MX2012005976A - Pharmaceutical compositions for the stimulation of stem cells. - Google Patents
Pharmaceutical compositions for the stimulation of stem cells.Info
- Publication number
- MX2012005976A MX2012005976A MX2012005976A MX2012005976A MX2012005976A MX 2012005976 A MX2012005976 A MX 2012005976A MX 2012005976 A MX2012005976 A MX 2012005976A MX 2012005976 A MX2012005976 A MX 2012005976A MX 2012005976 A MX2012005976 A MX 2012005976A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutical composition
- pharmaceutical
- factor
- previous
- fgf
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 52
- 210000000130 stem cell Anatomy 0.000 title claims abstract description 31
- 230000000638 stimulation Effects 0.000 title claims abstract description 10
- 239000002269 analeptic agent Substances 0.000 claims abstract description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 84
- 230000000747 cardiac effect Effects 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 claims description 22
- 102100037852 Insulin-like growth factor I Human genes 0.000 claims description 21
- 108010023082 activin A Proteins 0.000 claims description 16
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 claims description 15
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 claims description 15
- 230000008569 process Effects 0.000 claims description 15
- 241001465754 Metazoa Species 0.000 claims description 13
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 claims description 13
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 claims description 13
- 210000005003 heart tissue Anatomy 0.000 claims description 13
- 102000019034 Chemokines Human genes 0.000 claims description 12
- 108010012236 Chemokines Proteins 0.000 claims description 12
- LKBSMPFEKIBRGC-UHFFFAOYSA-N 2-[[2-(4-methoxyanilino)-4-pyrimidinyl]amino]ethanol Chemical compound C1=CC(OC)=CC=C1NC1=NC=CC(NCCO)=N1 LKBSMPFEKIBRGC-UHFFFAOYSA-N 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 11
- 102000004889 Interleukin-6 Human genes 0.000 claims description 10
- 108090001005 Interleukin-6 Proteins 0.000 claims description 10
- 239000013543 active substance Substances 0.000 claims description 10
- 229940100601 interleukin-6 Drugs 0.000 claims description 10
- 239000011164 primary particle Substances 0.000 claims description 9
- 102100024505 Bone morphogenetic protein 4 Human genes 0.000 claims description 8
- 102100028892 Cardiotrophin-1 Human genes 0.000 claims description 8
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 8
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 8
- 108010041776 cardiotrophin 1 Proteins 0.000 claims description 8
- -1 deirudina Chemical compound 0.000 claims description 8
- 229930002330 retinoic acid Natural products 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 229960001727 tretinoin Drugs 0.000 claims description 8
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 claims description 7
- 102100021866 Hepatocyte growth factor Human genes 0.000 claims description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- 230000008929 regeneration Effects 0.000 claims description 7
- 238000011069 regeneration method Methods 0.000 claims description 7
- 108010049955 Bone Morphogenetic Protein 4 Proteins 0.000 claims description 6
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 208000010125 myocardial infarction Diseases 0.000 claims description 6
- 239000011163 secondary particle Substances 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims description 5
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims description 5
- 108010009583 Transforming Growth Factors Proteins 0.000 claims description 5
- 102000009618 Transforming Growth Factors Human genes 0.000 claims description 5
- 102100040247 Tumor necrosis factor Human genes 0.000 claims description 5
- 239000003102 growth factor Substances 0.000 claims description 5
- 230000004936 stimulating effect Effects 0.000 claims description 5
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims description 5
- 102100021943 C-C motif chemokine 2 Human genes 0.000 claims description 4
- 102100021935 C-C motif chemokine 26 Human genes 0.000 claims description 4
- 102100032367 C-C motif chemokine 5 Human genes 0.000 claims description 4
- 102100032366 C-C motif chemokine 7 Human genes 0.000 claims description 4
- 229920001661 Chitosan Polymers 0.000 claims description 4
- 229920001634 Copolyester Polymers 0.000 claims description 4
- 229920002307 Dextran Polymers 0.000 claims description 4
- 102000018233 Fibroblast Growth Factor Human genes 0.000 claims description 4
- 108050007372 Fibroblast Growth Factor Proteins 0.000 claims description 4
- 102100020997 Fractalkine Human genes 0.000 claims description 4
- 102000004858 Growth differentiation factor-9 Human genes 0.000 claims description 4
- 108090001086 Growth differentiation factor-9 Proteins 0.000 claims description 4
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 claims description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 4
- 102100026236 Interleukin-8 Human genes 0.000 claims description 4
- 108090001007 Interleukin-8 Proteins 0.000 claims description 4
- 108010056852 Myostatin Proteins 0.000 claims description 4
- 102000015336 Nerve Growth Factor Human genes 0.000 claims description 4
- 102000007072 Nerve Growth Factors Human genes 0.000 claims description 4
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 claims description 4
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 claims description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 4
- 108010010469 Qa-SNARE Proteins Proteins 0.000 claims description 4
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 claims description 4
- 102400001320 Transforming growth factor alpha Human genes 0.000 claims description 4
- 101800004564 Transforming growth factor alpha Proteins 0.000 claims description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 4
- 230000000295 complement effect Effects 0.000 claims description 4
- 208000019622 heart disease Diseases 0.000 claims description 4
- 229960002897 heparin Drugs 0.000 claims description 4
- 229920000669 heparin Polymers 0.000 claims description 4
- 239000002502 liposome Substances 0.000 claims description 4
- 239000004005 microsphere Substances 0.000 claims description 4
- 239000002077 nanosphere Substances 0.000 claims description 4
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 4
- 229920001610 polycaprolactone Polymers 0.000 claims description 4
- 239000004632 polycaprolactone Substances 0.000 claims description 4
- 229920000728 polyester Polymers 0.000 claims description 4
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 claims description 3
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 claims description 3
- 102100036848 C-C motif chemokine 20 Human genes 0.000 claims description 3
- 102100036150 C-X-C motif chemokine 5 Human genes 0.000 claims description 3
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 claims description 3
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 claims description 3
- 102100034221 Growth-regulated alpha protein Human genes 0.000 claims description 3
- 241000282412 Homo Species 0.000 claims description 3
- 101000713099 Homo sapiens C-C motif chemokine 20 Proteins 0.000 claims description 3
- 101000947186 Homo sapiens C-X-C motif chemokine 5 Proteins 0.000 claims description 3
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 claims description 3
- 102100033237 Pro-epidermal growth factor Human genes 0.000 claims description 3
- 230000004520 agglutination Effects 0.000 claims description 3
- 208000031225 myocardial ischemia Diseases 0.000 claims description 3
- 210000003462 vein Anatomy 0.000 claims description 3
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 claims description 2
- BWRRWBIBNBVHQF-UHFFFAOYSA-N 4-(3-pyridin-2-yl-1,2,4-oxadiazol-5-yl)butanoic acid Chemical compound O1C(CCCC(=O)O)=NC(C=2N=CC=CC=2)=N1 BWRRWBIBNBVHQF-UHFFFAOYSA-N 0.000 claims description 2
- 108010038798 Actin Depolymerizing Factors Proteins 0.000 claims description 2
- 102000015693 Actin Depolymerizing Factors Human genes 0.000 claims description 2
- 102000009840 Angiopoietins Human genes 0.000 claims description 2
- 108010009906 Angiopoietins Proteins 0.000 claims description 2
- 102400000345 Angiotensin-2 Human genes 0.000 claims description 2
- 101800000733 Angiotensin-2 Proteins 0.000 claims description 2
- 101000840545 Bacillus thuringiensis L-isoleucine-4-hydroxylase Proteins 0.000 claims description 2
- 108010081589 Becaplermin Proteins 0.000 claims description 2
- 108010049931 Bone Morphogenetic Protein 2 Proteins 0.000 claims description 2
- 108010049976 Bone Morphogenetic Protein 5 Proteins 0.000 claims description 2
- 108010049974 Bone Morphogenetic Protein 6 Proteins 0.000 claims description 2
- 102100028728 Bone morphogenetic protein 1 Human genes 0.000 claims description 2
- 108090000654 Bone morphogenetic protein 1 Proteins 0.000 claims description 2
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 claims description 2
- 102100022526 Bone morphogenetic protein 5 Human genes 0.000 claims description 2
- 102100022525 Bone morphogenetic protein 6 Human genes 0.000 claims description 2
- 101710155857 C-C motif chemokine 2 Proteins 0.000 claims description 2
- 101710155834 C-C motif chemokine 7 Proteins 0.000 claims description 2
- 102100025279 C-X-C motif chemokine 11 Human genes 0.000 claims description 2
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 claims description 2
- 101800000594 Capsid protein 1 Proteins 0.000 claims description 2
- 102100025597 Caspase-4 Human genes 0.000 claims description 2
- 101710090338 Caspase-4 Proteins 0.000 claims description 2
- 108010075016 Ceruloplasmin Proteins 0.000 claims description 2
- 102100023321 Ceruloplasmin Human genes 0.000 claims description 2
- 108010083698 Chemokine CCL26 Proteins 0.000 claims description 2
- 108010055166 Chemokine CCL5 Proteins 0.000 claims description 2
- 108010078239 Chemokine CX3CL1 Proteins 0.000 claims description 2
- 108010008951 Chemokine CXCL12 Proteins 0.000 claims description 2
- 108010072220 Cyclophilin A Proteins 0.000 claims description 2
- 102000012192 Cystatin C Human genes 0.000 claims description 2
- 108010061642 Cystatin C Proteins 0.000 claims description 2
- 102000004127 Cytokines Human genes 0.000 claims description 2
- 108090000695 Cytokines Proteins 0.000 claims description 2
- 101800003838 Epidermal growth factor Proteins 0.000 claims description 2
- 102000003951 Erythropoietin Human genes 0.000 claims description 2
- 102100031939 Erythropoietin Human genes 0.000 claims description 2
- 108090000394 Erythropoietin Proteins 0.000 claims description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 claims description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 claims description 2
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 claims description 2
- 102000003971 Fibroblast Growth Factor 1 Human genes 0.000 claims description 2
- 108050003239 Fibroblast growth factor 12 Proteins 0.000 claims description 2
- 102100028417 Fibroblast growth factor 12 Human genes 0.000 claims description 2
- 102100035308 Fibroblast growth factor 17 Human genes 0.000 claims description 2
- 108050002085 Fibroblast growth factor 20 Proteins 0.000 claims description 2
- 102100031361 Fibroblast growth factor 20 Human genes 0.000 claims description 2
- 102100028072 Fibroblast growth factor 4 Human genes 0.000 claims description 2
- 108090000381 Fibroblast growth factor 4 Proteins 0.000 claims description 2
- 108090000380 Fibroblast growth factor 5 Proteins 0.000 claims description 2
- 102100028073 Fibroblast growth factor 5 Human genes 0.000 claims description 2
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 claims description 2
- 108010024164 HLA-G Antigens Proteins 0.000 claims description 2
- 108010007267 Hirudins Proteins 0.000 claims description 2
- 102000007625 Hirudins Human genes 0.000 claims description 2
- 101000897493 Homo sapiens C-C motif chemokine 26 Proteins 0.000 claims description 2
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 claims description 2
- 101000797758 Homo sapiens C-C motif chemokine 7 Proteins 0.000 claims description 2
- 101000858060 Homo sapiens C-X-C motif chemokine 11 Proteins 0.000 claims description 2
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 claims description 2
- 101000854520 Homo sapiens Fractalkine Proteins 0.000 claims description 2
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 claims description 2
- 101001055222 Homo sapiens Interleukin-8 Proteins 0.000 claims description 2
- 101001001487 Homo sapiens Phosphatidylinositol-glycan biosynthesis class F protein Proteins 0.000 claims description 2
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 claims description 2
- 101100273566 Humulus lupulus CCL10 gene Proteins 0.000 claims description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 2
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 claims description 2
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 claims description 2
- 102100039064 Interleukin-3 Human genes 0.000 claims description 2
- 108010002386 Interleukin-3 Proteins 0.000 claims description 2
- 102000004890 Interleukin-8 Human genes 0.000 claims description 2
- 102000004856 Lectins Human genes 0.000 claims description 2
- 108090001090 Lectins Proteins 0.000 claims description 2
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 2
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 claims description 2
- 101000878182 Mus musculus Fibroblast growth factor 15 Proteins 0.000 claims description 2
- 102100029268 Neurotrophin-3 Human genes 0.000 claims description 2
- 101800000838 Neutrophil cationic peptide 1 Proteins 0.000 claims description 2
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 claims description 2
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 claims description 2
- 108700023477 Nucleoside diphosphate kinases Proteins 0.000 claims description 2
- 102100034539 Peptidyl-prolyl cis-trans isomerase A Human genes 0.000 claims description 2
- 102100027913 Peptidyl-prolyl cis-trans isomerase FKBP1A Human genes 0.000 claims description 2
- 102100035194 Placenta growth factor Human genes 0.000 claims description 2
- 102000011195 Profilin Human genes 0.000 claims description 2
- 108050001408 Profilin Proteins 0.000 claims description 2
- 102000015799 Qa-SNARE Proteins Human genes 0.000 claims description 2
- 101001037255 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Indoleamine 2,3-dioxygenase Proteins 0.000 claims description 2
- 101710088580 Stromal cell-derived factor 1 Proteins 0.000 claims description 2
- 102000050707 Syntaxin-11 Human genes 0.000 claims description 2
- 108010006877 Tacrolimus Binding Protein 1A Proteins 0.000 claims description 2
- 229940122388 Thrombin inhibitor Drugs 0.000 claims description 2
- 102000036693 Thrombopoietin Human genes 0.000 claims description 2
- 102100034195 Thrombopoietin Human genes 0.000 claims description 2
- 108010041111 Thrombopoietin Proteins 0.000 claims description 2
- 102400000757 Ubiquitin Human genes 0.000 claims description 2
- 108090000848 Ubiquitin Proteins 0.000 claims description 2
- 108010073923 Vascular Endothelial Growth Factor C Proteins 0.000 claims description 2
- 102100038232 Vascular endothelial growth factor C Human genes 0.000 claims description 2
- 229950006323 angiotensin ii Drugs 0.000 claims description 2
- 229960003856 argatroban Drugs 0.000 claims description 2
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 claims description 2
- 210000001367 artery Anatomy 0.000 claims description 2
- 108010055460 bivalirudin Proteins 0.000 claims description 2
- 229960001500 bivalirudin Drugs 0.000 claims description 2
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 claims description 2
- 229960003850 dabigatran Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 229940116977 epidermal growth factor Drugs 0.000 claims description 2
- 229940105423 erythropoietin Drugs 0.000 claims description 2
- 210000002744 extracellular matrix Anatomy 0.000 claims description 2
- 108090000047 fibroblast growth factor 13 Proteins 0.000 claims description 2
- 210000003494 hepatocyte Anatomy 0.000 claims description 2
- 229940006607 hirudin Drugs 0.000 claims description 2
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 102000006495 integrins Human genes 0.000 claims description 2
- 108010044426 integrins Proteins 0.000 claims description 2
- 229940076264 interleukin-3 Drugs 0.000 claims description 2
- 229940096397 interleukin-8 Drugs 0.000 claims description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 239000002523 lectin Substances 0.000 claims description 2
- 229960004408 lepirudin Drugs 0.000 claims description 2
- OTQCKZUSUGYWBD-BRHMIFOHSA-N lepirudin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)[C@@H](C)O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 OTQCKZUSUGYWBD-BRHMIFOHSA-N 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 210000002540 macrophage Anatomy 0.000 claims description 2
- DKWNMCUOEDMMIN-PKOBYXMFSA-N melagatran Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](NCC(O)=O)C2CCCCC2)CC1 DKWNMCUOEDMMIN-PKOBYXMFSA-N 0.000 claims description 2
- 229960002137 melagatran Drugs 0.000 claims description 2
- 230000005012 migration Effects 0.000 claims description 2
- 238000013508 migration Methods 0.000 claims description 2
- 230000001002 morphogenetic effect Effects 0.000 claims description 2
- 229940053128 nerve growth factor Drugs 0.000 claims description 2
- 239000003900 neurotrophic factor Substances 0.000 claims description 2
- 108010017843 platelet-derived growth factor A Proteins 0.000 claims description 2
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000186 progesterone Substances 0.000 claims description 2
- 229960003387 progesterone Drugs 0.000 claims description 2
- 239000003868 thrombin inhibitor Substances 0.000 claims description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 claims description 2
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 claims description 2
- 229960001522 ximelagatran Drugs 0.000 claims description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims 4
- 102000004877 Insulin Human genes 0.000 claims 2
- 108090001061 Insulin Proteins 0.000 claims 2
- 102000014429 Insulin-like growth factor Human genes 0.000 claims 2
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 claims 2
- 229940125396 insulin Drugs 0.000 claims 2
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 claims 1
- 101710084373 Lipase 1 Proteins 0.000 claims 1
- 102100030335 Midkine Human genes 0.000 claims 1
- 108010092801 Midkine Proteins 0.000 claims 1
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 claims 1
- 102100037765 Periostin Human genes 0.000 claims 1
- 101710199268 Periostin Proteins 0.000 claims 1
- 102000056172 Transforming growth factor beta-3 Human genes 0.000 claims 1
- 108090000097 Transforming growth factor beta-3 Proteins 0.000 claims 1
- 101150109862 WNT-5A gene Proteins 0.000 claims 1
- 102000043366 Wnt-5a Human genes 0.000 claims 1
- 108700020483 Wnt-5a Proteins 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 230000007850 degeneration Effects 0.000 claims 1
- 230000002518 glial effect Effects 0.000 claims 1
- 230000002132 lysosomal effect Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 28
- 206010061216 Infarction Diseases 0.000 description 22
- 230000007574 infarction Effects 0.000 description 22
- 210000004165 myocardium Anatomy 0.000 description 15
- 230000000694 effects Effects 0.000 description 11
- 239000008055 phosphate buffer solution Substances 0.000 description 11
- 229920001184 polypeptide Polymers 0.000 description 11
- 102000004196 processed proteins & peptides Human genes 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 210000002216 heart Anatomy 0.000 description 9
- 210000000107 myocyte Anatomy 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 210000001185 bone marrow Anatomy 0.000 description 8
- 108090000190 Thrombin Proteins 0.000 description 7
- 210000004413 cardiac myocyte Anatomy 0.000 description 7
- 230000004069 differentiation Effects 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000008439 repair process Effects 0.000 description 6
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 5
- 208000003569 Central serous chorioretinopathy Diseases 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 229960004072 thrombin Drugs 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 102000013275 Somatomedins Human genes 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000006166 lysate Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000002107 myocardial effect Effects 0.000 description 4
- 230000002861 ventricular Effects 0.000 description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 210000004088 microvessel Anatomy 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 230000001172 regenerating effect Effects 0.000 description 3
- 231100000241 scar Toxicity 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 150000002266 vitamin A derivatives Chemical class 0.000 description 3
- 101000762379 Homo sapiens Bone morphogenetic protein 4 Proteins 0.000 description 2
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 2
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 2
- 239000008156 Ringer's lactate solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 101150067309 bmp4 gene Proteins 0.000 description 2
- 230000001010 compromised effect Effects 0.000 description 2
- 239000003636 conditioned culture medium Substances 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 210000002064 heart cell Anatomy 0.000 description 2
- 238000003364 immunohistochemistry Methods 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- QQAHYSZVJLHCNA-UHFFFAOYSA-N 2-[[2-(4-methoxyanilino)pyrimidin-4-yl]amino]ethanol;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1NC1=NC=CC(NCCO)=N1 QQAHYSZVJLHCNA-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102400001368 Epidermal growth factor Human genes 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 1
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 101001052035 Homo sapiens Fibroblast growth factor 2 Proteins 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 101000942967 Homo sapiens Leukemia inhibitory factor Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 1
- 102100026001 Lysosomal acid lipase/cholesteryl ester hydrolase Human genes 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010055297 Sterol Esterase Proteins 0.000 description 1
- 208000033774 Ventricular Remodeling Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- ZEWYCNBZMPELPF-UHFFFAOYSA-J calcium;potassium;sodium;2-hydroxypropanoic acid;sodium;tetrachloride Chemical compound [Na].[Na+].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[Ca+2].CC(O)C(O)=O ZEWYCNBZMPELPF-UHFFFAOYSA-J 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 230000003021 clonogenic effect Effects 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000037020 contractile activity Effects 0.000 description 1
- 210000003748 coronary sinus Anatomy 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 102000044162 human IGF1 Human genes 0.000 description 1
- 102000052611 human IL6 Human genes 0.000 description 1
- 102000046645 human LIF Human genes 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- 102000058223 human VEGFA Human genes 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000009168 stem cell therapy Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1833—Hepatocyte growth factor; Scatter factor; Tumor cytotoxic factor II
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1841—Transforming growth factor [TGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a human or veterinary pharmaceutical composition (B) for the stimulation of stem cells, comprising at least two stem-cells-stimulating- agents and at least one pharmaceutically acceptable excipient.
Description
PHARMACEUTICAL COMPOSITIONS FOR THE STIMULATION OF .LOS
CITOBLASTOS
Field of the Invention
The present invention relates generally to pharmaceutical compositions suitable for targeting organs and / or tissues. In particular, it relates to the treatment of heart diseases by means of the administration of cytoblast stimulating agents to the heart of an individual having a need for the regeneration of heart tissue. In particular, it discloses the use of such cytoblast stimulating agents to improve the regeneration of cardiac tissue from cardiac cytoblasts in vivo.
Background of the Invention
Myocardial infarction (MI) leads to loss of cardiomyocytes, scar formation, ventricular remodeling, and eventually heart failure. Pharmacological interventions, based on catheters and surgical, have led to improved survival of patients with coronary artery disease (CAD), although they fail to regenerate the dead myocardium. Consequently, reduced mortality is accompanied by increased morbidity due to ischemic heart failure. In years
REF.230761 recent, stem cell therapy has emerged as a potential new strategy for cardiac repair (Dimmeler S. et al., J Clin Invest 2005, 11, 572-583). The optimal source of cells to repair damaged myocardium is a topic of intense research. The important characteristics of the stem cells for cardiac regeneration include self-renewal, clonogenicity, and the ability to differentiate them in cardiomyocytes, endothelial cells and vascular smooth muscle cells.
Over the past 10 years, researchers have applied several progenitor / stem cells, derived from the bone marrow (BM), for cardiac repair therapy in animal studies, such as lineage BM stem cells. negative (lin neg), positive to c-kit (c-kit pos), (Orlic et al., Nature 2001; 410: 701-705; Kajstura et al., Circ Res. 2005; 96: 127-137; Rota et al., Proc Nati Acad Sci USA 2007; 104: 17783-17788), the mesenchymal stem cells derived from BM (MSCs) (Min et al., Ann Thor Surg 2002; 74: 1568-1575; Amado et al., Proc Nati Acad Sci USA 2005; 102: 11474-11479) and endothelial progenitor cells (EPCs) (Cho et al., J Exp Med 2007; 204: 3257-3269; Schuh et al., Basic Res Cardiol 2008; 103: 60-77). Although these studies show the differentiation of progenitor / stem cells, derived from BM in cells with the distinctive characteristics of cardiomyocytes and vascular cells, other studies suggested that transplanted BM stem cells do not actually acquire a cardiac phenotype. in the injured heart (Balsam et al., Nature 2004; 428: 668-673; Murry et al., Nature 2004; 428: 664-668; Nygren et al., Nat Med 2004; 10: 494-501).
Therefore, improving the differentiation of progenitor / stem cells derived from BM after transplantation remains a great challenge for researchers to effectively utilize these cells in cardiac regenerative therapy. Other sources of stem cells can be used for cardiac regenerative therapy apart from progenitor / stem cells derived from BM. In particular, resident cardiac cytoblasts (CSCs) were discovered in the heart itself (Beltrami et al., Cell 2003; 114: 763-776; Uranek et al., Proc Nati Sci USA 2006; 103: 9226-9231). Because the CSCs already reside within the heart and are programmed to generate cardiac tissue, they represent a logical source for exploitation in cardiac regenerative therapy, when a massive loss of cardiac tissue has occurred. Since the CSCs have unique characteristics, the identification of the resident CSCs create a great excitation and intense diffused stimulation, for the regeneration of the myocardium with the cells that are of the own heart and that for this reason are inherently programmed to reconstitute the cardiac tissue.
Myocardial repair requires the formation of new myocytes and coronary vessels, and can not be effected by a cell already fully compromised with respect to myocyte lineage. In the presence of an infarction, the generation of myocytes alone can not restore contractile functioning in the akinetic region, - the myocytes will not grow or survive in the absence of vessel formation. Arterioles are critical for blood supply, and oxygen supply is controlled by the capillary network. Similarly, neovasculogenesis alone could not restore the dead myocardium or reinstitute contractile activity in the infarcted portion of the ventricular wall. The observation that CSCs injected locally into the infarcted myocardium of animals repaired the necrotic tissue and improved ventricular function (Beltrami et al., Cell 2003; 114: 763-776; Bearzi et al., Proc Nati Sci USA 2007; 104: 14068-14073) has formed the basis of a new paradigm in which CSCs are involved in the normal turnover of myocytes, endothelial cells, smooth muscle cells, and fibroblasts. In an attempt to develop strategies that reveal the future treatment of patients, new hypotheses have emerged that move in the field in a direction that defines CSC therapy clinically on an individual basis.
