CN100406059C - Purposes of parathyroid hormone - Google Patents
Purposes of parathyroid hormone Download PDFInfo
- Publication number
- CN100406059C CN100406059C CNB2004100224314A CN200410022431A CN100406059C CN 100406059 C CN100406059 C CN 100406059C CN B2004100224314 A CNB2004100224314 A CN B2004100224314A CN 200410022431 A CN200410022431 A CN 200410022431A CN 100406059 C CN100406059 C CN 100406059C
- Authority
- CN
- China
- Prior art keywords
- parathyroid hormone
- pth
- dentin
- cell
- people
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 108090000445 Parathyroid hormone Proteins 0.000 title claims abstract description 76
- 102000003982 Parathyroid hormone Human genes 0.000 title claims abstract description 75
- 239000000199 parathyroid hormone Substances 0.000 title claims abstract description 75
- 229960001319 parathyroid hormone Drugs 0.000 title claims abstract description 75
- 210000004268 dentin Anatomy 0.000 claims abstract description 39
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 9
- 239000007929 subcutaneous injection Substances 0.000 claims description 9
- 238000010254 subcutaneous injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 31
- 239000003814 drug Substances 0.000 abstract description 22
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 19
- 239000011575 calcium Substances 0.000 abstract description 19
- 229910052791 calcium Inorganic materials 0.000 abstract description 19
- 239000011159 matrix material Substances 0.000 abstract description 13
- 230000009471 action Effects 0.000 abstract description 5
- ILYCWAKSDCYMBB-OPCMSESCSA-N dihydrotachysterol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1/C[C@@H](O)CC[C@@H]1C ILYCWAKSDCYMBB-OPCMSESCSA-N 0.000 abstract description 2
- 229960000465 dihydrotachysterol Drugs 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 102100036893 Parathyroid hormone Human genes 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 52
- 210000002992 dental papilla Anatomy 0.000 description 22
- 210000000988 bone and bone Anatomy 0.000 description 15
- 102100024504 Bone morphogenetic protein 3 Human genes 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 13
- 241000700159 Rattus Species 0.000 description 12
- 230000014509 gene expression Effects 0.000 description 12
- 101000762375 Homo sapiens Bone morphogenetic protein 3 Proteins 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 210000004416 odontoblast Anatomy 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 108010007726 Bone Morphogenetic Proteins Proteins 0.000 description 9
- 102000007350 Bone Morphogenetic Proteins Human genes 0.000 description 9
- 102100024506 Bone morphogenetic protein 2 Human genes 0.000 description 9
- 101000762366 Homo sapiens Bone morphogenetic protein 2 Proteins 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 229940112869 bone morphogenetic protein Drugs 0.000 description 9
- 230000004069 differentiation Effects 0.000 description 9
- 238000009396 hybridization Methods 0.000 description 9
- 208000009328 Dentinogenesis Imperfecta Diseases 0.000 description 8
- 230000008859 change Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 230000001939 inductive effect Effects 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 210000003074 dental pulp Anatomy 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 238000002372 labelling Methods 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- PCLFEHAPITXKJL-UHFFFAOYSA-N 5,8-dihydroxy-2-[2-(4-methoxyphenyl)ethyl]chromen-4-one Chemical compound C1=CC(OC)=CC=C1CCC1=CC(=O)C2=C(O)C=CC(O)=C2O1 PCLFEHAPITXKJL-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 101150006966 bmp3 gene Proteins 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 230000001002 morphogenetic effect Effects 0.000 description 5
- 210000002990 parathyroid gland Anatomy 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000012531 culture fluid Substances 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000007901 in situ hybridization Methods 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 108010049951 Bone Morphogenetic Protein 3 Proteins 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 3
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000004098 Tetracycline Substances 0.000 description 3
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 3
- 210000001053 ameloblast Anatomy 0.000 description 3
- 230000033558 biomineral tissue development Effects 0.000 description 3
- 230000024245 cell differentiation Effects 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 210000004262 dental pulp cavity Anatomy 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229960002180 tetracycline Drugs 0.000 description 3
- 229930101283 tetracycline Natural products 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 102000055006 Calcitonin Human genes 0.000 description 2
- 108060001064 Calcitonin Proteins 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- 101150106419 Dspp gene Proteins 0.000 description 2
- 108010022355 Fibroins Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000003305 autocrine Effects 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- 229940046011 buccal tablet Drugs 0.000 description 2
- 239000006189 buccal tablet Substances 0.000 description 2
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 2
- 229960004015 calcitonin Drugs 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000003716 mesoderm Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000010813 municipal solid waste Substances 0.000 description 2
- JPXMTWWFLBLUCD-UHFFFAOYSA-N nitro blue tetrazolium(2+) Chemical compound COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC(=CC=2)[N+]([O-])=O)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=C([N+]([O-])=O)C=C1 JPXMTWWFLBLUCD-UHFFFAOYSA-N 0.000 description 2
- 230000032724 odontogenesis Effects 0.000 description 2
- 229960002378 oftasceine Drugs 0.000 description 2
- 230000001582 osteoblastic effect Effects 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 230000003076 paracrine Effects 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QRXMUCSWCMTJGU-UHFFFAOYSA-L (5-bromo-4-chloro-1h-indol-3-yl) phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP([O-])(=O)[O-])=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-L 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- LHGMHYDJNXEEFG-UHFFFAOYSA-N 4-[4-(dimethylamino)phenyl]iminocyclohexa-2,5-dien-1-one Chemical compound C1=CC(N(C)C)=CC=C1N=C1C=CC(=O)C=C1 LHGMHYDJNXEEFG-UHFFFAOYSA-N 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 208000005335 Dentin Dysplasia Diseases 0.000 description 1
