JP6261512B2 - 心機能障害を治療及び/又は低減するためのビスホスホネート組成物並びに方法 - Google Patents
心機能障害を治療及び/又は低減するためのビスホスホネート組成物並びに方法 Download PDFInfo
- Publication number
- JP6261512B2 JP6261512B2 JP2014542390A JP2014542390A JP6261512B2 JP 6261512 B2 JP6261512 B2 JP 6261512B2 JP 2014542390 A JP2014542390 A JP 2014542390A JP 2014542390 A JP2014542390 A JP 2014542390A JP 6261512 B2 JP6261512 B2 JP 6261512B2
- Authority
- JP
- Japan
- Prior art keywords
- bisphosphonate
- heart
- cardiac
- pharmaceutical composition
- tissue
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229940122361 Bisphosphonate Drugs 0.000 title claims description 75
- 150000004663 bisphosphonates Chemical class 0.000 title claims description 40
- 238000000034 method Methods 0.000 title description 22
- 230000000747 cardiac effect Effects 0.000 title description 17
- 239000000203 mixture Substances 0.000 title description 16
- 230000004064 dysfunction Effects 0.000 title description 5
- -1 antihypertensive Substances 0.000 claims description 44
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims description 30
- 229960004276 zoledronic acid Drugs 0.000 claims description 25
- 206010019280 Heart failures Diseases 0.000 claims description 23
- 230000001965 increasing effect Effects 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 20
- 230000026731 phosphorylation Effects 0.000 claims description 20
- 238000006366 phosphorylation reaction Methods 0.000 claims description 20
- 230000000694 effects Effects 0.000 claims description 19
- 210000005003 heart tissue Anatomy 0.000 claims description 16
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 229930003316 Vitamin D Natural products 0.000 claims description 12
- 235000019166 vitamin D Nutrition 0.000 claims description 12
- 239000011710 vitamin D Substances 0.000 claims description 12
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 12
- 229940046008 vitamin d Drugs 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 7
- 210000004351 coronary vessel Anatomy 0.000 claims description 7
- 208000031225 myocardial ischemia Diseases 0.000 claims description 7
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 230000002861 ventricular Effects 0.000 claims description 5
- 102000019149 MAP kinase activity proteins Human genes 0.000 claims description 4
- 108040008097 MAP kinase activity proteins Proteins 0.000 claims description 4
- 102000001253 Protein Kinase Human genes 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 230000004071 biological effect Effects 0.000 claims description 4
- 108060006633 protein kinase Proteins 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 239000005541 ACE inhibitor Substances 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000009525 Myocarditis Diseases 0.000 claims description 3
- 206010071436 Systolic dysfunction Diseases 0.000 claims description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 3
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 claims description 3
- 208000019553 vascular disease Diseases 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 229940123413 Angiotensin II antagonist Drugs 0.000 claims description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 2
- 239000005557 antagonist Substances 0.000 claims description 2
- 239000003529 anticholesteremic agent Substances 0.000 claims description 2
- 229940127226 anticholesterol agent Drugs 0.000 claims description 2
- 239000002876 beta blocker Substances 0.000 claims description 2
- 231100000457 cardiotoxic Toxicity 0.000 claims description 2
- 230000001451 cardiotoxic effect Effects 0.000 claims description 2
- 239000002934 diuretic Substances 0.000 claims description 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- 230000003442 weekly effect Effects 0.000 claims description 2
- 208000007848 Alcoholism Diseases 0.000 claims 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims 1
- 206010052337 Diastolic dysfunction Diseases 0.000 claims 1
- 229940097420 Diuretic Drugs 0.000 claims 1
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 208000024799 Thyroid disease Diseases 0.000 claims 1
- 208000036142 Viral infection Diseases 0.000 claims 1
- 230000003276 anti-hypertensive effect Effects 0.000 claims 1
- 239000000480 calcium channel blocker Substances 0.000 claims 1
