MXPA06004730A - Dialysates and methods and systems related thereto - Google Patents
Dialysates and methods and systems related theretoInfo
- Publication number
- MXPA06004730A MXPA06004730A MXPA/A/2006/004730A MXPA06004730A MXPA06004730A MX PA06004730 A MXPA06004730 A MX PA06004730A MX PA06004730 A MXPA06004730 A MX PA06004730A MX PA06004730 A MXPA06004730 A MX PA06004730A
- Authority
- MX
- Mexico
- Prior art keywords
- pyrophosphate
- type compound
- dialysis
- groups
- individual
- Prior art date
Links
- 239000000385 dialysis solution Substances 0.000 title claims description 77
- 208000005475 Vascular Calcification Diseases 0.000 claims abstract description 56
- 238000001631 haemodialysis Methods 0.000 claims abstract description 56
- 230000000322 hemodialysis Effects 0.000 claims abstract description 56
- 239000000203 mixture Substances 0.000 claims abstract description 37
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical class [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 119
- 235000011180 diphosphates Nutrition 0.000 claims description 83
- 238000000502 dialysis Methods 0.000 claims description 59
- 150000001875 compounds Chemical class 0.000 claims description 58
- -1 alkali metal pyrophosphate Chemical class 0.000 claims description 36
- 239000012141 concentrate Substances 0.000 claims description 30
- 239000000651 prodrug Substances 0.000 claims description 28
- 229940002612 prodrugs Drugs 0.000 claims description 28
- 239000011780 sodium chloride Substances 0.000 claims description 27
- 210000004369 Blood Anatomy 0.000 claims description 26
- 239000008280 blood Substances 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 239000011575 calcium Substances 0.000 claims description 17
- 229910052791 calcium Inorganic materials 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 12
- FQENQNTWSFEDLI-UHFFFAOYSA-J Tetrasodium pyrophosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 claims description 11
- 239000012530 fluid Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 235000019818 tetrasodium diphosphate Nutrition 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 8
- 125000000524 functional group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000001768 cations Chemical class 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- GYQBBRRVRKFJRG-UHFFFAOYSA-L Disodium pyrophosphate Chemical compound [Na+].[Na+].OP([O-])(=O)OP(O)([O-])=O GYQBBRRVRKFJRG-UHFFFAOYSA-L 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 206010038435 Renal failure Diseases 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000004891 communication Methods 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 201000006370 kidney failure Diseases 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- JUNWLZAGQLJVLR-UHFFFAOYSA-J Calcium pyrophosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O JUNWLZAGQLJVLR-UHFFFAOYSA-J 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 235000019821 dicalcium diphosphate Nutrition 0.000 claims description 2
- 229910000393 dicalcium diphosphate Inorganic materials 0.000 claims description 2
- 235000019820 disodium diphosphate Nutrition 0.000 claims description 2
- 150000003957 organoselenium compounds Chemical class 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- RYCLIXPGLDDLTM-UHFFFAOYSA-J tetrapotassium;phosphonato phosphate Chemical compound [K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])([O-])=O RYCLIXPGLDDLTM-UHFFFAOYSA-J 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 3
- 239000011591 potassium Substances 0.000 claims 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 3
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 229940048084 Pyrophosphate Drugs 0.000 description 75
- 230000002308 calcification Effects 0.000 description 28
- 125000000623 heterocyclic group Chemical group 0.000 description 27
- 239000003795 chemical substances by application Substances 0.000 description 26
- 235000008504 concentrate Nutrition 0.000 description 24
- 210000000709 Aorta Anatomy 0.000 description 21
- 210000002381 Plasma Anatomy 0.000 description 20
- 230000002401 inhibitory effect Effects 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- 239000003814 drug Substances 0.000 description 18
- 229940079593 drugs Drugs 0.000 description 18
- 230000002829 reduced Effects 0.000 description 18
- 239000002609 media Substances 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
- 229960005069 Calcium Drugs 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 125000004432 carbon atoms Chemical group C* 0.000 description 10
- 229940048086 sodium pyrophosphate Drugs 0.000 description 9
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 7
- 210000003734 Kidney Anatomy 0.000 description 7
- 125000001589 carboacyl group Chemical group 0.000 description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 235000021317 phosphate Nutrition 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 210000004204 Blood Vessels Anatomy 0.000 description 6
- 230000037250 Clearance Effects 0.000 description 6
- 102000009617 Inorganic Pyrophosphatase Human genes 0.000 description 6
- 108010009595 Inorganic Pyrophosphatase Proteins 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 125000005907 alkyl ester group Chemical group 0.000 description 6
- 150000007860 aryl ester derivatives Chemical class 0.000 description 6
- 125000004104 aryloxy group Chemical group 0.000 description 6
- 239000004202 carbamide Substances 0.000 description 6
- 125000002837 carbocyclic group Chemical group 0.000 description 6
- 230000035512 clearance Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- JOYRKODLDBILNP-UHFFFAOYSA-N ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 6
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 6
- 150000003951 lactams Chemical class 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- 230000036470 plasma concentration Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 208000009863 Chronic Kidney Failure Diseases 0.000 description 5
- 208000001083 Kidney Disease Diseases 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 231100000486 side effect Toxicity 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 229940112871 Bisphosphonate drugs affecting bone structure and mineralization Drugs 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 210000003743 Erythrocytes Anatomy 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 150000004663 bisphosphonates Chemical class 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000005712 crystallization Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 201000000523 end stage renal failure Diseases 0.000 description 4
- 125000005842 heteroatoms Chemical group 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 230000003389 potentiating Effects 0.000 description 4
- 230000001225 therapeutic Effects 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- 229920002301 Cellulose acetate Polymers 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 230000036740 Metabolism Effects 0.000 description 3
- 230000036823 Plasma Levels Effects 0.000 description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- 229930003316 Vitamin D Natural products 0.000 description 3
- 229940046008 Vitamin D Drugs 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 230000000172 allergic Effects 0.000 description 3
- 125000003435 aroyl group Chemical group 0.000 description 3
- 125000004429 atoms Chemical group 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 239000012510 hollow fiber Substances 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 201000005991 hyperphosphatemia Diseases 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 150000004694 iodide salts Chemical class 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000035786 metabolism Effects 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000006011 modification reaction Methods 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
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- 231100000331 toxic Toxicity 0.000 description 3
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- 231100000419 toxicity Toxicity 0.000 description 3
- 235000019166 vitamin D Nutrition 0.000 description 3
- 239000011710 vitamin D Substances 0.000 description 3
- 150000003710 vitamin D derivatives Chemical class 0.000 description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- 206010054208 Aortic calcification Diseases 0.000 description 2
- 241001550224 Apha Species 0.000 description 2
- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 description 2
- 229960000693 Fosphenytoin Drugs 0.000 description 2
- WZUVPPKBWHMQCE-XJKSGUPXSA-N Haematoxylin Natural products C12=CC(O)=C(O)C=C2C[C@]2(O)[C@H]1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-XJKSGUPXSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 206010038444 Renal failure chronic Diseases 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
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 231100000765 Toxin Toxicity 0.000 description 2
- 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 description 2
- 230000002378 acidificating Effects 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 150000001649 bromium compounds Chemical class 0.000 description 2
- 150000001669 calcium Chemical class 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960004729 colecalciferol Drugs 0.000 description 2
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XPPKVPWEQAFLFU-VJJZLTLGSA-J dioxidophosphoryl phosphate Chemical compound [O-]P([O-])(=O)O[32P]([O-])([O-])=O XPPKVPWEQAFLFU-VJJZLTLGSA-J 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000011706 ferric diphosphate Substances 0.000 description 2
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- 238000001914 filtration Methods 0.000 description 2
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- 125000004435 hydrogen atoms Chemical class [H]* 0.000 description 2
- 230000003834 intracellular Effects 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
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- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
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- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
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- LSPHULWDVZXLIL-UHFFFAOYSA-L 1,2,2-trimethylcyclopentane-1,3-dicarboxylate Chemical class CC1(C)C(C([O-])=O)CCC1(C)C([O-])=O LSPHULWDVZXLIL-UHFFFAOYSA-L 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
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- KPKNTUUIEVXMOH-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decane Chemical compound O1CCOC11CCNCC1 KPKNTUUIEVXMOH-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-Chlorobutane Chemical class CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-Phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- 125000006087 2-oxopyrrolodinyl group Chemical group 0.000 description 1
- XXBMHUDJYDEMMT-UHFFFAOYSA-N 2-thiomorpholin-2-ylsulfinylthiomorpholine Chemical compound C1NCCSC1S(=O)C1CNCCS1 XXBMHUDJYDEMMT-UHFFFAOYSA-N 0.000 description 1
- VWYSBFKSQMMXTR-UHFFFAOYSA-N 2-thiomorpholin-2-ylsulfonylthiomorpholine Chemical compound C1NCCSC1S(=O)(=O)C1CNCCS1 VWYSBFKSQMMXTR-UHFFFAOYSA-N 0.000 description 1
- 125000004610 3,4-dihydro-4-oxo-quinazolinyl group Chemical group O=C1NC(=NC2=CC=CC=C12)* 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-M 3-cyclopentylpropanoate Chemical class [O-]C(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-M 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical class [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- VJPPDEZWWKCSIV-UHFFFAOYSA-N 6-azabicyclo[3.2.1]octane Chemical compound C1C2CNC1CCC2 VJPPDEZWWKCSIV-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
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- 229960003563 Calcium Carbonate Drugs 0.000 description 1
- QXDMQSPYEZFLGF-UHFFFAOYSA-L Calcium oxalate Chemical compound [Ca+2].[O-]C(=O)C([O-])=O QXDMQSPYEZFLGF-UHFFFAOYSA-L 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
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- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-M undecanoate Chemical class CCCCCCCCCCC([O-])=O ZDPHROOEEOARMN-UHFFFAOYSA-M 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 201000011528 vascular disease Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
Abstract
Compositions, systems, and methods of treating conditions such as vascular calcification conditions are disclosed. A representative method includes administering to an individual in need of treatment an effective amount of at least one effector agent. Another method includes prophylactically treating vascular calcification or vascular calcification-related conditions by administering to an individual in need of treatment an effective amount of at least one effector agent. Still another method includes treating vascular calcification by administering an effective amount of at least one effector agent to an individual in need of treatment via hemodialysis.
Description
SOLUTIONS FOR DIALYSIS AND METHODS AND SYSTEMS RELATED TO THEM
FIELD OF THE INVENTION
The present disclosure relates in general terms to compositions, systems, agents, and methods of administration to individuals and, more particularly, relates to compositions and agents designed for the treatment of vascular calcification.
BACKGROUND OF THE INVENTION
Hemodialysis is a process by which soluble microscopic toxins are removed from the blood using a filtration membrane such as a dialyzer. The dialysis treatment replaces the function of the kidneys, which normally serve as the body's natural filtration system. Through the use of a blood filter and a chemical solution known as a dialysis solution (dialysate), the treatment removes waste products and excess fluids from the bloodstream, while maintaining the proper chemical balance of the blood. . However, its most predominant application is in patients with temporary or permanent renal failure. For patients with end-stage renal disease (ESRD), whose kidneys can no longer adequately remove fluids and wastes from the body or maintain the proper level in the bloodstream of some kidney-regulated chemicals, Dialysis is the only treatment option available excluding kidney transplantation. Hemodialysis is the most commonly prescribed type of dialysis treatment in the United States of America. The treatment involves circulating the patient's blood outside the body through an extracorporeal circuit (ECC), or circuit for dialysis. Two needles are inserted into the patient's vein, or access site, and attached to the ECC, which includes plastic blood tubing, a filter known as a dialyzer (artificial kidney), and a dialysis machine that monitors and maintains the blood flow and administer the dialysis solution. Unwanted small compounds, for example toxins, diffuse from the blood to the solution for dialysis, while larger compounds such as proteins are retained in the blood. The dialysis solution is a chemical bath that is used to extract waste products out of the blood. Because small molecules that are normal constituents of the blood can also diffuse through the membrane, they are added to the dialysis solution to prevent depletion. Typically, the dialysis solution includes ions (eg, Na +, K +, Cl ", Ca2 +), pH regulators (HC03 ~), and glucose, to avoid the serious side effects that could result if blood levels were reduced. These important compounds in the hemodialysis procedure Since the 1980s, the majority of hemodialysis treatments in the United States of America have been carried out with hollow fiber dialyzers.A hollow fiber dialyzer is constituted by thousands of hollow fiber filaments tube type housed in a transparent plastic cylinder several centimeters in diameter.There are two compartments inside the dialyzer (the blood compartment and the compartment for the dialysis solution.) The membrane that separates these two compartments is semi-permeable. that allows the passage of molecules with a certain size through it, but prevents the passage of other larger molecules. As the blood is pushed through the blood compartment in one direction, the vacuum or suction pressure pulls the dialysis solution through the dialysis solution compartment in a countercurrent, or opposite, direction. These opposing pressures work to drain excess fluids out of the bloodstream and into the dialysis solution, a procedure called ultrafiltration. A second process called diffusion moves the waste products into the bloodstream through the membrane into the dialysis solution compartment., where they are transported out of the body. At the same time, electrolytes and other chemical compounds in the dialysis solution cross the membrane into the blood compartment. The purified, chemically balanced blood is then returned to the body. Many of the risks and side effects associated with dialysis are a combined result of both the treatment and the inadequate physical condition of the patient with ESRD. Current dialysis treatments have limited effectiveness and numerous serious unintentional side effects. These treatments have progressed only gradually since W.J. Kolff and H. Berk developed the first hemodialysis machine in humans practiced in 1943. A long-term side effect of hemodialysis and / or ESRD is the deposition of calcium within the blood vessels, known as vascular calcification.
This calcification occurs in the media of large and small arteries in the matrix between smooth muscle cells, also known as Monckeberg arteriosclerosis. Hyperphosphatemia is thought to be the basis of the mean vascular calcification in advanced renal failure, but calcification may occur under other conditions in the absence of hyperphosphatemia, indicating that additional factors also play a role. A side effect of hyperphosphatemia is the formation of calcium phosphate crystals in the blood and soft tissue. In clinical practice to avoid medial vascular calcification in ESRD is based on the assumption that this is only a manifestation of plasma Ca2 + and P03_ concentrations that are above that of the solubility product for Ca3 (P0) 2. However, abundant data indicates that this is not the complete explanation. Medial calcification is commonly observed in aging, and occurs in several genetic defects, all in the presence of normal plasma concentrations of calcium and phosphate. These observations suggest that calcification may occur at normal plasma concentrations of calcium and phosphate and that the mechanisms that inhibit this normally are in place in individuals. Therefore, vascular calcification can be considered a failure of these inhibitory mechanisms. In the prior art, there are no known methods for performing hemodialysis in a form that reduces calcium deposition.
SUMMARY OF THE INVENTION
Briefly described, embodiments of the present disclosure include solutions for dialysis and methods and systems related to dialysis solutions. More specifically, an exemplary method of the present disclosure includes providing therapy for vascular calcification to an individual in need of treatment, in which the provision of therapy includes administering to the individual an effective amount of pyrophosphate-like compound. Another example method of the present disclosure includes hemodialysis to an individual in need of the same, in which hemodialysis includes diffusing dialysis solution comprising at least one pyrophosphate-like compound through a membrane in a hemodialysis system, and exposing the individual to an effective amount of the pyrophosphate type compound. The solutions and compositions for dialysis included in the present disclosure relate to pyrophosphate-like compounds. For example, the present disclosure includes a pharmaceutical composition that includes at least one pyrophosphate-like compound in combination with a pharmaceutically acceptable carrier, wherein said at least one pyrophosphate-like compound is present at an effective dose level to treat calcification. vascular. Examples of additional compositions of the present disclosure are dialysis solution concentrates and dialysis solutions that include at least one pyrophosphate type compound. Also included in the present description are systems for subjecting patients to hemodialysis. An exemplary system includes a blood compartment, a membrane in fluid communication with the blood compartment, and the dialysis solution compartment, in which the dialysis solution compartment includes a dialysis solution having a pyrophosphate-like compound. . Other systems, methods, features, and advantages of the present disclosure will become apparent to the person skilled in the art after examining the following figures and detailed description. It is intended that all such additional systems, methods, features and advantages be included within this description, be within the scope of the present description, and be protected by the appended claims.