- 102400001059 Dentin sialoprotein Human genes 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Natural products C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 206010060891 General symptom Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 241001417092 Macrouridae Species 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 101710167839 Morphogenetic protein Proteins 0.000 description 1
- 108020004485 Nonsense Codon Proteins 0.000 description 1
- 241000906034 Orthops Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 108700020797 Parathyroid Hormone-Related Proteins 0.000 description 1
- 102000043299 Parathyroid hormone-related Human genes 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 101000688200 Prevotella intermedia Alkaline phosphatase Proteins 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 235000009233 Stachytarpheta cayennensis Nutrition 0.000 description 1
- 206010044041 Tooth hypoplasia Diseases 0.000 description 1
- 241001447056 Uristes Species 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- WYTGDNHDOZPMIW-RCBQFDQVSA-N alstonine Natural products C1=CC2=C3C=CC=CC3=NC2=C2N1C[C@H]1[C@H](C)OC=C(C(=O)OC)[C@H]1C2 WYTGDNHDOZPMIW-RCBQFDQVSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 235000013532 brandy Nutrition 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- MWKXCSMICWVRGW-UHFFFAOYSA-N calcium;phosphane Chemical compound P.[Ca] MWKXCSMICWVRGW-UHFFFAOYSA-N 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 201000002268 dental enamel hypoplasia Diseases 0.000 description 1
- 210000002709 dental papilla cell Anatomy 0.000 description 1
- 210000002986 dental sac Anatomy 0.000 description 1
- 108010088492 dentin sialophosphoprotein Proteins 0.000 description 1
- 230000013860 dentinogenesis Effects 0.000 description 1
- 230000035617 depilation Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- FFYPMLJYZAEMQB-UHFFFAOYSA-N diethyl pyrocarbonate Chemical compound CCOC(=O)OC(=O)OCC FFYPMLJYZAEMQB-UHFFFAOYSA-N 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 1
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000005221 enamel hypoplasia Effects 0.000 description 1
- 210000001080 enamel organ Anatomy 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 238000009164 estrogen replacement therapy Methods 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 235000002864 food coloring agent Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 210000004283 incisor Anatomy 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 230000037434 nonsense mutation Effects 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000004409 osteocyte Anatomy 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- ASJMRRUHURWTNM-NCWQDUMVSA-N pectenotoxin-11 Chemical compound C[C@@H]1CCO[C@](O)([C@H]2O[C@@H]3\C=C\C(\C)=C\[C@H](C)C[C@@]4(C)CC[C@@H](O4)[C@@]45CC[C@@](C)(C[C@@H](O4)[C@H]4O[C@](C)(CC4=O)[C@@H](O)[C@@H]4CC[C@@]6(CCC[C@H](O6)[C@@H](C)C(=O)O[C@@H]3[C@@H]2O)O4)O5)[C@@H]1O ASJMRRUHURWTNM-NCWQDUMVSA-N 0.000 description 1
- 230000003239 periodontal effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000007261 regionalization Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000025366 tissue development Effects 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- 230000008359 toxicosis Effects 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provides a new application of parathyroid hormone, particularly an application of parathyroid hormone for preparing a medicament for treating dentin and dentinal matrix. The medicament comprises an agent prepared from an effective amount of parathyroid hormone. The problem of synthesizing parathyroid hormone in vivo is solved, and the parathyroid hormone level is close to the physiological level. The medicament keeps PTH in a normal value level for a long time, avoids the side effects caused by a calcium agent, dihydrotachysterol and the like for clinical application by the action of the parathyroid hormone, and has the advantages of simple preparation, low price and easy popularization.
Description
Technical field
The present invention relates to the new purposes of parathyroid hormone (PTH), specifically, is the purposes of parathyroid hormone in the medicine of preparation treatment dentin and dentinal matrix.
Background technology
Parathyroid hormone (parathyroid hormone, PTH) make it to maintain a kind of important substance of normal level as regulating blood calcium, be to form by 84 amino acid residue condensations, the formation that promotes bone has been reported in the effect of its amino section 31～38 amino acid residues at present, and improve biomechanics of bone intensity, treat osteoporotic purposes.The patent No. is 94192745.8 to disclose " parathyroid hormone analogs and parathyroid hormone-related peptide: the purposes of synthetic and treatment osteoporosis ", but the dentin of one of whole body mineralized tissue form and mineralization process in have or not effect and what kind of effect arranged, the present domestic report that still do not have.Relevant PTH there is no report both at home and abroad at present to the influence of the dental papilla mesenchymal cells of one of odontoblast's precursor; Its mechanism of action is the growth by adjusting plasma calcium phosphorus concentration remote-effects tooth, or directly regulating dentinal matrix forms and mineralising, awaits determining, and reports as yet at present.
Parathyroid hormone (parathyroid hormone, PTH) also be to regulate a kind of important substance that blood calcium makes it to maintain normal level, studies show that: people's dental papilla mesenchymal cells (dentalpapilla mesenchymal, DPMC) reaction to parathyroid hormone has some osteoblastic characteristic, under the PTH effect, the DPMC under the condition of in vitro culture is to the direction differentiation with skeletonization characteristic cell
[1]But its mechanism of action does not still have relevant report.PTH is an important hormonal substance during the mineralized tissue metabolism is regulated, and in vivo alcium and phosphor metabolization is had important regulatory role.Discovery when the research parathyroid hormone influence the people DPMC biological characteristics of In vitro culture
[1]: PTH does not influence people's dental papilla mesenchymal cells propagation of In vitro culture, and only promotes the differentiation of cell and function to enliven.PTH is by cyclic adenosine monophosphate (cAMP) mediation in the cell.Make the active reduction of alkali phosphatase (ALP) in people's dental papilla mesenchymal cells, extracellular ALP is active to be increased and make, and prompting PTH may be the important medium of odontoblast's differentiation and mineralising.