- 239000002368 cardiac glycoside Substances 0.000 claims 1
- 229940097217 cardiac glycoside Drugs 0.000 claims 1
- 230000001882 diuretic effect Effects 0.000 claims 1
- 206010013663 drug dependence Diseases 0.000 claims 1
- 230000009395 genetic defect Effects 0.000 claims 1
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 claims 1
- 208000008494 pericarditis Diseases 0.000 claims 1
- 238000001959 radiotherapy Methods 0.000 claims 1
- 229930002534 steroid glycoside Natural products 0.000 claims 1
- 208000011117 substance-related disease Diseases 0.000 claims 1
- 208000021510 thyroid gland disease Diseases 0.000 claims 1
- 230000009385 viral infection Effects 0.000 claims 1
- 210000003976 gap junction Anatomy 0.000 description 22
- 210000002216 heart Anatomy 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 18
- 108091000080 Phosphotransferase Proteins 0.000 description 15
- 206010003119 arrhythmia Diseases 0.000 description 15
- 210000004165 myocardium Anatomy 0.000 description 15
- 102000020233 phosphotransferase Human genes 0.000 description 15
- 102000010970 Connexin Human genes 0.000 description 14
- 108050001175 Connexin Proteins 0.000 description 14
- 241001465754 Metazoa Species 0.000 description 14
- 208000031229 Cardiomyopathies Diseases 0.000 description 12
- 210000004413 cardiac myocyte Anatomy 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 11
- 230000006793 arrhythmia Effects 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 9
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 9
- 230000002107 myocardial effect Effects 0.000 description 9
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 108010069241 Connexin 43 Proteins 0.000 description 8
- 102000001045 Connexin 43 Human genes 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 101710125754 Farnesyl pyrophosphate synthase Proteins 0.000 description 7
- 102100035111 Farnesyl pyrophosphate synthase Human genes 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229960002061 ergocalciferol Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 235000001892 vitamin D2 Nutrition 0.000 description 6
- 239000011653 vitamin D2 Substances 0.000 description 6
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 6
- 108091006146 Channels Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 206010017076 Fracture Diseases 0.000 description 5
- 102000043136 MAP kinase family Human genes 0.000 description 5
- 108091054455 MAP kinase family Proteins 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 208000010125 myocardial infarction Diseases 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 4
- 235000021318 Calcifediol Nutrition 0.000 description 4
- 206010061818 Disease progression Diseases 0.000 description 4
- 206010020880 Hypertrophy Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229940062527 alendronate Drugs 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000001447 compensatory effect Effects 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 231100000517 death Toxicity 0.000 description 4
- 230000005750 disease progression Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 208000019622 heart disease Diseases 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 208000037891 myocardial injury Diseases 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000007634 remodeling Methods 0.000 description 4
- 230000010410 reperfusion Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000010392 Bone Fractures Diseases 0.000 description 3
- WRLFSJXJGJBFJQ-WPUCQFJDSA-N Calcifediol monohydrate Chemical compound O.C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C WRLFSJXJGJBFJQ-WPUCQFJDSA-N 0.000 description 3
- 208000020446 Cardiac disease Diseases 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 3
- 108090000862 Ion Channels Proteins 0.000 description 3
- 102000004310 Ion Channels Human genes 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 206010063837 Reperfusion injury Diseases 0.000 description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229960004361 calcifediol Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 210000002808 connective tissue Anatomy 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229940009626 etidronate Drugs 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 229940014259 gelatin Drugs 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000000004 hemodynamic effect Effects 0.000 description 3
- 229940015872 ibandronate Drugs 0.000 description 3
- 238000003119 immunoblot Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000001365 lymphatic vessel Anatomy 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 description 3
- 229950011129 minodronic acid Drugs 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229940089617 risedronate Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 3
- 208000002150 Arrhythmogenic Right Ventricular Dysplasia Diseases 0.000 description 2
- 201000006058 Arrhythmogenic right ventricular cardiomyopathy Diseases 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 2
- 102100022361 CAAX prenyl protease 1 homolog Human genes 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 2
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 2
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010020100 Hip fracture Diseases 0.000 description 2
- 101000824531 Homo sapiens CAAX prenyl protease 1 homolog Proteins 0.000 description 2
- 208000025500 Hutchinson-Gilford progeria syndrome Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010048858 Ischaemic cardiomyopathy Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000010191 Osteitis Deformans Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 208000027067 Paget disease of bone Diseases 0.000 description 2
- 208000031481 Pathologic Constriction Diseases 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000007932 Progeria Diseases 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- 206010038748 Restrictive cardiomyopathy Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 2
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 210000003403 autonomic nervous system Anatomy 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 208000016738 bone Paget disease Diseases 0.000 description 2
- 229960005084 calcitriol Drugs 0.000 description 2
- 235000020964 calcitriol Nutrition 0.000 description 2
- 239000011612 calcitriol Substances 0.000 description 2
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 2
- 229960002286 clodronic acid Drugs 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 238000010217 densitometric analysis Methods 0.000 description 2
- 230000030609 dephosphorylation Effects 0.000 description 2
- 238000006209 dephosphorylation reaction Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000003205 diastolic effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 210000004126 nerve fiber Anatomy 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- 229940046231 pamidronate Drugs 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 230000036262 stenosis Effects 0.000 description 2
- 208000037804 stenosis Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 229940019375 tiludronate Drugs 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 235000005282 vitamin D3 Nutrition 0.000 description 2
- 239000011647 vitamin D3 Substances 0.000 description 2
- 229940021056 vitamin d3 Drugs 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 101710165761 (2E,6E)-farnesyl diphosphate synthase Proteins 0.000 description 1
- JWUBBDSIWDLEOM-XHQRYOPUSA-N (3e)-3-[(2e)-2-[1-(6-hydroxy-6-methylheptan-2-yl)-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol Chemical compound C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2\C1=C\C=C1/CC(O)CCC1=C JWUBBDSIWDLEOM-XHQRYOPUSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 0 *=P(C(C[n]1cncc1)(O)P(O)(O)=O)O Chemical compound *=P(C(C[n]1cncc1)(O)P(O)(O)=O)O 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 102000008122 Casein Kinase I Human genes 0.000 description 1
- 108010049812 Casein Kinase I Proteins 0.000 description 1
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101710156207 Farnesyl diphosphate synthase Proteins 0.000 description 1
- 101710089428 Farnesyl pyrophosphate synthase erg20 Proteins 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 206010053759 Growth retardation Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001023007 Homo sapiens Farnesyl pyrophosphate synthase Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000001284 I-kappa-B kinase Human genes 0.000 description 1
