JP2004277402A - 胃切除術を受けた個体の低体重及び低体脂肪量を治療するためのグレリンの使用 - Google Patents
胃切除術を受けた個体の低体重及び低体脂肪量を治療するためのグレリンの使用 Download PDFInfo
- Publication number
- JP2004277402A JP2004277402A JP2003352592A JP2003352592A JP2004277402A JP 2004277402 A JP2004277402 A JP 2004277402A JP 2003352592 A JP2003352592 A JP 2003352592A JP 2003352592 A JP2003352592 A JP 2003352592A JP 2004277402 A JP2004277402 A JP 2004277402A
- Authority
- JP
- Japan
- Prior art keywords
- ghrelin
- medicament
- acyl group
- group
- minutes before
- 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.)
- Granted
Links
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 title claims abstract description 107
- 101800001586 Ghrelin Proteins 0.000 title claims abstract description 78
- 238000013110 gastrectomy Methods 0.000 title claims abstract description 43
- 210000000577 adipose tissue Anatomy 0.000 title claims abstract description 31
- 230000037396 body weight Effects 0.000 title claims abstract description 24
- 102000012004 Ghrelin Human genes 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 31
- 239000004480 active ingredient Substances 0.000 claims abstract description 23
- 230000036528 appetite Effects 0.000 claims abstract description 15
- 235000019789 appetite Nutrition 0.000 claims abstract description 15
- 230000002265 prevention Effects 0.000 claims abstract description 8
- 206010006895 Cachexia Diseases 0.000 claims abstract description 4
- 230000037406 food intake Effects 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 102
- 150000001413 amino acids Chemical class 0.000 claims description 98
- 102400000442 Ghrelin-28 Human genes 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 67
- 239000003814 drug Substances 0.000 claims description 61
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 48
- 125000002252 acyl group Chemical group 0.000 claims description 46
- 235000012054 meals Nutrition 0.000 claims description 42
- -1 prostaglandin E2 Chemical compound 0.000 claims description 41
- 102000005962 receptors Human genes 0.000 claims description 35
- 108020003175 receptors Proteins 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 30
- 229940079593 drug Drugs 0.000 claims description 25
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 23
- 239000000556 agonist Substances 0.000 claims description 20
- 108010051696 Growth Hormone Proteins 0.000 claims description 18
- 102000018997 Growth Hormone Human genes 0.000 claims description 17
- 239000000122 growth hormone Substances 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 14
- 239000000194 fatty acid Substances 0.000 claims description 14
- 229930195729 fatty acid Natural products 0.000 claims description 14
- 125000001165 hydrophobic group Chemical group 0.000 claims description 14
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical class OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 11
- 101710151321 Melanostatin Proteins 0.000 claims description 11
- 102400000064 Neuropeptide Y Human genes 0.000 claims description 11
- 239000005557 antagonist Substances 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 150000004665 fatty acids Chemical class 0.000 claims description 9
- 230000002496 gastric effect Effects 0.000 claims description 9
- 230000001965 increasing effect Effects 0.000 claims description 9
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 8
- 230000036541 health Effects 0.000 claims description 8
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 claims description 7
- 102100037852 Insulin-like growth factor I Human genes 0.000 claims description 7
- 208000002720 Malnutrition Diseases 0.000 claims description 7
- 230000001071 malnutrition Effects 0.000 claims description 7
- 235000000824 malnutrition Nutrition 0.000 claims description 7
- 208000015380 nutritional deficiency disease Diseases 0.000 claims description 7
- 239000000018 receptor agonist Substances 0.000 claims description 7
- 229940044601 receptor agonist Drugs 0.000 claims description 7
- 102400001132 Melanin-concentrating hormone Human genes 0.000 claims description 6
- 101800002739 Melanin-concentrating hormone Proteins 0.000 claims description 6
- 102000001796 Melanocortin 4 receptors Human genes 0.000 claims description 6
- 102000008318 Type 3 Melanocortin Receptor Human genes 0.000 claims description 6
- 108010021433 Type 3 Melanocortin Receptor Proteins 0.000 claims description 6
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 claims description 6
- ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 claims description 6
- 230000002685 pulmonary effect Effects 0.000 claims description 6
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 claims description 6
- 150000003180 prostaglandins Chemical class 0.000 claims description 5
- 238000013518 transcription Methods 0.000 claims description 5
- 230000035897 transcription Effects 0.000 claims description 5
- 230000004584 weight gain Effects 0.000 claims description 5
- 235000019786 weight gain Nutrition 0.000 claims description 5
- 102400000921 Gastrin Human genes 0.000 claims description 4
- 108010052343 Gastrins Proteins 0.000 claims description 4
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 claims description 4
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims description 4
- 229960002986 dinoprostone Drugs 0.000 claims description 4
- 229960001340 histamine Drugs 0.000 claims description 4
- BPGXUIVWLQTVLZ-OFGSCBOVSA-N neuropeptide y(npy) Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 BPGXUIVWLQTVLZ-OFGSCBOVSA-N 0.000 claims description 4
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 claims description 4
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 3
- 108700021677 Agouti-Related Proteins 0.000 claims description 3
- 102100020948 Growth hormone receptor Human genes 0.000 claims description 3
- 101710099093 Growth hormone receptor Proteins 0.000 claims description 3
- 101000986786 Homo sapiens Orexin/Hypocretin receptor type 1 Proteins 0.000 claims description 3
- 101150106280 Mchr1 gene Proteins 0.000 claims description 3
- 108010047068 Melanin-concentrating hormone receptor Proteins 0.000 claims description 3
- 102000029828 Melanin-concentrating hormone receptor Human genes 0.000 claims description 3
- 102100027375 Melanin-concentrating hormone receptor 1 Human genes 0.000 claims description 3
- 108700036626 Melanin-concentrating hormone receptor 1 Proteins 0.000 claims description 3
- 101800001751 Melanocyte-stimulating hormone alpha Proteins 0.000 claims description 3
- 102400000740 Melanocyte-stimulating hormone alpha Human genes 0.000 claims description 3
- 101710200814 Melanotropin alpha Proteins 0.000 claims description 3
- 108050000742 Orexin Receptor Proteins 0.000 claims description 3
- 102000008834 Orexin receptor Human genes 0.000 claims description 3
- 108050001089 Orexin receptor 2 Proteins 0.000 claims description 3
- 102100028141 Orexin/Hypocretin receptor type 1 Human genes 0.000 claims description 3
- 102100027467 Pro-opiomelanocortin Human genes 0.000 claims description 3
- 102100024735 Resistin Human genes 0.000 claims description 3
- 108010047909 Resistin Proteins 0.000 claims description 3
- 229940025084 amphetamine Drugs 0.000 claims description 3
- 235000012631 food intake Nutrition 0.000 claims description 3
- 239000002865 melanocortin Substances 0.000 claims description 3
- 238000007911 parenteral administration Methods 0.000 claims description 3
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 206010021654 increased appetite Diseases 0.000 claims 1
- 229940029329 intrinsic factor Drugs 0.000 claims 1
- 235000013305 food Nutrition 0.000 abstract description 9
- 230000001133 acceleration Effects 0.000 abstract 2
- 235000001014 amino acid Nutrition 0.000 description 94
- 229940024606 amino acid Drugs 0.000 description 92
- 230000000694 effects Effects 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 20
- 239000004094 surface-active agent Substances 0.000 description 20
- 239000000126 substance Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 16
- 238000003556 assay Methods 0.000 description 16
- 230000027455 binding Effects 0.000 description 16
- 239000012528 membrane Substances 0.000 description 16
- 210000004379 membrane Anatomy 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- 239000002552 dosage form Substances 0.000 description 15
- 239000000693 micelle Substances 0.000 description 15
- 210000003491 skin Anatomy 0.000 description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000006467 substitution reaction Methods 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 102000000393 Ghrelin Receptors Human genes 0.000 description 13
- 108010016122 Ghrelin Receptors Proteins 0.000 description 13
- 229920001184 polypeptide Polymers 0.000 description 13
- 210000002784 stomach Anatomy 0.000 description 13
- 239000003085 diluting agent Substances 0.000 description 12
- 239000003937 drug carrier Substances 0.000 description 12
- 125000000539 amino acid group Chemical group 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 10
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 125000003275 alpha amino acid group Chemical group 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000002271 resection Methods 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 8
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 8
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 8
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 8
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 8
- 238000001356 surgical procedure Methods 0.000 description 8
- 102100039256 Growth hormone secretagogue receptor type 1 Human genes 0.000 description 7
- 101710202385 Growth hormone secretagogue receptor type 1 Proteins 0.000 description 7
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 7
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 7
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 7
- 239000000443 aerosol Substances 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 235000019197 fats Nutrition 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 208000016261 weight loss Diseases 0.000 description 7
- 230000004580 weight loss Effects 0.000 description 7
- YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 description 6
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 6
- 108010010803 Gelatin Proteins 0.000 description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 6
- 108010088847 Peptide YY Proteins 0.000 description 6
- 102100029909 Peptide YY Human genes 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 102000014384 Type C Phospholipases Human genes 0.000 description 6
- 108010079194 Type C Phospholipases Proteins 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 150000003863 ammonium salts Chemical class 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 239000008273 gelatin Substances 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 235000011852 gelatine desserts Nutrition 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 230000000580 secretagogue effect Effects 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 238000011200 topical administration Methods 0.000 description 6
- 125000000998 L-alanino group Chemical group [H]N([*])[C@](C([H])([H])[H])([H])C(=O)O[H] 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 5
- 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 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000002270 dispersing agent Substances 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 239000006210 lotion Substances 0.000 description 5
- 239000007937 lozenge Substances 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 5
- 239000003607 modifier Substances 0.000 description 5
- 239000002736 nonionic surfactant Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000004006 olive oil Substances 0.000 description 5
- 235000008390 olive oil Nutrition 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 229920002635 polyurethane Polymers 0.000 description 5
- 239000004814 polyurethane Substances 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- 239000002562 thickening agent Substances 0.000 description 5
- 230000032258 transport Effects 0.000 description 5
- 230000001515 vagal effect Effects 0.000 description 5
- DUGMCDWNXXFHDE-UHFFFAOYSA-N 2-amino-2-methyl-n-[1-(1-methylsulfonylspiro[2h-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1CC2(C3=CC=CC=C3N(C2)S(C)(=O)=O)CCN1C(=O)C(NC(=O)C(C)(N)C)COCC1=CC=CC=C1 DUGMCDWNXXFHDE-UHFFFAOYSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 4
- 240000007472 Leucaena leucocephala Species 0.000 description 4
- 235000019483 Peanut oil Nutrition 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 235000021355 Stearic acid Nutrition 0.000 description 4
- 208000007107 Stomach Ulcer Diseases 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- 230000002708 enhancing effect Effects 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000003324 growth hormone secretagogue Substances 0.000 description 4
- 239000000017 hydrogel Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012669 liquid formulation Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 4
- 229960002446 octanoic acid Drugs 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 4
- 239000000312 peanut oil Substances 0.000 description 4
- 230000001817 pituitary effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000008117 stearic acid Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 102100033367 Appetite-regulating hormone Human genes 0.000 description 3
- 101710111255 Appetite-regulating hormone Proteins 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 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 3
- 239000004472 Lysine Substances 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 235000009697 arginine Nutrition 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 206010017758 gastric cancer Diseases 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 229940088597 hormone Drugs 0.000 description 3
- 239000005556 hormone Substances 0.000 description 3
- 239000003906 humectant Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 239000001814 pectin Substances 0.000 description 3
- 235000010987 pectin Nutrition 0.000 description 3
- 229920001277 pectin Polymers 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 235000004400 serine Nutrition 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- DXOFMKNITCKTIS-QXMHVHEDSA-N (z)-2-ethyloctadec-9-enoic acid Chemical compound CCCCCCCC\C=C/CCCCCCC(CC)C(O)=O DXOFMKNITCKTIS-QXMHVHEDSA-N 0.000 description 2
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- DUGMCDWNXXFHDE-VZYDHVRKSA-N 2-amino-2-methyl-n-[(2r)-1-(1-methylsulfonylspiro[2h-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C([C@@H](NC(=O)C(C)(N)C)C(=O)N1CCC2(C3=CC=CC=C3N(C2)S(C)(=O)=O)CC1)OCC1=CC=CC=C1 DUGMCDWNXXFHDE-VZYDHVRKSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 102000003916 Arrestin Human genes 0.000 description 2
- 108090000328 Arrestin Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108091006027 G proteins Proteins 0.000 description 2
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 2
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 2
- 102000030782 GTP binding Human genes 0.000 description 2
- 108091000058 GTP-Binding Proteins 0.000 description 2
- BCCRXDTUTZHDEU-VKHMYHEASA-N Gly-Ser Chemical group NCC(=O)N[C@@H](CO)C(O)=O BCCRXDTUTZHDEU-VKHMYHEASA-N 0.000 description 2
- 102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 description 2
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000038455 IGF Type 1 Receptor Human genes 0.000 description 2
- 108010031794 IGF Type 1 Receptor Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 125000000510 L-tryptophano group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C(C([H])([H])[C@@]([H])(C(O[H])=O)N([H])[*])C2=C1[H] 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 101500028462 Rattus norvegicus Ghrelin Proteins 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 101710142969 Somatoliberin Proteins 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- INAPMGSXUVUWAF-GCVPSNMTSA-N [(2r,3s,5r,6r)-2,3,4,5,6-pentahydroxycyclohexyl] dihydrogen phosphate Chemical compound OC1[C@H](O)[C@@H](O)C(OP(O)(O)=O)[C@H](O)[C@@H]1O INAPMGSXUVUWAF-GCVPSNMTSA-N 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000003862 amino acid derivatives Chemical class 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 208000022531 anorexia Diseases 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000003093 cationic surfactant Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- FDJOLVPMNUYSCM-UVKKECPRSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7, Chemical compound [Co+3].N#[C-].C1([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)[N-]\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O FDJOLVPMNUYSCM-UVKKECPRSA-L 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 206010061428 decreased appetite Diseases 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 238000009513 drug distribution Methods 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 229920001971 elastomer Polymers 0.000 description 2
- 239000008393 encapsulating agent Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 235000003642 hunger Nutrition 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000002267 hypothalamic effect Effects 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 206010025482 malaise Diseases 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 210000003928 nasal cavity Anatomy 0.000 description 2
- 235000021096 natural sweeteners Nutrition 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 150000002895 organic esters Chemical class 0.000 description 2
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000000606 toothpaste Substances 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 230000037317 transdermal delivery Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- XOFLBQFBSOEHOG-UUOKFMHZSA-N γS-GTP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=S)[C@@H](O)[C@H]1O XOFLBQFBSOEHOG-UUOKFMHZSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- FPJGLSZLQLNZIW-VIFPVBQESA-N (2s)-2-amino-3-(4-methyl-1h-indol-3-yl)propanoic acid Chemical compound CC1=CC=CC2=C1C(C[C@H](N)C(O)=O)=CN2 FPJGLSZLQLNZIW-VIFPVBQESA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- RHLBOBPOIZROJX-UHFFFAOYSA-N 1-acetylpyrrolidine-2,5-dione Chemical compound CC(=O)N1C(=O)CCC1=O RHLBOBPOIZROJX-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- XXCVIFJHBFNFBO-UHFFFAOYSA-N 1-ethenoxyoctane Chemical group CCCCCCCCOC=C XXCVIFJHBFNFBO-UHFFFAOYSA-N 0.000 description 1
- MIJDSYMOBYNHOT-UHFFFAOYSA-N 2-(ethylamino)ethanol Chemical compound CCNCCO MIJDSYMOBYNHOT-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- HNLXNOZHXNSSPN-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCOCCOCCOCCO)C=C1 HNLXNOZHXNSSPN-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- UMUPQWIGCOZEOY-JOCHJYFZSA-N 2-amino-2-methyl-n-[(2r)-1-(1-methylsulfonylspiro[2h-indole-3,4'-piperidine]-1'-yl)-1-oxo-3-phenylmethoxypropan-2-yl]propanamide Chemical compound C([C@@H](NC(=O)C(C)(N)C)C(=O)N1CCC2(C3=CC=CC=C3N(C2)S(C)(=O)=O)CC1)OCC1=CC=CC=C1 UMUPQWIGCOZEOY-JOCHJYFZSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- IADUEWIQBXOCDZ-VKHMYHEASA-N Azetidine-2-carboxylic acid Natural products OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 229920002284 Cellulose triacetate Polymers 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 108090000317 Chymotrypsin Proteins 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical class CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical class CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- MFBYPDKTAJXHNI-VKHMYHEASA-N Gly-Cys Chemical group [NH3+]CC(=O)N[C@@H](CS)C([O-])=O MFBYPDKTAJXHNI-VKHMYHEASA-N 0.000 description 1
- LBDXVCBAJJNJNN-WHFBIAKZSA-N Gly-Ser-Cys Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(O)=O LBDXVCBAJJNJNN-WHFBIAKZSA-N 0.000 description 1
- WCORRBXVISTKQL-WHFBIAKZSA-N Gly-Ser-Ser Chemical compound NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O WCORRBXVISTKQL-WHFBIAKZSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 244000043261 Hevea brasiliensis Species 0.000 description 1
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 1
- 206010062767 Hypophysitis Diseases 0.000 description 1
- 101150088952 IGF1 gene Proteins 0.000 description 1
- 208000015580 Increased body weight Diseases 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
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- GHSJKUNUIHUPDF-BYPYZUCNSA-N L-thialysine Chemical compound NCCSC[C@H](N)C(O)=O GHSJKUNUIHUPDF-BYPYZUCNSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 244000062730 Melissa officinalis Species 0.000 description 1
- 235000010654 Melissa officinalis Nutrition 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical class NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229920001730 Moisture cure polyurethane Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028289 Muscle atrophy Diseases 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 101100221606 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) COS7 gene Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 208000010399 Wasting Syndrome Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000003522 acrylic cement Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002313 adhesive film Substances 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 150000001484 arginines Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical class CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 229940087373 calcium oxide Drugs 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 210000002318 cardia Anatomy 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 229960002152 chlorhexidine acetate Drugs 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960002376 chymotrypsin Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 229940018557 citraconic acid Drugs 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical class CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000000806 elastomer Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000003890 endocrine cell Anatomy 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000002710 gonadal effect Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 230000030214 innervation Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 210000001596 intra-abdominal fat Anatomy 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 210000001595 mastoid Anatomy 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000011785 micronutrient Substances 0.000 description 1
- 235000013369 micronutrients Nutrition 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- HEGSGKPQLMEBJL-UHFFFAOYSA-N n-octyl beta-D-glucopyranoside Natural products CCCCCCCCOC1OC(CO)C(O)C(O)C1O HEGSGKPQLMEBJL-UHFFFAOYSA-N 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 229920002114 octoxynol-9 Polymers 0.000 description 1
- 229940098514 octoxynol-9 Drugs 0.000 description 1
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229940116315 oxalic acid Drugs 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 210000003635 pituitary gland Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920002523 polyethylene Glycol 1000 Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920005606 polypropylene copolymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- UIIIBRHUICCMAI-UHFFFAOYSA-N prop-2-ene-1-sulfonic acid Chemical compound OS(=O)(=O)CC=C UIIIBRHUICCMAI-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MCSINKKTEDDPNK-UHFFFAOYSA-N propyl propionate Chemical compound CCCOC(=O)CC MCSINKKTEDDPNK-UHFFFAOYSA-N 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000004767 rumen Anatomy 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000037307 sensitive skin Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 210000004003 subcutaneous fat Anatomy 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Marine Sciences & Fisheries (AREA)
- Nutrition Science (AREA)
- Obesity (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Gas Separation By Absorption (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Abstract
【解決手段】 本発明は、以下の:胃切除術を受けた個体の体重及び体脂肪の損失の治療又は予防、悪液質の予防又は治療、食欲増進、食物摂取の促進、体重増加の促進又は体脂肪量の増加の1以上のための有効成分としてグレリン又はそのアナログを含む薬剤に関する。
【選択図】 なし
Description
本発明は、胃切除術を受けた個体の栄養失調を治療するためのグレリン又はそのアナログの使用に関する。特に、本発明は、胃切除術を受けた個体の体重、体脂肪量、食欲及び健康の増進のためのグレリン又はそのアナログの使用に関する。
グレリンは、体部及び基底部にある酸分泌腺に主に見られる、ヒトの胃の中の特定の細胞型、すなわち、いわゆるA細胞において単離された28個のアミノ酸の長さのアシル化ペプチドである。それらは、セリン残基を結合したオクタノイル・エステルを含む(Kojima et al., Nature, 402, (1999), 656-660)。グレリン及びそのアナログは、動物及びヒトの成長ホルモンの誘発因子であることが知られている。これらのペプチドは、視床下部と脳下垂体の両方に存在する7膜貫通型Gタンパク質共役レセプターを介して作用する(Smith et al Endocr Rev 18, (1997), 621-45)。
本発明は、胃切除術を受けている個体の栄養失調の徴候を治療するためのグレリン又はそのアナログの使用に関する。特に、本発明は、胃切除術を受けた個体の体重、体脂肪量、食欲、及び健康の増進のためのグレリン又はそのアナログ若しくは分泌促進薬の使用に関係する。
アミノ酸:炭素原子又は少なくとも1つの側鎖若しくは官能基を含む炭素原子の鎖を含む中心部分により分割されたアミノ末端部分(NH2)とカルボキシル末端部分(COOH)を含む物体。NH2は、アミノ酸又はペプチドのアミノ末端に存在するアミノ基を表し、COOHは、アミノ酸又はペプチドのカルボキシル末端に存在するカルボキシル基を表す。一般的な用語、アミノ酸は、天然及び非天然のアミノ酸を含む。J. Biol. Chem., 243:3552-59 (1969) and adopted in 37 C.F.R., section 1.822(b)(2)に列挙されている天然のアミノ酸の標準的な命名法は、本明細書中の以下の表1に列挙されたアミノ酸の群を成す。非天然アミノ酸は表1に列挙されていないものである。非天然アミノ酸の例は、例えば37 C.F.R.の1.822(b)(4)節で列挙されたものであり、その全てを本明細書中に援用する。非天然アミノ酸のさらなる例は、本明細書中、以下に列挙される。本明細書中に記載されるアミノ酸残基は、「D」又は「L」異性体の形態であるかもしれない。
GHS-R 1A:GHSのためのレセプター。GHS-R 1AはGHS1aで示されもする。
個体:生きている動物又はヒト。好ましい態様において、対象は、ヒト及び犬、猫、豚、雌牛、羊、ヤギ、馬、ラット及びマウスのようなヒト以外の哺乳動物を含む哺乳動物である。最も好ましい態様において、対象はヒトである。
「体脂肪の損失」:本明細書中で個体の全脂肪量の減少、又は個体の体脂肪率の低下と定義される。
本発明は、胃切除術を受けた個体における減量及び関連した健康状態を治療及び/又は予防するためのグレリン又はそのアナログに関する。従って、本発明は、体重と体脂肪の損失の治療及び/又は予防、体重増加の促進、並びに体脂肪量の増加に関する。特に本発明は、体重及び体脂肪の損失の治療及び/又は予防、又は体重増加の促進、より好ましくは体重と体脂肪の損失の治療及び/又は予防に関する。すでに生じている減量が進行をやめ、そして体重増加が始まるとき、治療と予防を経験する。これは、おそらく、食欲を促進し、それによって食物摂取を促進する、胃切除術を受けた個体におけるグレリン又はそのアナログの驚異的な効果による。本発明は、胃切除術を受けた個体の食欲の促進、そして食物摂取の促進、より特に食欲の促進にも関する。よって、本発明は、胃切除術を受けた個体の悪液質の予防及び/又は治療に関する。
Z1−(X1)m−(X2)−(X3)n−Z2、
{式中、
Z1は、場合により存在する保護基であり、
各X1は、アミノ酸から独立に選ばれ、ここで、上記アミノ酸は天然及び合成アミノ酸から選ばれる、
mは、1〜10の整数であり、
nは、0であるか又は1〜35の整数である。}
によって規定される構造を含む化合物である。
従って、用語「グレリン様化合物」は、天然の28aaヒト・グレリン、配列番号1に示されるアミノ酸配列、並びに天然の27aaヒト・グレリン、配列番号2に示されるアミノ酸配列を含む。このように、本発明は、それにグレリン又はそのペプチド相同体の使用に関する。グレリンは、コジマによりNature (1999), vol. 402,656-660中に説明される。
より好ましくは、(X1)mは、Gly-Ser及びGly-Cys、最も好ましくはGly-Serから選ばれる。
式(II) Z1−Gly-(X1)m-1−(X2)−(X3)n−Z2、
式(III) Z1−Gly−Ser−(X2)−(X3)n−Z2、及び
式(IV) Z1−Gly−(X2)−(X3)n−Z2、
から選ばれる。
そしてより好ましくは、グレリン様化合物は式(III)によって表される。
先に記載のように、X2は、バルキーな疎水基により修飾されたいずれかのアミノ酸である。特にX2は、修飾されたSer、Cys、Asp、Lys、Trp、Phe、Ile及びLeuの群から選ばれる。より好ましくは、X2は、修飾されたSer、修飾されたCys及び修飾されたLysの群から選ばれ、そして最も好ましくは、X2は、修飾されたSerである。
好ましい態様において、グレリン様化合物の長さは、ヒト・グレリンの長さ、すなわち27又は28アミノ酸と実質的に類似している。従って、nは、好ましくは1〜25、例えば1〜24、例えば1〜15、例えば1〜10、又は例えば10〜25、例えば10〜24、例えば15〜25、例えば15〜24の整数である。
あるいは、以下の配列:
あるいは、以下の配列:
あるいは、以下の配列:
他の態様において、(X3)nは、好ましくは以下の配列:
機能性
本明細書中で説明されるグレリン様化合物は、GHSレセプターにおいて活性である。この化合物は、前記レセプターに結合することができ、好ましくは、レセプター活性を促進する。
あるいは、活性化されたグレリン・レセプターへの蛍光でタグを付けられたアレスチンの結合も使用されうる。
用語「同一性」又は「相同性」は、全配列に関して、そして配列相同性の一部としてあらゆる保存的な置換を考慮することなく相同性の最大パーセントを得る必要があるとき、配列をアラインして、ギャップを導入した後に、比較されたものの対応する配列の残基と一致する候補者配列のアミノ酸残基の割合を意味すると解釈されるであろう。
本発明によるグレリン様化合物のバルキーな疎水基は、3位のSer残基がこのバルキーな疎水基により修飾された場合、GHS-R 1aに対して結合親和性を有する脱アシル化28aaヒト・グレリンを提供することができるあらゆるバルキーな疎水基である。
さらに、前記修飾されたアミノ酸は、EP 1 197 496(Kangawa)に記載のとおり基が修飾されているあらゆるアミノ酸であるかもしれない。前記文献を本明細書中に援用する。
本発明によるグレリン様化合物は、N末端かC末端、又はその両方に保護基を含むかもしれない。
グレリン様化合物は、例えば、その半減期を延ばすために、グレリン様化合物が他の物体に抱合された形態で投与されもする。
本発明の1の側面において、グレリン又はそのアナログは、そのような治療の必要な個体による使用のための薬剤の製造のために使用される。好ましくは、前記薬剤は、胃切除術を受けた個体の体重及び/又体脂肪の損失の治療のために使用される。他の好ましい態様において、この治療は、個体の食欲を促進して及び/又は栄養失調を防ぐ。用語「栄養失調」は、それにより個体が、元気及び健康を維持するために1以上の主要又は微量栄養素の十分なレベルが彼らの体内に摂取、吸収又は貯蔵されない状態を表す。他の、同様に好ましい態様において、前記治療は、胃切除術を受けた個体の健康感及び生活の質を改善することを含む。
「胃由来因子」に加えて、グレリンは、「胃由来因子」と同じレセプターに作用する、あらゆる合成低又は高分子アゴニストと組み合わせて使用されうる。
本発明の化合物又は塩に関して、未加工の化学薬品として投与されることが可能であるが、それらを医薬組成物の形態で提供することが好ましい。従って、本発明は、本明細書中で規定されているグレリン又はそのアナログ若しくは医薬として許容される塩、並びにそれらのための医薬として許容される担体を含む、薬用適用のための医薬組成物をさらに提供する。好ましくは、本発明の前述の組成物は、好ましくは食欲増進及び/又は栄養失調の予防、及び/又は個体の健康感又は生活の質の改善により、有益な効果を得るためにあらゆる手段によって個体にデリバリーされる。1の好ましい態様において、本発明による組成物は、経口、経鼻、肺、経皮又は腸管外経路を介して投与される。より好ましい態様において、組成物は、経口又は肺経路を介して投与される。薬物を標的部位にデリバリーするか又は薬物を血流に導入するために有効である他の薬物投与方法が考慮されもする。
好ましくは、前記組成物は、胃切除術を受けた個体の体重の損失と体脂肪の治療のための、グレリン又はそのアナログ若しくは医薬として許容される塩、そして医薬として許容される担体、媒質及び/又は、賦形剤及び/又は輸送分子を含む。
例えば、Szoka et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980)、米国特許番号第4,235,871号、同第4,501,728号及び同第4,837,028号に記載の種々の方法がリポソームを製造するために利用可能である。
本発明のさらなる側面において、当該化合物は、体重を増加させることが知られている追加の薬理学的に活性な物質、例えばメラニン凝集ホルモン(MCH)、MCHレセプター・アゴニスト、特にMCHレセプター1アゴニスト、神経ペプチドY(NPY)、NPYレセプター1アゴニスト及びNPYレセプター5アゴニスト、ペプチドYY(PYY)及びPYY(3-36)を含むNPYレセプター2アンタゴニスト、α−メラノサイト刺激ホルモン(α-MSH、α−メラノコルチン)、メラノコルチン−3レセプター(MC3R)アンタゴニスト、メラノコルチン−4レセプター(MC4R)アンタゴニスト、アグーチ関連ペプチド(Agrp)、Agrp−アゴニスト、コカイン−及びアンフェタミンに制御される転写(CART)アンタゴニスト、オレキシン・レセプター1及びレセプター2アゴニスト、成長ホルモン(GH)、GHレセプター・アゴニスト、並びにインシュリン様成長因子−1(IGF−1)、IGF−1レセプター1アゴニスト、又は他の薬理学的に活性な物質と組み合わせて投与されうる。しかも、この追加の活性物質は、これだけに制限されることなく、ガストリン、パンクレオスタチン、ヒスタミン、レジスチン、プロスタグランジン、例えばプロスタグランジンE2、内性因子を含む、他の胃由来因子を含む。前記組み合わせ物は、キット−イン−パート・システムの形態である、ここで、組み合わされた活性物質は、同時か、続けてか又は別々の投与のために使用されうる。
本発明の化合物は、幅広い種類の経口投与剤形で処方される。この医薬組成物及び投与形態は、活性成分として本発明の化合物又はその医薬として許容される塩若しくはその結晶形態を含む。医薬として許容される担体は、固体又は液体のいずれかでありうる。固形の製剤は、散剤、錠剤、丸剤、カプセル、カシェ剤、坐剤、及び分散性顆粒剤を含む。固体担体は、希釈剤、香料添加剤、溶解補助剤、潤滑剤、懸濁化剤、結合剤、保存剤、加湿剤、、錠剤崩壊剤、又はカプセル封入材として働く1以上の物質の可能性もある。
本発明の化合物は、腸管外投与(例えば、注射、例えばボーラス注射又は連続的な注入)のために処方され、そしてアンプル、事前充填注射器中に単位投与形態で、又は少量注入又は保存剤を添加された複数投与容器で提供される。前記組成物は、油性又は水性の媒質中に懸濁剤、溶液又はエマルジョン、例えば水性ポリエチレングリコールによる溶液のような形態を取るかもしれない。油性又は非水性の担体、希釈剤、溶剤又は媒質の例は、プロピレングリコール、ポリエチレングリコール、植物油(例えば、オリーブ油)及び注射可能な有機エステル(例えば、エチルオレイン酸)を含み、かつ、処方されうる薬剤(formulatory agent)、例えば保存剤、加湿剤、乳化剤又は懸濁化剤、安定化及び/又は分散剤を含む。あるいは、有効成分は、好適な媒質、例えば、無菌、パイロジェン・フリーの水による使用前の形成のための、無菌の固体の無菌分離、又は溶液からの凍結乾燥により得られる粉末状である。水性溶液は、必要ならば好適に緩衝化されるべきであって、そして液状の希釈剤は、十分な生理食塩液又はグルコースによりまず等張にされた。水性溶液は、静中、筋中、皮下、腹膜内投与に特に好適である。利用された無菌水性媒質は、当業者に知られた標準的な技術によって全てが容易に利用可能である。
本発明の化合物は、局所的にデリバリーされることもできる。局所投与のための部位は、皮膚表面、及び直腸、鼻、口及び咽喉の粘膜組織も含む。皮膚及び粘膜を介した局所投与のための組成物は、炎症のサイン、例えば腫脹又は発赤を生じさせてはならない。
本発明の化合物は、坐剤としての投与のために処方されうる。低融点ワックス、例えば脂肪酸グリセリドの混合物又はカカオ脂をまず溶かし、そして活性成分を、例えば撹拌により、均一に分散させる。次に、溶解した均一な混合物を、好都合なサイズの鋳型)に注ぎ、冷やし、そして凝固させる。
本発明の化合物は経鼻投与のために処方されうる。溶液又は懸濁液は、慣習的な手段、例えばドロッパー、ピペット又はスプレー剤によって直接的に鼻腔に適用される。この組成物は、単回又は複数回投与形態で提供される。後者のドロッパー又はピペットの場合において、これは、適切で、規定の量の溶液又は懸濁液を投与した患者によって得られる。スプレー剤の場合において、これは、例えば計量アトマイジング・スプレー・ポンプによって達成される。
本発明の化合物は、特に気道へのエアゾール投与のために処方され、そして経鼻投与を含む。この化合物は、5ミクロン(5 μm)未満の大きさの水準の小さな粒径を一般に有する。そのような粒径は、本技術分野で知られている手段、例えば微粒子化によって得られる。有効成分は、好適な高圧ガス、例えばクロロフルオロカーボン(CFC)、例えばジクロロジフルオロメタン、トリクロロフルオロメタン又はジクロロテトラフルオロエタン、二酸化炭素、あるいは他の好適なガスによる加圧パックで提供される。エアゾールは、都合よくレシチンのような界面活性剤をも含むかもしれない。薬物の投与量は、計量弁で制御されうる。あるいは、有効成分は、乾燥粉末、例えば好適な散剤ベース、例えばラクトース、スターチ、スターチ誘導体、例えばヒドロキシプロピルメチルセルロース及びポリビニルピロリドン(PVP)による化合物の粉末ミックスの形態で提供される。粉末担体は、鼻腔内でゲルを形成する。粉末組成物は、例えばゼラチンのカプセル若しくはカートリッジ、又はそこから粉末が吸入器によって投与されうる、ブリスターパックのような単位投与形態で提供れる。
製造されうる即席の化合物の医薬として許容される塩は、本願発明によってカバーされうることが意図されもする。これらの塩は、医薬としての使用へのそれらの適用に許容されるものである。それにより、この塩が親化合物の生物活性を維持し、かつ、この塩がその適用、及び病気の治療における使用において不利な又は有害な効果をもたないことを意味する。
本明細書中に記載の製剤は、好ましくは単位投与形態である。そのような形態において、製剤は、適当な分量の活性成分を含む単位投与量に小分けされる。この単位投与形態は、包装された製剤であるかもしれず、この包装は、別個の分量の製剤、例えば包装された錠剤、カプセル、並びにバイアル又はアンプル中の散剤を含む。また、この単位投与形態は、カプセル、錠剤、カシェ剤又はロゼンジ自体であるか、あるいはそれは、包装された形態での適当数のこれらのいずれかであるかもしれない。所望であれば、組成物は、有効成分の徐放又は制御放出投与のために適合させた腸溶コーティングにより製造されうる。
グレリン様化合物は、本技術分野で周知の技術を使って製造されうる。例えば、グレリン様化合物のポリペプチド部位は、化学的に又は生化学的に合成されて、そして修飾されうる。ポリペプチドの化学合成技術は、本技術分野で周知である(例えば、Vincent in Peptide and Protein Drug Delivery, New York, N. Y., Dekker, 1990を参照のこと)。細胞内への核酸の導入及び核酸の発現を伴う生化学的合成技術の例は、Molecular Biology, John Wiley, 1987-1998, and Sambrook et al., in Molecular Cloning, A Laboratory Manual, 2d Edition, Cold Spring Harbor Laboratory Press, 1989中、Ausubel, Current Protocolsにより提供される。
実施例1
胃全摘術を実施し、その後Lehto-Axtelius D., et al. Osteopenia after gastrectomy, fundectomy or antrectomy: an experimental study in the rat., Regul. Pept. 78 (1998), 41-50に記載のとおり、食道と十二指腸の間に端々吻合を実施した。前記胃切除術は、噴門部のレベルでの全迷走神経切断を伴った。偽手術を、腹部の切開、そして胃を動かすことによって実施した。見せ掛けの胃切除術を受けたラットにおいて、グレリン・レベルは、2.06±0.22 ng/mlであったが、一方胃切除術後、それらはアッセイの最小検出可能レベル、すなわち0.25 ng/mlよりも少なかった。胃切除術後4週間から、動物に1日につき1回胃管栄養法により水又はグレリン・アナログMK-0677を与えた(4 mg/kg/日)。
競合結合アッセイ
トランスフェクトしたCOS-7細胞を、トランスフェクションの翌日、放射性リガンドの5〜8%結合を狙って1つのウェルにつき1×105細胞の密度で培養皿に移した。トランスフェクションの2日後、25 pMの125I−グレリン(Amersham, Little Chalfont, UK)を使って、競合結合実験を4℃で3時間実施した。
レセプター活性化アッセイ
グレリン・レセプターを活性化するグレリン様化合物の能力に関する単純な目安の1つが、そのEC50、すなわち化合物が化合物の最大の効果の半分までレセプターのシグナリングを活性化することができるの投与量、を測定することである。
実施例4
グレリン様化合物の合成による製造
アミノ酸誘導体及び合成試薬を、商業的な供給元から得た。ペプチド鎖伸長を、主にPerkin Elmer製のApplied Biosystem 433Aシンセサイザーを使うことによって実施し、そして保護ペプチド誘導体−樹脂をBoc又はFmoc法により構築した。Boc法によって得られた保護ペプチド樹脂を、p−クレゾールの存在下、無水フッ化水素(HF)により脱保護し、それによりその後精製するペプチドを放出した。Fmoc法によって得られた保護ペプチド樹脂を、様々なスカベンジャを含むトリフルオロ酢酸(TFA)又は低濃度のTFAにより脱保護し、そして放出されたペプチドを精製した。精製をC4又はC18カラムを用いた逆相HPLCにより実施した。精製産物の純度を、逆相HPLCによって確認し、その構造をアミノ酸組成解析及び質量分析によって確認した。
Claims (32)
- 胃切除術を受けた個体の
体重及び体脂肪の損失の治療又は予防、
悪液質の予防又は治療、
食欲の増進、
食物摂取の促進、
体重増加の促進、及び/又は
体脂肪量の増加、
のための薬剤であって、有効成分としてグレリン又はそのアナログを含む上記薬剤。 - 前記グレリン又はそのアナログが、グレリン様化合物又は医薬として許容されるその塩である、請求項1に記載の薬剤であって、上記グレリン様化合物が、以下の式(I):
Z1−(X1)m−(X2)−(X3)n−Z2
{式中、
Z1は、場合により存在する保護基であり、
各X1は、アミノ酸から独立に選ばれ、ここで、上記アミノ酸は、天然及び合成アミノ酸から選ばれる、
X2は、天然及び合成により生じるアミノ酸から選ばれるあらゆるアミノ酸であり、上記アミノ酸は、バルキーな疎水基、好ましくはアシル基、又は脂肪酸によって修飾される、
各X3は、アミノ酸から独立に選ばれ、ここで、上記アミノ酸は、天然及び合成アミノ酸から選ばれる、
ここで、X1及びX3の1つ以上は、場合によりバルキーな疎水基、好ましくはアシル基、又は脂肪酸によって修飾される、
Z2は、場合により存在する保護基であり、
mは、1〜10の整数であり、
nは、0であるか又は1〜35の整数である。}によって規定される構造を含む、上記薬剤。 - 前記mが、1〜9、例えば1〜8、例えば1〜7、例えば1〜6、例えば1〜5、例えば1〜4、例えば1〜3、例えば1〜2の整数、例えば2である、請求項1又は2に記載の薬剤。
- 前記X2が、修飾されたSer、修飾されたCys及び修飾されたLysの群から選ばれる、例えば、ここで、X2が修飾されたSerである、請求項2又は3に記載の薬剤。
- 前記グレリン様化合物が、以下の化合物:
式(II) Z1−Gly−(X1)m-1−(X2)−(X3)n−Z2
式(III) Z1−Gly−Ser−(X2)−(X3)n−Z2、及び
式(IV) Z1−Gly−(X2)−(X3)n−Z2、
から選ばれる、請求項1〜4のいずれか1項に記載の薬剤。 - 前記グレリン様化合物が、式(III)により表される、請求項5に記載の薬剤。
- 前記nが、1〜25、例えば1〜24、例えば1〜15、例えば1〜10、例えば10〜25、例えば10〜24、例えば15〜25、例えば15〜24の整数である、請求項1〜7のいずれか1項に記載の薬剤。
- 前記アシル基が、C1−C35アシル基、例えばC1−C20アシル基、例えばC1−C15アシル基、例えばC6−C15アシル基、例えばC6−C12アシル基、例えばC8−C12アシル基から選ばれる、請求項1〜9のいずれか1項に記載の薬剤。
- 前記アシル基が、C7アシル基、C8アシル基、C9アシル基、C10アシル基、C11アシル基及びC12アシル基の群から選ばれる、請求項1〜10のいずれか1項に記載の薬剤。
- 前記アシル基が、C8アシル基及びC10アシル基の群から選ばれる、請求項1〜11のいずれか1項に記載の薬剤。
- 前記アシル基が、C7アシル基、C9アシル基及びC11アシル基の群、例えばC9アシル基及びC11アシル基の群から選ばれる、請求項1〜12のいずれか1項に記載の薬剤。
- 前記薬剤が、グレリン様化合物又はその塩の溶液を含む、請求項1〜13のいずれか1項に記載の薬剤。
- 溶媒が生理食塩液である、請求項14に記載の薬剤。
- 前記治療が、個体の食欲を促進し、そして栄養失調を防ぐ、請求項1〜15のいずれか1項に記載の薬剤。
- 前記治療が、個体の健康感及び生活の質を改善することを含む、請求項1〜16のいずれか1項に記載の薬剤。
- 前記薬剤が、他の胃由来因子を含む、請求項1〜17のいずれか1項に記載の薬剤。
- 前記胃由来因子が、パクリアスタチン、ガストリン、ヒスタミン、レジスチン、プロスタグランジン、例えばプロスタグランジンE2、内性因子から選ばれる、請求項18に記載の薬剤。
- 前記薬剤が、他の体重及び体脂肪増加因子をも含む、請求項1〜19のいずれか1項に記載の薬剤。
- 前記因子が、メラニン凝集ホルモン(MCH)、MCHレセプター・アゴニスト、特にMCHレセプター1アゴニスト、神経ペプチドY(NPY)、NPYレセプター1アゴニスト、NPYレセプター5アゴニスト及びペプチドYY(PYY)とPYY(3−36)を含むNPYレセプター2アンタゴニスト、α−メラノサイト刺激ホルモン(α-MSH、α−メラノコルチン)、メラノコルチン−3レセプター(MC3R)アンタゴニスト、メラノコルチン−4レセプター(MC4R)アンタゴニスト、アグーチ関連ペプチド(Agrp)、Agrp−アゴニスト、コカイン−及びアンフェタミンに制御される転写(CART)アンタゴニスト、オレキシン・レセプター1及びレセプター2アゴニスト、成長ホルモン(GH)、GHレセプター・アゴニスト、インシュリン様成長因子−1(IGF-1)、及びIGF-1レセプター1アゴニストから選ばれる、請求項20に記載の薬剤。
- 前記薬剤が、経口、経鼻、経皮、肺又は腸管外投与に好適である、請求項1〜21のいずれか1項に記載の薬剤。
- 前記薬剤が経口投与のための製剤で存在する、請求項1〜22のいずれか1項に記載の薬剤。
- 前記薬剤が経鼻投与のための製剤で存在する、請求項1〜23のいずれか1項に記載の薬剤。
- 前記薬剤が経皮投与のための製剤で存在する、請求項1〜24のいずれか1項に記載の薬剤。
- 前記薬剤が肺投与のための製剤で存在する、請求項1〜25のいずれか1項に記載の薬剤。
- 前記薬剤が腸管外投与のための製剤で存在する、請求項1〜26のいずれか1項に記載の薬剤。
- 活性化合物が、1日に約0.01 μg/kg体重〜10 mg/kg体重、好ましくは0.1〜10 μg/kg体重の投与量で投与される、請求項1〜27のいずれか1項に記載の薬剤。
- 前記薬剤が、体重1 kgにつき10 ng〜10 mgグレリンに相当する濃度で投与される、請求項1〜28のいずれか1項に記載の薬剤。
- 前記薬剤が、食前又は食事中に投与される、請求項1〜29のいずれか1項に記載の薬剤。
- 前記薬剤が、1日に1〜3回投与される、請求項1〜30のいずれか1項に記載の薬剤であって、各投与が、食事中であるか又は遅くとも食前90分以内、例えば遅くとも食前85分以内、例えば遅くとも食前80分以内、例えば遅くとも食前75分以内、例えば遅くとも食前70分以内、例えば遅くとも食前65分以内、例えば遅くとも食前60分以内、例えば遅くとも食前55分以内、例えば遅くとも食前50分以内、例えば遅くとも食前45分以内、例えば遅くとも食前30分以内、例えば遅くとも食前25分以内、例えば遅くとも食前20分以内、例えば遅くとも食前15分以内、例えば遅くとも食前10分以内、例えば遅くとも食前5分以内に行われる上記薬剤。
- 前記薬剤が、1日に3回投与される、請求項1〜31のいずれか1項に記載の薬剤。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP20020022705 EP1407779A1 (en) | 2002-10-10 | 2002-10-10 | Use of ghrelin for treating low body weight and body fat in gastrectomized individuals |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2004277402A true JP2004277402A (ja) | 2004-10-07 |
JP4177224B2 JP4177224B2 (ja) | 2008-11-05 |
Family
ID=32010955
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2003352592A Expired - Fee Related JP4177224B2 (ja) | 2002-10-10 | 2003-10-10 | 胃切除術を受けた個体の低体重及び低体脂肪量を治療するためのグレリンの使用 |
Country Status (9)
Country | Link |
---|---|
US (1) | US7592305B2 (ja) |
EP (2) | EP1407779A1 (ja) |
JP (1) | JP4177224B2 (ja) |
KR (1) | KR20050057650A (ja) |
CN (1) | CN1723035A (ja) |
AT (1) | ATE324904T1 (ja) |
AU (1) | AU2003299710A1 (ja) |
DE (1) | DE60305055T2 (ja) |
WO (1) | WO2004032952A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9078868B2 (en) | 2010-01-15 | 2015-07-14 | University Of Miyazaki | Therapeutic agent for accelerating recovery of animal under medical treatment |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1688696A (zh) * | 2002-09-18 | 2005-10-26 | 蒙特利尔大学医疗中心 | Ghrh类似物 |
USRE42624E1 (en) | 2003-06-18 | 2011-08-16 | Tranzyme Pharma Inc. | Methods of using macrocyclic modulators of the ghrelin receptor |
WO2005097174A2 (en) * | 2004-04-07 | 2005-10-20 | Gastrotech Pharma A/S | Uses of a combination of ghrelin and somatotropin for the treatment of cachexia |
US20080171700A1 (en) * | 2004-04-07 | 2008-07-17 | Gastrotech Pharma A/S | Use Of Secretagogue For The Teatment Of Ghrelin Deficiency |
KR20070050871A (ko) * | 2004-05-11 | 2007-05-16 | 더 거번먼트 오브 더 유나이티드 스테이츠 오브 어메리카 애즈 레프리젠티드 바이 더 세크러터리 오브 더 디파트먼트 오브 헬쓰 앤드 휴먼 써비시즈 | 그렐린을 사용하여 전염증성 사이토킨 발현을 억제하는방법 |
BRPI0514408B8 (pt) * | 2004-08-24 | 2021-05-25 | Asubio Pharma Co Ltd | preparação liquida de peptídeo fisiologicamente ativo |
JP2008521840A (ja) * | 2004-11-30 | 2008-06-26 | ガストロテック・ファルマ・アクティーゼルスカブ | 成長ホルモン分泌促進物質レセプター1aリガンド |
MX2009001133A (es) * | 2006-08-01 | 2009-02-11 | Scripps Research Inst | Vacunas y metodos para controlar adiposidad. |
CA2677045C (en) | 2007-01-31 | 2016-10-18 | Dana-Farber Cancer Institute, Inc. | Stabilized p53 peptides and uses thereof |
WO2008100220A1 (en) * | 2007-02-14 | 2008-08-21 | Karolinska Innovations Ab | Compositions for increasing body weight, use and methods |
CA2682174C (en) | 2007-03-28 | 2021-04-06 | President And Fellows Of Harvard College | Stitched polypeptides |
US8324151B2 (en) * | 2007-11-20 | 2012-12-04 | The Feinstein Institute For Medical Research | Treatment of sepsis and septic shock using ghrelin and growth hormone |
US8013015B2 (en) * | 2008-10-02 | 2011-09-06 | Board Of Regents, The University Of Texas System | Small molecule inhibitors of ghrelin O-acyltransferase |
WO2012021876A2 (en) | 2010-08-13 | 2012-02-16 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
EP2672982B1 (en) * | 2011-02-09 | 2019-09-04 | The Scripps Research Institute | Ghrelin mimetic polypeptide hapten immunoconjugates having improved solubility and immunogenicity and methods of use thereof |
CN108929375A (zh) | 2011-10-18 | 2018-12-04 | 爱勒让治疗公司 | 拟肽大环化合物 |
WO2013123267A1 (en) | 2012-02-15 | 2013-08-22 | Aileron Therapeutics, Inc. | Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles |
ES2817877T3 (es) | 2012-02-15 | 2021-04-08 | Aileron Therapeutics Inc | Macrociclos peptidomiméticos |
JP6526563B2 (ja) | 2012-11-01 | 2019-06-05 | エイルロン セラピューティクス,インコーポレイテッド | 二置換アミノ酸ならびにその調製および使用の方法 |
US20160250224A1 (en) * | 2013-09-24 | 2016-09-01 | The Board Of Regents Of The University Of Texas System | Orexin-control of bone formation and loss |
SG10201902594QA (en) | 2014-09-24 | 2019-04-29 | Aileron Therapeutics Inc | Peptidomimetic macrocycles and uses thereof |
CA2979847A1 (en) | 2015-03-20 | 2016-09-29 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
WO2023161226A1 (en) * | 2022-02-22 | 2023-08-31 | Pephexia Therapeutics Aps | Ghrelin agonists with improved potency |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ195098A3 (cs) | 1995-12-22 | 1998-10-14 | Novo Nordisk A/S | Sloučeniny uvolňující růstový hormon |
WO1999045029A1 (en) | 1998-03-03 | 1999-09-10 | Novo Nordisk A/S | New salt forms of (2e)- 5-amino-5- methylhex-2- enoic acid n-methyl-n-((1r)-1-(n- methyl-n-((1r)-1-(methylcarbamoyl)-2- phenylethyl)carbamoyl)-2- (2-naphtyl)ethyl)amide |
DE69941255D1 (de) | 1998-05-11 | 2009-09-24 | Novo Nordisk As | Verbindungen mit wachstumshormon freisetzenden eigenschaften |
BR9915009A (pt) | 1998-11-03 | 2001-08-07 | Novo Nordisk As | Composto, composição farmacêutica, método de estimular a liberação do hormÈnio do crescimento da pituitária de um mamìfero, e, uso de um composto ou de um sal farmaceuticamente aceitável do mesmo |
CN100506844C (zh) | 1999-07-23 | 2009-07-01 | 寒川贤治 | 新的肽 |
AU2001228325A1 (en) * | 2000-02-01 | 2001-08-14 | Novo-Nordisk A/S | Use of compounds for the regulation of food intake |
US7244701B2 (en) * | 2000-06-16 | 2007-07-17 | Zealand Phama A/S | Diuretic peptide conjugate |
-
2002
- 2002-10-10 EP EP20020022705 patent/EP1407779A1/en not_active Withdrawn
-
2003
- 2003-10-09 KR KR1020057006275A patent/KR20050057650A/ko not_active Application Discontinuation
- 2003-10-09 WO PCT/DK2003/000679 patent/WO2004032952A1/en not_active Application Discontinuation
- 2003-10-09 DE DE60305055T patent/DE60305055T2/de not_active Expired - Lifetime
- 2003-10-09 US US10/530,866 patent/US7592305B2/en not_active Expired - Fee Related
- 2003-10-09 AU AU2003299710A patent/AU2003299710A1/en not_active Abandoned
- 2003-10-09 EP EP03756447A patent/EP1553969B1/en not_active Expired - Lifetime
- 2003-10-09 CN CNA2003801057083A patent/CN1723035A/zh active Pending
- 2003-10-09 AT AT03756447T patent/ATE324904T1/de not_active IP Right Cessation
- 2003-10-10 JP JP2003352592A patent/JP4177224B2/ja not_active Expired - Fee Related
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9078868B2 (en) | 2010-01-15 | 2015-07-14 | University Of Miyazaki | Therapeutic agent for accelerating recovery of animal under medical treatment |
JP2015227367A (ja) * | 2010-01-15 | 2015-12-17 | 国立大学法人 宮崎大学 | 加療中動物の回復促進治療剤 |
JP6057314B2 (ja) * | 2010-01-15 | 2017-01-11 | 国立大学法人 宮崎大学 | 加療中動物の回復促進治療剤 |
Also Published As
Publication number | Publication date |
---|---|
ATE324904T1 (de) | 2006-06-15 |
US20060217296A1 (en) | 2006-09-28 |
EP1553969A1 (en) | 2005-07-20 |
EP1407779A1 (en) | 2004-04-14 |
EP1553969B1 (en) | 2006-05-03 |
KR20050057650A (ko) | 2005-06-16 |
WO2004032952A1 (en) | 2004-04-22 |
AU2003299710A1 (en) | 2004-05-04 |
US7592305B2 (en) | 2009-09-22 |
JP4177224B2 (ja) | 2008-11-05 |
DE60305055D1 (de) | 2006-06-08 |
CN1723035A (zh) | 2006-01-18 |
DE60305055T2 (de) | 2006-12-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4177224B2 (ja) | 胃切除術を受けた個体の低体重及び低体脂肪量を治療するためのグレリンの使用 | |
KR102126484B1 (ko) | 개선된 펩티드 제약 | |
JP2007532495A (ja) | グレリン欠乏を治療するための分泌促進薬の使用 | |
US20080300180A1 (en) | Growth Hormone Secretagogue Receptor 1A Ligands | |
US8981054B2 (en) | Compositions and methods for stimulating gastrointestinal motility | |
CA2560174A1 (en) | Y4 selective receptor agonists for therapeutic interventions | |
JP3830520B2 (ja) | リラキシン様因子およびその方法と使用 | |
US9315546B2 (en) | Growth hormone secretatogue receptor antagonists and uses thereof | |
CA2559838A1 (en) | Y2 selective receptor agonists for therapeutic interventions | |
KR20160075794A (ko) | 질환 및 질병 치료용 칼시토닌 모방체 | |
US20200392198A1 (en) | Peptide dual agonists of gipr and glp2r | |
US11572399B2 (en) | Long-acting GIP peptide analogues | |
EP1812044A2 (en) | Uses of growth hormone secretagogues in the treatment of individuals suffering from renal and/or liver failure | |
US10526383B2 (en) | Ghrelin splice variant for treating neuronal damage, neurodegenerative disease, parkinsons disease, alzheimers disease, and/or depression | |
JP2007523048A (ja) | 分泌促進物質の使用 | |
WO2006045710A2 (en) | Insulin receptor binding peptides with non-insulin gene activation profiles and uses thereof | |
JP2009502976A (ja) | 親水性ペプチド鎮痛薬の経口送達のためのペプチドコンジュゲート | |
WO2005097174A2 (en) | Uses of a combination of ghrelin and somatotropin for the treatment of cachexia | |
Dubreuil et al. | Growth hormone-releasing factor: structural modification or protection for more potent analogs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20070306 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20070606 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20070703 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20071031 Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20071004 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20071106 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20080219 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20080514 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20080722 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20080821 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20110829 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120829 Year of fee payment: 4 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130829 Year of fee payment: 5 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130829 Year of fee payment: 5 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130829 Year of fee payment: 5 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130829 Year of fee payment: 5 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20130829 Year of fee payment: 5 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |