WO1996019246A1 - Continuous low-dose administration of parathyroid hormone or its agonist - Google Patents
Continuous low-dose administration of parathyroid hormone or its agonist Download PDFInfo
- Publication number
- WO1996019246A1 WO1996019246A1 PCT/US1995/016554 US9516554W WO9619246A1 WO 1996019246 A1 WO1996019246 A1 WO 1996019246A1 US 9516554 W US9516554 W US 9516554W WO 9619246 A1 WO9619246 A1 WO 9619246A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nle
- arg
- tyr
- phe
- bpth
- Prior art date
Links
- 239000000556 agonist Substances 0.000 title claims abstract description 31
- 108090000445 Parathyroid hormone Proteins 0.000 title abstract description 47
- 102000003982 Parathyroid hormone Human genes 0.000 title abstract description 8
- 239000000199 parathyroid hormone Substances 0.000 title abstract description 8
- 229960001319 parathyroid hormone Drugs 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 28
- 230000011164 ossification Effects 0.000 claims abstract description 8
- 230000001737 promoting effect Effects 0.000 claims abstract description 6
- 102000043299 Parathyroid hormone-related Human genes 0.000 claims description 28
- 108700020797 Parathyroid Hormone-Related Proteins 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 238000001802 infusion Methods 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 claims description 5
- 238000013268 sustained release Methods 0.000 claims description 5
- 239000012730 sustained-release form Substances 0.000 claims description 5
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 4
- 208000006386 Bone Resorption Diseases 0.000 claims description 3
- 230000024279 bone resorption Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 2
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 2
- DEFJQIDDEAULHB-IMJSIDKUSA-N L-alanyl-L-alanine Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(O)=O DEFJQIDDEAULHB-IMJSIDKUSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002071 phenylalkoxy group Chemical group 0.000 claims description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims 1
- 102100036893 Parathyroid hormone Human genes 0.000 description 39
- 210000000988 bone and bone Anatomy 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 17
- 108090000765 processed proteins & peptides Proteins 0.000 description 16
- 230000000694 effects Effects 0.000 description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
- 239000011575 calcium Substances 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- 230000001195 anabolic effect Effects 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- -1 t-butoxycarbonyl Chemical group 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 230000001593 cAMP accumulation Effects 0.000 description 5
- 230000002124 endocrine Effects 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 description 4
- 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 102000058004 human PTH Human genes 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 210000000963 osteoblast Anatomy 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 101001135732 Bos taurus Parathyroid hormone Proteins 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 230000001009 osteoporotic effect Effects 0.000 description 3
- 230000000849 parathyroid Effects 0.000 description 3
- 238000000159 protein binding assay Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 101000606274 Bos taurus Parathyroid hormone-related protein Proteins 0.000 description 2
- 241000557626 Corvus corax Species 0.000 description 2
- 101001135738 Homo sapiens Parathyroid hormone-related protein Proteins 0.000 description 2
- 102000004067 Osteocalcin Human genes 0.000 description 2
- 108090000573 Osteocalcin Proteins 0.000 description 2
- 102000006461 Parathyroid Hormone Receptors Human genes 0.000 description 2
- 108010058828 Parathyroid Hormone Receptors Proteins 0.000 description 2
- 101710123753 Parathyroid hormone-related protein Proteins 0.000 description 2
- 101001135767 Rattus norvegicus Parathyroid hormone Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 238000007470 bone biopsy Methods 0.000 description 2
- 230000008468 bone growth Effects 0.000 description 2
- 230000008416 bone turnover Effects 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229940122361 Bisphosphonate Drugs 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000012422 Collagen Type I Human genes 0.000 description 1
- 108010022452 Collagen Type I Proteins 0.000 description 1
- 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 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241001622557 Hesperia Species 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 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 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 238000011444 antiresorptive therapy Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000004663 bisphosphonates Chemical class 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000018678 bone mineralization Effects 0.000 description 1
- 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 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940096422 collagen type i Drugs 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 229940095074 cyclic amp Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000001739 density measurement Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009547 dual-energy X-ray absorptiometry Methods 0.000 description 1
- 230000004821 effect on bone Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000004898 n-terminal fragment Anatomy 0.000 description 1
- 230000010807 negative regulation of binding Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000003715 nutritional status Nutrition 0.000 description 1
- 238000009806 oophorectomy Methods 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000001300 stimulation of adenylate cyclase Effects 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 108010063331 type 2 taste receptors Proteins 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/635—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- 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
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- 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
Definitions
- Parathyroid hormone has been shown to effect a positive bone balance (reviewed in Dempster, D. . et al., Endocrine Rev., 1993, 14, 690-709; Riggs, L. , Amer. J. Med., 1991, 91 (Suppl 5B) , 37S-41S) .