Accordingly, several attempts have been made to use the discovered CSCs for clinical applications. The first method is the isolation, cultivation, cloning and expansion of CSCs. Such cells could be injected back into the infarcted heart in an attempt to regenerate the functional myocardium. However, the healing capacity of the CSC cell population, combined with the strict conditions of cell culture and poor yield, are limiting factors for using this method. The other alternative described in the art is the recruitment and differentiation of endogenous CSCs using exogenous agents. However, no clear evidence on the efficacy of this method has been described, causing uncertainty about the ability to recruit and effectively differentiate CSCs in vivo.
Brief Description of the Invention
The present invention provides a totally novel method for stimulating resident CSCs in vivo and, in one aspect, for committing them to the cardiac lineage particularly to obtain from them a significant number of satisfactorily functional cells with the distinctive characteristics of cardiomyocytes.
The invention relates to a human or veterinary pharmaceutical composition (B) for the stimulation of the stem cells, comprising at least two agents stimulating the stem cells and at least one pharmaceutically acceptable excipient.
At least two cytoblast stimulating agents can be selected from the group consisting of TGFp-1, BMP-4, FGF-2, IGF-1, Activin-A, alf-thrombin, Cardiotrophin 1, Cardiogenol C and mixtures thereof. . In particular, at least two cytoblast stimulating agents can be selected from the group consisting of TGFp-1, BMP-4, FGF-2, IGF-1, Activin-A, Cardiotrophin 1, Cardiogenol C and mixtures thereof.
The invention also relates to a pharmaceutical cocktail comprising a pharmaceutical composition (B) according to the present invention and a composition (A) comprising at least one pharmaceutically active substance. The composition or cocktail of the present invention makes it possible to provide cytoblasts guided by the stimulating agent which means that the resistant cardiac stem cells, after having been put in contact with the composition or cocktail, are stimulated to enter into differentiation. Therefore, stimulated stem cells can be involved in a cardiac lineage and can become cardiomyocytes.
Within the framework of this document, and unless there is an indication to the contrary, the terms subsequently designated in quotation marks have the following definitions.
When used herein, the term "stimulation or stimulant" refers to the recruitment, proliferation, survival and / or differentiation of the stem cells.
When used herein, the terms "cardiac tissue" and "myocardium" refer to myocytes, blood vessels and fibroblasts.
"Cardiac cytoblast" (CSC), "cardiac progenitor cell", "resident cardiac cytoblast" or "resident cardiac progenitor cell" designates the cytoblast that is present in the myocardium. They are self-renewing, clonogenic, multipotent and can generate the myocardium.
A "stimulating agent of the stem cells" is an agent that improves the capacity of the stem cells, to be recruited to the site to be regenerated, so that they proliferate and differentiate in the cardiac tissue.
A "composition of the cytoblast stimulating agent" is a composition comprising at least two cytoblast stimulating agents.
A "cytoblasto guided by the stimulating agent" is a cytoblast that was in contact with a composition of the cytoblast stimulating agent as defined above and that also enters into differentiation, that is, is compromised in the cardiac lineage.
"Differentiation" is the process by which a less specialized cell becomes a more specialized cell.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person with ordinary experience in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated for reference in their entirety. In case of conflict, the present specification, including the definitions, will control the meaning of the terms of the present invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.
Detailed description of the invention
In a preferred embodiment, the pharmaceutical composition (B) can comprise at least five cytoblast stimulating agents selected from the group consisting of TGFp-1, BMP-4, FGF-2, IGF-1, Activin-A, Cardiotrophin 1, Cardiogenol C and mixtures thereof.
In particular, the pharmaceutical composition (B) may comprise TGFp-1, BMP-4, FGF-2, IGF-1, Activin-A, Cardiotrophin 1, and Cardiogenol C.
In addition, the pharmaceutical composition (B) may optionally further comprise alpha-thrombin. The pharmaceutical composition (B) may further comprise thrombin inhibitors, such as hirudin, bivalirudin, lepirudin, deirudin, argatroban, melagatran, ximelagatran, dabigatran, and heparin. Alpha-thrombin is a coagulating agent. Alternatively, in some cases, the pharmaceutical composition (B) may optionally be free of alpha-thrombin.
The pharmaceutical composition (B) of the present invention may further comprise at least one substance selected from the group consisting of growth factors, cytokines, hormones and combinations thereof. At least one substance can be selected from the group consisting of:
- Morphogenetic bone proteins (BMPs) such as BMP-1, BMP-2, BMP-5, BMP-6;
- the epidermal growth factor (EGF, for its acronym in English);
- erythropoietin (EPO, for its acronym in English);
- Fibroblast growth factors (FGF) such as FGF-1, FGF-4, FGF-5, FGF-12, FGF-13, FGF-15, FGF-20;
the granulocyte colony stimulating factor (G-GSF, for its acronym in English)
the stimulating factor of the macrophage-granulocyte colony (GM-CSF, for its acronym in English);
- the growth differentiation factor 9 (GDF-9);
the growth factor of hepatocytes (HGF, for its acronym in English);
- the insulin-like growth factor (IGF) such as IGF-2;
- myostatin (GDF-8);
- neurotrophins such as NT-3, NT-4, NT-1 and nerve growth factor (NGF, for its acronym in English);
the platelet derived growth factor (PDGF) such as PDGF-beta, PDGF-AA, PDGF-BB;
- thrombopoietin (TPO, for its acronym in English);
TGF- (transforming growth factor alpha)
p transformation growth factors, (TGF-β) such as TGF-β ?, TGF-02, TGF-p3;
- VEGF (vascular endothelial growth factor) such as VEGF-A, VEGF-C;
- TNF-a, Leukemia inhibitor factor (LIF), interleukin 6 (IL-6), retinoic acid, SDF-1 C (stromal cell-derived factor 1), BDNF ( neurotrophic factor derived from the brain), Periostine, Angiotensin II, Ligand FIt3, Glial Derived Neurotrophic Factor, Heparin, Agglutination Protein 3 to Insulin-like Growth Factor, Agglutination Protein 5 to Insulin-like Growth Factor, Interleukin 3, Interleukin 8, Midchin, Progesterone, Putrescein, Cytoblast Factor, TGF-alpha, ntl, nt3a, nt5a, caspase-4, chemokine ligand 1, chemokine ligand 2, chemokine ligand 5, ligand 7 of the chemokine, ligand 11 of the chemokine, ligand 20 of the chemokine, haptaglobin, lectin, 25-hydroxylase cholesterol, syntaxin-8, syntaxin-11, ceruloplasmin, component 1 of the complement, component 3 of the complement, alpha integrin 6, 1 lysosomal acid lipase, -2 ml croglobulin, ubiquitin, macrophage migration inhibiting factor, cofilin, cyclophilin A, FKBP12, NDPK, profilin 1, cystatin C, calcicin, staiocalcin-1, PGE-2, mpCCL2, IDO, iNOS, HLA-G5, M-CSF , angiopoietin, PIGF, CP-1, extracellular matrix molecules, CCL2 (MCP-1), CCL3 (??? - 1a), CCL4 (??? - 1Âß), CCL5 (RANTES), CCL7 (MCP-3) ), CCL20 (?? - 3a), CCL26 (eotaxin-3), CX3CL1 (fractalkine), CXCL5 (??? - 78), CXCL11 (i-TAC), CXCL1 (GROOÍ), CXCL2 (GROp), CXCL8 ( IL-8), CCL10 (??? 10) and combinations thereof.
The stem cells that are to be stimulated may be resident cardiac cytoblasts (CSCs) or circulating cytoblasts or injected stem cells.
The pharmaceutical composition may comprise primary particles. The primary particles may be selected from the group consisting of alginates, chitosan, dextran, cellulose, liposomes, or microspheres or polyester nanospheres such as PLGA, polycaprolactone or copolyesters. Preferably, the primary particles can encapsulate at least two cytoblast stimulating agents of the pharmaceutical composition (B). Accordingly, the primary particles can encapsulate the cytoblast stimulating agents comprised in the pharmaceutical composition (B). The term "primary" means that the pharmaceutical composition can be encapsulated in a first type of particles as defined above.
Preferably, the pharmaceutical composition (B) can be combined with a composition (A) comprising at least one pharmaceutically active substance to form a pharmaceutical cocktail. In one embodiment, at least one pharmaceutically active substance can be selected from the group consisting of insulin-like growth factor 1 (IGF-1), hepatocyte growth factor (HGF) and / or variants thereof such as NK1, 1K1, 1K2, HP11, or HP21, and combinations thereof. In another embodiment, the composition (A) may further comprise SCF-1. The composition (A) may further comprise secondary particles selected from the group consisting of alginates, chitosan, dextran, cellulose, liposomes, or microspheres or nanospheres of polyesters such as PLGA, polycaprolactone or copolyesters. The secondary particles can encapsulate at least one pharmaceutically active substance. The term "secondary" means that the composition (A) can be encapsulated in a second type of particles as defined above. In addition, the secondary particles can be configured to allow a supply of the substances encapsulated there before the delivery of the substance encapsulated in the primary particles.
The pharmaceutical cocktail may comprise a sample of the composition (B) and a sample of the composition (A). Alternatively, both compositions (A) and (B) can be mixed together in a single sample. When mixed together, the compositions (A) and (B) may, however, be administered to, or supplied in the area, or surrounding the area to be treated separately.
The pharmaceutical composition of the present invention or the pharmaceutical cocktail can be used as a medicine. Alternatively, the pharmaceutical composition of the present invention or the pharmaceutical cocktail can be used for the regeneration of cardiac tissue. Alternatively, the pharmaceutical composition of the present invention or the pharmaceutical cocktail can be used for the treatment of heart disease, including heart failure, cardiac ischemia or myocardial infarction.
In another aspect of the present invention, a process for acting in vivo or ex vivo on the CSCs of humans or animals is provided. The process comprises the step of administering the pharmaceutical composition (B) or the pharmaceutical cocktail of the present invention to humans or animals.
The administration of the pharmaceutical composition (B) can follow a preliminary administration of a composition (A) comprising at least one pharmaceutically active substance.
The administration can be effected by the consecutive injection of the composition A, B or the cocktail.
In addition, the duration between two successive administrations of the pharmaceutical composition or the pharmaceutical cocktail of the present invention may be from one hour to 180 days. Each administration can be repeated. Alternatively, each or some of the composition administrations (A) may be optional.
Accordingly, the pharmaceutical composition (B) or the pharmaceutical cocktail can be administered parenterally. In addition, the pharmaceutical composition (B) or the pharmaceutical cocktail can be administered in the circulatory system of a human or animal. The pharmaceutical composition (B) or the pharmaceutical cocktail can be administered in the veins and / or the arteries.
The pharmaceutical composition (B) or the pharmaceutical cocktail of the present invention can be administered to cardiac tissue. In the preferred embodiment, the administration can be intracoronary for the pharmaceutical composition (B) and intravenous for the preliminary administration of the composition (A).
TGFp as used herein refers to TGFp-1, TGFp-2 or TGFp-3 and can be any polypeptide having TGFp activity, such as human TGF. For example, TGF can be recombinant TGF. In one modality,, # 1. TGF can be TGFp-1. Any appropriate concentration of TGFp can be used. For example, between 0.1 and 100 ng of TGF-β per ml (for example, approximately 33 ng of TGFp per ml) can be used.
The BMP can be any polypeptide having BMP activity, such as human BMP. For example, BMP can be recombinant BMP. In one embodiment, the BMP may be the BMP4. Any concentration of BMP can be used. For example, between 0.1 and 200 ng of BMP per ml (for example, approximately 65 ng of BMP4 per ml) can be used.
FGF-2 can be any polypeptide having the FGF-2 activation, such as human FGF-2. For example, FGF-2 can be recombinant FGF-2. Any concentration of FGF-2 can be used. For example, between 0.1 and 200 ng of FGF-2 per ml (eg, approximately 65 ng of FGF-2 per ml) can be used.
IGF-1 can be any polypeptide having IGF-1 activity, such as human IGF-1. For example, IGF-1 may be recombinant IGF-1. Any concentration of IGF-1 can be used. For example, between 1 and 1000 ng of IGF-1 per ml (for example, approximately 650 ng of IGF-1 per ml) can be used.
Activin-A can be any polypeptide having the activity of Activin-A, such as human Activin-A. For example, Activin-A may be recombinant Activin-A. Any concentration of Activin-A can be used. For example, between 0.1 and 500 ng of Activin-A per me (for example, approximately 130 ng of Activin-A per me) can be used.
The α-thrombin may be any polypeptide having the α-thrombin activation, such as human α-thrombin. For example, the -trombine can be recombinant a-thrombin or synthetic a-thrombin. Any concentration of α-thrombin can be used. For example, between 0.05 and 100 units of a-thrombin per me can be used.
Cardiotrophin can be any polypeptide having the activity of cardiotrophin, such as human cardiotrophin. For example, cardiotrophin can be recombinant cardiotrophin. Any concentration of cardiotrophin can be used. For example, between 0.05 and 100 ng of cardiotrophin per ml (for example, approximately 13 ng of cardiotrophin per ml) can be used.
IL-6 can be any polypeptide having the activity of IL-6, such as human IL-6. For example, IL-6 can be recombinant IL-6. Any concentration of IL-6 can be used. For example, between 10 and 400 NG of IL-6 per me can be used.
Any concentration of Cardiogenol C or a pharmaceutically acceptable salt thereof (eg, Cardiogenol C hydrochloride) can be used. For example, between 1 and 1000 ng of Cardiogenol C per ml (for example, approximately 350 ng per ni of Cardiogenol C) can be used.
The retinoic acid can be any molecule that has the activity of retinoic acid, such as synthetic retinoic acid, natural retinoic acid, a metabolite of vitamin A, a natural derivative of vitamin A or a synthetic derivative of vitamin A. Any concentration of retinoic acid can be used. For example, between 1 x 10"7 and 4 x 10 ~ 6 μ? Of retinoic acid can be used.
In some cases, serum-containing or serum-free medium supplemented with TGF-1 (for example, 2.5 ng / ml), BMP 4 (for example, 5 ng / ml), FGF-2 (for example, 5 ng / ml) ), IGF-1 (e.g., 50 ng / ml), Activin A (e.g., 10 ng / ml), Cardiotrophin (e.g., 1 ng / ml), ot-thrombin (e.g., 1 unit / ml) and Cardiogenol C (for example, 100 nM) can be used. In some cases, the medium (e.g., the serum-containing or serum-free medium) may contain the platelet lysate (e.g., a human platelet lysate).
In some cases the composition used to stimulate CSCs may contain additional optional factors such as TNF-, LIF, and VEGF-A.
TNF-α can be any polypeptide having a TNF-α activity, such as human TNF-α. For example, TNF- may be recombinant TNF-α. Any concentration of TNF-a can be used. For example, between 0.5 and 100 ng of TNF-a can be used for me.
The LIF can be any polypeptide having a LIF activity, such as human LIF. For example, the LIF may be the recombinant LIF. Any concentration of LIF can be used. For example, between 0.25 and 200 ng of LIF can be used for me.
The VEGF-A can be any polypeptide having a VEGF-A activity, such as human VEGF-A. For example, VEGF-A can be recombinant VEGF-A. Any concentration of VEGF-A can be used. For example, between 0.5 and 400 ng of VEGF-A per my can be used.
A composition provided herein can be prepared using any suitable method. For example, a composition provided herein can be prepared using commercially available stimulating agents. In some cases, a composition provided herein may be prepared to contain cell lysates (e.g., a platelet lysate) or a conditioned medium of cells such as cardiomyocyte cells or endothermic cells stimulated with TNF-a. For example, a composition provided herein can be prepared using a platelet lysate, supplemented with commercially available factors. In some cases, a composition provided herein can be prepared using the factors isolated from the conditioned medium. In some cases, the factors can be dissolved in a medium such as the culture medium of the cells that contain or do not contain the serum.
