MXPA06006220A - Pharmaceutical combinations - Google Patents
Pharmaceutical combinationsInfo
- Publication number
- MXPA06006220A MXPA06006220A MXPA/A/2006/006220A MXPA06006220A MXPA06006220A MX PA06006220 A MXPA06006220 A MX PA06006220A MX PA06006220 A MXPA06006220 A MX PA06006220A MX PA06006220 A MXPA06006220 A MX PA06006220A
- Authority
- MX
- Mexico
- Prior art keywords
- arthritis
- mtor inhibitor
- combination
- agent
- medicament
- Prior art date
Links
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims abstract description 36
- 206010003246 Arthritis Diseases 0.000 claims abstract description 23
- 201000003068 rheumatic fever Diseases 0.000 claims abstract description 19
- 206010072736 Rheumatic disease Diseases 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 50
- 239000003795 chemical substances by application Substances 0.000 claims description 30
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 14
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- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000005755 formation reaction Methods 0.000 claims description 4
- HKVAMNSJSFKALM-SQMKDCFHSA-N Everolimus Chemical group C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-SQMKDCFHSA-N 0.000 claims 1
- 229940079593 drugs Drugs 0.000 claims 1
- 230000001747 exhibiting Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 24
- QFJCIRLUMZQUOT-HPLJOQBZSA-N Sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 23
- 239000004480 active ingredient Substances 0.000 description 18
- 229960002930 sirolimus Drugs 0.000 description 17
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- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 7
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- 229960000485 methotrexate Drugs 0.000 description 7
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- 239000007924 injection Substances 0.000 description 4
- 108010045030 monoclonal antibodies Proteins 0.000 description 4
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- 239000003981 vehicle Substances 0.000 description 4
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- 102000003777 Interleukin-1 beta Human genes 0.000 description 3
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- 241001465754 Metazoa Species 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- WOVKYSAHUYNSMH-RRKCRQDMSA-N Bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 2
- 229950004398 Broxuridine Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 108010053490 Infliximab Proteins 0.000 description 2
- 206010023203 Joint destruction Diseases 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N Phenylacetic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 102000003993 Phosphatidylinositol 3-Kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-Kinases Proteins 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 210000002966 Serum Anatomy 0.000 description 2
- 108060008683 Tumor Necrosis Factor Receptors Proteins 0.000 description 2
- 102000003298 Tumor Necrosis Factor Receptors Human genes 0.000 description 2
- YYSFXUWWPNHNAZ-PKJQJFMNSA-N Umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[C@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 description 2
- 230000002917 arthritic Effects 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037240 fusion proteins Human genes 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 230000003834 intracellular Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229960000994 lumiracoxib Drugs 0.000 description 2
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000000651 prodrug Chemical group 0.000 description 2
- 229940002612 prodrugs Drugs 0.000 description 2
- -1 pyridinyl imidazole compound Chemical class 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3E)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 1
- HMLGSIZOMSVISS-ONJSNURVSA-N (7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(2,2-dimethylpropanoyloxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(C=C)CSC21)C(O)=O)=O)C(=O)\C(=N/OCOC(=O)C(C)(C)C)C1=CSC(N)=N1 HMLGSIZOMSVISS-ONJSNURVSA-N 0.000 description 1
- SJSYJHLLBBSLIH-SDNWHVSQSA-N (E)-3-(2-methoxyphenyl)-2-phenylprop-2-enoic acid Chemical compound COC1=CC=CC=C1\C=C(\C(O)=O)C1=CC=CC=C1 SJSYJHLLBBSLIH-SDNWHVSQSA-N 0.000 description 1
- ZMELOYOKMZBMRB-DLBZAZTESA-N 2-[6-chloro-5-[(2R,5S)-4-[(4-fluorophenyl)methyl]-2,5-dimethylpiperazine-1-carbonyl]-1-methylindol-3-yl]-N,N-dimethyl-2-oxoacetamide Chemical compound C([C@@H](C)N(C[C@@H]1C)C(=O)C=2C(=CC=3N(C)C=C(C=3C=2)C(=O)C(=O)N(C)C)Cl)N1CC1=CC=C(F)C=C1 ZMELOYOKMZBMRB-DLBZAZTESA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- FUAPHHUJDLVHAG-UHFFFAOYSA-N 5-bromo-N-(4,6-dimethylpyridin-2-yl)furan-2-carboxamide Chemical compound CC1=CC(C)=NC(NC(=O)C=2OC(Br)=CC=2)=C1 FUAPHHUJDLVHAG-UHFFFAOYSA-N 0.000 description 1