- the mammalian parathyroid hormone is a polypeptide product of the parathyroid glands.
- the mature circulating form of the hormone is comprised of 84 amino acid residues.
- Parathyroid hormone-related protein (“PTHrP”) is a 139 to 173 amino acid-protein with N-terminal homology to PTH. PTHrP shares many of the biological effects of PTH including binding to a common PTH/PTHrP receptor
- PTHi. 34 is a synthetic amino-terminal fragment of PTH 1 _ 8 (Tregear, G.W. , et al., Endocrinology, 1973, 93, 1349-1353; Mosekilde, L. , et al., Endocrinology, 1991, 129, 421-428).
- the invention features a method of promoting bone formation in a human patient (e.g., a patient who suffers f om osteoporosis) .
- the method includes the steps of administering (e.g., transmucously, intravenously, transdermally, subcutaneously, via implantation, or via infusion) continuously to the patient PTH (mature form) , PTHrP, or an agonist thereof for a period of at least one month (as long as the life time of the patient, if necessary) at a dosage between 10 and 400 units/24 hrs.
- PTH and PTHrP include, but are not limited to, human PTH (hPTH) , human PTHrP (hPTHrP) , bovine PTH (bPTH) , bovine PTHrP (bPTHrP) , and rat PTH (rPTH) .
- An agonist of PTH or PTHrP is a peptide which is a structural analog or fragment (preferably, an N-terminal fragment containing 50 or fewer amino acids) of a naturally occurring PTH or PTHrP and, like PTH and PTHrP, also capable of binding to PTH receptor and, thereby, promoting bone formation.
- Examples of such an agonist include, but are not limited to, hPTH 1 _ 34 NH 2 , hPTH 1 _ 38 NH 2 , hPTH !
- NH 2 denotes amidation of the carboxyl group (-CO*OH) of the C-terminal amino acid to form -CO*NH 2 .
- the following publications disclose the sequences of PTH peptides: The Parathyroids Basic and Clinical Concepts, ed. John P. Bilezikian, 239-258 (Raven Press, NH 1994); Nissenson, R. , et al., Structure & Function of the Receptor for Parathyroid Hormone and Parathyroid Hormone-Releasing Hormone, 3 Receptor 193-202 1993; Bachem California 1993-1994 Catalog (Torrance, CA) ; and Sigma Peptides and Amino Acids 1994 Catalog (St. Louis, MO) .
- partial PTH agonists can also be used to practice the method of this invention.
- Examples of partial PTH agonists include, but are not limited to, N- terminal deletion analogs (e.g., [Tyr 34 ]bPTH 3 _ 34 NH 2 ; see U.S. Patent No. 4,771,124 (1988).
- Preferred ranges of dosages include 10-300 units/24 hrs, 10-200 units/24 hrs, 10-100 units/24 hrs, 100-400 units/24 hrs, 200-400 units/24 hrs, and 300-400 units/24 hrs.
- PTH, PTHrP, or an agonist thereof is defined by utilizing an in vitro cAMP accumulation assay with human SaOS-2 cells.
- Human SaOS-2 cells respond upon exposure to PTH, PTHrP, or an agonist thereof with a dose-dependent stimulation of cAMP accumulation.