Examples
Tests were performed on sharply infarcted pigs. The following protocol is established. The infarction is performed at T0 for 90 minutes of left anterior descending occlusion (LAD) followed by a 30-minute reperfusion. At the end of the reperfusion (TI), a primary composition is administered parenterally to the animals by distal intercoronary supply with respect to the site of the occlusion. An osmotic pump loaded with BrdU is also implanted subcutaneously in IT. Fourteen days later (T2) a secondary composition is administered parenterally to the animals. The administration of both compositions can be achieved with different methods of administration such as intravenous injection, intramuscular injection or intracoronary injection. Finally, at 42 days (T3) the euthanasia of the pigs is carried out.
The concentration of the constituents is mentioned in brackets. Two compositions, alone or in combination, are tested:
- Composition A consists of IGF-1 (8 pg in 15 ml of the Phosphate Buffer Solution (PBS)) and HGF (2 ug in 15 ml of PBS) and
- composition B consists of TGFp-1 (0.5 ig in 15 ml of PBS), BMP 4 (1 xg in 15 ml of PBS), FGF-2 (1 pg in 15 ml of PBS), IGF-1 (10 μg in 15 ml of PBS), Activin A (2 pg in 15 ml of PBS), Cardiotrophin 1 (0.2 g in 15 ml of PBS) and Cardiogenol C (5.2 pg in 15 ml of PBS).
Both compositions are in a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be a phosphate buffered solution (PBS), Hartmann's solution, Ringer's lactate, physiological NaCl (0.9% NaCl) supplemented or not with albumin or with any suitable protein stabilizing composition.
Five treatment groups of 5 animals each are evaluated.
- Treatment group 1 is a control group and only receives the saline solution in TI and T2.
- Treatment group 2 receives a solution containing composition A in TI and a saline solution in T2, designated as mixture A.
- Treatment group 3 receives a solution containing composition A in TI and a solution containing composition B in T2, marked mixture A + B.
- Treatment group 4 receives a solution containing composition B in TI and T2, marked mixture B + B.
- Treatment group 5 receives a solution containing composition B in IT and a saline solution in T2, marked mixture B.
The protocol is summarized in table 1.
Table 1
The blood tests were carried out at different intervals. Blood samples were collected from 2 pigs per treatment group in the coronary sinus by means of the jugular vein and venous blood through the vein of the ear. After primary administration, samples are collected at Tl + 5 min; Tl + 1 h and Tl + 6 h. After secondary administration, samples are collected at T2 + 5 min; T2 + 1 h, T2 + 6 h and T2 + 24 h. The ELISA immunoassays were carried out with the samples for the quantification of IGF-1 and the concentration of cardiotrophin 1.
Magnetic resonance imaging (MRI) is also performed on all animals at Tl + 3 days; T2 and T3 to study the healing area, the global left ventricular function, the regional function (movement and thickening of the wall) and the regional perfusion of the ventricle. MRI allows to detect and confirm the presence of new vessels, tissues or cells that improve ventricular function.
Histopathology is also performed to determine the area of scarring, identification and quantification of cardiac positive cytoblasts in kit c. Histopathology also provides data on the distribution, size and density of new vessels and cardiomyocytes. Histopathology allows to document the repair process in the tissue and at the cellular level.
Critical variables have been considered in the analysis of cardiac repair: (1) the amount of reconstituted tissue or myocardial mass and the coronary vasculature; < 2) the number and size of the myocytes and the restored vessels; (3) the integration of myocytes and vessels recently formed with the surrounding myocardium, and / or (4) the origin of the regenerated myocardial structures.
Heart attack result
The imaging images by MRI were used to evaluate the infarct size, the infarction weight and the infarct area. The results are listed in Table 2 below.
Table 2
The experiments show that the area of infarction was approximately 19.8% for the control group and approximately 19% for groups 2 and 4 where mixture A and mixture B + B respectively were used. Surprisingly, using composition (B) according to the present invention, the infarct area was limited to 13.7% for group 5 (mixture B). Accordingly, composition (B) according to the present invention was very efficient to treat infarction, such as myocardial infarction, compared to the other composition.
In addition, it was also surprisingly observed that when the injection of mixture B followed by the preliminary injection of mixture A, the infarcted area was further limited to the value of approximately 9.6%. This is a result that could not be expected based on the results observed for the other groups. Actually, the mixture A used for group 2 was almost inefficient when alone. A synergistic effect was observed using a pharmaceutical cocktail according to the present invention. This result was confirmed with histopathology and immunohistochemistry tests.
Histopathology
The results were compiled separately for the sections taken in the boundary zone or within the central areas of the inf orto. The results for all groups are listed in Table 3 below. The data shown in Table 3 are average data of the heart slices analyzed for an animal of each group.
Table 3
The relationship between infarction and scar size represents the size of the infarction, while transmurality is a parameter that establishes whether the infarct is located strongly on the outer surface of the myocardium or extends through the internal surface of the myocardium. The higher the value of the transmurality, the greater the infarction.
With regard to the borderline infarction, Table 3 shows that the mixture A, the B + B mixture or the control mixture had almost no impact on the infarct size. In these cases, the relationship between the infarction and the size of the scar varied from 31.4% to 36.0%. On the contrary, when the composition according to the present invention is used (ie, mixture B), the ratio between the infarct and the size of the scar was surprisingly reduced up to 26%. This value can be further reduced to 20% when the pharmaceutical cocktail according to the present invention (ie mixture A + B) was used. This experiment demonstrates that the present pharmaceutical composition and the pharmaceutical cocktail are effective in treating heart disease. This was also confirmed when the experiments were carried out in the infarct zone.
Additionally, it was surprisingly demonstrated that the transmurality was reduced with mixture B alone or with mixture A + B. This means that the composition (B) of the present invention alone or when combined with the composition (A) allows the limitation of the infarction expansion to the outer surface of the myocardium. This is further evidence that the pharmaceutical composition and the pharmaceutical cocktail according to the present invention are powerful compositions for treating diseases or heart problems.
Accordingly, it is clear from the experiments described above that both the pharmaceutical composition and the pharmaceutical cocktail according to the present invention are suitable for the treatment of heart failure in a secondary manner with respect to myocardial ischemia, ischemia or infarction. of myocardium.
Immunohistochemistry
The tests were performed to evaluate, within the infarction sections, the density of the microvessels (vWF-positive vessels / mm2), the BrdU-positive cells and the kit-positive cells c. The quantification of the density of microvessels using von ilebrand factor (vWF) allows the determination of the quantity of new blood vessels created in the infarct zone. Tests of BrdU-positive cells represent the proliferation of cells, including cardiac cells. Tests of cells positive to kit c show the amount of CSC within selected sections of infarction. The results are listed in Table 4. These tests were performed only for group 1 (Control group), group 3 (Mixture A + B) and group 5 (Mixture B).
Table 4
The results show that when the compositions (A) and (B) in combination or the composition (B) alone, according to the invention, are injected into the heart, they have a great impact on the stimulation of cardiac or cytoblast cells. the proliferation of cardiac cells. Actually, the density of the microvessels is improved and the new blood vessels were created during the stimulation with the present composition or the present cocktail. The results obtained with groups 3 or 5 reached 34.2 and 34.3 respectively, compared with 27.9 for the control group. This is confirmed with the BrdU positive cell test which shows that the proliferation of the cells was improved with the composition of the present invention and that strong cell activity is observed. When Mix B was injected, 36.0% of the BrdU positive cells were observed compared to only 22.1% for the control group. This clearly emphasizes that the pharmaceutical composition according to the present invention promotes cell proliferation and therefore the formation of new myocytes and vessels with the surrounding myocardium. This can be further improved when the pharmaceutical cocktail according to the present invention was used. A value of 52.7% was reached with such a cocktail. Accordingly, both the pharmaceutical composition and the pharmaceutical cocktail according to the present invention are suitable for improving the regeneration of heart tissue.
The ability of the pharmaceutical cocktail to induce and promote the activation and proliferation of CSC was confirmed by testing the cells positive to kit c. Testing cells positive to kit c allows demonstrating that resident CSCs are consumed since their amount has been significantly reduced when the A + B mixture was used compared to the control group. Consequently, the regenerated myocardial structures are originated from resident cardiac cytoblasts. The present composition and / or cocktail are effective for in vivo stimulation of resident cardiac cytoblasts.
The terms and descriptions used here are described by way of illustration only and are not understood as limitations. Those skilled in the art will recognize that many variations are possible within the spirit and scope of the invention as defined in the following claims, and their equivalents, in which all of the terms are to be understood in their broadest possible sense to unless indicated otherwise. As a consequence, all modifications and alterations will occur to other people during the reading and understanding of the previous description of the invention. In particular, the dimensions, materials, and other parameters, given in the above description, may vary depending on the needs of the application.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (32)
1. A human or veterinary pharmaceutical composition (B) for the stimulation of the stem cells, characterized in that it comprises at least two agents stimulating the stem cells and at least one pharmaceutically acceptable excipient.