BRIEF DESCRIPTION OF THE FIGURES
Many aspects of the description can be understood more adequately with reference to the following figures. The components in the figures are not necessarily to scale, emphasis being placed instead on clearly strating the principles of the present description. Figure 1 is an exemplary graph strating pyrophosphate plasma concentrations in normal individuals (n = 36) and in patients for hemodialysis before dialysis (n = 38). The bars indicate the averages. Figure 2 is an exemplary graph strating the results of in vitro dialysis of pyrophosphate. 4 liters of pyrophosphate solution are circulated in physiological saline solution without calcium through a cellulose acetate dialyzer of 2.1 m2 at 400 ml / mm against a standard clinical bath without calcium. The pyrophosphate concentration is measured at the indicated times. The line represents an individual exponential adjustment. Figure 3 is an exemplary graph strating the change in plasma pyrophosphate concentrations after hemodialysis. Samples are drawn immediately before and immediately after dialysis from the pre-dialyzer tubing. The lines to the left and to the right indicate the average values before and after dialysis respectively. Figure 4 is an exemplary graph strating the change in pyrophosphate content in erythrocytes after hemodialysis. Plasma samples are removed immediately before and immediately after dialysis from the pre-dialyzer tubing and washed erythrocytes are extracted with HC10. The lines to the left and to the right indicate the average values before and after dialysis respectively. Figure 5 is an exemplary bar diagram strating the inhibition of vascular calcification by pyrophosphate. Specifically, Figure 5 demonstrates the incorporation of calcium in aortas incubated for 9 days in DMEM medium containing 3.8 mM P0 ~ 3 with or without 12-20 units / ml inorganic pyrophosphatase. The results shown are averages of at least 10 aortic rings; in which p < 0.001 against control. Figure 6 is an exemplary micrograph of a transparency illustrating the histology of aortas incubated for 9 days with inorganic pyrophosphatase, shown with hematoxylin and eosin staining with luminal surface on the left and magnification at 400 X. Figure 7 is a micrograph Example of a transparency illustrating the histology of aortas incubated for 9 days with inorganic pyrophosphatase, shown with von Kossa staining with luminal surface on the left and amplification at 400 X. FIG. 8 is an exemplary chart illustrating the suppression of calcification in aortas injured by pyrophosphate. The injured aortas are incubated for 6 days in DMEM medium containing 3.8 mM P0 ~ 3 and varying concentrations of pyrophosphate. The results are the averages of at least 4 aortic rings. Figure 9 is a block diagram of an exemplary hemodialysis system that includes the compositions described and that can be used to perform the described methods.
DETAILED DESCRIPTION OF THE INVENTION
The present description can be more easily understood with reference to the following detailed description and to the examples included therein. Before the present compounds, compositions and methods are disclosed and described, it should be understood that this disclosure is not limited to specific pharmaceutical carriers, or to particular pharmaceutical formulations or to particular administration regimens, since these, of course, may vary. It should also be understood that the terminology used in the present invention is for purposes of describing particular embodiments only and is not intended to be limiting.
Definitions The term "individual" or "patient" refers to any living entity that has at least one cell. A living organism can be as simple as, say, a single eukaryotic cell or as complex as a mammal, including a human being. The term "pyrophosphate" and "pyrophosphate type compound" are used interchangeably throughout the reference and refer to any compound or formulation that includes the chemical formula (P207) 4_, which includes the acid anhydride formulation, as well as any salt or ester of pyrophosphoric acid. The term "ester" includes functional groups having the general formula RCOOR, in which the R groups represent the same or different aliphatic groups (for example, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, etc.), groups aromatics (for example, heterocyclic groups, aryl groups, etc.), and / or hydrogen ions. Examples of pyrophosphate salts are described in greater detail in Kirk and Othmer, Encyclopedia of Chemical Technology, Second Edition, Volume 15, Interscience Publishers (1968). Although these pyrophosphate salts serve as examples, the present disclosure is not limited solely to the specific pyrophosphate salts listed by Kirk and Othmer. The term "derivative" means a modification to the disclosed compounds including, but not limited to, hydrolysis products, reduction or oxidation, of the described compounds. Hydrolysis, reduction and oxidation reactions are known in the art. The term "therapeutically effective amount" as used in the present invention refers to that amount of the compound that is administered which can alleviate to some degree one or more of the symptoms of the disorder being treated. With reference to vascular calcification or pathologies related to vascular calcification, a therapeutically effective amount refers to that amount which has the effect of: (1) reducing the amount of vascular calcification; (2) inhibit (ie, decelerate to a certain degree, and preferably stop) vascular calcification; (3) prevent and / or reduce vascular calcification; (4) alleviating to some degree (or, preferably, eliminating) one or more symptoms associated with a related pathology or caused in part by vascular calcification; and / or (6) avoid the chain of events downstream of an initial ischemic condition that leads to the pathology. By the phrase "a therapeutically effective amount" of one or more of the effector agents is meant a sufficient amount of one or more of the effector agents to treat vascular calcification and conditions related to vascular calcification at a reasonable benefit / risk ratio that is It can apply to any medical treatment. For example, a "therapeutically effective amount" of one or more of the effector agents is an amount sufficient to alleviate, decrease, stabilize, reverse, decelerate, and / or delay the advancement or onset of the disease state as compared to not administering one or more of the effector agents. However, it should be understood that the total daily utilization of the effector agents of the present description will be decided by the attending physician within the field of substantiated medical judgment. The specific therapeutically effective dose level for any particular individual will depend on a variety of factors, including, for example, the disorder being treated and the severity of the disorder; the activity of the specific effector agents used; the specific effector agents used, the patient's age, body weight, health status, sex and diet; the time of administration; route of administration; rate of excretion of the specific effector agents employed; the duration of the treatment; drugs used in combination or coincident with the specific composition used; and similar factors well known in the medical arts. For example, it is within the skill of the skilled artisan to initiate doses of the effector agents at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The effector agents are preferably formulated in unit dosage form for ease of administration and dose uniformity. "Unit dosage form" as used in the present invention refers to a physically discrete unit of the effector agents appropriate for the individual to be treated. Each dose should contain the amount of effector agents calculated to produce the desired therapeutic effect either as such, or in combination with the selected pharmaceutical carrier medium. Preferred unit dose formulations are those containing a dose or unit, daily sub-dose, or an appropriate fraction thereof normally administered in a dialysis treatment session, of the administered effector agent. In this sense, studies are carried out to evaluate the dose regimen for pyrophosphate compounds (PPi). The effector agents and their compositions (hereinafter "effector agents") of this disclosure can be used to treat conditions such as, but not limited to, vascular calcification and diseases related to vascular calcification. In addition, the effector agents of this disclosure can be used prophylactically to inhibit the development and / or slow down the development of vascular calcification and conditions related to vascular calcification and / or advanced stages of vascular calcification and conditions related to vascular calcification. The effector agents of the present disclosure can be used as the active ingredient in combination with one or more pharmaceutically acceptable vehicle means and / or excipients. "Pharmaceutically acceptable salt" refers to those salts which preserve the effectiveness and biological properties of the free bases and which are obtained by reaction with inorganic or organic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, acid nitric, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, melicic acid, maleic acid, succinic acid, tartaric acid, citric acid, and the like. By the phrase "pharmaceutically acceptable salt" is meant those salts which are, within the scope of appropriate medical judgment, suitable for use in contact with the tissues of individuals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio and are effective for its intended use. The salts can be prepared in situ during the isolation and final purification of one or more effector agents, or separately by reacting the free base functional group with an appropriate organic acid. The term "pharmaceutically acceptable esters" as used in the present invention refers to those esters of one or more effector agents that are appropriate, within the field of well-founded medical judgment, for use in contact with the tissues of individuals without undue toxicity. , irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and are effective for the intended use. The term "prodrugs" as used in the present invention refers to those prodrugs of one or more effector agents which, within the field of informed medical judgment, are suitable for use in contact with the tissues of individuals without undue toxicity, irritation, allergic response, and the like, are commensurate with a reasonable benefit / risk ratio, and are effective for the intended use. The pharmaceutically acceptable prodrugs also include zwitterionic forms, in cases where possible, of one or more compounds of the composition. The term "prodrug" refers to compounds that are rapidly transformed in vivo to produce the parent compound, for example by hydrolysis in blood. A "pharmaceutical composition" refers to a mixture of one or more of the compounds described in the present invention, or pharmaceutically acceptable salts thereof, with other chemical components, such as physiologically acceptable carriers and excipients. One purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism. As used in the present invention, a