- [Nle 8 ' 18 ,Tyr 34 ]hPTH 1 _ 34 NH 2 as the reference standard analog (10,000 units/mg) a dose-response relationship can be generated using standard non-linear regression analysis.
- the relative potency for various PTH analogs (in units/mg) can be determined from the ratio of the EC 50 of the reference standard analog to that of the PTH analog.
- EC 50 is defined as the dose that evokes a half maximal response — cAMP accumulation herein.
- the detailed procedure for handling the cells, setting up the assay, as well as methods for cAMP quantitation, is described in Sistane, E. , et al., Pharmacopeial Forum 20(3), 7509-7520 (1994).
- an ambulatory e.g., MINIMEDTM 404-SP, MiniMed Technologies, Sylmar, CA; Pharmacia Deltec CADD-MICRO MODELTM S900, Pharmacia Deltec Inc., St. Paul, MN; or Disetronic Medical System's PANOMATTM, Madison, MN
- an implantable pump e.g., MEDTRONIC SYNCROMEDTM, Medtronic, Inc., Minneapolis, MN
- MEDTRONIC SYNCROMEDTM Medtronic, Inc., Minneapolis, MN
- PTH, PTHrP, or an agonist thereof is administered as a sustained release formulation.
- the formulation may contain a homo- or a co- polymer prepared from lactic acid (D-isomer, L-isomer, or a racemate) , glycolide, glycolic acid, or caprolactone.
- suitable sustained release formulations can be found in the following publications: U.S. Patent No. 3,773,919 (1973) U.S. Patent No. 5,187,150 (1993) U.S. Patent No. 4,767,628 (1988)
- the sustained release formulations can be administered parenterally (e.g. subcutaneously, or intravenously) or by inhalation (e.g. using an aerosol delivery system; e.g., see WO93/00951 and WO94/07514) .
- PTH, PTHrP, or an agonist thereof can be administered transmucously (e.g. nasal, vaginal, rectal) or transdermally (e.g. iontophoretic patch) .
- a bone resorption inhibiting agent can also be administered during performance of the above-described method.
- a suitable bone resorption inhibiting agent include, but are not limited to, estrogen, calcitonin, bisphosphonate, tamoxifen, vitamin D, and calcium. Also, see U.S. Patent No. 5,118,667 (1992).
- the preferred dose and duration for practicing the above-described method varies depending upon the manner of administration, the age and the body weight of the subject and the condition of the subject to be treated, and ultimately will be decided by the attending physician.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient(s) into association with the carrier which constitutes one or more accessory ingredients.
- the formulations for tablets or powders are prepared by uniformly and intimately blending the active ingredient (e.g., hPTH) with finely divided solid carriers, and then, if necessary as in the case of tablets, forming the product into the desired shape and size.
- the invention also features novel PTH or PTHrP agonists of the following formula: ⁇
- a 2 is Ser or Ala
- a 7 is Leu or Phe
- a 12 is Gly, Aib, Ala, or D-Ala;
- a 16 is Asn, Ser or Ala;
- a 19 is Glu, Arg, Lys, Asp, Ser, Thr, Gin, Asn, or Ala;
- a 21 is Val, Met, Arg, Lys, Glu, Asp, Ser, Thr, Gin, Asn, Leu, lie, Nle, Ala, Phe, or p-X-Phe where X is OH, CH 3 , N0 2 , or a halogen;
- a 22 is Glu, Asp, Phe, p-X-Phe where X is OH, CH 3 , N0 2 or a halogen, Ser, Thr, Gin, Asn, Leu, lie, Nle, Val, Ala, or Met;
- a 23 is Trp, 1-Nal, or 2-Nal;
- a 34 is Phe, or p-X-Phe where X is OH, CH 3 , N0 2 , or a halogen;
- W is OH, C ⁇ _ 12 alkoxy, c 7 - 20 phenylalkoxy, C 11 _ 20 napthylalkoxy, or NR 3 R 4 ; provided that when A 12 is Gly,
- a ⁇ g is Glu, A 21 is Val, and A 22 is Gin, then A 23 must be 1- Nal or 2-Nal; and each of R 2 , R 2 , R 3 , and R 4 is, independently, H, c ⁇ -i 2 alkyl, C 7 _ 10 phenylalkyl, or CO * E where E is C x _ 12 alkyl, C 2 _ 12 alkenyl, phenyl, naphthyl, or C 7 _ 20 phenylalkyl; or a pharmaceutically acceptable salt thereof.