2. A pharmaceutical composition according to claim 1, wherein at least two stimulating agents stem cells are selected from the group consisting of TGFP-l, BMP-4, FGF-2, IGF-1, Activin A, Cardiotrophin 1 Cardiogenol C and the mixtures thereof.
3. A pharmaceutical composition according to claim 2, characterized in that the stimulating agents of the stem cells are TGFp-1, BMP-4, FGF-2, IGF-1, Activin A, Cardiotrophin 1 and Cardiogenol C.
4. A pharmaceutical composition according to any of the previous, claims, characterized in further comprising thrombin inhibitors selected from the group consisting of hirudin, bivalirudin, lepirudin, deirudina, argatroban, melagatran, ximelagatran, dabigatran, and heparin.
5·. A pharmaceutical composition according to any of the previous claims, characterized in that it also comprises at least one substance selected from the group consisting of the growth factors, cytokines, hormones and combinations thereof.
6. A pharmaceutical composition according to claim 5, characterized in that at least one substance is selected from the group consisting of: - Morphogenetic bone proteins (BMPs) such as BMP-1, BMP-2, BMP-5, BMP-6; - the epidermal growth factor (EGF, for its acronym in English); - erythropoietin (EPO, for its acronym in English); fibroblast growth factors (FGF) such as FGF-1, FGF-4, FGF-5, FGF-12, FGF-13, FGF-15, FGF-20; the granulocyte colony-stimulating factor (G-CSF, for its acronym in English); the stimulating factor of the macrophage-granulocyte colony (GM-CSF); the growth differentiation factor 9 (GDF-9); the growth factor of hepatocytes (HGF, for its acronym in English); - the insulin-like growth factor (IGF) such as IGF-2; - myostatin (GDF-8, for its acronym in English); - neurotrophins such as NT-3, NT-4, NT-1 and nerve growth factor (NGF, for its acronym in English); the platelet derived growth factor (PDGF) such as PDGF-beta, PDGF-AA, PDGF-BB; - thrombopoietin (TPO, for its acronym in English); - TGF- (transforming growth factor alpha) ß transforming growth factors, (TGF-ß) such as TGF-ß ?, TGF-p2, TGF-ß3; - VEGF (vascular endothelial growth factor) such as VEGF-A, VEGF-C; - TNF-a, Leukemia inhibitor factor (LIF), interleukin 6 (IL-6), retinoic acid, SDF-1 C (stromal cell-derived factor 1), BDNF ( brain-derived neurotrophic factor), periostin, Angiotensin II, Ligand Flt3, the derived neurotrophic factor Glial, Heparin, Protein 3 Agglutination factor like growth Insulin, Protein 5 Clumping factor like growth Insulin, interleukin 3, interleukin 8, midkine, Progesterone, Putresceina, Factor of stem cells, TGF-alpha, ntl, Wnt3a, Wnt5a, caspase-4, ligand-1 chemokine ligand 2 chemokine ligand 5 of the chemokine ligand 7 of the chemokine, ligand 11 of the chemokine, ligand 20 of the chemokine, haptaglobin, lectin, 25-hydroxylase cholesterol, syntaxin-8, syntaxin-11, ceruloplasmin, component 1 of the complement, component 3 of complement, alpha integrin 6, lipase 1 of lysosomal acid,? -2 microglobulin, ubiquitin, macrophage migration inhibiting factor, cofilin, cyclophilin A, FKBP12, NDPK, profilin 1, cystatin C, calciclin, staiocalcin- l, PGE-2, mpCCL2, IDO, iNOS, HLA-G5, M-CSF, angiopoietin, PIGF, CP-1, extracellular matrix molecules, CCL2 (MCP-1), CCL3 (??? - 1a), CCL4 (MIP-? ß), CCL5 (RANTES), CCL7 (MCP-3), CCL20 (MIP-3a), CCL26 (eotaxin-3), CX3CL1 (fractalkine), CXCL5 (ENA-78), CXCL11 (i- TAC), CXCL1 (GROa), CXCL2 (GRC), CXCL8 (IL-8), CCL10 (IP-10) and combinations thereof.
7. A pharmaceutical composition according to any one of the preceding claims, characterized in that the cytoblasts to be stimulated are resident cardiac cytoblasts or circulating cytoblasts or injected cytoblasts.
8. A pharmaceutical composition according to any of the previous claims, characterized in that it comprises primary particles.
9. A pharmaceutical composition according to claim 8, characterized in that the primary particles are selected from the group consisting of alginates, chitosan, dextran, cellulose, liposomes, and microspheres or polyester nanospheres such as PLGA, polycaprolactone or copolyesters.
10. A pharmaceutical composition according to claim 8 or 9, characterized in that the primary particles encapsulate the cytoblast stimulating agents of the pharmaceutical composition.
11. A pharmaceutical cocktail, characterized in that it comprises a pharmaceutical composition (B) according to any of the previous claims and a composition (A) comprising at least one pharmaceutically active substance.
12. A pharmaceutical cocktail according to claim 11, characterized in that at least one pharmaceutically active substance is selected from the group consisting of the insulin-like growth factor 1 (IGF-1), the hepatocyte growth factor (HGF) and / or the variants thereof such as NK1, 1K1, 1K2, HP11, or HP21, and combinations thereof.
13. A pharmaceutical cocktail according to claims 11 or 12, characterized in that at least one pharmaceutically active substance further comprises SCF-I.
14. A pharmaceutical cocktail according to any of the previous claims 11 to 13, characterized in that the composition (A) further comprises secondary particles selected from the group consisting of alginates, chitosan, dextran, cellulose, liposomes, or microspheres or polyester nanospheres such as PLGA, polycaprolactone or copolyesters.
15. A pharmaceutical cocktail according to claim 14, characterized in that the secondary particles encapsulate at least one pharmaceutically active substance.
16. A pharmaceutical cocktail according to claim 14 or 15, characterized in that the secondary particles are configured to allow a supply of the substance encapsulated therein prior to the delivery of the substance encapsulated in the primary particles.
17. A pharmaceutical composition according to any of claims 1 to 10, or a pharmaceutical cocktail according to any of claims 11 to 16, characterized in that they are used as a medicine.
18. A pharmaceutical composition according to any of claims 1 to 10, or a pharmaceutical cocktail according to any of claims 11 to 16, characterized in that they are used for the regeneration of cardiac tissue.
19. A pharmaceutical composition according to any of claims 1 to 10, or a pharmaceutical cocktail according to any of claims 11 to 16, characterized in that they are used in the treatment of cardiac tissue degeneration.
20. A pharmaceutical composition according to any one of claims 1 to 10, or a pharmaceutical cocktail according to any of claims 11 to 16, characterized in that they are used in the treatment of heart disease, including heart failure, cardiac ischemia. or myocardial infarction.
21. A process for acting in vivo or ex vivo on cardiac cytoblasts of a human being or animals, characterized in that a pharmaceutical composition (B) according to claims 1 to 10, is administered to humans or animals.
22. A process according to claim 21, characterized in that the administration of the composition (B) follows a preliminary administration of the composition (A) comprising at least one pharmaceutically active substance.
23. A process according to claims 21 or 22, characterized in that the administration is effected by injection.
24. A process according to any of the preceding claims 21 to 23, characterized in that the administration is a consecutive injection.
25. A process according to any of the previous claims 21 to 24, characterized in that the duration between two successive administrations of the pharmaceutical composition (B) according to any of the previous claims 1 to 10, is from 1 hour to 180 days.
26. A process according to any of the previous claims 21 to 25, characterized in that each administration is repeated.
27. A process according to any of the previous claims 21 to 26, characterized in that the compositions (A) or (B) are administered parenterally.
28. A process according to any of the previous claims 21 to 27, characterized in that the compositions (A) or (B) are administered in the circulatory system of a human or animal.
29. A process according to any of the previous claims 21 to 28, characterized in that the compositions (A) or (B) are administered in the veins and / or the arteries.
30. A process according to any of the previous claims 21 to 29, characterized in that the compositions (A) or (B) are administered to the cardiac tissue.
31. A process according to any of the previous claims 21 to 30, characterized in that the administration is intracoronary for the pharmaceutical composition (B) and intravenous for the preliminary administration of the composition (A).