- 108060006678 I-kappa-B kinase Proteins 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
- 206010061216 Infarction Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000010428 Muscle Weakness Diseases 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- OENAEYITXILMMP-UHFFFAOYSA-N O=P(=O)C(P(O)(O)=O)(O)CN1C=CN=C1 Chemical compound O=P(=O)C(P(O)(O)=O)(O)CN1C=CN=C1 OENAEYITXILMMP-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 208000001164 Osteoporotic Fractures Diseases 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 206010063493 Premature ageing Diseases 0.000 description 1
- 208000032038 Premature aging Diseases 0.000 description 1
- 101710150389 Probable farnesyl diphosphate synthase Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000032023 Signs and Symptoms Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000012338 Therapeutic targeting Methods 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 206010047626 Vitamin D Deficiency Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- UGEPSJNLORCRBO-UHFFFAOYSA-N [3-(dimethylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid Chemical compound CN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O UGEPSJNLORCRBO-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical class 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 150000001450 anions Chemical group 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000003126 arrythmogenic effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 210000001736 capillary Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 210000005242 cardiac chamber Anatomy 0.000 description 1
- 230000022900 cardiac muscle contraction Effects 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 230000005800 cardiovascular problem Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 230000008828 contractile function Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000004177 elastic tissue Anatomy 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000008393 encapsulating agent Substances 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 210000001174 endocardium Anatomy 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 201000005219 extrinsic cardiomyopathy Diseases 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009093 first-line therapy Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- GVVPGTZRZFNKDS-JXMROGBWSA-N geranyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O GVVPGTZRZFNKDS-JXMROGBWSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000001 growth retardation Toxicity 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 210000003709 heart valve Anatomy 0.000 description 1
- 208000018578 heart valve disease Diseases 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000006749 inflammatory damage Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003601 intercostal effect Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 201000007170 intrinsic cardiomyopathy Diseases 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 238000012933 kinetic analysis Methods 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000030991 negative regulation of bone resorption Effects 0.000 description 1
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 1
- 229950010733 neridronic acid Drugs 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960000987 paricalcitol Drugs 0.000 description 1
- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 201000003144 pneumothorax Diseases 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-M pravastatin(1-) Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 229940107023 reclast Drugs 0.000 description 1
- 230000036387 respiratory rate Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 208000008203 tachypnea Diseases 0.000 description 1
- 206010043089 tachypnoea Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- JREYOWJEWZVAOR-UHFFFAOYSA-N triazanium;[3-methylbut-3-enoxy(oxido)phosphoryl] phosphate Chemical compound [NH4+].[NH4+].[NH4+].CC(=C)CCOP([O-])(=O)OP([O-])([O-])=O JREYOWJEWZVAOR-UHFFFAOYSA-N 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
Images
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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Addiction (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