"Pharmaceutically acceptable carrier" refers to a vehicle or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the compound administered. As used in the present invention, "pharmaceutically acceptable carrier medium" includes any and all vehicles, solvents, diluents, or other liquid carriers, dispersion or suspension aids, surfactants, isotonic agents, thickening agents or emulsifiers, preservatives , solid binders, lubricants, adjuvants, vehicles, delivery systems, disintegrants, absorbents, preservatives, surfactants, colorants, flavors or sweeteners and the like, as appropriate to the particular dosage form desired. Preferably, the pharmaceutically acceptable vehicle medium is a solution for dialysis. An "excipient" refers to an inert substance that is added to a pharmaceutical composition to further facilitate the administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. "Treating" or "treating" a disease includes preventing the disease from occurring in an animal that may be pre-disposed to the disease but does not yet experience or present symptoms of the disease
(prophylactic treatment), inhibit the disease (slow or stop its development), provide relief of symptoms or side effects of the disease (including palliative treatment), and alleviate the disease (cause the regression of the disease). With regard to vascular calcification, these terms simply mean that the life expectancy of an affected individual with vascular calcification increases or that one or more of the symptoms of the disease are reduced. The term "prodrug" refers to an agent that becomes a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. These can, for example, remain bioavailable by oral administration while the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions with respect to the precursor drug. A prodrug can be converted to the precursor drug by various mechanisms, including enzymatic procedures and metabolic hydrolysis. Harper, N. J. (1962). Drug Latentiation in Jucker, ed. Progress in Drug Research, 4: 221-294; Morozo ich et al. (1977). Application of Physical Organic Principles to Prodrug Design in E. B. Roche ed. Design of Biopharmaceutical Properties through Prodrugs and Analogs, APhA; Acad. Pharm. Sci .; E. B. Roche, ed. (1977). Bioreversible Carriers in Drug in Drug Design, Theory and Application, APhA; H. Bundgaard, ed. (1985) Design of Prodrugs, Elsevier; Wang et al. (1999) Prodrug approaches to the improved delivery of peptide drug, Curr. Pharm. Design 5 (4): 265-287; Pauletti et al. (1997). Improvement in peptide bioavailability: Peptidomimetics and Prodrug Strategies, Adv. Drug Delivery Rev. 27: 235-256; Mizen et al. (1998). The Use of Esters as Prodrugs for Oral Delivery of ß-Lactam antibiotics, Pharm. Biotech 11 ,: 345-365; Gaignault et al. (nineteen ninety six). Designing Prodrugs and Bioprecursors I. Carrier Prodrugs, Pract. Med. Chem. 671-696; M. Asgharnejad (2000). Improving Oral Drug Transport Via Prodrugs, in G. L. Amidon, P. I. Lee and E. M. Topp, Eds. , Transport Processes in Pharmaceutical Systems, Marcell Dekker, p. 185-218; Balant et al. (1990) Prodrugs for the improvement of drug absorption via different routes of administration, Eur. J. Drug Metab. Pharmacokinet. , fifteen
(2): 143-53; Balimane and Sinko (1999). Involvement of multiple transporters in the oral absorption of nucleoside analogues, Adv. Drug Delivery Rev., 39 (1-3): 183-209; Browne (1997). Fosphenytoin (Cerebyx), Clin. Neuropharmacol. 20 (1): 1-12; Bundgaard (1979). Bioreversible derivatization of drugs-principie and applicability to improve the therapeutic effects of drugs, Arch. Pharm. Chemi. 86 (1): 1-39; H. Bundgaard, ed. (1985) Design of Prodrugs, New York: Elsevier; Fleisher et al. (nineteen ninety six) .
Improved oral drug delivery: solubility limitations overeóme by the use of prodrugs, Adv. Drug Delivery Rev. 19 (2): 115-130; Fleisher et al. (1985). Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting, Methods Enzymol. 112: 360-81; Farquhar D, et al. (1983). Biologically Reversible Phosphate-Protective Groups, J. Pharm. Sci. , 72 (3): 324-325; Han, H. K. et al. (2000). Targeted prodrug design to optimize drug delivery, AAPS PharmSci. , 2 (1): E6; Sadzuka Y. (2000). Effective prodrug liposome and conversion to active metabolite, Curr. Drug Metab. , 1 (1): 31-48; D. M. Lambert (2000). Rationale and applications of lipids as prodrug carriers, Eur. J. Pharm. Sci. , 11 Suppl 2: Sl5-27; Wang, W. et al. (1999). Prodrug approaches to the improved delivery of peptide drugs. Curr. Pharm. Des. , 5 (4): 265-87. The terms "ale" or "alkyl" refer to straight or branched chain hydrocarbon groups having from 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc. Lower alkyl groups, i.e., alkyl groups of 1 to 6 carbon atoms, are generally more preferred. The term "substituted alkyl" refers to alkyl groups substituted with one or more groups, which are preferably selected from aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, halogen, hydroxy, alkoxy (optionally substituted) , aryloxy (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl, etc. The term "alkoxy" means an alkyl group linked to oxygen, therefore: R-O-. In this functional group, R represents alkyl group. An example could be the methoxy CH3O- group. The term "alkenyl" refers to straight or branched chain hydrocarbon groups having from 2 to 12 carbon atoms, preferably 2 to 4 carbon atoms, and at least one carbon carbon double bond (either cis or trans) , as ettenilo. The term "substituted alkenyl" refers to alkenyl groups substituted with one or more groups, which are preferably selected from aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, halogen, hydroxy, alkoxy (optionally substituted) , aryloxy (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl, etc. The term "alkynyl" refers to straight or branched chain hydrocarbon groups having from 2 to 12 carbon atoms, preferably from 2 to 4 carbon atoms, and at least one carbon carbon triple bond, such as ethynyl. The term "substituted alkynyl" refers to alkynyl groups substituted with one or more groups, which are preferably selected from aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle, halogen, hydroxy, alkoxy (optionally substituted) , aryloxy
(optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl, etc. The terms "ar" or "aryl" refer to groups containing monocyclic, bicyclic or tricyclic homocyclic (eg hydrocarbon) aromatic rings preferably having 6 to 12 members such as phenyl, naphthyl and biphenyl. Phenyl is a preferred aryl group. The term "substituted aryl" refers to substituted aryl groups with one or more groups, which are preferably selected from alkyl, substituted alkyl, alkenyl (optionally substituted), aryl (optionally substituted), heterocycle (optionally substituted), halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl ( optionally substituted), aroyl, (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), cyano, nitro, amino, substituted amino, amido, lactam, urea, urethane, sulfonyl, etc., in which optionally one or more pairs of substituents together with the atoms to which these are attached form a 3 to 7 membered ring. The terms "cycloalkyl" and "cycloalkenyl" refer to monocyclic, bicyclic or tri-homocyclic ring groups of 3 to 15 carbon atoms which are, respectively, fully saturated and partially unsaturated. The term "cycloalkenyl" includes bicyclic and tricyclic ring systems which are not aromatic as a whole, but which contain aromatic portions (e.g., fluororene, tetrahydronaphthalene, dihydroindene, and the like). The ring rings of multiple ring cycloalkyl groups can be fused, bridged and / or linked through one or more spiro-type bonds. The terms "substituted cycloalkyl" and "substituted cycloalkenyl" refer, respectively, to cycloalkyl and cycloalkenyl groups substituted with one or more groups, which are preferably selected from aryl, substituted aryl, heterocycle, substituted heterocycle, carbocycle, substituted carbocycle. , halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), alkanoyl (optionally substituted), aryol (optionally substituted), cyano, nitro, amino, amino substituted, amido, lactam, urea, urethane, sulfonyl, etc. The terms "carbocycle", "carbocyclic" or "carbocyclic group" refer to both cycloalkyl groups and cycloalkenyl groups. The terms "substituted carbocycle", "substituted carbocyclic" or "substituted carbocyclic group" refers to carbocyclic or carbocyclic groups substituted with one or more groups as described in the definition of cycloalkyl and cycloalkenyl. The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine. The terms "heterocycle", "heterocyclic", "heterocyclic group" or "heterocycle" refer to fully saturated or partially or completely unsaturated cyclic groups, including cyclic aromatic ("heteroaryl") or non-aromatic cyclic groups (e.g., ring systems) monocyclic from 3 to 13 members, bicyclics of 7 to 17 members, or tricyclics of 10 to 20 members, preferably containing a total of 3 to 10 ring atoms) having at least one heteroatom in at least one ring that contains a carbon atom. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms which are selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, in which the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom of the ring or ring system. Multi-ring heterocyclic rings may be fused, bridged and / or linked through one or more spiro-type bonds. Examples of monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl. , piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperazinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrahydropyranyl, tetrazoyl, triazolyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro -1, 1-dioxothienyl, and the like. Examples of bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, benzodioxolyl, dihydrobenzodioxolyl, benzodioxinyl, cinolinyl, quinoxalinyl. , indazolyl, pyrrolopyridyl, furopyridinyl (such as furo [2, 3-c] pyridinyl, furo [3,2-b] pyridinyl] or furo [2, 3-b] pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3, 4 -dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, azabicycloalkyls (such as 6-azabicyclo [3.2.1] octane), azaspiroalkyls (such as 1,4-dioxa-8-azaspiro [4.5] decane), imidazopyridinyl (such as imidazo) [1,5-a] pyridin-3-yl), triazolopyridinyl (such as 1, 2,4-triazolo [4, 3-a] pyridin-3-yl), and hexahydroimidazopyridinyl (such as 1.5, 6, 7, 8, 8a-hexahydroimidazo [1, 5-a] pyridin-3-yl), and simi lares. Examples of tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrylyl, acridinyl, phenanthridinyl, xanthenyl, and the like. The terms "substituted heterocycle",