32. A process according to any of the previous claims 21 to 26, characterized in that each administration of the composition (A) is optional.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP2009066251 | 2009-12-02 | ||
| PCT/EP2010/068700 WO2011067317A1 (en) | 2009-12-02 | 2010-12-02 | Pharmaceutical compositions for the stimulation of stem cells. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MX2012005976A true MX2012005976A (en) | 2012-06-25 |
Family
ID=42316097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX2012005976A MX2012005976A (en) | 2009-12-02 | 2010-12-02 | Pharmaceutical compositions for the stimulation of stem cells. |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JP2013512877A (en) |
| KR (1) | KR20120099751A (en) |
| CN (1) | CN102711798A (en) |
| AU (1) | AU2010326633A1 (en) |
| BR (1) | BR112012013164A2 (en) |
| CA (1) | CA2781493A1 (en) |
| IL (1) | IL219901A0 (en) |
| MX (1) | MX2012005976A (en) |
| NZ (1) | NZ599930A (en) |
| RU (1) | RU2012120834A (en) |
| TW (1) | TW201141510A (en) |
| WO (1) | WO2011067317A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106456676B (en) * | 2014-07-07 | 2021-07-23 | 米迪波斯特股份有限公司 | Hair growth promoting function of medium of stimulated stem cells and application thereof |
| CN105079791A (en) * | 2015-09-18 | 2015-11-25 | 郑榆坤 | Composition for stimulating endogenous stem cells in vivo and application of composition |
| RU2634576C1 (en) * | 2016-10-24 | 2017-10-31 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Method for tissue regeneration stimulation |
| CN107050428B (en) * | 2017-03-23 | 2020-05-05 | 温州医科大学 | FGF20 medicament and application thereof in treatment of cerebral trauma |
| CN107648592B (en) * | 2017-11-13 | 2021-05-14 | 深圳市喆邦生物工程有限公司 | Application of chemokine CCL4 in preparation of medicine for treating bone fracture |
| RU2686718C1 (en) * | 2018-03-12 | 2019-04-30 | Федеральное государственное бюджетное научное учреждение "Томский национальный исследовательский медицинский центр Российской академии наук" (Томский НИМЦ) | Agent stimulating mesenchymal progenitor cell functions in vitro |
| KR102106710B1 (en) | 2018-10-11 | 2020-05-04 | 강원대학교산학협력단 | hematopoietic differentiation of human pluripotent stem cells in a developmental stage-specific manner |
| CN111195350A (en) * | 2020-01-15 | 2020-05-26 | 重庆大学 | Application of combination of IGF1 and IGF1Ec24 in preparation of medicines for promoting tissue repair and regeneration |
| US20240058389A1 (en) * | 2020-03-17 | 2024-02-22 | Hierabio Inc. | Composition for preventing or treating ischemic diseases, comprising cardiac stem cells |
| CN111621525B (en) * | 2020-06-18 | 2021-04-23 | 中赛干细胞基因工程有限公司 | Application of STX1B gene in promoting growth and differentiation of human adipose-derived mesenchymal stem cells |
| CN116836920B (en) * | 2023-08-21 | 2024-05-24 | 广东横琴粤澳深度合作区齐美国际干细胞医院有限公司 | Serum-free culture medium and method for preparing mesenchymal stem cells by using same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015127A2 (en) * | 2004-07-30 | 2006-02-09 | Mayo Foundation For Medical Education And Research | Treating cardiovascular tissue |
| ATE481978T1 (en) * | 2005-01-25 | 2010-10-15 | Five Prime Therapeutics Inc | COMPOSITIONS AND METHODS FOR TREATING HEART DISEASES |
| US9765298B2 (en) * | 2006-07-24 | 2017-09-19 | Mayo Foundation For Medical Education And Research | Methods and materials for providing cardiac cells |
| US8481075B2 (en) * | 2007-12-13 | 2013-07-09 | Beijing Shengyiyao Science & Technology Development Co. Ltd. | Preparation and application of biodegradable-material-made microsphere vascular embolus containing liposome-encapsulated cytokines |
-
2010
- 2010-12-02 WO PCT/EP2010/068700 patent/WO2011067317A1/en active Application Filing
- 2010-12-02 JP JP2012541498A patent/JP2013512877A/en not_active Withdrawn
- 2010-12-02 AU AU2010326633A patent/AU2010326633A1/en not_active Abandoned
- 2010-12-02 BR BR112012013164A patent/BR112012013164A2/en not_active IP Right Cessation
- 2010-12-02 KR KR1020127017238A patent/KR20120099751A/en not_active Application Discontinuation
- 2010-12-02 TW TW099141986A patent/TW201141510A/en unknown
- 2010-12-02 NZ NZ599930A patent/NZ599930A/en not_active IP Right Cessation
- 2010-12-02 RU RU2012120834/15A patent/RU2012120834A/en not_active Application Discontinuation
- 2010-12-02 MX MX2012005976A patent/MX2012005976A/en unknown
- 2010-12-02 CN CN201080053800XA patent/CN102711798A/en active Pending
- 2010-12-02 CA CA2781493A patent/CA2781493A1/en not_active Abandoned
-
2012
- 2012-05-20 IL IL219901A patent/IL219901A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2010326633A1 (en) | 2012-05-31 |
| TW201141510A (en) | 2011-12-01 |
| WO2011067317A1 (en) | 2011-06-09 |
| KR20120099751A (en) | 2012-09-11 |
| NZ599930A (en) | 2014-04-30 |
| RU2012120834A (en) | 2014-01-20 |
| JP2013512877A (en) | 2013-04-18 |
| IL219901A0 (en) | 2012-07-31 |
| BR112012013164A2 (en) | 2016-03-01 |
| CN102711798A (en) | 2012-10-03 |
| CA2781493A1 (en) | 2011-06-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2506867B1 (en) | Pharmaceutical compositions for the stimulation of stem cells. | |
| MX2012005976A (en) | Pharmaceutical compositions for the stimulation of stem cells. | |
| Kawamoto et al. | Nerve growth factor and wound healing | |
| US8617889B2 (en) | Methods and compositions for the repair and/or regeneration of damaged myocardium using cytokines and variants thereof | |
| CA2381780C (en) | Dose of an angiogenic factor and method of administering to improve myocardial blood flow | |
| RU2311921C2 (en) | Drugs for treatment of ishemic diseases | |
| US20060110374A1 (en) | Method to accelerate stem cell recruitment and homing | |
| EP1465653B1 (en) | Therapeutic application of g-csf | |
| Cho et al. | Enhancement of angiogenic efficacy of human cord blood cell transplantation | |
| Jeon et al. | Synergistic effect of sustained delivery of basic fibroblast growth factor and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs | |
| Bulgin | Therapeutic angiogenesis in ischemic tissues by growth factors and bone marrow mononuclear cells administration: biological foundation and clinical prospects | |
| EP2431046B1 (en) | Use of olive leaf extracts in a pharmaceutical composition for inducing angiogenesis and vasculogenesis | |
| US20200009226A1 (en) | Compositions and Methods for Treating Stroke | |
| Širmenis et al. | Recovery of infarcted myocardium in an in vivo experiment | |
| JP4790195B2 (en) | Tissue regeneration agent | |
| Gojo et al. | Cardiac Regenerative Medicine Cellular Therapy and Tissue Engineering | |
| Zelarayán et al. | Emerging Concepts in Myocardial Pharmacoregeneration | |
| Hiesinger et al. | Angiogenic Cytokine Th erapy for Ischemic Heart Disease | |
| Zimmermann | Emerging Concepts in Myocardial Pharmacoregeneration | |
| Beohar et al. | Cytokine treatment for cardioprotection and cardiac regeneration | |
| Rao | Epicardial cell engraftment and signaling promote cardiac repair after myocardial infarction | |
| Sano et al. | Recent innovation in pretreatment for skin grafts using regenerative medicine in the East | |
| Cai | Mechanisms for the effects of adipose tissue-derived stromal/stem cells on angiogenesis and tissue repair in ischemic diseases | |
| Brunt et al. | 577 Aged Cardiac Patients Show Impaired Mesenchymal Stem Cell Differentiation to a Myogenic Phenotype Due to Depressed WNT/β-Catenin Signaling | |
| Zisa et al. | Intramuscular VEGF activates an SDF1-dependent progenitor cell 2 cascade and an SDF1-independent muscle paracrine cascade for 3 cardiac repair 4 |