Bone morphogenetic protein(BMP) (BMP) is to form the extremely close cytokine of relation with bone and hard tooth tissue.Existing scholar
[2～5]Adopt immunohistochemistry, situ hybridization technology, studied BMP, BMP2A, BMP3cDNA respectively in dental gram and distribution in people pulp tissue and expression, thought that they play an important role in the growth course of dental gram and dental pulp self repair process.Bone morphogenetic protein(BMP) (BMP) is a kind of bone Induced substance efficiently, is the initially signal molecule of mesenchymal cell to the differentiation of osteocyte system.In bone formation and growth course, BMP has important effect for chemotactic, mitosis and the differentiation of cell.In embryo development procedure, when the BMP molecule when some special areas is expressed, can induce the gathering of its peripheral cell, and then to bone and cartilage differentiation.BMP2 is member the closest with bone formation in the BMP family.Nakashima
[14]Can induce Dentinal formation Deng report: BMP2 and collagen stroma after compound.Lyons
[3]With high beautiful good
[4]Deng utilization in situ hybridization technology for detection BMP2A expression of gene and distribution in the dental gram, found that in enamel organ epithelial cell, dental papilla cells, Dental Follicle Cells and the dental gram osteoblast on every side all has a large amount of positive signal to occur, and the result is consistent with immunohistochemical study.Think activation and the expression that in the dental germ during development process, is accompanied by the BMP gene.BMP3 is the non-collagen sugar albumen of a kind of hydrophobicity, and molecular weight 30～40KD is the dimeric structure of disulfide-bonded.BMP3 is with after carrier combines, and can activate osteoblastic expression and have induced activity by inducing
[15]Simultaneously, BMP3 takes place in the bone form
[16]With people's embryo tissue development
[17]In also play an important role.There is the BMP3 expression of gene at the glaze joint place (Enamal knot) of discovery rat molar dental grams such as Thomas
[18]Tabas
[19]Deng utilizing the somatic hybridization strain, BMP1,2,3, the position of 4 genes on chromosome have been determined with cDNA probe hybridization technology, found that BMP3 is positioned at No. 4 chromosome P18.4-q21 zone of people, overlapping with the gene loci of two type dentin dysplasia (dentinogenesis imperfecta typeII), prompting BMP3 gene may be significant in dentin form generating process.BMP3mRNA mainly is distributed in the tissue and the cell in neuroderm source
[16], and the binding site of BMP3 is rich in the tissue in mesoderm source, prompting BMP3 has significance for epithelium-mesochymal reciprocal action.BMP3 induces effect in the differentiation in odontoblast, does not still have relevant report at present.Wang Zhongdong
[5]Discover that sophisticated functional odontoblast is under dental caries source property inflammatory stimulus to a certain degree, its BMP3 gene activation is also expressed, participate in the atomization of inducing of pulp cells, self repair process to dental pulp may be significant, thinks that BMP3 gene expression is strong and weak relevant with the differentiation degree and the residing functional status of cell.There are some researches show
[6～12]It is significant equally during the dentin of BMP in dental germ during development and dental pulp self repair process forms.Nakashima
[8]BMP is placed the perforation of pulp chamber point place of Canis familiaris L. tooth, observe the formation of reparative dentin, think that BMP can promote dental pulp mesenchymal cell propagation, induce osteoid dentin to form, and the differentiation that can induce odontoblast the latter.High jade is good etc.
[11]Find that BMP can promote people's pulp cells of subculture In vitro culture
3H-TdR mixes, and improves propagation phase ALPase activity, thinks that BMP has regulating action to the differentiation of inducing of pulp cells.The ameloblast of organic centre occurs early than odontoblast in the tooth development, BMP content in the ameloblast is always abundant than odontoblast, and the existence of BMP before occurring, the odontoblast of its corresponding site just arranged in the endochylema, the prompting ameloblast is by synthetic and secretion BMP, induce the differentiation of odontoblast, and then form dentin
[13]At present, to Dentinal effect, only limit to the research of rationale at PTH, no relevant report is used for clinical with medicament forms.