"substituted heterocyclic", "substituted heterocyclic group" and "substituted heterocycle" refer to heterocycle, heterocyclic and heterocycle groups substituted with 1 or more groups which are preferably selected from alkyl, substituted alkyl, alkenyl, oxo, aryl, aryl substituted, heterocycle, substituted heterocycle, carbocycle (optionally substituted), halogen, hydroxy, alkoxy (optionally substituted), aryloxy (optionally substituted), alkanoyl (optionally substituted), aroyl (optionally substituted), alkyl ester (optionally substituted), aryl ester (optionally substituted), cyano, nitro, amido, amino, substituted amino, lactam, urea, urethane, sulfonyl, etc., in which optionally one or more pairs of substituents together with the atoms to which they are attached form a ring of 3 to 7 members. The term "alkanoyl" refers to an alkyl group (which may be optionally substituted as described above) linked to a carbonyl group (ie, -C (O) -alkyl). Likewise, the term "aroyl" refers to an aryl group (which may be optionally substituted as described above) linked to a carbonyl group (ie, -C (0) -aryl). Throughout the description, groups and substituents thereof can be chosen to provide stable portions and compounds. The compounds described form salts that are also within the scope of this description. It is understood that reference to a compound of any of the formulas of the present invention includes reference to salts thereof, unless otherwise indicated. The term "salt (s)", as used in the present invention, indicates basic salts and / or acids formed with inorganic and / or organic acids and bases. Further, when a compound of any of the formulas I or II (provided below) contains both a basic portion and an acid portion, zwitterions ("inner salts") can be formed and included within the term "salt (s)". as used in the present invention. Preferred are pharmaceutically acceptable salts (for example, non-toxic, physiologically acceptable), although other salts are also useful (for example, in the isolation or purification steps that can be used during the preparation). The salts of the compounds of any of the formulas I or II can be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as that in which the salt precipitates. or in an aqueous medium followed by lyophilization. The disclosed compounds containing a basic portion can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or tri-halogenic acetic acid, eg, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates. , citrates, camphorates, camphor sulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glycoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), bromohydrates (formed with hydrogen bromide), iodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulphates ( such as those formed with sulfuric acid), sulfonates (such as aquell mentioned in the present invention), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like. The disclosed compounds containing an acidic portion can form salts with a variety of organic and inorganic bases. Examples of basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases (e.g. organic amines) such as benzathines, dicyclohexylamines, hydrabamines
(formed with N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butylamines, and salts with amino acids such as arginine, usin, and the like. Groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides (for example, methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (eg, dimethyl sulfates, diethyl sulfates, dibutyl, and diamyl), long chain halides (eg, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (eg, benzyl and phenethyl bromides), and others. The solvates of the compounds of the description are also contemplated in the present invention. The solvates of the compounds are preferably hydrates. To the extent that the described compounds, and salts thereof, may exist in their tautomeric form, all of said tautomeric forms are contemplated by the present invention as part of the present disclosure. All stereoisomers of the compounds herein, such as those which may exist due to asymmetric carbons in the various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, are contemplated within the scope of the invention. field of this description. The individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or may be mixed, for example, as racemates or with all others, or other selected stereoisomers. The chiral centers of the compounds of the present disclosure may have the S or R configuration as defined by the 1974 IUPAC Recommendations. The terms "including", "such as", "for example", and the like, are intended to refer to exemplary embodiments and do not limit the scope of the present disclosure. The present disclosure provides compositions and agents that can be used to treat individuals who
have vascular calcification and conditions related to vascular calcification. In addition, the present disclosure provides compositions and methods for treating individuals who are predisposed to vascular calcification and conditions related to vascular calcification. The compositions
they include at least one pyrophosphate type compound. Pyrophosphate type compounds may include,
but they are not limited to, the structure of formula I
illustrated later:
0"X + O" ^ + o = p-o-P = 0 0'X + O "? +
Formula I
More particularly, the type compounds
pyrophosphate can include any number of X + cations,
or substituents ionically bound to or in free association
with oxygen anions (0 ~). The examples of X cations
include, but are not limited to, Li, Na, K, Ca, Mg, Cr, Mn,
Faith and / or Zn. Each of the X cations may be the same or different from the other X cations. For example, the
Pyrophosphate type compound can be alkaline tetrametal pyrophosphate, dimetal diacid pyrophosphate
alkaline, trimetal alkaline monoacid pyrophosphate, or mixtures thereof. More specifically, the pyrophosphate type compound can be, for example, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, dicalcium pyrophosphate, phosphoric acid, sodium acid pyrophosphate, sodium dihydrogen pyrophosphate, or mixtures thereof. The pyrophosphate type compounds can also include the following structure of formula II:
O-R O-R I i = p-o-P = 0 I I O-R O-R
Formula II
in which the example functional groups of the pyrophosphate type compounds are indicated as R. Each of the functional groups R may individually include, but is not limited to, hydrogen, alkyl groups, aryl groups, halo groups (F, Cl, Br, and I), hydroxy groups, alkoxy groups, alkylamino groups, dialkylamino groups, acyl groups, carboxyl groups, carboamido groups, sulfonamide groups, aminoacyl groups, amide groups, amine groups, nitro groups, organo-selenium compounds, hydrocarbons, cyclic hydrocarbons, hydrogen, nitrogen, oxygen, sulfur, NR, and CR. Each of the functional groups R may be the same or different from the other functional groups R. In cases where such forms exist, pyrophosphate-like compounds may include, but are not limited to, pyrophosphate derivatives that function to treat vascular calcification. and conditions related to vascular calcification in an individual, and / or function in a prophylactic manner. In addition, in cases where such forms exist, the pyrophosphate-like compounds may include pharmaceutically acceptable salts, esters and prodrugs of the pyrophosphate-type compounds described or referred to above. In the present description, dialysis solutions are included which include at least one pyrophosphate-type compound as described above. An example dialysis solution includes a pyrophosphate concentration of at least about 1 μM. More specifically, the pyrophosphate concentration may be from about 1 μM to about 10 μM, or from about 3 μM to about 5 μM. Included in the present disclosure are dialysis solution concentrates that include at least one pyrophosphate-type compound as described above. An exemplary concentrate for dialysis solution includes a pyrophosphate concentration from about 50 μM to 1 mM. Included in the present disclosure are methods for providing therapy for vascular calcification to an individual in need of treatment. An example of such methods include administering to the individual a therapeutically effective amount of a pyrophosphate-like compound. When used in the above treatment or in other treatments, a therapeutically effective amount of one or more of the effector agents can be used in pure form or, in cases where such forms exist, in the form of a pharmaceutically acceptable salt, ester and prodrug. acceptable. In addition, the therapeutically effective amount may be administered in a unit dosage form that is constant, or may vary with the individual needs of the patient. Preferably, the therapeutically effective amount of the pyrophosphate-like compound is administered in a pharmaceutically acceptable vehicle or medium. Additional excipients may be administered with the pyrophosphate type compound. In one embodiment, the pyrophosphate-like compound is administered to the individual in a solution fluid for dialysis, or during dialysis. The pyrophosphate type compound can be administered to the individual in a solution fluid for dialysis at a pyrophosphate-type compound concentration of at least about 1 μM. The pyrophosphate concentration can be from about 1 μM to about 10 μM, or from about 3 μM to about 5 μM. Hemodialysis systems are included in the present description. An example of a system for hemodialysis is shown in Figure 9. The hemodialysis system 10 shown in Figure 9 includes a blood compartment 12, a compartment for dialysis solution 14, the blood compartment 12 and the dialysis solution compartment. 14 are separated by a membrane 16. The membrane 16 creates a semi-permeable fluid communication path between the blood compartment 12 and the solution compartment for dialysate 14. The dialysis solutions described in the present invention are placed within the compartment of dialysis solution 14 and from here they can diffuse into the blood compartment 12, which is re-circulated towards an individual, whereby a pyrophosphate-like compound is administered to the individual. It should be noted that the hemodialysis system 10 shown in Figure 9 is an extremely simplified block diagram version which is only intended to illustrate the principles of the described compositions and methods.