- 108010007562 Adalimumab Proteins 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
- 206010002556 Ankylosing spondylitis Diseases 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 241000287523 Ara Species 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
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- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000020504 Collagenase family Human genes 0.000 description 1
- 108060005980 Collagenase family Proteins 0.000 description 1
- BUROJSBIWGDYCN-GAUTUEMISA-N Deforolimus Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 1
- 210000003743 Erythrocytes Anatomy 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N Etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 102100014139 FKBP1A Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229960002743 Glutamine Drugs 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229940048921 Humira Drugs 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- BYPIURIATSUHDW-UHFFFAOYSA-N Ibuproxam Chemical compound CC(C)CC1=CC=C(C(C)C(=O)NO)C=C1 BYPIURIATSUHDW-UHFFFAOYSA-N 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
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- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
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- 102100000918 MAPK14 Human genes 0.000 description 1
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- XXRSWDBWKFKQEB-UHFFFAOYSA-N N-(4,6-dimethylpyridin-2-yl)furan-2-carboxamide Chemical compound CC1=CC(C)=NC(NC(=O)C=2OC=CC=2)=C1 XXRSWDBWKFKQEB-UHFFFAOYSA-N 0.000 description 1
- 229920000272 Oligonucleotide Polymers 0.000 description 1
- 108091000081 Phosphotransferases Proteins 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 102000017975 Protein C Human genes 0.000 description 1
- 229960000856 Protein C Drugs 0.000 description 1
- 102000001253 Protein Kinases Human genes 0.000 description 1
- 206010037162 Psoriatic arthropathy Diseases 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N Rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 229960005322 Streptomycin Drugs 0.000 description 1
- 229960001940 Sulfasalazine Drugs 0.000 description 1
- 210000001258 Synovial Membrane Anatomy 0.000 description 1
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 1
- CGTADGCBEXYWNE-BJFMSCRISA-N Zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](C(C)=CC=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-BJFMSCRISA-N 0.000 description 1
- 229950009819 Zotarolimus Drugs 0.000 description 1
- HEMCLPYZHCWCMG-UHFFFAOYSA-N [NH-]C1=CC=CC=N1 Chemical compound [NH-]C1=CC=CC=N1 HEMCLPYZHCWCMG-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229960004238 anakinra Drugs 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000003502 anti-nociceptive Effects 0.000 description 1
- 230000001754 anti-pyretic Effects 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 102000024070 binding proteins Human genes 0.000 description 1
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- 229960002424 collagenase Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
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- 239000002988 disease modifying antirheumatic drug Substances 0.000 description 1
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- 239000003937 drug carrier Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 230000002905 effect on arthritis Effects 0.000 description 1
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- 150000004677 hydrates Chemical class 0.000 description 1
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 1
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- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
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- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 201000001263 psoriatic arthritis Diseases 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2(1H)-one Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000000552 rheumatic Effects 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
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- 230000020341 sensory perception of pain Effects 0.000 description 1
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- 230000001225 therapeutic Effects 0.000 description 1
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- 239000012588 trypsin Substances 0.000 description 1
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
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Abstract
Pharmaceutical combinations comprising at least one mTOR inhibitor and their uses in treating arthritis or rheumatic arthritis and disorders associated therewith.