- the N-terminus is at the left and the C-terminus at the right in accordance with the conventional representation of a polypeptide chain.
- R is - CH(CH 3 ) 2 for Val.
- the amino acid residue is optically active, it is the L-form configuration that is intended unless D-form is expressly designated.
- Preferred groups of compounds covered by the above formula include (i) those where h- is Ala; A 7 is Phe; and A 16 is Ser; (ii) those where A 19 is Glu or Arg; and A 21 is Val or Arg; and (iii) those where A 22 is p-X-Phe where X is OH, CH 3 , N0 2 , or a halogen.
- PTH and PTH-like agonist activities of peptide fragments or derivatives of parathyroid hormone or PTHrP can be tested by contacting a concentration range of the test compound with the cells in culture and assessing the stimulation of the PTH/PTHrP receptors.
- Receptor stimulation is evidenced by the activation of second messenger molecules coupled to the receptors, for example, a stimulation of cyclic AMP accumulation in the cell or an increase in enzymatic activity of protein kinase C, both of which are readily monitored by conventional assays (Jouis Subscribe, H. , et al., Endocrinology, 1992, 130, 53-60; Abou-Samra, A.B. , et al..
- PTH-like agonist activities of subfragments of PTH have been successfully analyzed by contacting peptides with rat kidney cells in culture and assessing cyclic AMP accumulation (Blind, E. , et al., Clin. Endocrinol., 1993, 101, 150-155) and the stimulation of 1,25- dehydroxyvitamin D 3 production (Janulis, M. , et al., Endocrinology, 1993, 133, 713-719).
- PTH or PTHrP agonists of the invention were synthesized on an APPLIED BIOSYSTEMSTM 430A Automated Peptide Synthesizer (Applied Biosystems Inc. , Foster City, CA) using version 1.40 of the software for NMP/HOBt Boc-based chemistry.
- Boc for t-butoxycarbonyl
- For for formayl cycHx for cyclohexyl
- Cl-Z for 2- chlorobenzyloxycarbonyl
- OBzl is O-benzyl
- BOM for benzyloxymethyl
- Bzl for benzyl
- Br-Z for 2-bromo- benzyloxycarbonyl
- I ⁇ -Tosyl for tosyl at guanidyl site
- pMBHA-R paramethoxybenzhydrylamine resin.
- the crude peptides were purified on a WATERS DELTA PREPTM 4000 (Waters, Milford, MA), preparative HPLC system, connected to a PrepPack cartridge of VydacTM C18 300A, 15-20 ⁇ [47 x 300 mm] (Waters, Milford, MA) at a flow rate of 70 mL/min monitored at 220 nm.
- the analytical HPLC system included the following components: Waters 600E multisolvent delivery system, 490E programmable multiwavelength detector, 717 autosampler and a 747 data module.
- the samples were analyzed on a VYDACTM C18 218TP5415 (150 x 4.6 mm, 5 ⁇ m) , The Separation Group (Hesperia, CA) at a flow rate of 1 mL/min monitored at 220 nm.
- the solvent mixtures for both the analytical and preparative HPLC were: A: 0.1% TFA in H 2 0, and B: 0.1% TFA in acetonitrile.
- the purity of the peptides and their derivatives exceeded 99% as determined from the analytical RP-HPLC.
- Example 2 SaOS-2 BIO cells were maintained in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS) and 2 mM glutamine at 37°C in a humidified atmosphere of 5% C0 2 in air. The medium was changed every three or four days, and the cells were subcultured every week by trypsinization.
- FBS fetal bovine serum
- SaOs-2 BIO cells were maintained for four days after they had reached confluence.