At present, dentin form disorder disease mainly be imperfect hereditary dentinogenesis (dentinogenesis imperfecta, DGI), it is a kind of autosomal dominant inherited disease, sickness rate is about 1/8000, penetrance is about 100%.Be divided into three types clinically; I type (DGI-I), the patient is except that dentinogenesis imperfecta, and also with the undergrown symptom of skeletonization, its cause of disease is type i collagen gene mutation widely.II type (GI-II), have another name called hereditary opalescent dentin, its show as the tooth color and luster from translucent to light blue to dark-brown and opalescence sample color occurs, tooth often has heavy wear, the minority case can be with enamel hypoplasia, but without dysosteogenesis, the visible root of the tooth of X-ray film is short, pulp chamber and root pipe complete atresia.Aplin etc. are in the scope of 2cm with its gene mapping hereditism's distance between 4q21 zone GATA6211 and D4S1563, scholars such as Grosby are defined as candidate gene with the DSPP gene in this scope, scholars find that by order-checking there is a C → T sudden change in No. 3 exon 3658 sites of DSPP gene, formed the synthetic terminator of albumen, this nonsense mutation makes reading frame in advance, cause dentin sialoprotein and dentin squama protein delation, thereby caused HAP nucleation and mineralising incomplete, finally form pathologic DGI-II.III type (DGI-III) claims brandy type hypoplasia of dentin again, for isolating 3 special hereditary opalescent dentines of isolating among the national group that betide the Maryland State, it is characterized by dentin as thin as a wafer, and pulp chamber and root pipe obviously increase.In the tooth development process,, also can cause hypoplasia of dentin if the alcium and phosphor metabolization obstacle that a variety of causes causes takes place.The medicine of the disease of treatment dentin and dentinal matrix has calcium and vitamin D, calcitonin, estrogen replacement therapy and diphosphate etc. at present, its defective comprises: use the toxic and side effects of calcium preparation and vitamin D treatment that the toxic and side effects of (1) chemical compound itself is arranged: the local excitation symptom has gastrointestinal symptoms such as nauseating, vomiting, gastrointestinal upset, loss of appetite, constipation, and the pain of injection site, necrosis etc.; General Symptoms comprises: the calcium preparation that comes into operation in a large number can disturb absorbing of biological elements such as phosphorus, zinc, ferrum; Injecting too fast arrhythmia that causes so that chamber quivers etc.(2) toxic and side effects of additive or field trash: the toxic and side effects of additive: adding citric acid, acetic acid etc. in the calcium preparation influences mouthfeel; Add artificial coloring, essence or glucide etc., infant is had a negative impact, the also toxic effect of the nerve of undeveloped mature; Add sugar, can influence appetite and nutritive equilibrium.The toxic and side effects of field trash, biology or mineral sources preparation are often polluted or are mixed harmful elements such as lead, hydrargyrum, cadmium, although they in calcium preparation content seldom, calcium preparation mostly is month after month or takes throughout the year, many clothes have the possibility that causes retention toxicosis.Estrogenic use has higher requirement at dosage with on the course of treatment, dosage must be to be increased gradually by low amount, until optimal dose.Have report to think any and can increase estrogen content in the blood, the treatment that increases the estrogen metabolism level all can increase breast carcinoma, and the danger of carcinoma of endometrium and venous thrombosis adds simultaneously with low dose of progestogen and can reduce side effect.The calcitonin past attempts is used for subcutaneous injection and is used for nose now spraying into, and this usage is rarely had report by most of people accept side effect.The diphosphonates side effects of pharmaceutical drugs are that the gastrointestinal untoward reaction may appear in medication person, as diarrhoea and dyspepsia etc.
Summary of the invention
Technical scheme to be solved by this invention provides the new purposes of parathyroid hormone, specifically, is the purposes of parathyroid hormone in the medicine of the disease of preparation treatment dentin and dentinal matrix.
The invention provides the purposes of parathyroid hormone in the disease of preparation treatment dentin and dentinal matrix.
Further, be the purposes of parathyroid hormone in the medicine of preparation treatment hypoplasia of dentin.
The present invention also provides a kind of pharmaceutical composition, and it comprises the preparation that the parathyroid hormone of effective dose is made.
Parathyroid hormone 0.5mg～4mg is contained in wherein every preparation unit.The scope that this pharmaceutical composition acts on the intravital blood drug level of people is: 8～42nmol/ml, to act on the intravital blood drug level of people be 33.3nmol/ml to this pharmaceutical composition further.
The present invention also provides the purposes of this pharmaceutical composition in the disease of preparation treatment dentin and dentinal matrix.
Further, the present invention also provides the purposes of this pharmaceutical composition in the medicine of the disease of treatment dentin for preparing the subcutaneous injection administration and dentinal matrix.Wherein said medicine composition injection or injectable powder.
The present invention also provides the purposes of this pharmaceutical composition in the medicine of the disease of treatment dentin for preparing oral administration and dentinal matrix.Further, described preparation is an oral formulations.
The present invention also provides this pharmaceutical composition to suck purposes in the medicine of disease of the treatment dentin of administration and dentinal matrix in preparation.Further, described buccal lozenge is buccal tablet, oral cavity adhesion tablet, membrane, spray.The present invention also provides the purposes of parathyroid hormone in the medicine of preparation treatment hypoplasia of dentin.
The present invention adopts modern cell culture technology, utilize the experimental model of precursor-dental papilla mesenchymal cells of the people odontoblast of external foundation, cDNA probe with digoxigenin labeled, people's dental papilla mesenchymal cells BMP2mRNA and BMP3mRNA expression to In vitro culture, and cell is behind PTH effect 5d, the situation of change of cellular expression is observed, and inquires into influence and the approach of PTH to people's dental papilla mesenchymal cells.A little less than found that people's dental papilla mesenchymal cells BMP2mRNA of In vitro culture and BMP3mRNA positive hybridization signal are; Cell is behind PTH effect 5d, and the expression of BMP2mRNA does not have significant change, and in cytoplasm, the BMP3mRNA positive hybridization signal occurs.Illustrate that people's dental papilla mesenchymal cells of In vitro culture has the potential of synthetic BMP2 and BMP3, PTH significantly improves the ability of the synthetic BMP3 of cell.When the present invention compares by the mineralization ability of people DPMC under the PTH effect, finder's blood drug level is that the PTH of 33.3nmol/ml significantly increases the mineralising tuberosity of cell and the number of matrix vesicle, pass through In vitro culture, illustrate that PTH can significantly improve the mineralization degree of people DPMC, promote cell differentiation.
Under the effect of PTH, the BMP3 gene is activated, expresses, participate in inducing of dental papilla mesenchymal cells and break up by autocrine and paracrine action, promote the formation of dentin and dentin sample substrate, reach the purpose of treatment hypoplasia of dentin, adopt purposes of the present invention, solved the problem of synthetic PTH in the body, and PTH is near physiological level, and it is longer at the normal value leveled time to keep PTH, by the PTH effect, avoided the side reaction of clinical practice calcium preparation, dihydro-tachysterol etc., and simple for production, expense is cheap, is easy to promote.