Description
PHARMACEUTICAL COMBINATIONS
The present invention relates to pharmaceutical combinations comprising at least one mTOR inhibitory agent, for example rapamycin or a rapamycin derivative, and to its uses in the treatment of arthritis or rheumatic arthritis and disorders associated therewith. Rheumatoid arthritis (RA) affects between 1 and 2 percent of the population, and is a progressive disease that has the potential to cause joint destruction and functional disability. It is characterized by hyperproliferation of the synovial membrane, with the subsequent formation of fibrous pannus, which invades and erodes cartilage and bone. In accordance with the foregoing, there is a need for agents that are effective in the treatment of arthritis or rheumatic arthritis, for example including reduction, alleviation, stabilization, or release of symptoms or disease affecting the organism, in particular to joints or vertebrae, including also slowing down the progress (destruction of the joints) in moderate to severe rheumatoid arthritis; and progressive or erosive rheumatoid arthritis that has an inadequate response to treatment with disease-modifying antirheumatic drugs. An additional need is the reduction of side effects. It has now been found that a combination comprising at least one mTOR inhibiting agent and a co-agent, for example as defined below, has a beneficial effect on arthritis or on rheumatic arthritis and the disorders associated therewith, for example reduction of the signs and symptoms of arthritis or rheumatic arthritis. According to the particular findings of the present invention, there is provided: 1. A pharmaceutical combination comprising: a) an mTOR inhibitor, and b) at least one co-agent demonstrating clinical activity against arthritis or rheumatic arthritis. , for example RA. 2.1 A method for the treatment of arthritis, rheumatic arthritis, or disorders associated therewith, in a subject in need thereof, which comprises co-administration to this subject, for example in a concomitant or sequential manner, of a therapeutically effective amount of an mTOR inhibitor, for example rapamycin or a derivative thereof, for example as defined hereinafter, and at least one co-agent, for example as indicated hereinafter.
Examples of arthritis and rheumatoid arthritis are, for example, RA, chronic progredient arthritis, arthritis deformans, psoriatic arthritis, polyarthritis, ankylosing spondylitis, polychondritis, or osteoarthritis. The disorders associated with these diseases include, for example, pain, pyresis, proliferation of macrophages or synovial fibroblasts, or volume formation of invasive fibrous pannus. 2.2 A method for slowing the progress, for example, joint destruction, in a subject having moderate to severe rheumatoid arthritis, which comprises co-administration to this subject, for example concomitantly or in sequence, of a therapeutically effective amount of an mTOR inhibitor, for example rapamycin or a derivative thereof, for example as hereinafter defined, and at least one co-agent, for example as indicated hereinafter. Accordingly, the present invention also provides: 2.3 A method for reducing or inhibiting the proliferation of macrophages or synovial fibroblasts in a subject in need, which comprises administering to this subject a therapeutically effective amount of an inhibitor of mTOR, for example rapamycin or a derivative thereof, for example as hereinafter defined, optionally in combination, for example, concomitantly or in sequence, with a therapeutically effective amount of at least one co-agent, for example as indicated hereinafter. 2.4 A method for reducing or inhibiting volume formation of invasive fibrous pannus in a subject in need, which comprises administering to this subject a therapeutically effective amount of an mTOR inhibitor, for example rapamycin or a derivative thereof , for example as hereinafter defined, optionally in combination, for example concomitantly or in sequence, with a therapeutically effective amount of at least one co-agent, for example as indicated hereinafter. 2.5 A method for preventing, alleviating, or treating pain, for example associated with arthritis or with rheumatic arthritic diseases, in a subject in need thereof, which comprises administering to this subject a therapeutically effective amount of an mTOR inhibitor, for example rapamycin or a derivative thereof, for example as hereinafter defined, optionally in combination, for example, concomitantly or in sequence, with a therapeutically effective amount of at least one co-agent, for example as indicated below in the present. 2.6 A method for preventing, alleviating, or treating piresis, for example associated with arthritis or rheumatic arthritis diseases, in a subject in need thereof, which comprises administering to this subject a therapeutically effective amount of an mTOR inhibitor, for example rapamycin or a derivative thereof, for example as hereinafter defined, optionally in combination, for example, concomitantly or in sequence, with a therapeutically effective amount of at least one co-agent, for example as indicated below in the present. 