Pyrophosphate levels in patients with hemodialysis Pyrophosphate (PPi) is a known inhibitor of hydroxyapatite formation and has been shown to inhibit media vascular calcification in toxic rats with vitamin D. It has been shown that endogenous PPi production prevents calcification of rat aorta cultured in high concentrations of Ca and P0. To determine if PPi metabolism is altered or not in patients with hemodialysis, plasma levels and PPI dialysis clearance are measured in patients with stable hemodialysis. Samples of pre-dialysis plasma are obtained from 15 patients in an external patient dialysis unit and from 23 internal patients. Inpatients are clinically stable and are admitted for transplant evaluation or access problems for dialysis. The concentration [PPi] in plasma is 26 ± 0.19 μM compared to 3.26 ± 0.17 in 36 normal individuals (P <0.01). Approximately 30% is bound to protein and this is not altered in dialysis patients. There is only a weak inverse correlation with age, and the levels do not vary between inter-dialytic periods of 2 or 3 days. The [PPi] in plasma is reduced by 32% ± 5% after standard hemodialysis in 17 patients. The in vitro clearance of PPi by a cellulose acetate dialyzer of 2.1 m2 is 36% and the average PPi removal in 5 patients is 43 ± 5 μmol, consistent with a similar in vivo clearance. The PPi removed is greater than the combined plasma but less than the combined extracellular fluid calculated. The content of PPI in erythrocytes is reduced by 24 ± 4%, which indicates that the intracellular PPi is also eliminated. As a result, it is concluded that the [PPi] in plasma is reduced in patients with hemodialysis and PPi is eliminated by dialysis. Plasma levels in some patients are below those previously shown to prevent calcification of blood vessels in culture, suggesting that altered metabolism of PPi may contribute to vascular calcification in hemodialysis patients. Rat aortas can not be calcified when grown in very high concentrations of calcium and phosphate, and this is due to an inhibiting effect of pyrophosphate produced by blood vessels. This inhibition occurs at concentrations of PPi normally present in human plasma. PPi is well established as an inhibitor of calcification in cartilage and the crystallization of calcium oxalate in kidney, and inhibits vascular calcification in toxic rats by vitamin D. This is a direct and potent inhibitor of the formation of hydroxyapatite in vitro and even small plasma concentrations (2-4 M) are sufficient to completely avoid crystallization from saturated calcium and phosphate solutions. Humans with low levels of PPi due to the absence of the PPi-producing enzyme develop severe, fatal arterial calcification that can be prevented by therapy with bis-phosphonates (also known as diphosphonates), which are non-hydrolysable analogs of PPi . These findings suggest that vascular calcification can not occur in the presence of normal pyrophosphate concentrations and that the mean vascular calcification in ESRD must be associated with the altered pyrophosphate metabolism. The comparison of [PPi] in plasma in normal individuals and in hemodialysis patients (pre-dialysis) is shown in the following table 1. The average concentration is 31% lower in hemodialysis patients. Due to the fact that dialysis patients are significantly older due to a sub-population of older adults not represented in the normal ones, data for ages under 60 are also analyzed. Plasma [PPi] is still lower in hemodialysis patients despite similar ages (47 versus 41 in normal, p = NS).
TABLE 1 Levels of plasma pyrosphosphate in normal individuals and in patients with hemodialysis before dialysis
As shown in Figure 1, the [PPi] in reduced average plasma is due to a subset of patients with very low levels. While the highest levels in normal individuals and hemodialysis patients are similar, 15 patients have levels below the lowest level in normal individuals. The effect of the other parameters on the [PPi] in plasma in patients with hemodialysis is shown in the following table 2.
TABLE 2 Plasma pyrophosphate levels in patients with hemodialysis before dialysis
TABLE 2 (cont.)
Several studies are carried out to determine the degree of PPi removal with dialysis. In vitro PPi clearance is determined by dialyzing a solution of 4 liters of PPi in physiological saline solution at a flow rate of 400 ml / minute against a standard clinical dialysis solution without calcium (to avoid precipitation of PPi) at a rate flow rate of 800 ml / minute using a cellulose acetate membrane of 2.1 m2. As shown in Figure 2, the disappearance of PPi is adjusted to an individual exponential function and reveals a dialyzer clearance of 36%. In 17 patients, some of whom are included in the pre-dialysis data, the plasma concentration of PPi is measured before and after dialysis (figure 3). The level is reduced in all but one patient with an average reduction of 32 ± 2.7%, but the interval is large (4% to 59%, excluding that patient in whom an increase occurs). The content of PPi in erythrocytes is reduced with dialysis in 12 of 13 patients, with the level unchanged in the other patient (Figure 4). The average reduction is 24 ± 7%. The solution for dialysis is collected during 4 treatments in 4 different patients in order to measure the total amount of PPi eliminated. The total amounts eliminated in these treatments are (in μmoles) 42, 42, 32, and 57. The average value is 43 ± 5 μmoles. Despite the fact that the kidney normally removes PPi, plasma levels are reduced in hemodialysis patients. In addition, its clearance by dialysis increases the [PPi] in reduced plasma, which results in an additional reduction of 32%. Therefore, the end of dialysis, levels at about half the normal level. The reduced pyrophosphate levels in hemodialysis patients and the additional reduction during dialysis have important implications, because PPi is a potent inhibitor of hydroxyapatite crystallization. The normal plasma concentration of [PPi] prevents crystallization from super-saturated calcium and phosphate solutions. It has previously been shown that this concentration also prevents calcification of rat aortic bundle in culture. See Lomashvili KA, Cobbs S, Hennigar RA, Hardcastle KJ, O'Neill WC: Phosphate-induced vascular calcification: role of pyrophosphate and osteopontin. J Am Soc Nephrol 15: 1392-1401,2004. Therefore, reduced levels in hemodialysis patients may promote the formation of hydroxyapatite. The administration of PPi to toxic vitamin D rats inhibits vascular calcification (see Schibler D, Russell GG, Fleisch H: Inhibition by pyrophosphate and polyphosphate of aortic calcification induced by vitamin D3 in rats, Clin Sci 35: 363-372.1968) , suggesting that PPi and bisphosphonate analogs can be therapeutic.