Since PTH has ossification, broken bone effect is arranged again, as hormone medicine, different medicine prescription methods can produce different consequences, and the present invention adopts to be interrupted and gives administration, intermittent subcutaneous injection: carry out subcutaneous injection 8～9 of early mornings every day one time, inferior on every Saturdays, repeated (physiological rhythm of parathyroid hormone reaches the highest in early morning every day, later on slowly decline) at interval in one day again, by the use of this medication, can effectively improve bone mass.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
Embodiment 1
The parathyroid hormone of effective dose (1-2mg) is made aqueous injection with adjuvant (or additives).
Embodiment 2
The parathyroid hormone of effective dose (1-2mg) is made solution with adjuvant (or additives), drying, and injectable powder is made in sterilization.
Embodiment 3 pharmaceutical composition buccal tablet preparations of the present invention
PTH is fully mixed with blank granule, direct compression under normal temperature condition, every contains PTH is 2～4mg.
Embodiment 4 pharmaceutical composition adhesion tablets of the present invention
Divide three layers with adjuvant, PTH: lower floor makes substrate with HPC/CP, and the middle level is PTH, and the upper strata is a lactose, direct compression, and every contains PTH0.5～1mg.
Embodiment 5 medicine membrane preparations of the present invention
Make substrate with polyethylene, with molding machine direct compression film former, every contains PTH0.5～1mg.
Embodiment 6 medicament spraying agents of the present invention
Spray adjuvant with routine mixes with PTH, and be prepared into the PTH spray, specification: 2～4mg/ presses.
Below by concrete experiment in vitro, animal pharmacodynamics evidence beneficial effect of the present invention.
Experimental example 1 pharmaceutical composition parathyroid hormone of the present invention is expressed people's dental papilla mesenchymal cells bone morphogenetic protein(BMP)
1, material
Parathyroid hormone (Bachem Japan)
Plasmid pSP65-BMP2 and pGEX2T-BMP3 (the Dr Wozney of U.S. gene studies institute is so kind as to give)
2, method
2.1 grouping
Matched group: DMEM (Dulbecco ' s Modified Eagle ' sMedium:Dulbecco the improves cell culture fluid) culture fluid that contains 2%FCS (hyclone).
Experimental group: PTH is diluted with the DMEM culture fluid that contains 2%FCS, and concentration is 33.3nmol/L.
2.2 cell culture
Get the dental papilla tissue of legal 7 monthly ages of induction of labor with water bag man tire.Carry out primitive cell culture with tissue block method, SABC is carried out origin of cell and is identified.Get well-grown the 4th generation people dental papilla mesenchymal cells, after 0.25% trypsinization, with 2 * 10
3Cell concentration is inoculated into and is covered with sterility cover slide (6mm
2) 24 orifice plates in, containing respectively, hatch 24h under the standard environment with containing in the DMEM culture fluid of 10%FCS.Discard cell culture supernatant, change matched group and experimental group culture fluid respectively into, continue to cultivate 5d, have the coverslip of cell to take out with long, 95% ethanol is 30min fixedly, and is standby.
2.3 hybridizing method
2.3.1 probe preparation and labelling
Plasmid pSP65-BMP2 and pGEX2T-BMP contain the cDNA fragment of BMP2 and BMP3 respectively, use the alkaline lysis method of extracting plasmid, enzyme action behind the purification, reclaim required fragment, adopt random priming label probe (DIG DNA Labeling and Detection kit, BoehringerMannheim Company)
2.3.2 in situ hybridization step
Paraffin section dewaxes to DEPC (pyrocarbonic acid diethyl ester) water and 0.1mol/LPBS (pH7.4,0.1mol/LPBS:NaCl8.5g, KH through routine
2PO
40.2g, Na
2HPO
4.12H
2O 2.9g, KCl 0.2g is with supplying 100ml behind the dissolved in distilled water.) after, use 0.2mol/L HCL and E.C. 3.4.21.64 (1ug/ml) to handle respectively, in 0.2% glycine and 10 minutes, after 4% paraformaldehyde room temperature is fixed 30 minutes; Gradient alcohol dehydration, drying at room temperature, the BMPs concentration and probe concentration is 1ug/ml, 42 ℃ of wet box hybridization are after 20 hours, 2 * SSC (2 * SSC:0.3mol/L sodium chloride, 0.03mol/L sodium citrate) room temperature is shaken and is washed 15 minutes * 3,1 * SSC (1 * SSC solution: 0.15mol/LNaCl, 0.015mol/L sodium citrate) room temperature is shaken and is washed 15 minutes * 3,0.5 * SSC37 ℃ is shaken and washes 15 minutes * 3, Buffer (buffer agent) I (100mmol/L Tris-HCL pH7.5,150mmol/LNaCl) sealing of thorough washing 15 minutes * 2.2% normal sheep serum is after 30 minutes, drip anti-labelling alkali phosphatase DigiTAb (1: 100) 2 hours (37 ℃), through Buffer I, BufferIII (100mmol/L Tris-HCl pH9.5,100mmol/L NaCl, 50mmol/L MgCl
2) successively the washing after, with showing liquid BufferIII1000 μ l, levamisole 0.24mg, NBT (nitroblue tetrazolium) 4.5 μ l and BCIP (5-bromo-4-chloro-3-indyl phosphate ester, 5-Bromo-4-chloro-3-indolyl phosphate) colour developing of 3.5 μ l dark places is 2 hours, TE liquid stopped reaction, redye at the C.I. 42590 end, the transparent mounting of conventional dehydration.