3. A pharmaceutical combination as disclosed herein, for use in any of methods 2.1 to 2.6. 4.1 A pharmaceutical composition for use in any of the methods 2.1 to 2.6, which comprises an mTOR inhibitor, for example rapamycin or a derivative thereof, for example as hereinafter defined, together with one or more diluents or pharmaceutically acceptable vehicles for the same. 4.2 An mTOR inhibitor, for example rapamycin or a derivative thereof, for example as defined hereinafter, for example a compound of Formula I, for use in any of the methods 2.1 to 2.6. 4.3 An mTOR inhibitor, for example rapamycin or a derivative thereof, for example as defined hereinafter, for example a compound of Formula I, for use in the preparation of a medicament for use in any of the methods 2.1 to 2.6. The term "pharmaceutical combination", as used herein, means a product resulting from the mixture or combination of more than one active ingredient, and includes both the fixed and non-fixed combinations of the active ingredients. The terms "co-administration" or "combined administration", or the like, as used herein, are intended to encompass the administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens wherein the agents are not necessarily administered by the same route of administration or at the same time. The term "fixed combination", as this term is used herein, means that the active ingredients, for example the mTOR inhibitor and a co-agent, are both administered to a patient in a simultaneous manner in the form of a single entity or dosage. The term "non-fixed combination", as this term is used herein, means that the active ingredients, for example the mTOR inhibitor and a co-agent, are both administered to a patient as separate entities, either in a manner simultaneous, concurrent, or sequential, without specific time limits, where this administration provides therapeutically effective levels of the two compounds in the body, preferably at the same time. As an example, a non-fixed combination would be 2 capsules, each containing an active ingredient, wherein the purpose is to make the patient achieve the treatment with both active ingredients together in the body. An mTOR inhibitor is a compound that directs intracellular mTOR ("mammalian target of rapamycin"). mTOR is a member of the kinase family related to the phosphatidyl-inositol 3-kinase (PI-3 kinase). Rapamycin and rapamycin derivatives inhibit the mTOR pathway by means of a complex with its intracellular receptor FKBP12 (binding protein 12 of FK506). Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopic? S. Derivative of rapamycin means a substituted rapamycin which has mTOR inhibitory properties, for example rapamycin substituted at position 40 and / or 16 and / or 32, for example a compound of the Formula
wherein: Ri is CH 3 or alkynyl and 3 to 6 carbon atoms, R 2 is H, -CH 2 -CH 2 -OH, 3-hydroxy-2- (hydroxy-methyl) -2-propanoyl or tetrazolyl, and X is = 0 , (H, H), or (H, OH), with the understanding that R2 is different from H when X is = 0 and R1 is CH3, or a prodrug thereof, where R2 is -CH2-CH2-OH , for example a physiologically hydrolysable ether thereof, for example -CH2-CH2-0-alkyl of 1 to 8 carbon atoms. Representative rapamycin derivatives of Formula I are, for example, 32-deoxo-rapamycin, 16-pent-inyloxy-32-deoxo-rapamycin, 16-pent-2-ynyloxy-32 (S or R) -dihydro-rapamycin. , 1 -pent-2-ynyloxy-32 (S, or R) -dihydro-40-O- (2-hydroxy-ethyl) -rapamycin, 40- [3-hydroxy-2- (hydroxy-methyl) -2- methyl-propanoatoj-rapam icine (also called CCI779) or 40-epi- (tetrazolyl) -rapamycin (also called ABT578). A preferred compound is, for example, the 40-0- (2-hydroxyethyl) -rapamycin disclosed in Example 8 of International Publication Number WO 94/09010 (hereinafter referred to as Compound A) , or 32-deoxo-rapamycin or 16-pent-2-ynyloxy-32 (S) -dihydro-rapamycin, as disclosed in International Publication Number WO 96/41807. The rapamycin derivatives may also include so-called rapporteurs, for example as disclosed in International Publications Nos. WO 98/02441, WO01 / 14387 and WO 03/64383, for example AP23573, AP23464, AP23675, or AP23841. Other examples of a rapamycin derivative are those disclosed under the name TAFA-93, biolimus 7, or biolimus 9. The co-agent b) to be used according to the invention can be selected from the following groups of compounds: i) an anti-metabolite, for example methotrexate; i) a TNF inhibitor; for example a biological molecule, for example produced by recombinant DNA technology, for example an antibody against TNF-α, for example a human monoclonal antibody, such as adalimumab (Humira ™), a chimeric monoclonal antibody (mouse and human) such as infliximab (RemicadeMR), a fusion protein comprising a ligand binding portion of the TNF receptor, for example Etanercept (EnbrelMR), which is a dimeric fusion protein of