[001] 本PCT国際出願及び発明は、2011年11月16日に出願された米国仮出願第61/560,328号の優先権を主張するものであり、その内容はあらゆる目的のため参照により本明細書に組み込まれる。
[002] 発明の分野
[003] 本発明は、少なくとも1つのビスホスホネート化合物を投与することにより、心不全に起因する心機能障害を低減又は阻害することに関し、より詳細には、該ビスホスホネート化合物は、心臓組織において生物学的活性を有する少なくとも1つのキナーゼの発現及び/又はリン酸化を増加させる。
[005] 人口が高齢化するにつれて、心不全(「HF」)の罹患率は、流行の割合まで増大している。HFは、多くの型の心疾患により引き起こされ得る。心不全の一般的な原因としては、下記のものが挙げられる:心臓の筋肉に血液を供給する動脈の狭窄(冠動脈性心疾患)、心臓の正常な機能を妨げるだけの大きさの瘢痕組織を生じる以前の心臓発作(心筋梗塞)、高血圧、過去のリウマチ熱又は出生時に存在する異常に起因する心臓弁膜症、心臓の筋肉自体の原発性疾患(心筋症)、並びに心臓の弁及び/又は筋肉自体の感染(心内膜炎及び/又は心筋炎)。これらの疾患プロセスの各々は、心臓の筋肉の収縮強度を低減することにより、あるいは器質的問題又は拡張期弛緩の減損に起因して、心室の血液で充満する能力を限定することにより、又は心腔を過剰の血液で充満させることにより、心不全をもたらし得る。
[0032] 本明細書で用いられる用語「ビスホスホネート」は、中央の酸素が炭素で置き換えられた内在性ピロリン酸の類似体である、任意の化合物を意味する。用語「ビスホスホネート」は、そのプロドラッグ及びアミノビスホスホネートを包含する。ビスホスホネートとしては、以下の化合物:ゾレドロン酸、リセドロネート、アレンドロネート、シマドロネート、クロドロネート、チルドロネート、ミノドロネート、WO10/33981、WO10/33980及びWO10/33978に記載のビスホスホネート化合物、エチドロネート、オルパドロネート、ネリドロネート、イバンドロネート、ピリドロネート、又はパミドロネート、その機能的類似体、並びにそのプロドラッグが挙げられるがこれらに限定されない。
[0066]
[0068] ヒドロキシアパタイトに対する親和性及びFFPP酵素阻害を決定するための異なるビスホスホネートの試験
[0070] ヒドロキシアパタイトに対するミネラル親和性を、異なるビスホスホネート化合物のクロマトグラフィープロファイリングにより評価した。ヒドロキシアパタイト(HAP)セラミック球(直径20mm、BioRad)を、0.66×6.5cmガラスカラム(Omnifit(登録商標))に詰めた。HAPカラムを、pH6.8の1mM KPO3のランニングバッファーによるWaters 650E Advanced Protein Purification System(FPLC)(Millipore)に取り付けた。各化合物を、pH6.8の1mM KPO3バッファー中で調製し、400μモルを、FPLCシステムに注入した。ビスホスホネート化合物を、1mMから1000mMまで濃度が上昇するリン酸バッファーの勾配で溶出させ、Waters 484 UV吸光度検出器(Millipore)により、その最適波長にて検出した。表1に記載した結果は、各化合物のHAP保持プロファイル、及び一部の化合物がより長い保持時間を有することを示す。明らかに、ゾレドロニック(zoledronic)及びアレンドロネートが最長の保持時間を有し、それにより、最大のヒドロキシアパタイトに対する親和性を有する。
[0072] 窒素含有ビスホスホネート化合物の主な分子標的である、ヒトファルネシルピロリン酸シンターゼ(FPPS)のin vitroでの阻害について、化合物を評価した。FPPSの阻害は、in vivoにおける骨吸収の阻害と相関する。したがって、FPPS阻害は、ビスホスホネート化合物の効力の指標である。組換えヒトFPPSを、Dunfordら、J.Med.Chem.、51:2187頁〜2195頁(2008)に記載の通りに発現させ、精製した。動態分析については、純粋FPPシンターゼ40ng(1pmol)を、5OmM Tris pH7.7、2mM MgCl2、0.5mM TCEP、及び20μg/mL BSAを含有するバッファーの最終体積100μl中でアッセイした。標準反応物において、基質、GPP及びIPP(14C-IPP、400KBq/μmol)の濃度は、それぞれ10μMであった。反応物は、適切な濃度の適切なビスホスホネート化合物も含有していた。反応は、酵素希釈バッファー(10mM HEPES pH 7.5、500mM NaCl、5%グリセロール、2mM TCEP、20μg/mL BSA)中の2μg/mLの酵素を添加することで開始させ、37℃にて適切な時間にわたり進行させた。次に、反応混合物をリグロイン0.4mLで抽出して、未使用の基質から反応生成物を分離し、徹底的に混合した後、リグロイン上相の0.2mLを汎用シンチラント4mLと合わせた。最終IC50値を計算した。これらのデータは、表1に示されているが、本明細書に記載されたビスホスホネート化合物の酵素阻害活性を実証し、また、ゾレドロネート、Ox−14、及びミノドロネートが、FPPS酵素活性の50%を阻害するのにそれぞれ4.1nM、2.5nM及び1.9nMを要することを示すことで、それらが最も有効な阻害効力(IC50)を呈することを示している。
[0074] 心筋組織におけるERKの発現及び活性化に対するビスホスホネートの作用の測定
[0076] ビスホスホネート化合物
[0077] ゾレドロン酸(Zometa(登録商標)、Reclast(登録商標))骨密度維持剤
IUPAC:(1−ヒドロキシ−2−イミダゾール−1−イル−1−ホスホエチル)ホスホン酸
MF:C5H10N2O7P2/Entrez PCCompound CID:68740
[0080] 1−フルオロ−2−(イミダゾ−[1,2−α]ピリジン−3−イル)−エチル−ビスホスホン酸は、WO10/33978に記載の通り調製し、以下の構造を有する:
[0082] ゾレドロン酸の試験用量は500ug/kgであり、Ox−14の試験用量はゾレドロン酸のモル当量であった。すべての用量は、皮下投与した。各薬物(ゾレドロン酸及びOx-14)の10mMストック溶液を調製し、次に、滅菌生理食塩水で10倍に段階希釈し、最終濃度0.1mMとした。したがって、最終ストック濃度は、ゾレドロン酸については0.0274mcg/マイクロリットルであり、Ox−14については0.0391mcg/マイクロリットルであった。そのため、25gのマウスの場合、ゾレドロン酸12.5mcgを投与して、500mcg/kgの用量を達成した。0.1mMストックのゾレドロン酸456マイクロリットルの注射が、適切な用量であった。同様に、モル当量のOx−14 456マイクロリットルの注射により、17.8mcg(712ug/kg)を送達した。
[0090] 本明細書で引用されるすべての参考文献は、ここであらゆる目的のため参照により本明細書に組み込まれる。
[0091] Colon-Emeric C, Caminis J, Suh TT, Pieper CF, Janning C, Magaziner J, Adachi J, Rosario-Jansen T, Mesenbrink P, Horowitz ZD, Lyles KW The HORIZON Recurent Fracture Trial: Design of a clinical trial in the prevention of subsequestn fractures in elders after low trauma hip fracture repair. Curr Med Opin Res., 2004; 20:903-910.
[0092] Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hylstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S. Zoledronic acid and clinical Fractures and Mortality after Hip Fracture. N Engl J Med., 2007; 357:1799-1809.
[0093] Rockman HA, Ross R, Harris AN, et al., Segregation of atrial-specific and inducible expression of an atrial natriuretic factor transgene in an in vivo murine model of cardiac hypertrophy. PNAS, 1991; 88:8277-8281.
[0094] Rosen, CJ. Postmenopausal Osteoporosis. N Engl J Med, 2005; 353:595-603.
[0095] Varela I, Pereira S, Ugalde AP, Navarro CL, Suarez MF, Cau P, Cadinanos J, Osorio FG, Foray N, Cobo J, de Carlos F, Levy N, Freije JMP, Lopez-Otin C., Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nature Medicine, 2008; 14:767-772.
Claims (5)