Experiment contrast is set up blank and the RNase digestion contrast that does not add probe simultaneously, and positive control is for proving the osteosarcoma of positive reaction repeatedly, and every routine specimen is all done HE dyeing simultaneously.
3, result:
3.1 cell growing state
Being organized between people's dental papilla has primary cell to swim out of from the piece of tissue edge in 2～5d, be that the center is the radial arrangement growth with the piece of tissue.People's dental papilla mesenchymal cells mostly is fusiformis or star fibroblast-like cells greatly, and early stage cell is less lance shape cell, and minority has the projection more than 3, and cell broadens subsequently, and cell space is abundant, and endochylema is even, the nuclear circle, and kernel is clear.Cell cell growth before 18 generations is vigorous, and growth conditions is good, and is stable, cell poor growth then later on, aging.
3.2 cell growth curve, doubling time and origin are identified
1d after inoculation, people's dental papilla mesenchymal cells number descends to some extent, the bottom out of 2d cell number, and enter exponential phase.Cell growth curve is serpentine.People's dental papilla mesenchymal cells doubling time is 40.1h.
Adopt the method for ABC SABC that people's dental papilla mesenchymal cells of being cultivated is carried out anti-waveform fibroin, anti-keratin dyeing, cell is the tangible anti-waveform fibroin positive, is evenly distributed in the endochylema; The anti-keratin feminine gender.Show that cultured cells is not the fibroblast-like cells in epithelial cell but mesoderm source.
3.3 in situ hybridization result
People's dental papilla mesenchymal cells BMP2mRNA of In vitro culture and BMP3mRNA positive hybridization signal a little less than; Cell is behind PTH effect 5d, and the expression of BMP2mRNA does not have significant change; And in cytoplasm, the BMP3mRNA positive hybridization signal appears, the hybridization positive material is a bluish violet fine particulate in the endochylema.
The influence that experimental example 2 pharmaceutical compositions of the present invention form dentin
Set up the animal model of hypoplasia of dentin by excising the rat parathyroid gland, observe the influence that hypoparathyroidism forms dentin.
Behind this laboratory observation excision rat parathyroid gland, manually give the change that dentin forms behind the PTH of various dose, observe with administration of PTH dosage and have or not dependency, detect total calcium content in the serum, observe the relation of calcium level and dentin formation.
One, experimental procedure
32 of the pure lines male SD rats of age 35d (5 week) are selected in laboratory animal and grouping for use, are divided into eight groups at random
I: normal control group (control)
II:: parathyroid gland is from body plantation group (PTT)
III. parathyroidectomy group (PTX), normal saline subcutaneous injection 1ml
IV: parathyroidectomy group (PTX), PTH subcutaneous injection every day 50 μ g/kg, inferior on every Saturdays.
V: parathyroidectomy group (PTX), PTH subcutaneous injection every day 100 μ g/kg, inferior on every Saturdays.
VI: parathyroidectomy group (PTX), PTH subcutaneous injection every day 200 μ g/kg, inferior on every Saturdays.
VII: parathyroidectomy group (PTX); Vitamin D3 intramuscular injection 2000U/ only, the next day once.
VIII: parathyroidectomy group (PTX); The PTH preparation is once oral every day, and is inferior on every Saturdays.
Two, method
21 operation methods
Rat with 2% penta crust than sodium intraperitoneal injection of anesthesia (40mg/kg), the depilation of 8% sodium sulfide cervical region, flushing is fixed on the operating-table, sterilization, drape vertically cuts skin, subcutaneous tissue at the neck middle part, exposes the thyroid parathyroid gland, grouping is later on carried out.
2.1.1II group: separate parathyroid gland, plant in the animal cervical region subcutaneous again.Postoperative 48h and 7d detect total calcium concentration in the blood.The rat that has only total calcium concentration to be maintained at normal level is used for further observation.After animal revived, free diet was fed in cage.
2.1.2III, IV, V, VI, VII, VIII group: parathyroidectomize fully, sew up.Postoperative is organized with I.
2.2 total calcium is measured
Rat tails venous blood collection 0.3ml, operation the previous day blood sampling once, blood sampling in later per three days is once measured the blood total calcium content with MTB (methyl Bai Lixiang phenol blue laws), until putting to death rat the previous day.Reduce to 6mg/dl when following (being about PTX11 day) when blood calcium, count experiment 0 day, each group is put to death the animal of half around the experiment, remaining half continue experiment to 12 weeks and put to death.
2.3 labelling
Each is organized all and is testing day the previous day and putting to death rat and to injecting tetracycline (10mg/kg) in the rat peritoneum dentin is carried out labelling the previous day.After injecting tetracycline for the first time, give the intraperitoneal injection of rat 10mg/kg calcein two weeks.
2.4 draw materials with sample process
Put to death rat, take off tooth jaw tissue, pull out the lower jaw incisor, be separately fixed at a week in 10% formalin solution, with compound sour decalcification, conventional dehydration, defat, embedding, cut along lower jaw incisor center sagittal, be made into the section of thickness＜10 μ m, under fluorescence microscope, observe.
Three, result
1, postoperative animal ordinary circumstance record:
2, fluorescence microscope is observed down:
3, dentin deposition (injecting the labelling latter end calcein and the second time distance between the tetracycline, μ m per day):
IV, V, VI organize the dentin deposition between III group and I, II group, and raise with the PTH injected dose.
VII, VIII group dentin deposition is higher than the III group, compares with IV, V, VI group.