the ligand binding region of the 75 kD TNF receptor (p75) linked to the Fe portion of human IgG 1, an anti-sense oligonucleotide, for example ISIS 104838; or a low molecular weight compound, for example a pyridinyl amide, for example JM34 [N- (4,6-dimethyl-pyridin-2-yl) -furan-2-carboxamide] or JM42 [N- (4, 6-dimethyl-pyridin-2-yl) -5-bromo-furan-2-carboxamide]; iii) an interleukin antagonist, for example an inhibitor of IL-1R, for example anakinra (Kineret ™), an inhibitor of IL-6R, for example an anti-IL-6R monoclonal antibody, for example a humanized monoclonal antibody, such as atlizumab (Chugai IVIRÁ); iv) a p38 MAP kinase inhibitor, for example a pyridinyl imidazole compound, for example SB 203580; a quinolin-2-one or isoxazolo- [3,4-c] -quinolin-2-one, for example ICX 56238890 or ICX 56319223 (3- [3- (4-chloro-f-enyl) -3-naphthalene-2 -ylamino) -propanoyl] -4-hydroxy-1-methyl-quinolin-2 (1H) -one); SCIO-323, SCIO-469; VX-702; v) a cyclooxygenase inhibitor, for example celecoxib (CelebrexMR), rofecoxib (VioxxMR), etoricoxib, valdecoxib, or a 5-alkyl-2-aryl-amine and non-phenyl-acetic acid, for example lumiracoxib (Prexige ™); vi) a sulfonamide compound useful in rheumatoid arthritis, for example sulfasalazine (5- (lp- (2-pyridyl-sulfamoyl) -phenylazo) -salicylic acid); vii) a compound against malaria, for example hydroxy-chloroquinine, or chloroquinine; v i i) an analgesic, for example salicylic acid or a derivative thereof, for example acetylsalicylic acid, or a benzene-acetic acid derivative, for example ibufenac, ibuprofen, or ibuproxam. In each case, when citing patent applications or scientific publications, the subject matter relating to the compounds is incorporated by the same to the present application by reference. In the same way, the pharmaceutically acceptable salts thereof are included, the corresponding racemates, diastereoisomers, enantiomers, tautomers, as well as the corresponding crystal modifications of the above-disclosed compounds, when present, for example solvates, hydrates, and polymorphs, which are disclosed therein. The compounds used as active ingredients in the combinations of the invention can be prepared and administered as described in the cited documents, respectively. It is also within the scope of this invention, the combination of more than two separate active ingredients as stipulated above, that is, a pharmaceutical combination within the scope of this invention could include three or more active ingredients. In addition, both the first agent and the coagent are not identical ingredients. The utility of mTOR inhibitors and their combinations in the treatment of arthritis or rheumatic arthritis diseases, as specified hereinabove, can be demonstrated in animal testing methods, as well as in the clinic, for example in accordance with the methods described later in the present. A.1 Effect on the spontaneous proliferation of human rheumatoid synovial fibroblasts. Synovial cells obtained by digestion with collagenase from the synovial tissue of patients with rheumatoid arthritis are dissociated with trypsin / EDTA, and are cultured in gelatin-coated Petri dishes, as suspension cultures in RP I 1640 medium supplemented with fetal serum from 10 percent calf, 2 mM L-glutamine, 50 units / milliliter of penicillin-50 milligrams / milliliter of streptomycin (all from Gibco), and 10 mM HEPES. The synovial cells are used in passages 2 to 8 for the experiments. An evaluation of cell growth is made using either direct detection of DNA synthesis in the cells, as determined by the incorporation of bromo-deoxy-uridine, using a test kit obtained in Amersham, or by direct counting the viable cells at the end of the incubation period. The cells are initially seeded at 2x105 cells per well. The statistical analysis is by Student's test. The mTOR inhibitor, for example a compound of Formula I, for example Compound A, significantly suppresses the growth of synovial cells by both criteria. In the case of the bromo-deoxy-uridine method, the maximum effects are observed in concentrations of 10 pM. The direct count of the cells shows the maximum effects when the concentration reaches 10 nM. Studies with rapamycin show that, when the growth of synovial cells is evaluated by measuring the total intracellular ATP levels, the suppression is maximal at 10 pM. A.2 Antipyretic effects. Fever by LPS. An injection of I ipopol isaccharide (LPS) is subcutaneously placed in a dose of 100 micrograms / kilogram in 5 milliliters / kilogram, and 2 hours later, the temperature is measured using a rectal thermocouple. The rats are then placed in paired treatment groups according to their temperature responses. In the time +4 hours, the mTOR inhibitor is administered orally, and the final temperatures are measured again in the time of +6 hours. The increase in temperature for each animal is calculated, and the percentage of inhibition is determined for each treatment group, compared to the vehicle control group. Fever for IL-1. The