- 対象の心臓組織における細胞外シグナル調節プロテインキナーゼ(ERK1/2)の生物学的活性を増加させるための医薬組成物であって、
ビスホスホネート、又は薬学的に許容されるその塩を備え、
前記ビスホスホネート、又は薬学的に許容されるその塩が、ゾレドロン酸、又は1−フルオロ−2−(イミダゾ−[1,2−α]ピリジン−3−イル)−エチル−ビスホスホン酸であって、
前記増加される生物的活性が、心臓組織における(i)ERK1/2の増加される発現、(ii)心臓組織におけるERK1/2の増加されるリン酸化、又は(iii)それらの組み合わせを含み、
前記生物学的活性における増加が、前記ビスホスホネートを投与されなかった心臓組織における活性に対する増加である、
医薬組成物。 - 毎年、半年毎、毎月、毎週、又は毎日投与される、請求項1に記載の医薬組成物。
- 硝酸薬、β−アドレナリン遮断薬、アンジオテンシン変換酵素阻害薬、カルシウムチャネル拮抗薬、降圧剤、コレステロール低下剤、利尿薬、ACE阻害薬、強心配糖体、非ペプチド性アンジオテンシンII拮抗薬、IIb/IIIa拮抗薬、及びアスピリンからなる群から選択される少なくとも一つの他の治療剤をさらに含む、請求項1に記載の医薬組成物。
- 前記心臓組織が、高血圧症、虚血性心疾患、心毒性化合物への曝露、放射線療法、心筋炎、甲状腺疾患、ウイルス感染、薬物中毒、アルコール中毒、心膜炎、アテローム性動脈硬化症、血管疾患、肥大型心筋症、急性心筋梗塞、心室収縮機能障害、心室拡張機能障害、冠動脈バイパス手術、又は遺伝的欠陥に起因する心不全を受けたものである、請求項1に記載の医薬組成物。
- 前記ビスホスホネートが、投薬量のビタミンD投与の前に、それに続いて、又はそれと同時に投与されるためのものである、請求項1に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161560328P | 2011-11-16 | 2011-11-16 | |
US61/560,328 | 2011-11-16 | ||
PCT/US2012/064958 WO2013074587A1 (en) | 2011-11-16 | 2012-11-14 | Bishophonate compositions and methods for treating and/or reducing cardiac dysfunction |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2014533691A JP2014533691A (ja) | 2014-12-15 |
JP6261512B2 true JP6261512B2 (ja) | 2018-01-17 |
Family
ID=48430098
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014542390A Active JP6261512B2 (ja) | 2011-11-16 | 2012-11-14 | 心機能障害を治療及び/又は低減するためのビスホスホネート組成物並びに方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US9949992B2 (ja) |
EP (1) | EP2780021A4 (ja) |
JP (1) | JP6261512B2 (ja) |
CN (1) | CN104010647A (ja) |
CA (1) | CA2856030A1 (ja) |
WO (1) | WO2013074587A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10058630B2 (en) | 2012-10-22 | 2018-08-28 | Concievalve, Llc | Methods for inhibiting stenosis, obstruction, or calcification of a stented heart valve or bioprosthesis |
US20140257473A1 (en) * | 2012-10-22 | 2014-09-11 | Nalini Marie Rajamannan | Methods for inhibiting stenosis, obstruction, or calcification of a stented heart valve or bioprosthesis |
US10939164B2 (en) * | 2016-05-10 | 2021-03-02 | Rovi Guides, Inc. | Method and system for transferring an interactive feature to another device |
US20190321515A1 (en) * | 2016-06-27 | 2019-10-24 | ConcieValve LLC | Improved methods for inhibiting stenosis, obstruction, or calcification of a stented heart valve or bioprosthesis |
CA3111848A1 (en) * | 2018-09-09 | 2020-03-12 | Qanatpharma Ag | Use of casein kinase 1 inhibitors for treating vascular diseases |
US20230149430A1 (en) * | 2020-04-06 | 2023-05-18 | Duke University | Compositions and methods for the treatment of infection-induced cardiomyopathy |
WO2024044642A2 (en) * | 2022-08-23 | 2024-02-29 | The Board Of Regents Of The University Of Texas System | Compositions and methods for treating cardiomyopathies |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2405254C2 (de) | 1974-02-04 | 1982-05-27 | Henkel KGaA, 4000 Düsseldorf | Verwendung von 3-Amino-1-Hydroxypropan-1, 1-diphosphonsäure oder ihrer wasserlöslichen Salze bei der Beeinflußung von Calciumstoffwechselstörungen im menschlichen oder tierischen Körper |
DE3428524A1 (de) | 1984-08-02 | 1986-02-13 | Boehringer Mannheim Gmbh, 6800 Mannheim | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
US4639338A (en) | 1984-08-06 | 1987-01-27 | Ciba-Geigy Corporation | Preparation of crystalline disodium 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate |
DE3770982D1 (de) | 1986-04-24 | 1991-08-01 | Fujisawa Pharmaceutical Co | Diphosphonsaeure-verbindungen, verfahren zu deren herstellung und sie enthaltende arzneimittel. |
DE3623397A1 (de) | 1986-07-11 | 1988-01-14 | Boehringer Mannheim Gmbh | Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel |
ES2038692T4 (es) | 1986-11-21 | 2012-02-10 | Novartis Ag | Procedimiento para la obtencion de acidos alcanodifosfonicos substituidos. |
US5057505A (en) | 1986-11-21 | 1991-10-15 | Ciba-Geigy Corporation | Substituted aminomethanediphosphonic acids and use in medicaments |
GB8808138D0 (en) | 1988-04-07 | 1988-05-11 | Leo Pharm Prod Ltd | Chemical compounds |
EP0544812B1 (en) | 1990-08-21 | 1995-04-05 | The Upjohn Company | Bisphosphonic acid derivatives as anti-arthritic agents |
US5157027A (en) | 1991-05-13 | 1992-10-20 | E. R. Squibb & Sons, Inc. | Bisphosphonate squalene synthetase inhibitors and method |