The yellow rate of labelling latter end calcium plain with inject Dentinal area (mm2) between the tetracycline second time:
IV, V, VI organize the dentin area between III group and I, II group, and raise with the PTH injected dose.
VII, VIII group dentin area is higher than the III group, compares with IV, V, VI group.
3, total calcium content changes
Draw five groups of total calcium content change curves, I, II group blood calcium is kept normally constant substantially, and the III group is maintained at low-level, and IV, V, VI group all are higher than the III group, are lower than the I group, and raise with the PTH injected dose.VII, VIII group is higher than the III group, compares with IV, V, VI group.
Above-mentioned experiment proves that fully parathyroid hormone has the effect of treatment hypoplasia of dentin, has the purposes that promotes that people's dental papilla mesenchymal cells bone morphogenetic protein(BMP) is expressed, under the effect of PTH, the BMP3 gene is activated, expresses, participate in inducing of dental papilla mesenchymal cells and break up by autocrine and paracrine action, promote the formation of dentin and dentin sample substrate, solved the problem of synthetic PTH in the body, and PTH is near physiological level, it is longer at the normal value leveled time to keep PTH, and have no side effect, be easy to apply.
List of references
1, Chen Xinmei Xiao Mingzhen Ni Longxing etc. parathyroid hormone is to the influence of people's dental papilla mesenchymal cells alkaline phosphatase activities of cultivating. tooth body dental pulp periodontal magazine, 1999,9 (3): 2272, Jin Y, Yang LJ.Immunohistochemical analysis of bonemorphogenetic protein (BMP) in osteosarcoma.J Oral Pathol Med, 1990; 19:152～154
3、Lyons?KM，Pelton?RW，Hogan?BLM.Organization?and?patternformation?in?the?mouse，RNA?distribution?patterns?suggest?a?rolefor?bone?morphogenetic?protein-2A(BMP2A).Development.1991；109：822～844
4, high beautiful good, Yang Lianjia. BMP2A gene expression in situ hybridization research in people's dental gram. practical stomatology magazine, 1994; 10 (4): 239～241
5, Wang Zhongdong. the people normally reaches distribution characteristics and the Dynamic variation of NOS and BMP3mRNA in the inflammatory pulpal tissue. the master thesis .p25 of The Fourth Military Medical University～36
6、Bessho?K，Tanaka?N，Matsuoto?J，et?al.Human?dentin-matrix-derived?bone?morphogenetic?protein.J?Dent?Res，1990；70：171～175
7、Kawai?D?and?Urist?MR.Bovin?tooth-derived?bone?morphogeneticprotein.J?Dent?Res，1989；68：1069～1074
8、Nakashima?M.The?inductive?of?reparative?dentine?in?theamputated?dental?pulp?of?the?dog?by?bone?morphogenetic?protein.Arch?Oral?Biol，1990；35(7)：493
9, high beautiful good, Yang Lianjia, Zhang Shaozhang, etc. the experimentation that bone morphogenetic protein(BMP) induces dentin to form. practical stomatology magazine, 1989; 59 (4): 250～251
10、Nakashima?M.The?effects?growth?factors?on?DNA?synthesis，proteoglycan?synthesis?and?alkaline?phosphatase?activity?inbovine?dental?pulp?cells.Arch?Oral?Biol，1992；37(3)：231
11, high beautiful good, Yang Lianjia. bone morphogenetic protein(BMP) influences the observation in vitro of people's dental pulp fibroblast-like cell biological characteristics. practical stomatology magazine, 1993; 9 (4): 246～248
12, high beautiful good, Suwa visits Wen Yan, and Tian Yibang too is etc. the inducing action of the external people pulp tissue to cultivation of. bone morphogenetic protein(BMP). The Fourth Military Medical University's journal, 1994; 15 (5); 328～331,
13, banket, summary. the relation of tooth and bone morphogenetic protein(BMP) (BMP). foreign medical science stomatology fascicle, 1992; 10 (6): 345～346
14、Nakashima?M.Induction?of?dentine?in?amputates?pulp?of?dogsby?recombinant?human?BMP2?and-4?with-collagen?matrix.Archs?OralBiol，1994；39(12)：1085～1089
15, Ma Zhensheng, summary. the osteogenin progress. The Fourth Military Medical University's journal, 1994; 15:79～80
16、Vukicevic?S，Paralkar?VM，Cunningham?NS，et?al.Autoradiographic?localiation?of?osteogenin?binding?sites?incartilage?and?bone?during?rat?embryonic?development.Dev?Biol，1990；40：209～214
17、Vukicevic?S，Helder?MN，Luyten?FP.Developing?human?lungand?kidney?are?major?sites?for?synthesis?of?bone?morphogeneticprotein-3(Osteogenin).J?histoche?Cytoche，1994；42：869～873
18、Aberg?T，Wozney?J，Thesleff?I.Expression?of?BMP2，4and?7in?the?enamal?knot，the?signaling?center?for?tooth?morphogenesis.Bone?morphogenetic?proteins?experimental?and?clinical?aspectstoday.Abstracts.Abstracts，June?17-19，1996
19、Tabas?JA，Hahn?GV，Cohen?RB，et?al.Chromosomal?assignmentof?the?human?gene?for?bone?morphogenetic?Protein4.Clin?Orthop，1993；293：310～316
Claims (5)
1. the purposes of parathyroid hormone in the pharmaceutical composition of preparation treatment hypoplasia of dentin disease.
2. purposes according to claim 1 is characterized in that: described pharmaceutical composition is injection or injectable powder.
3. purposes according to claim 1 is characterized in that: described pharmaceutical composition is the subcutaneous injection agent.
4. purposes according to claim 1, its feature exists: described pharmaceutical composition is an oral formulations.