temperature of the baseline is measured, and the rats are placed in paired groups. The animals are dosed with the mTOR inhibitor (0.5, 2, or 4 milligrams / kilogram) orally, and 30 minutes later, they are given an injection of 100 nanograms of IL-1β intravenously. In the time of +4 hours, the final temperatures are measured, and the inhibition percentage is calculated as for the LPS fever. In these trials, the mTOR inhibitor inhibits fever induced by LPS and IL-1β. Compound A shows a dose-related inhibition of both LPS-induced fever and IL-1ß-induced fever in rats with ED50s of 1.9 (1.21-2.41) 95o / o and <0.54 milligrams / kilogram orally, respectively. A.3 Anti-nociceptive activity in a model of inflammatory pain. Hyperalgesia is induced by intra-plantar yeast injection, and nociception is measured by increasing pressure applied to the paw, until the animal vocalizes or removes its paw from the pressure pad. The baseline pressure required to induce vocalization or removal of the paw of male OFA rats is measured (-2 hours), followed by an intra-plantar injection of 100 microliters of a 20 percent yeast suspension in water in the hind leg. The rats are treated orally with rapamycin or a derivative thereof (0.5, 2, or 4 milligrams / kilogram), or with vehicle (serum) orally, 2 hours later (0 hours), and pressure test 1 is repeated and 2 hours after dosing. The pressure required to induce vocalization or removal of the paw of the rats treated with the compound at these points of time is compared with that of the animals treated with vehicle. In these trials, the mTOR inhibitor inhibits foot hyperalgesia. Compound A significantly inhibits hyperalgesia of the paw after 1 hour with the dose of 2 milligrams / kilogram, and both at 1 and 2 hours, with the oral dose of 4 milligrams / kilogram. B. Clinical study. Suitable clinical studies are, for example, open-label studies without random selection, dose scale, in patients with rheumatoid arthritis. These studies can prove, for example, the synergism of the active ingredients of the combination of the invention. The beneficial effects on arthritic diseases can be determined directly through the results of these studies, or through changes in the design of the study, which are known to a person skilled in the art. These studies, in particular, are suitable for comparing the effects of a monotherapy using the active ingredients, and a combination of the invention. Preferably, the dose of the mTOR inhibitor (a) is scaled until the Maximum Tolerated Dosage is reached, * and the co-agent (b) is administered at a fixed dose. Alternatively, the agent (a) is administered in a fixed dose, and the dose of the co-agent (b) is scaled. Each patient receives the doses of the mTOR inhibitor (a) either daily or intermittently. The effectiveness of the treatment can be determined in these studies, for example, after 12, 18, or 24 weeks, by evaluating the hypersensitive joint count and the swollen joint count. Alternatively, a double-blind, placebo-controlled study may be employed in order to prove the benefits of the combination of the invention, mentioned herein. One hundred and twenty patients who are partial responders to methotrexate are randomized into two groups, to receive the mTOR inhibitor (a) or the placebo once a day for 12 weeks, while continuing their treatment with methotrexate in the background. There is an Initial Selection appointment (days -21 to -7) before the baseline. The condition of the disease is evaluated in the Selection and Baseline appointments. During the 12-week treatment period, patients will be seen in Weeks 1, 2, 4, 8, and 12, and in the follow-up period in Weeks 14, 16, 20, and 24. The criteria to include to patients in the study: they must have a diagnosis of rheumatoid arthritis, as defined by the ARA criteria reviewed in 1988, with a duration of the disease of not less than 6 months. All patients must have active rheumatoid arthritis, as defined by the following parameters: at least 6 swollen joints and 9 hypersensitive joints, based on the count of 58/60 joints upon entering the study, one of the following: sedimentation rate of erythrocytes (ESR) >; 28 millimeters / hour, reactive protein-C (CRP) > 1.5 milligrams / deciliter, or morning stiffness > 45 minutes. Patients must have received methotrexate for at least 16 weeks, and must be at a dose (> 7.5 milligrams / week) and route of administration stable for at least 8 weeks before Day 1. They continue to receive the same daily dose of methotrexate during the course of the treatment of 12 weeks. The measurement of the primary efficacy result is the obtaining of the ACR20 criterion for the improvement of rheumatoid arthritis, and the proportion of patients in each group that satisfy the ACR20 criteria is determined. The ACR20 criteria define the clinical response as a 20 percent improvement in both the hypersensitive joint count, the swollen joint count, in addition to the 20 percent improvement in at least three of five variables (degree of disability HAQ, global patient assessment, overall physician assessment, pain, and CRP / ESR levels). The mTOR inhibitor, for example Compound A, administered, for example in a dose of 6 milligrams / day, in combination with methotrexate, conducts a response in accordance with higher ACR20, compared to the placebo group. For example, the results obtained with Compound A are as follows:
The administration of a pharmaceutical combination of the invention results in a beneficial effect, for example a synergistic therapeutic effect, for example with respect to alleviating, delaying the progress of, or inhibiting symptoms, and / or for effects such as, for example, a better quality of life or a diminished pathology, comparing with a monotherapy applying only one of the pharmaceutically active ingredients used in the combination of the invention. An additional benefit is that lower doses of the active ingredients of the combination of the invention can be used, for example, that the dosages not only need to be often smaller, but also that they are applied less frequently, which can decrease the incidence or severity of side effects. This is in accordance with the wishes and requirements of the patients to be treated. It is an object of this invention to provide a pharmaceutical composition comprising an amount, which is jointly therapeutically effective against arthritis, rheumatic arthritis, or disorders associated therewith, which comprises a combination of the invention. In this composition, the mTOR inhibitor (a) and the co-agent (b) can be administered together, one after the other, or separately, in a combined unit dosage form, or in two separate unit dosage forms. The unit dosage form can also be a fixed combination. The pharmaceutical compositions for the separate administration of the mTOR inhibitor (a) and the coagent (b), or for administration in a fixed combination, ie, a single galenic composition comprising at least two combination components (a) and ( b), according to the invention, can be prepared in a manner known per se, and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including humans, comprising a therapeutically effective amount of at least one pharmacologically active combination component alone, for example as indicated above, or in combination with one or more pharmaceutically acceptable carriers or diluents, especially suitable for enteral or parenteral application. Suitable pharmaceutical compositions contain, for example, from about 0.1 percent to about 99.9 percent, preferably from about 1 percent to about 60 percent of the active ingredients. Pharmaceutical preparations for combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as tablets, capsules, or suppositories, or ampoules. If not stated otherwise, they are prepared in a manner known per se, for example by means of conventional mixing, granulating, dissolving, or lyophilizing processes. It will be appreciated that the unit content of a combination component contained in a single dose of each dosage form need not constitute an effective amount by itself, because the effective amount needed can be achieved by administering a plurality of units. of dosage. For example, the method of progress delay or treatment of arthritis, rheumatic arthritis, or disorders associated therewith, according to the invention, may comprise: (i) administration of the mTOR inhibitor (a) in a free form or of pharmaceutically acceptable salt, and (i) the administration of a co-agent (b) in free or pharmaceutically acceptable salt form, in a simultaneous or sequential manner in any order, in mutually therapeutically effective amounts, preferably in amounts synergistically effective, for example in daily or intermittent dosages, for example corresponding to the amounts described herein. The individual combination components of the combination of the invention can be administered separately at different times during the course of therapy, or in a concurrent manner in divided or individual combination forms. Additionally, the term "administer" also encompasses the use of a prodrug of a combination component that becomes in vivo in the combination component as such. Accordingly, it should be understood that the present invention encompasses all of these simultaneous or alternate treatment regimens, and the term "administer" should be construed accordingly. The effective dosage of each of the combination components used in the combination of the invention may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition that is being treated. A physician, clinician, or veterinarian of ordinary experience can easily determine and prescribe the effective amount of the individual active ingredients required to alleviate, counteract, or halt the progress of the condition. The optimal precision to achieve the concentration of the active ingredients within the range that produces efficacy without toxicity, requires a regimen based on the kinetics of the availability of