Pyrophosphate as an inhibitor of vascular calcification Pyrophosphate is also being investigated as a possible inhibitor of calcification by studying the rat aortic rings. This is not present in the DMEM medium (Mediatech, Herndon, Virginia, USA), but its concentration after 3 days of aortic ring culture is 0.44 ± 0.33 μM (an aortic annulus and 500 μl medium), which indicates that this is produced by the aortas. These measurements are made in normal DMEM to prevent the sequestration of pyrophosphate in calcium phosphate deposits. The elimination of pyrophosphate by adding inorganic pyrophosphatase (as assessed from the disappearance of [32 P] pyrophosphate, not shown) induces calcification of normal aortas (Figure 5). Focal medial calcification is apparent with haematoxylin and eosin staining (Figure 6), and von Kossa staining reveals calcification of some elastin fibers (Figure 7). The addition of pyrophosphate prevents calcification in injured aortas (Figure 8), which confirms that pyrophosphate inhibits mean calcification. Inhibition is not present with 2.5 μM but almost complete inhibition with 10 μM pyrophosphate. Based on the rate of hydrolysis of [32 P] pyrophosphate in aortic cultures (not shown) the concentrations calculated 3 days after adding 5, 10, and 30 μM pyrophosphate are 18 μM, 3.1 μM, and 7.9 μM, respectively. Therefore, the inhibition of calcification by pyrophosphate is actually more potent than that indicated in Figure 8. The rate of occurrence of pyrophosphate in culture medium is substantially reduced in injured aortas (36 + 4 μmoles / mg / d, n = 12, against 145 + 8 μmol / mg / d in normal aortas, n - 22) and alkaline phosphatase activity is significantly increased in injured aortas (1.16 + 0.17 units / mg, n = 15 versus 0.43 + 0.04 units / mg, n = 12, in unharmed aorta). This study shows that medial calcification can be induced in intact rat aorta cultured with alkaline phosphatase or inorganic pyrophosphatase. The calcification is in the form of hydroxyapatite, requires a high concentration of P04-3, and is histologically similar to the calcification observed in blood vessels from uraemic patients and rats with chronic renal failure. Rat aortas cultured without these enzymes and not subjected to injury do not present calcification in the medium with a high P0 ~ 3 content, even up to 21 days in culture. The initial, small incorporation of 45Ca under normal conditions possibly represents the equilibrium with intracellular Ca and Ca normally bound to the extra cellular matrix because it increases with the passage of time. The concentrations of both Ca2 + and P04 ~ 3 are elevated in medium with a high P04 ~ 3 content compared to human serum and, based on free concentrations, can be equivalent to a calcium-total phosphorus product in human serum of 180 mg2 / dl2, which is well above the generally accepted clinical threshold values. Therefore, a high calcium-phosphorus product is not sufficient to produce medial calcification in vi tro. Vascular calcification is a chronic process in vivo and the possibility that longer culture times are required to observe the calcification of normal blood vessels in vitro can not be excluded. However, the absence of any increase in 45Ca deposition over 3 weeks argues against this. The absence of calcification is due to the inhibitory activity in normal aortas and this inhibition can be explained by the release of pyrophosphate from the smooth muscle. Alkaline phosphatase and inorganic pyrophosphatase induce calcification of normal aortas and pyrophosphate inhibits the calcification of injured aortas. Pyrophosphate inhibits the formation of hydroxyapatite in vitro and exogenous pyrophosphate inhibits aortic calcification in rats given large doses of vitamin D3. Bisphosphonates, which are pyrophosphate analogs, have the same properties. It is likely that inhibition by endogenous pyrophosphate demonstrated in rat aortas in culture is also present in vivo because the concentration that maximally inhibits calcification in injured aortas (approximately 3 μM) is similar to that reported for normal human plasma . Also, the deficiency of PC-1, an ecto-ATPase that produces pyrophosphate, results in reduced levels of pyrophosphate in plasma and exhaustive arterial calcification in humans, which can be avoided with bisphosphonate therapy. Mice lacking ANK, a putative pyrophosphate transporter, presents reduced pyrophosphate production and extensive ectopic calcification, although not in blood vessels.
Addition of pyrophosphate to dialysis solution in hemodialysis treatment Pyrophosphate, a small molecule, susceptible to dialysis present in normal blood, is a potent inhibitor of vascular calcification in vitro. There is strong but indirect evidence that pyrophosphate inhibits vascular calcification in vivo, including in humans. In vitro studies indicate that this inhibition occurs at concentrations normally present in human plasma (3-5 μM). Recent studies have shown that plasma pyrophosphate levels are reduced in hemodialysis patients and even reduced further during hemodialysis. The addition of pyrophosphate to the dialysis solution should prevent the net loss of pyrophosphate in the blood of patients undergoing dialysis, and may reduce or prevent vascular calcification in hemodialysis patients. Accordingly, the description includes compositions of dialysis solution concentrates having pyrophosphate in a concentration greater than about 50 μM and less than about 1 mM. In a standard 45 X dialysis system, the bicarbonate concentrate is diluted approximately 25 X with water and the acid concentrate to produce the final dialysis solution. Also included are final dialysis solution compositions comprising pyrophosphate concentrations of at least about 1 μM. The pyrophosphate concentration of the dialysis solution may be from about 1 μM to about 10 μM, or from about 3 μM to about 5 μM, in which the final composition is the dialysis composition to which the hemodialysis patient is exposed. Also included are methods for reducing or preventing vascular calcification by administering dialysis solution to patients in whom the final dialysis solution comprises a pyrophosphate concentration of at least about 1 μM. The pyrophosphate concentration can be from about 1 μM to about 10 μM, or from about 3 μM to about 5 μM, in which the final composition is the dialysis composition to which the hemodialysis patient is exposed. Different dialysis systems work in different ways. The present disclosure is intended to cover methods and compositions in which the final dialysis solution includes a pyrophosphate concentration is at least about 1 μM. The pyrophosphate concentration can be from about 1 μM to about 10 μM, or from about 3 μM to about 5 μM. The final pyrophosphate concentration can be achieved in different dialysis systems in a number of different ways, for example: (1) through dilution of a basic concentrate containing pyrophosphate. Typically, dialysis solution concentrates are diluted approximately 25 times, although the range typically is 20 to 30 times. Accordingly, the concentration of pyrophosphate in the basic concentrate typically ranges from about 60 μM to about 15 μM; (2) through dilution of a powder concentrate containing pyrophosphate. Either the acid bath or the basic bath, or both, can be obtained by solubilization and dilution of a solid composition (eg, powder, granular and crystalline) containing pyrophosphate; and (3) by dilution of an acid bath concentrate containing pyrophosphate. Typically, acid bath concentrates are diluted by a factor between 30 times and 45 times. Therefore, the concentration of pyrophosphate in the acid concentrate typically varies from
90 μM approximately up to 225 μM. In addition, the description also covers methods for reducing or preventing vascular calcification that include administering dialysis solution to patients in which the dialysis solution includes a pyrophosphate concentration of at least about 1 μM. The pyrophosphate concentration can be from about 1 μM to about 10 μM, or from about 3 μM to about 5 μM, and a bicarbonate concentration from about 10 mM to about 100 mM, in which the final composition is the dialysis composition to which the hemodialysis patient is exposed. The description contemplates the incorporation of sodium pyrophosphate in the solution for dialysis. Sodium pyrophosphate can be combined with other pyrophosphate salts as well. For example, sodium pyrophosphate can be combined with ferric pyrophosphate, which may have the added benefit of providing the body with soluble iron. These described compositions and methods provide a significant advantage over the prior art in preventing the depletion of pyrophosphate in hemodialysis patients, and thus avoid, reduce, or potentially reverse vascular calcification.
EXAMPLE 1
A pyrophosphate-bicarbonate dialysis concentrate is prepared, which includes sodium pyrophosphate
(125 μM) and sodium bicarbonate (967 mM). The solution for dialysis is usually constituted during hemodialysis by mixing two concentrated solutions (concentrate for acid bath and concentrate for basic bath) with appropriate amounts of water. The pyrophosphate is added to the bicarbonate concentrate. It is found that pyrophosphate is stable and soluble at a concentration of
125 μM in the bicarbonate solution. The pyrophosphate remains soluble after the bicarbonate concentrate is diluted and combined with the acid dialysis solution to produce the final dialysis solution.
EXAMPLE 2
A concentrate of dialysis solution based on pyrophosphate-bicarbonate is prepared, which includes sodium pyrophosphate (125 μM) and sodium bicarbonate (967 mM). It is found that pyrophosphate is stable and soluble at a concentration of 125 μM in the bicarbonate solution. The pyrophosphate remains soluble after the bicarbonate concentrate is diluted and combined with an acid dialysis solution to produce the final dialysis solution. The resulting final dialysis solution is used to perform hemodialysis in a human with kidney disease. The patient experiences reduced calcium deposition in relation to what would have been expected if the patient had been treated with conventional hemodialysis solutions lacking pyrophosphate.