5. according to each described purposes of claim 1～4, it is characterized in that: parathyroid hormone 0.5mg～4mg is contained in every preparation unit of described pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100224314A CN100406059C (en) | 2004-04-30 | 2004-04-30 | Purposes of parathyroid hormone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100224314A CN100406059C (en) | 2004-04-30 | 2004-04-30 | Purposes of parathyroid hormone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1689642A CN1689642A (en) | 2005-11-02 |
| CN100406059C true CN100406059C (en) | 2008-07-30 |
Family
ID=35345596
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100224314A Expired - Fee Related CN100406059C (en) | 2004-04-30 | 2004-04-30 | Purposes of parathyroid hormone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100406059C (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1142772A (en) * | 1993-12-23 | 1997-02-12 | 艾里利克斯生物药物公司 | Parathyroid hormone formulation |
| US20020094951A1 (en) * | 1997-07-22 | 2002-07-18 | Noboru Horiuchi | Dental remedies containing pth |
-
2004
- 2004-04-30 CN CNB2004100224314A patent/CN100406059C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1142772A (en) * | 1993-12-23 | 1997-02-12 | 艾里利克斯生物药物公司 | Parathyroid hormone formulation |
| US20020094951A1 (en) * | 1997-07-22 | 2002-07-18 | Noboru Horiuchi | Dental remedies containing pth |
Non-Patent Citations (2)
| Title |
|---|
| 甲状旁腺激素对牙乳头间充质细胞、组织影响的实验研究. 陈新梅，肖明振，论文正文第59,64,65,75,76和83页，中国优秀博硕士学位论文全文数据库. 1998 |
| 甲状旁腺激素对牙乳头间充质细胞、组织影响的实验研究. 陈新梅，肖明振，论文正文第59,64,65,75,76和83页，中国优秀博硕士学位论文全文数据库. 1998 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1689642A (en) | 2005-11-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lamghari et al. | Stimulation of bone marrow cells and bone formation by nacre: in vivo and in vitro studies | |
| Dan et al. | The influence of cellular source on periodontal regeneration using calcium phosphate coated polycaprolactone scaffold supported cell sheets | |
| Gonçalves et al. | Dental cementum reviewed: development, structure, composition, regeneration and potential functions | |
| TWI749415B (en) | Novel peptide and a pharmaceutical composition, a quasi-drug composition and a health functional food composition comprising the same | |
| US8993000B2 (en) | Method for inducing differentiation of dental pulp cells into odontoblasts | |
| Smith et al. | Transdentinal stimulation of reactionary dentinogenesis in ferrets by dentine matrix components | |
| Ohlsson et al. | Effects of tri-iodothyronine and insulin-like growth factor-I (IGF-I) on alkaline phosphatase activity,[3H] thymidine incorporation and IGF-I receptor mRNA in cultured rat epiphyseal chondrocytes | |
| KR20090119718A (en) | Osteogenic synthetic peptides, pharmaceutical compositions comprising the same, and medium containing the same | |
| Tziafa et al. | Dentinogenic activity of biodentine in deep cavities of miniature swine teeth | |
| Duarte et al. | Alendronate may protect against increased periodontitis‐related bone loss in estrogen‐deficient rats | |
| Fu et al. | Matrigel scaffolding enhances BMP9-induced bone formation in dental follicle stem/precursor cells | |
| CN102643330A (en) | Synthetic method for aspartate hexapeptide danshensu as bone targeted drug and medical application of aspartate hexapeptide danshensu | |
| BR112020012054A2 (en) | unpublished peptide | |
| Young | Growth hormone and insulin-like growth factor-I in odontogenesis | |
| CN117982532A (en) | Nanocomposite and preparation method and application thereof | |
| CN102755667A (en) | Preparation method and application of tissue-engineering human tooth root implantation material | |
| Tziafas et al. | Dentine-pulp tissue engineering in miniature swine teeth by set calcium silicate containing bioactive molecules | |
| Özdal-Kurt et al. | Attachment and growth of dental pulp stem cells on dentin in presence of extra calcium | |
| CN110499285A (en) | Application of the ALPL gene in the product of preparation prevention and/or treatment low alkalinity phosphatase disease | |
| Ishikawa et al. | Effects of calcitonin and parathyroid hormone on calcification of primary cultures of chicken growth plate chondrocytes | |
| CN100406059C (en) | Purposes of parathyroid hormone | |
| Kline et al. | Effects of Calcitonin, Calcitonin Gene-Related Peptide, Human Recombinant Bone Morphogenetic Protein-2, and Parathyroid Hormone–Related Protein on Endodontically Treated Ferret Canines | |
| CN104306958B (en) | Application of the insulin-like growth factor binding protein 5 in promoting paradenlal tissue regeneration | |
| US20020169210A1 (en) | Method for treating or preventing bone fracture | |
| CN102256996A (en) | Treatment of early-stage osteoarthritis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20081226 Address after: No. 24, south section, first ring road, Chengdu, Sichuan: 610065 Co-patentee after: Stomatological Hospital, Military Surgeon Univ. No.4, PLA Patentee after: Sichuan University Address before: No. 8, unit 2, 4 Xi'an Middle Road, Jinniu District, Chengdu, Sichuan 8, zip code: 610041 Co-patentee before: Xiao Mingzhen Patentee before: Chen Xin Mei Co-patentee before: Ni Longxing Co-patentee before: Zhang Yaqing |
|
| ASS | Succession or assignment of patent right |
Owner name: SICHUAN UNIVERSITY Free format text: FORMER OWNER: CHEN XINMEI Effective date: 20081226 |
|
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080730 Termination date: 20130430 |