JPH07502012A (ja) | 1991-05-28 | 1995-03-02 | ザ、プロクター、エンド、ギャンブル、カンパニー | カルシウム、微量ミネラル、ビタミンd及び薬物療法剤組合せ |
AU670337B2 (en) | 1992-11-30 | 1996-07-11 | Novartis Ag | Use of certain methanebisphosphonic acid derivatives in fracture healing |
EP0600834A1 (en) | 1992-11-30 | 1994-06-08 | Ciba-Geigy Ag | Use of methanebisphosphonic acid derivatives for the manufacture of a medicament for fracture healing |
US5403829A (en) | 1993-03-24 | 1995-04-04 | Leiras Oy | Use of bisphosphonates in endo-osteal bone surgery |
FI92465C (fi) | 1993-04-14 | 1994-11-25 | Risto Tapani Lehtinen | Menetelmä endo-osteaalisten materiaalien käsittelemiseksi |
US5646134A (en) | 1994-04-21 | 1997-07-08 | Merck & Co., Inc. | Alendronate therapy to prevent loosening of, or pain associated with, orthopedic implant devices |
GB9408775D0 (en) | 1994-05-04 | 1994-06-22 | Ciba Geigy Ag | Use of certain methanebisphosphonic acid derivatives to prevent prothesis loosening and prothesis migration |
US6117856A (en) | 1996-02-14 | 2000-09-12 | Binderman; Itzhak | Topical bisphosphonates for prevention of bone resorption |
UA53716C2 (uk) * | 1997-06-25 | 2003-02-17 | Пфайзер Продактс Інк. | Тартратна сіль заміщеного дипептиду, спосіб її одержання, проміжні сполуки та спосіб їх одержання, фармацевтична композиція (варіанти), спосіб підвищення рівнів ендогенного гормону росту та спосіб лікування або профілактики захворювань (варіанти) |
DE19738005A1 (de) | 1997-08-30 | 1999-03-04 | Bayer Ag | Verwendung von substituierten 1,1-Bisphosphonaten |
EP1051511A1 (en) | 1998-01-29 | 2000-11-15 | Merck & Co., Inc. | Methods of identifying modulators of kinases responsive to stress |
US6984400B2 (en) | 1998-07-14 | 2006-01-10 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Method of treating restenosis using bisphosphonate nanoparticles |
EP1267888A4 (en) | 2000-01-04 | 2005-12-28 | Univ California | USE OF LOW-DOSEED BISPHOSPHONATES FOR PREVENTING THE CALIBRATION OF HEART AND ARTERIES |
GB0012209D0 (en) | 2000-05-19 | 2000-07-12 | Novartis Ag | Organic compounds |
SK287278B6 (sk) | 2000-06-20 | 2010-05-07 | Novartis Ag | Použitie kyseliny 1-hydroxy-2-(imidazol-1-yl)etán-1,1- difosfónovej na prípravu liečiva na liečenie stavov abnormálne zvýšeného kostného obratu |
CN1355299A (zh) * | 2000-12-01 | 2002-06-26 | 复旦大学 | 一种新的多肽——人尿嘧啶二里酸葡萄糖焦磷酸化酶100.43和编码这种多肽的多核苷酸 |
US20030064965A1 (en) | 2001-10-02 | 2003-04-03 | Jacob Richter | Method of delivering drugs to a tissue using drug-coated medical devices |
CA2480814A1 (en) | 2002-04-05 | 2003-10-23 | Merck & Co., Inc. | Method for inhibiting bone resorption with an alendronate and vitamin d formulation |
WO2003094851A2 (en) | 2002-05-11 | 2003-11-20 | Ilex Products, Inc. | 1,1- and 1,2-bisphosphonates as apoliprotein e modulators |
US20050026871A1 (en) | 2002-07-17 | 2005-02-03 | Moshe Flashner-Barak | Method of increasing bioavailability of alendronate or other bis-phosphonate by predose administration of vitamin D derivative |
US20060275294A1 (en) * | 2002-08-22 | 2006-12-07 | Omoigui Osemwota S | Method of prevention and treatment of aging, age-related disorders and/or age-related manifestations including atherosclerosis, peripheral vascular disease, coronary artery disease, osteoporosis, arthritis, type 2 diabetes, dementia, alzheimers disease and cancer |
PT1542700E (pt) | 2002-09-16 | 2012-02-01 | Novartis Ag | Método para prevenir ou reduzir fracturas secundárias após a fractura da anca |
AU2003268939A1 (en) | 2002-10-15 | 2004-05-04 | Novartis Ag | Bisphosphonates for the treatment of antheroscleorosis and devices comprising them |
US20050112128A1 (en) * | 2003-05-21 | 2005-05-26 | Myogen, Inc. And Board Of Regents, The University Of Texas System | Inhibition of protein kinase c-mu (PKD) as a treatment for cardiac hypertrophy and heart failure |
US20060051407A1 (en) | 2003-06-27 | 2006-03-09 | Yoram Richter | Method of treating ischemia-reperfusion injury |
WO2005002545A1 (en) | 2003-06-27 | 2005-01-13 | Biorest Ltd. | Method of treating acute coronary syndromes |
US10517883B2 (en) | 2003-06-27 | 2019-12-31 | Zuli Holdings Ltd. | Method of treating acute myocardial infarction |
NZ545804A (en) | 2003-09-19 | 2009-09-25 | Wisconsin Alumni Res Found | Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-or-vitamin D derivatives and a bisphosphonate |