- the medium was replaced with 5% FBS RPS/1640 medium and incubated for 2 hrs at room temperature with 10 x 10 4 cpm mono- 125" I- [Nle 8 ' 18 ,Tyr 34 (3-I 125 ) ]bPTH 1 _ 34 NH 2 in the presence or absence of a competing tested PTH agonist.
- the cells were washed four times with ice-cold PBS and lysed with 0.1 M NaOH, and the radioactivity associated with the cells was counted in a scintillation counter. Synthesis of the radiolabelled [Nle 8 ' 18 . Tyr 34 (3-I 125 ) ]bPTH 1 _ 34 NH, was carried out as described in Goldman ME et al., Endocrinology, 1988, 123, 1468-1475.
- the binding assay was conducted on Analogs I-IV and Analog V (i.e., [Nle 8 , Nle 18 , Tyr 3 ]bPTH 1 _ 34 NH 2 ) .
- the IC 5 ⁇ 0n '' s (half maximal inhibition of binding of mono- 125 I- ' [Nle 8 ' 18 ,Tyr 34 (3-I 125 )]bPTH 1 _ 34 NH 2 ) for the five tested analogs were calculated and shown in Table IV below:
- In vivo bone anabolic activities of PTH/PTHrP agonists are tested by administering the peptide or a formulation containing the peptide into intact animals or an experimental animal model of osteopenia.
- the animal model can be osteoporosis in rats induced by ovariectomy (Hori, M. , et al., Bone Miner., 1988, 3, 193-199; Geral, et al., J. Bone Miner. Res., 1989, 4, Suppl. 1, S303; Liu C-C. & Kalu, D.N., J. Bone Miner. Res., 1990, 5, 973-982; Mosekilde, L.
- the bone anabolic effects of the compound are determined following 12 to 60 days of treatment by assessing the change in bone mineral density by dual energy x-ray absorptiometry or dry weight of femurs or total ash weight (Hori, H. , et al., Bone Miner., 1988, 3, 193-199; Hefti, E. , et al., Clin. Sci., 1982, 62, 389- 396) .
- Increase in the rate of bone formation and mineralization are assessed using metabolic labels, e.g. tetracycline (Tam, C.S., et al., Endocrinology, 1982, 110, 506-512).
- the patients prior to the study are subject to the following: complete health and physical examination, evaluation of the nutritional status (particularly of calcium intake and serum calcium) , full analysis of biomarkers for bone-turnover (Riis, B.J. , Amer. J. Med. 1993, 95 [Suppl 5A] , 17s-21s; Delmas, P.D. , Amer. J.
- the treatments are extended to twelve months, wherein bone mass measurements and bone biopsy further provide clear indication of bone growth in the population treated with continuous infusion hPTH 1 _ 34 .
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Endocrinology (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8519949A JPH10511095A (en) | 1994-12-19 | 1995-12-19 | Low dose continuous administration of parathyroid hormone or its agonist |
AU44728/96A AU4472896A (en) | 1994-12-19 | 1995-12-19 | Continuous low-dose administration of parathyroid hormone or its agonist |
EP95943474A EP0800405A4 (en) | 1994-12-19 | 1995-12-19 | Continuous low-dose administration of parathyroid hormone or its agonist |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US35929394A | 1994-12-19 | 1994-12-19 | |
US08/359,293 | 1994-12-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996019246A1 true WO1996019246A1 (en) | 1996-06-27 |
Family
ID=23413202
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/016554 WO1996019246A1 (en) | 1994-12-19 | 1995-12-19 | Continuous low-dose administration of parathyroid hormone or its agonist |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0800405A4 (en) |
JP (1) | JPH10511095A (en) |
AU (1) | AU4472896A (en) |
CA (1) | CA2205959A1 (en) |
WO (1) | WO1996019246A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998014478A1 (en) * | 1996-09-30 | 1998-04-09 | Beth Israel Deaconess Medical Center | Continuous low-dose administration of parathyroid hormone or its agonist |
WO1998030590A2 (en) * | 1997-01-07 | 1998-07-16 | Biomeasure Incorporated | Analogs of parathyroid hormone |
US5969095A (en) * | 1995-07-13 | 1999-10-19 | Biomeasure, Inc. | Analogs of parathyroid hormone |
US6544949B1 (en) * | 1995-07-13 | 2003-04-08 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Analogs of parathyroid hormone |
WO2003053167A1 (en) | 2001-12-11 | 2003-07-03 | Societe Des Produits Nestle S.A. | Composition for promotion of bone growth and maintenance of bone health |
US7393837B2 (en) | 1998-09-28 | 2008-07-01 | Mcgill University | Inhibition of PEX in the treatment of metabolic bone diseases |
US7410948B2 (en) | 1995-07-13 | 2008-08-12 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas | Analogs of parathyroid hormone |
US7994129B2 (en) | 2005-11-10 | 2011-08-09 | Michigan Technological University | Methods of using black bear parathyroid hormone |
US8987201B2 (en) | 2009-12-07 | 2015-03-24 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DZ2873A1 (en) * | 1998-08-19 | 2003-12-15 | Lilly Co Eli | Method for increasing bone hardness and stiffness. |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4656250A (en) * | 1983-08-05 | 1987-04-07 | Toyo Jozo Kabushiki Kaisha | [Nle8, Nle18, Tyr34 or Phe34 ]-h-PTH peptide derivatives |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4747825A (en) * | 1984-06-29 | 1988-05-31 | Ferring Laboratories, Inc. | Apparatus and methodology for pulsed administration of growth promoting agents |
JP2653255B2 (en) * | 1990-02-13 | 1997-09-17 | 武田薬品工業株式会社 | Long-term sustained release microcapsules |
WO1993011786A1 (en) * | 1991-12-17 | 1993-06-24 | Procter & Gamble Pharmaceuticals, Inc. | Methods for the treatment of osteoporosis using bisphosphonates and parathyroid hormone |
-
1995
- 1995-12-19 JP JP8519949A patent/JPH10511095A/en active Pending
- 1995-12-19 AU AU44728/96A patent/AU4472896A/en not_active Abandoned
- 1995-12-19 WO PCT/US1995/016554 patent/WO1996019246A1/en not_active Application Discontinuation
- 1995-12-19 CA CA002205959A patent/CA2205959A1/en not_active Abandoned
- 1995-12-19 EP EP95943474A patent/EP0800405A4/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4656250A (en) * | 1983-08-05 | 1987-04-07 | Toyo Jozo Kabushiki Kaisha | [Nle8, Nle18, Tyr34 or Phe34 ]-h-PTH peptide derivatives |
Non-Patent Citations (1)
Title |
---|
See also references of EP0800405A4 * |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7632811B2 (en) | 1995-07-13 | 2009-12-15 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas | Analogs of parathyroid hormone |
USRE40850E1 (en) | 1995-07-13 | 2009-07-14 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Analogs of parathyroid hormone |
US5955574A (en) * | 1995-07-13 | 1999-09-21 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Analogs of parathyroid hormone |
US5969095A (en) * | 1995-07-13 | 1999-10-19 | Biomeasure, Inc. | Analogs of parathyroid hormone |
US6544949B1 (en) * | 1995-07-13 | 2003-04-08 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Analogs of parathyroid hormone |
US7410948B2 (en) | 1995-07-13 | 2008-08-12 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas | Analogs of parathyroid hormone |
US6921750B2 (en) | 1995-07-13 | 2005-07-26 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Analogs of parathyroid hormone |
WO1998014478A1 (en) * | 1996-09-30 | 1998-04-09 | Beth Israel Deaconess Medical Center | Continuous low-dose administration of parathyroid hormone or its agonist |
CZ298937B6 (en) * | 1997-01-07 | 2008-03-19 | Societe De Conseils De Recherches Et D´Applications Scientifiques, S.A.S. | Peptide being an analog of parathyroid hormone fragment and peptides of protein related to the parathyroid hormone |
EP1645566A3 (en) * | 1997-01-07 | 2006-10-11 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Analogs of parathyroid hormone |
EP1645566A2 (en) * | 1997-01-07 | 2006-04-12 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Analogs of parathyroid hormone |
CZ301497B6 (en) * | 1997-01-07 | 2010-03-24 | Societe De Conseils De Recherches Et D´Applications Scientifiques, S.A.S. | Peptide variant of fragment of parathyroid hormone and parathyroid hormone-related protein peptides |
WO1998030590A3 (en) * | 1997-01-07 | 1998-12-10 | Biomeasure Inc | Analogs of parathyroid hormone |
WO1998030590A2 (en) * | 1997-01-07 | 1998-07-16 | Biomeasure Incorporated | Analogs of parathyroid hormone |
US7393837B2 (en) | 1998-09-28 | 2008-07-01 | Mcgill University | Inhibition of PEX in the treatment of metabolic bone diseases |
EP2135517A1 (en) | 2001-12-11 | 2009-12-23 | Société des Produits Nestlé S.A. | Composition for promotion of bone growth and maintenance of bone health |
WO2003053167A1 (en) | 2001-12-11 | 2003-07-03 | Societe Des Produits Nestle S.A. | Composition for promotion of bone growth and maintenance of bone health |
EP2263480A1 (en) | 2001-12-11 | 2010-12-22 | Société des Produits Nestlé S.A. | Composition for promotion of bone growth and maintenance of bone health, comprising Mentha extracts |
EP2272382A1 (en) | 2001-12-11 | 2011-01-12 | Société des Produits Nestlé S.A. | Composition for promotion of bone growth and maintenance of bone health, comprising soybean or soybean extracts |
EP2286675A1 (en) | 2001-12-11 | 2011-02-23 | Société des Produits Nestlé S.A. | Composition for promotion of bone growth and maintenance of bone health |
US7994129B2 (en) | 2005-11-10 | 2011-08-09 | Michigan Technological University | Methods of using black bear parathyroid hormone |
US8987201B2 (en) | 2009-12-07 | 2015-03-24 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
Also Published As
Publication number | Publication date |
---|---|
AU4472896A (en) | 1996-07-10 |
EP0800405A4 (en) | 1998-11-11 |
JPH10511095A (en) | 1998-10-27 |
EP0800405A1 (en) | 1997-10-15 |
CA2205959A1 (en) | 1996-06-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5747456A (en) | Continuous low-dose administration of parathyroid hormone or its agonist | |
JP4008825B2 (en) | Analogs of parathyroid hormone | |
US7632811B2 (en) | Analogs of parathyroid hormone | |
JP3963482B2 (en) | Analogs of parathyroid hormone | |
US7410948B2 (en) | Analogs of parathyroid hormone | |
US6316410B1 (en) | Parathyroid hormone analogues for the treatment of osteoporosis | |
US5717062A (en) | Cyclic analogs of PTH and PTHrP | |
US7521528B2 (en) | Conformationally constrained parathyroid hormone (PTH) analogs with lactam bridges | |
EP2201960A1 (en) | Conformationally constrained parathyroid hormones with alpha-helix stabilizers | |
WO1996019246A1 (en) | Continuous low-dose administration of parathyroid hormone or its agonist | |
JP2002513801A (en) | PTH2 receptor selective compound | |
Rossowski et al. | Galanin: structure-dependent effect on pancreatic amylase secretion and jejunal strip contraction | |
CN1916025B (en) | Analogs of parathyroid hormone | |
CZ20003999A3 (en) | PTH analog, method for selective binding to receptor, method of inducing agonistic and antagonistic response, pharmaceutical preparation and therapy method | |
CA2508765A1 (en) | Bone growth factor | |
CA2599885A1 (en) | Parathyroid hormone analogues for the treatment of osteoporosis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TT UA UG UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2205959 Country of ref document: CA Ref country code: CA Ref document number: 2205959 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1995943474 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWP | Wipo information: published in national office |
Ref document number: 1995943474 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1995943474 Country of ref document: EP |