1, wherein the cytokine storm syndrome (CSS) is associated with cytokine release syndrome (CRS), familial hemophagocytic lymphohistiocytosis (FHLH), Epstein-Barr virus associated HLH (EBV-HLH), or systemic juvenile idiopathic arthritis associated macrophage activation syndrome (systemic JIA-MAS).
[Aspect 3]
2. The method of claim 1, wherein the cytokine storm syndrome (CSS) is associated with sepsis or related bacterial-induced inflammation.
[Aspect 4]
The cytokine storm syndrome (CSS) is
(a) Coronavirus disease 2019 (COVID-19)
(b) Severe Acute Respiratory Syndrome (SARS)
(c) Middle East Respiratory Syndrome (MERS)
(d) Influenza
(e) Human immunodeficiency virus (HIV)
(f) Malaria
(g) Tuberculosis
(h) Dengue fever
(i) Ebola Virus Disease (EVD)
(j) Hepatitis A virus, Hepatitis B virus, or Hepatitis C virus
(k) Nipah virus (NiV) infection
(l) Plague
(m) Pneumonia
(n) Rabies
(o) Staphylococcal infection
(p) Typhoid fever
(q) Zika virus (ZIKV)
(r) West Nile fever
(s) Vibrio parahaemolyticus enteritis
(t) Various types of encephalitis
(u) Tetanus
(v) Listeriosis
(w) Lyme disease
(x) Measles
(y) Meningitis
(z) Mumps; and
(aa) pelvic inflammatory disease
The method of embodiment 1, wherein the infection is associated with an infection selected from the group consisting of:
[Aspect 5]
2. The method of aspect 1, wherein the cytokine storm syndrome (CSS) is associated with a cell therapy selected from chimeric antigen receptor (CAR) T cell therapy or NK cell therapy, or is associated with an antibody therapy.
[Aspect 6]
2. The method of embodiment 1, wherein said cytokine storm syndrome (CSS) is associated with a gene therapy comprising a viral delivery system.
[Aspect 7]
The method according to any one of the preceding aspects, wherein said compound is pimozide, or a pharma- ceutically acceptable salt or solvate thereof.
[Aspect 8]
The method according to any one of the preceding aspects, wherein said compound is artemisinin or a derivative thereof.
[Aspect 9]
Aspect 9. The method of any one of aspects 1-8, further comprising administering a therapeutically effective amount of an antibody against IL-1 alpha, IL-1 beta, IL-2, TNF alpha, IFN gamma, IL-6, GMCSF, M-CSF, IL-12, IL-17, IL-23, IL-28, type I IFN, CCL2, CXCL8, CXCL9, CXCL10, CXCL11, CCL11, and their respective receptors.
[Aspect 10]
Aspect 9. The method of any one of aspects 1-8, further comprising administering a therapeutically effective amount of an antibody against CD20, CD47, BLyS, APRIL, and their respective receptors.
[Aspect 11]
Aspect 9. The method of any one of aspects 1-8, further comprising administering a therapeutically effective amount of a compound selected from chloroquine, hydroxychloroquine, remdesivir, favipiravir, lopinavir, ritonavir, fingolimod, darunavir, cobicistat, thalidomide, lenalidomide, tetrandrine, and methylprednisolone.
[Aspect 12]
Aspect 9. The method of any one of aspects 1-8, further comprising administering a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor.
[Aspect 13]
13. The method of claim 12, wherein the BTK inhibitor is selected from ibrutinib, zanubrutinib, and acalabrutinib.
[Aspect 14]
The method of any one of the preceding aspects, further comprising administering a therapeutically effective amount of an NF-κB inhibitor.
[Aspect 15]
15. The method of claim 14, wherein the NF-κB inhibitor is selected from TPCA-1, BOT-64, BMS 345541, SC-514, IMD-0354, BAY 11-7082, JSH-23, GYY4137, CV-3988, LY294002, wortmannin, and mesalamine.
[Aspect 16]
1. A method of treating cytokine storm syndrome (CSS) associated with COVID-19 in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of pimozide, or a pharma- ceutically acceptable salt, or solvate thereof.
[Aspect 17]
The method of embodiment 16, wherein pimozide is administered to said subject in an amount between about 0.1 mg/kg body weight to about 0.5 mg/kg body weight per day.
[Aspect 18]
The method of aspect 16, wherein pimozide is administered to said subject in an amount between about 0.1 mg/kg body weight to about 0.3 mg/kg body weight per day.