the active ingredients for the target sites, particularly when the coagent (b) is a small molecule. The daily dosages for the mTOR inhibitor (a), of course, will vary depending on a variety of factors, for example the selected compound, the particular condition to be treated, and the desired effect. However, in general, satisfactory results are obtained with the administration of the agent (a) in daily dosage rates of the order of about 0.01 to 5 milligrams / kilogram per day, in particular 0.5 to 5 milligrams / kilogram per day, as a single dose or in divided doses. A preferred daily dosage range is from about 0.1 to 30 milligrams as a single dose or in divided doses. The mTOR inhibitor (a), for example, Compound A, can be administered by any conventional route, in particular enterally, for example orally, for example in the form of tablets, capsules, solutions for drinking, or parenterally, for example in the form of injectable solutions or suspensions. Suitable unit dosage forms for oral administration comprise from about 0.05 to 15 milligrams of active ingredient, usually from 0.25 to 10 milligrams, for example from Compound A, together with one or more pharmaceutically acceptable diluents or carriers therefor. The co-agent (b) can be administered in a dosage range known in the art, for example in the lowest known dosage ranges. Methotrexate can be administered to a human in the following dosing intervals: 0.1 milligrams / kilogram daily every 2 or 3 days, orally. Infliximab can be administered to a human in the following dosage ranges: 3 milligrams / kilogram intravenously in an intermittent manner, for example in weeks 1, 2, and 6, and then every 8th week. Etanercept can be administered to a human in the following dosing intervals: 2 x 25 milligrams / week. Celecoxib can be administered to a human in the following dosing intervals: 200 to 400 milligrams / day orally. Rapamycin or derivatives thereof are well tolerated in the dosages required to be used in accordance with the present invention. For example, the NTEL for Compound A in a toxicity study of 4 weeks is 0.5 milligrams / kilogram / day in rats, and 1.5 milligrams / kilogram / day in monkeys.
Claims (10)
1. A pharmaceutical combination, which comprises: a) an mTOR inhibitor, and b) at least one co-agent that shows clinical activity against arthritis or against rheumatoid arthritis.
2. The use of an mTOR inhibitor in the preparation of a medicament for the treatment of arthritis, rheumatic arthritis, or disorders associated therewith, to be used in combination with at least one co-agent that shows clinical activity against arthritis or rheumatic arthritis.
3. The use according to claim 2, wherein the medicament is used to slow down the progress, in a subject having moderate to severe rheumatoid arthritis, and is used in combination with at least one co-agent that shows having clinical activity against arthritis or rheumatic arthritis.
4. The use of an mTOR inhibitor in the preparation of a medicament for reducing or inhibiting the proliferation of macrophages or synovial fibroblasts in a subject, wherein the medicament is optionally used in combination with a therapeutically effective amount of at least one drug. -an agent that shows clinical activity against arthritis or rheumatic arthritis.
5. The use according to claim 4, wherein the medicament is used to reduce or inhibit the volume formation of invasive fibrous pannus in a subject.
6. The use of an mTOR inhibitor in the preparation of a medicament for preventing, alleviating, or treating pain, wherein the medicament is optionally used in combination with a therapeutically effective amount of at least one co-agent exhibiting clinical activity against arthritis or rheumatic arthritis.
7. The use of an mTOR inhibitor in the preparation of a medicament for preventing, alleviating, or treating piresis, wherein the medicament is optionally used in combination with a therapeutically effective amount of at least one co-agent that shows clinical activity against arthritis or rheumatic arthritis.
8. A pharmaceutical composition for reducing or inhibiting the proliferation of macrophages or synovial fibroblasts, for preventing, alleviating, or treating pain, or for preventing, alleviating, or treating piresis, which comprises an mTOR inhibitor, together with one or more diluents or pharmaceutically acceptable vehicles therefor.
9. A method for the treatment of arthritis, rheumatic arthritis, or disorders associated therewith, in a subject in need thereof, which comprises co-administering to this subject a therapeutically effective amount of an mTOR inhibitor, and at least one co-agent that shows clinical activity against arthritis or rheumatic arthritis.
10. The use, composition, or method according to any of the preceding claims, wherein the mTOR inhibitor is 40-O- (2-hydroxy-ethyl) -rapamycin.
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GB0327840.5 | 2003-12-01 |
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