EXAMPLE 3
A concentrate of pyrophosphate-bicarbonate dialysis solution, which includes sodium pyrophosphate (100 μM) and sodium bicarbonate (967 mM), will be prepared. The basic dialysis solution is diluted with water, after mixing with the acid dialysis solution to produce the final dialysis solution. The resulting final dialysis solution is used to perform hemodialysis in a human with kidney disease.
EXAMPLE 4
A concentrate of pyrophosphate-bicarbonate dialysis solution is prepared, which includes sodium pyrophosphate (75 μM) and sodium bicarbonate (967 mM). The basic dialysis solution is diluted 25 times with water, then mixed with the acid dialysis solution to produce the final dialysis solution. The resulting final dialysis solution is used to perform hemodialysis in a human with kidney disease.
EXAMPLE 5
A concentrate for pyrophosphate-bicarbonate dialysis solution is prepared, which includes sodium pyrophosphate (90 μM), ferric pyrophosphate (10 μM) and sodium bicarbonate (967 mM). The basic dialysis solution is diluted 25 times with water, then mixed with the acid dialysis solution to produce the final dialysis solution. The resulting final dialysis solution is used to perform hemodialysis in a human with kidney disease.
EXAMPLE 6
A solution concentrate for acidic dialysis is prepared using standard ingredients in addition to sodium pyrophosphate (136 μM). The acid dialysis solution concentrate is diluted 34 times with water, then mixed with the basic dialysis solution to produce the final dialysis solution. The resulting final dialysis solution is used to perform hemodialysis in a human with kidney disease. It should be emphasized that the above described embodiments of the present description are only possible examples of implementations, and are indicated only for a clear understanding of the principles of the description. Many variations and modifications can be made to the embodiments of the description described above without departing substantially from the scope and principles of the description. All of said modifications and variations are intended to be included in the present invention within the scope of their description and protected by the following claims.
Claims (29)
1. A method for providing vascular calcification therapy to an individual in need of treatment comprising the step of administering to the individual an effective amount of a pyrophosphate-like compound.
2. The method according to claim 1, characterized in that the pyrophosphate type compound is an alkali metal pyrophosphate.
3. The method according to claim 1, characterized in that the pyrophosphate type compound is chosen from alkaline tetrametal pyrophosphate, diacid alkali metal dimetal pyrophosphate, mono-trimetal alkaline pyrophosphate, and mixtures thereof.
4. The method of according to claim 1, characterized in that the pyrophosphate type compound is chosen from tetrasodium pyrophosphate, tetrapotassium pyrophosphate, dicalcium pyrophosphate, phosphoric acid, sodium acid pyrophosphate, sodium dihydrogen pyrophosphate, and mixtures thereof.
5. - The method according to claim 1, characterized in that the vascular calcification is caused by disease or renal failure.
6. The method according to claim 1, which also comprises treating the individual with dialysis solution.
7. The method according to claim 1, characterized in that the pyrophosphate type compound is administered to the individual in a solution fluid for dialysis.
8. - The method according to claim 1, characterized in that the pyrophosphate type compound is administered to the individual during dialysis.
9. The method according to claim 1, characterized in that the pyrophosphate type compound has the following structural formula: 0"X + I?" X + o = p-o-P = 0 0"X ^ O"? + wherein X is chosen from at least one of a hydrogen and a cation.
10. - The method according to claim 9, characterized in that each X is chosen individually to be at least one of: hydrogen, sodium, potassium, and calcium.
11. The method according to claim 1, characterized in that the pyrophosphate type compound is administered to the individual in a dialysis solution fluid at a pyrophosphate-type compound concentration of at least about 1 μM.
12. The method according to claim 1, characterized in that the pyrophosphate type compound is administered to the individual in a solution fluid for dialysis at a pyrophosphate-type compound concentration from approximately 1 μM to approximately 10 μM.
13. The method according to claim 1, characterized in that the pyrophosphate type compound is administered to the individual in a solution for dialysis at a concentration of approximately 3 μM to approximately 5 μM.
14. A method for prophylactically treating vascular calcification comprising administering to an individual in need of treatment an effective amount of at least one pyrophosphate-like compound.
15. The method according to claim 14, characterized in that the pyrophosphate type compound is an alkali metal pyrophosphate.
16. The method according to claim 14, characterized in that the pyrophosphate type compound is administered to the individual in a solution for dialysis.
17. A pharmaceutical composition comprising at least one pyrophosphate-type compound in combination with a pharmaceutically acceptable carrier, characterized in that said at least one pyrophosphate-like compound is present at an effective dose level to treat vascular calcification.
18. The pharmaceutical composition according to claim 17, characterized in that said at least one pyrophosphate type compound is an alkali metal pyrophosphate.
19. The pharmaceutical composition according to claim 17, characterized in that said at least one pyrophosphate type compound includes pharmaceutically acceptable salts of the pyrophosphate type compound.
20. The pharmaceutical composition according to claim 17, characterized in that said at least one pyrophosphate type compound includes pharmaceutically acceptable prodrugs of the pyrophosphate type compound.
21. The pharmaceutical composition according to claim 17, characterized in that the pharmaceutically acceptable carrier is a solution for dialysis.
22. A method for hemodialyzing an individual in need of the same, comprising the steps of: diffusing dialysis solution comprising at least one pyrophosphate-like compound through a membrane in a hemodialysis system, and exposing the individual to an effective amount of the pyrophosphate type compound.
23. The method according to claim 22, characterized in that the pyrophosphate type compound is an alkali metal pyrophosphate.
24. The method according to claim 22, which also comprises treating vascular calcification in the individual by exposing the individual to an effective amount of the pyrophosphate-type compound.
25. A concentrate of dialysis solution comprising at least one pyrophosphate type compound.
26. The dialysis solution concentrate according to claim 25, characterized in that said at least one pyrophosphate type compound has the formula of the following structure: 0'X + or "? + O = p I - o- -PI = 0 1. 0"X + 0" X + wherein X is chosen from at least one of a hydrogen and a cation.
27. The dialysis solution concentrate according to claim 26, characterized in that each X is chosen individually to be at least one of: hydrogen, sodium, potassium, and calcium.
28. The dialysis solution concentrate according to claim 25, characterized in that the pyrophosphate type compound is present in the concentrate of dialysis solution at a concentration from 50 μM to approximately 1 mM.
29. - The dialysis solution concentrate according to claim 25, characterized in that said at least one pyrophosphate type compound has the formula of the following structure: O-R O-R I I o = p-o-p = o I I O-R O-R wherein R is individually selected such that it is a functional group of at least one of hydrogen, alkyl groups, aryl groups, halogen groups (F, Cl, Br, and I) hydroxy groups, alkoxy groups, alkylamino groups, dialkylamino groups, acyl groups, carboxyl groups, carboamido groups, sulfonamide groups, aminoacyl groups, amide groups, amine groups, nitro groups, organo-selenium compounds, hydrocarbons, cyclic hydrocarbons, hydrogen, nitrogen, oxygen, sulfur, NR, and CR . 30.- A system for hemodialysis, which includes: a compartment for blood; a membrane in fluid communication with the blood compartment; and the dialysis solution compartment, the dialysis solution compartment comprises a dialysis solution comprising a pyrophosphate-like compound. 31. The system for hemodialysis according to claim 30, characterized in that the pyrophosphate type compound is an alkali metal pyrophosphate. 32. The system for hemodialysis according to claim 30, characterized in that the pyrophosphate type compound has the formula of the following structure: 0"X + O" v + II i = p-o-p = o 0'X + O "? + In which X is chosen from at least one of a hydrogen and a cation 33.- The system for hemodialysis according to claim 32, characterized in that each X is chosen individually to be at least one of: hydrogen, sodium, potassium and calcium 34.- The hemodialysis system according to claim 30, characterized in that The pyrophosphate type compound is administered to the individual in a solution for dialysis at a concentration of at least about 1 μM.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/515,174 | 2003-10-28 |
Publications (1)
Publication Number | Publication Date |
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MXPA06004730A true MXPA06004730A (en) | 2006-10-17 |
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