[Aspect 19]
17. The method of aspect 16, wherein pimozide is administered to the subject in an amount of about 0.3 mg/kg body weight or less per day.
[Aspect 20]
Aspect 20. The method of any one of aspects 16-19, wherein pimozide is administered orally to said subject.
[Aspect 21]
Aspect 20. The method of any one of aspects 16-19, wherein pimozide is administered to said subject by parenteral injection.
[Aspect 22]
22. The method of any one of aspects 16-21, further comprising administering a therapeutically effective amount of an antibody against IL-1 alpha, IL-1 beta, IL-2, TNF alpha, IFN gamma, IL-6, GMCSF, M-CSF, IL-12, IL-17, IL-23, IL-28, type I IFN, CCL2, CXCL8, CXCL9, CXCL10, CXCL11, CCL11, and their respective receptors.
[Aspect 23]
Aspect 22. The method of any one of aspects 16-21, further comprising administering a therapeutically effective amount of an antibody against CD20, CD47, BLyS, APRIL, and their respective receptors.
[Aspect 24]
22. The method of any one of aspects 16-21, further comprising administering a therapeutically effective amount of a compound selected from chloroquine, hydroxychloroquine, remdesivir, favipiravir, lopinavir, ritonavir, fingolimod, darunavir, cobicistat, thalidomide, lenalidomide, tetrandrine, and methylprednisolone.
[Aspect 25]
22. The method of any one of aspects 16-21, further comprising administering a therapeutically effective amount of a Bruton's tyrosine kinase (BTK) inhibitor.
[Aspect 26]
26. The method of claim 25, wherein the BTK inhibitor is selected from ibrutinib, zanubrutinib, and acalabrutinib.
[Aspect 27]
22. The method of any one of aspects 16-21, further comprising administering a therapeutically effective amount of an NF-κB inhibitor.
[Aspect 28]
28. The method of aspect 27, wherein the NF-κB inhibitor is selected from TPCA-1, BOT-64, BMS 345541, SC-514, IMD-0354, BAY 11-7082, JSH-23, GYY4137, CV-3988, LY294002, wortmannin, and mesalamine.
Claims (28)
（ａ）コロナウイルス感染症２０１９（ＣＯＶＩＤ－１９）
（ｂ）重症急性呼吸器症候群（ＳＡＲＳ）
（ｃ）中東呼吸器症候群（ＭＥＲＳ）
（ｄ）インフルエンザ
（ｅ）ヒト免疫不全ウイルス（ＨＩＶ）
（ｆ）マラリア
（ｇ）結核
（ｈ）デング熱
（ｉ）エボラウイルス病（ＥＶＤ）
（ｊ）Ａ型肝炎ウイルス、Ｂ型肝炎ウイルス又はＣ型肝炎ウイルス
（ｋ）ニパウイルス（ＮｉＶ）感染症
（ｌ）ペスト
（ｍ）肺炎
（ｎ）狂犬病
（ｏ）ブドウ球菌感染症
（ｐ）チフス熱
（ｑ）ジカウイルス（ＺＩＫＶ）
（ｒ）西ナイル熱
（ｓ）腸炎ビブリオ菌腸炎
（ｔ）各種脳炎
（ｕ）破傷風
（ｖ）リステリア症
（ｗ）ライム病
（ｘ）麻疹
（ｙ）髄膜炎
（ｚ）流行性耳下腺炎、及び
（ａａ）骨盤内炎症性疾患
から選択される感染症と関連している、請求項１に記載の医薬品。 The cytokine storm syndrome (CSS) is
(a) Coronavirus disease 2019 (COVID-19)
(b) Severe Acute Respiratory Syndrome (SARS)
(c) Middle East Respiratory Syndrome (MERS)
(d) Influenza (e) Human immunodeficiency virus (HIV)
(f) Malaria (g) Tuberculosis (h) Dengue fever (i) Ebola virus disease (EVD)
(j) Hepatitis A virus, Hepatitis B virus or Hepatitis C virus; (k) Nipah virus (NiV) infection; (l) Plague; (m) Pneumonia; (n) Rabies; (o) Staphylococcal infection; (p) Typhoid fever; (q) Zika virus (ZIKV)
2. The pharmaceutical product of claim 1, which is associated with an infectious disease selected from: (r) West Nile fever, (s) Vibrio parahaemolyticus enteritis, (t) various types of encephalitis, (u) tetanus, (v) listeriosis, (w) Lyme disease, (x) measles, (y) meningitis, (z) mumps, and (aa) pelvic inflammatory disease .
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