EP1796683A1 (en) | 2004-07-15 | 2007-06-20 | Nanobac Life Sciences | Methods and compositions for the administration of calcium chelators, bisphosphonates and/or citrate compounds and their pharmaceutical uses |
US20060069068A1 (en) | 2004-07-15 | 2006-03-30 | Nanobac Pharmaceuticals, Inc. | Methods and compositions for the treatment of diseases characterized by pathological calcification |
DE602006018735D1 (de) * | 2005-06-10 | 2011-01-20 | Univ Madrid Autonoma | Neuer phosphorylierungsstandort für mitogenaktivierte proteinkinasen und modifizierte proteine sowie anwendungen davon |
US20080146489A1 (en) | 2006-12-15 | 2008-06-19 | Pacetti Stephen D | Regional delivery of therapeutic agents for the treatment of vascular diseases |
US20100144679A1 (en) | 2007-03-21 | 2010-06-10 | Duke University | Medication kits and formulations for preventing, treating or reducing secondary fractures after previous fracture |
HUE043897T2 (hu) | 2007-09-25 | 2019-09-30 | Solubest Ltd | Lipofil hatóanyagot tartalmazó készítmények és eljárás elõállításukra |
WO2009082437A2 (en) | 2007-12-21 | 2009-07-02 | Ligand Pharmaceuticals Incorporated | Selective androgen receptor modulators (sarms) and uses thereof |
WO2009148709A1 (en) | 2008-04-16 | 2009-12-10 | University Of Utah Research Foundation | Pharmacological targeting of vascular malformations |
JP5823862B2 (ja) * | 2008-09-22 | 2015-11-25 | アイシス イノベイション リミテッド | イミダゾ[1,2‐α]ピリジニルビスホスホネート |
CN102257392A (zh) * | 2008-10-31 | 2011-11-23 | 杜克大学 | 预防心力衰竭的方法 |
JP2012518686A (ja) * | 2009-02-25 | 2012-08-16 | メリオン・リサーチ・Iii・リミテッド | ビスホスホネート類の組成物および薬物送達 |
HUE025737T2 (en) * | 2009-09-01 | 2016-05-30 | Univ Duke | Bisphosphonate compositions and methods for treating heart failure |
-
2012
- 2012-11-14 CA CA2856030A patent/CA2856030A1/en not_active Abandoned
- 2012-11-14 CN CN201280063024.0A patent/CN104010647A/zh active Pending
- 2012-11-14 US US14/358,468 patent/US9949992B2/en active Active
- 2012-11-14 JP JP2014542390A patent/JP6261512B2/ja active Active
- 2012-11-14 WO PCT/US2012/064958 patent/WO2013074587A1/en active Application Filing
- 2012-11-14 EP EP12849346.7A patent/EP2780021A4/en not_active Ceased
Also Published As
Publication number | Publication date |
---|---|
US9949992B2 (en) | 2018-04-24 |
CA2856030A1 (en) | 2013-05-23 |
EP2780021A4 (en) | 2015-08-05 |
US20140296166A1 (en) | 2014-10-02 |
WO2013074587A1 (en) | 2013-05-23 |
EP2780021A1 (en) | 2014-09-24 |
JP2014533691A (ja) | 2014-12-15 |
CN104010647A (zh) | 2014-08-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6261512B2 (ja) | 心機能障害を治療及び/又は低減するためのビスホスホネート組成物並びに方法 | |
JP5903081B2 (ja) | 再狭窄の治療 | |
TWI275393B (en) | Use of bisphosphonates for pain treatment | |
US20180125869A1 (en) | Bisphosphonate compositions and methods for treating heart failure | |
SK13512003A3 (sk) | Použitie N-bisfosfonátu na prípravu liečiva na liečenie kostných metastáz spojených s karcinómom prostaty | |
EP1178810B1 (en) | Use of bisphosphonic acids for treating angiogenesis | |
KR20060069857A (ko) | N-(3-메톡시-5-메틸피라진-2-일)-2-(4-[1,3,4-옥사디아졸-2-일]페닐)피리딘-3-설폰아미드 및 lhrh 유사체및/또는 비스포스포네이트를 포함하는 조합물 | |
JP2006500401A (ja) | ビスホスホネートおよびhmg−coaレダクターゼインヒビターを含む組合せ治療 | |
WO2005117864A1 (en) | Combination product comprising anastrozole and a dual prenyl transferase inhibitor | |
US6255288B1 (en) | Certain methanebisphosphonic acid derivatives in fracture healing | |
JP2002541096A (ja) | 医薬組成物および使用 | |
Wolska | Bisophosphonates in the treatment of osteoporosis in women with breast cancer | |
US8623845B1 (en) | Pharmaceutical composition for preventing or treating Diabetes mellitus comprising bisphophonates | |
RU2261100C2 (ru) | Применение бисфосфоновых кислот для лечения ангиогенеза | |
JP4692283B2 (ja) | 悪性黒色腫治療剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20150818 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160331 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160629 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20160908 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171019 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20171212 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6261512 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |