WO2008072056A1 - Use of mtp inhibitors for the treatment of obesity using low doses and dose-escalation - Google Patents
Use of mtp inhibitors for the treatment of obesity using low doses and dose-escalation Download PDFInfo
- Publication number
- WO2008072056A1 WO2008072056A1 PCT/IB2007/003842 IB2007003842W WO2008072056A1 WO 2008072056 A1 WO2008072056 A1 WO 2008072056A1 IB 2007003842 W IB2007003842 W IB 2007003842W WO 2008072056 A1 WO2008072056 A1 WO 2008072056A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dose level
- day
- dose
- weight
- mtp inhibitor
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 104
- 208000008589 Obesity Diseases 0.000 title claims abstract description 36
- 235000020824 obesity Nutrition 0.000 title claims abstract description 36
- 238000011282 treatment Methods 0.000 title description 69
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 claims abstract description 99
- 238000000034 method Methods 0.000 claims abstract description 51
- 230000000694 effects Effects 0.000 claims abstract description 27
- 238000012423 maintenance Methods 0.000 claims abstract description 24
- 235000012631 food intake Nutrition 0.000 claims abstract description 20
- 208000030814 Eating disease Diseases 0.000 claims abstract description 16
- 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 235000014632 disordered eating Nutrition 0.000 claims abstract description 16
- 208000035475 disorder Diseases 0.000 claims abstract description 11
- 229960002551 dirlotapide Drugs 0.000 claims description 74
- TUOSYWCFRFNJBS-BHVANESWSA-N dirlotapide Chemical compound O=C([C@@H](NC(=O)C=1N(C2=CC=C(NC(=O)C=3C(=CC=CC=3)C=3C=CC(=CC=3)C(F)(F)F)C=C2C=1)C)C=1C=CC=CC=1)N(C)CC1=CC=CC=C1 TUOSYWCFRFNJBS-BHVANESWSA-N 0.000 claims description 72
- 206010047700 Vomiting Diseases 0.000 claims description 20
- 206010061428 decreased appetite Diseases 0.000 claims description 13
- 206010012735 Diarrhoea Diseases 0.000 claims description 9
- 206010024264 Lethargy Diseases 0.000 claims description 9
- 208000022531 anorexia Diseases 0.000 claims description 8
- HQSRVYUCBOCBLY-XOOFNSLWSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2s,4r)-2-(4-chlorophenyl)-2-[(4-methyl-1,2,4-triazol-3-yl)sulfanylmethyl]-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3O[C@@](CSC=4N(C=NN=4)C)(OC3)C=3C=CC(Cl)=CC=3)=CC=2)C=C1 HQSRVYUCBOCBLY-XOOFNSLWSA-N 0.000 claims description 5
- 229950000884 mitratapide Drugs 0.000 claims description 3
- PKHKBSZSOWOOPU-LHEWISCISA-N 2-[[2-(4-tert-butylphenyl)benzoyl]amino]-n-[(1s)-2-[(4-fluorophenyl)methylamino]-2-oxo-1-phenylethyl]quinoline-6-carboxamide Chemical compound C1=CC(C(C)(C)C)=CC=C1C1=CC=CC=C1C(=O)NC1=CC=C(C=C(C=C2)C(=O)N[C@H](C(=O)NCC=3C=CC(F)=CC=3)C=3C=CC=CC=3)C2=N1 PKHKBSZSOWOOPU-LHEWISCISA-N 0.000 claims description 2
- HMTLPJFACYNTHS-KDXMTYKHSA-N n-[(1s)-2-[(4-fluorophenyl)methyl-methylamino]-2-oxo-1-phenylethyl]-2-[[2-(4-propan-2-yloxyphenyl)benzoyl]amino]quinoline-6-carboxamide Chemical compound C1=CC(OC(C)C)=CC=C1C1=CC=CC=C1C(=O)NC1=CC=C(C=C(C=C2)C(=O)N[C@H](C(=O)N(C)CC=3C=CC(F)=CC=3)C=3C=CC=CC=3)C2=N1 HMTLPJFACYNTHS-KDXMTYKHSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- MMESQDYAUPPESO-UHFFFAOYSA-N 2-amino-n-[(4-fluorophenyl)methyl]-n-methyl-2-phenylacetamide Chemical compound C=1C=CC=CC=1C(N)C(=O)N(C)CC1=CC=C(F)C=C1 MMESQDYAUPPESO-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 241000282472 Canis lupus familiaris Species 0.000 description 100
- 208000016261 weight loss Diseases 0.000 description 90
- 108010038232 microsomal triglyceride transfer protein Proteins 0.000 description 88
- 230000004580 weight loss Effects 0.000 description 76
- 230000037396 body weight Effects 0.000 description 49
- 239000000902 placebo Substances 0.000 description 39
- 229940068196 placebo Drugs 0.000 description 39
- 241001465754 Metazoa Species 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 22
- 239000000203 mixture Substances 0.000 description 18
- 230000003247 decreasing effect Effects 0.000 description 14
- 239000008177 pharmaceutical agent Substances 0.000 description 14
- 238000002560 therapeutic procedure Methods 0.000 description 11
- 235000013305 food Nutrition 0.000 description 10
- 238000003556 assay Methods 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 9
- 206010033307 Overweight Diseases 0.000 description 8
- 230000000968 intestinal effect Effects 0.000 description 8
- -1 4-fluoro-benzylcarbamoyl Chemical group 0.000 description 7
- 239000000883 anti-obesity agent Substances 0.000 description 7
- 229940125710 antiobesity agent Drugs 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 230000003442 weekly effect Effects 0.000 description 7
- 208000021017 Weight Gain Diseases 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 235000005911 diet Nutrition 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 230000008673 vomiting Effects 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 6
- 235000019786 weight gain Nutrition 0.000 description 6
- 230000037221 weight management Effects 0.000 description 6
- 239000013585 weight reducing agent Substances 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000001186 cumulative effect Effects 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000037406 food intake Effects 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 241000640882 Condea Species 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 235000019577 caloric intake Nutrition 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000037081 physical activity Effects 0.000 description 4
- 229940044551 receptor antagonist Drugs 0.000 description 4
- 239000002464 receptor antagonist Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000011269 treatment regimen Methods 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 208000031648 Body Weight Changes Diseases 0.000 description 3
- 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 3
- 241000282465 Canis Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 108010088847 Peptide YY Proteins 0.000 description 3
- 102100029909 Peptide YY Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920000080 bile acid sequestrant Polymers 0.000 description 3
- 230000004579 body weight change Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 235000020805 dietary restrictions Nutrition 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 2
- UDPREAJJGGXUGR-KDXMTYKHSA-N 2-[[2-(4-tert-butylphenyl)benzoyl]amino]-n-[(1s)-2-[(4-fluorophenyl)methyl-methylamino]-2-oxo-1-phenylethyl]quinoline-6-carboxamide Chemical compound O=C([C@@H](NC(=O)C=1C=C2C=CC(NC(=O)C=3C(=CC=CC=3)C=3C=CC(=CC=3)C(C)(C)C)=NC2=CC=1)C=1C=CC=CC=1)N(C)CC1=CC=C(F)C=C1 UDPREAJJGGXUGR-KDXMTYKHSA-N 0.000 description 2
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 2
- 101150102415 Apob gene Proteins 0.000 description 2
- 101710150887 Cholecystokinin A Proteins 0.000 description 2
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 2
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000282324 Felis Species 0.000 description 2
- 239000006000 Garlic extract Substances 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 102000016267 Leptin Human genes 0.000 description 2
- 108010092277 Leptin Proteins 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 241001504505 Troglodytes troglodytes Species 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 239000003529 anticholesteremic agent Substances 0.000 description 2
- 229940127226 anticholesterol agent Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 229940096699 bile acid sequestrants Drugs 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- PUXBGTOOZJQSKH-UHFFFAOYSA-N carprofen Chemical compound C1=C(Cl)C=C2C3=CC=C(C(C(O)=O)C)C=C3NC2=C1 PUXBGTOOZJQSKH-UHFFFAOYSA-N 0.000 description 2
- WAZQAZKAZLXFMK-UHFFFAOYSA-N deracoxib Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 WAZQAZKAZLXFMK-UHFFFAOYSA-N 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 108010017796 epoxidase Proteins 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 2
- 229940125753 fibrate Drugs 0.000 description 2
- 235000020706 garlic extract Nutrition 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 2
- 229960001243 orlistat Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000004059 squalene synthase inhibitor Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AMNXBQPRODZJQR-DITALETJSA-N (2s)-2-cyclopentyl-2-[3-[(2,4-dimethylpyrido[2,3-b]indol-9-yl)methyl]phenyl]-n-[(1r)-2-hydroxy-1-phenylethyl]acetamide Chemical compound C1([C@@H](C=2C=CC=C(C=2)CN2C3=CC=CC=C3C3=C(C)C=C(N=C32)C)C(=O)N[C@@H](CO)C=2C=CC=CC=2)CCCC1 AMNXBQPRODZJQR-DITALETJSA-N 0.000 description 1
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- OVYMWJFNQQOJBU-UHFFFAOYSA-N 1-octanoyloxypropan-2-yl octanoate Chemical compound CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC OVYMWJFNQQOJBU-UHFFFAOYSA-N 0.000 description 1
- 102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 description 1
- 101710186107 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 description 1
- BVBVOYDAGRVTPH-UHFFFAOYSA-N 2-amino-n-pentyl-2-phenylacetamide Chemical compound CCCCCNC(=O)C(N)C1=CC=CC=C1 BVBVOYDAGRVTPH-UHFFFAOYSA-N 0.000 description 1
- NFIHXTUNNGIYRF-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate Chemical compound CCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCC NFIHXTUNNGIYRF-UHFFFAOYSA-N 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000054930 Agouti-Related Human genes 0.000 description 1
- 101710127426 Agouti-related protein Proteins 0.000 description 1
- 102000018616 Apolipoproteins B Human genes 0.000 description 1
- 108010027006 Apolipoproteins B Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 108010051479 Bombesin Proteins 0.000 description 1
- 102000013585 Bombesin Human genes 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WSYALRNYQFNNGP-UHFFFAOYSA-N COC(C(c1ccccc1)N(CC1)CCC1c(cc1)ccc1NC(c(cccc1)c1-c1ccc(C(F)(F)F)cc1)=O)=O Chemical compound COC(C(c1ccccc1)N(CC1)CCC1c(cc1)ccc1NC(c(cccc1)c1-c1ccc(C(F)(F)F)cc1)=O)=O WSYALRNYQFNNGP-UHFFFAOYSA-N 0.000 description 1
- 101150071146 COX2 gene Proteins 0.000 description 1
- 101100496968 Caenorhabditis elegans ctc-1 gene Proteins 0.000 description 1
- 101100114534 Caenorhabditis elegans ctc-2 gene Proteins 0.000 description 1
- 241001408630 Chloroclystis Species 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- 229940123239 Cholesterol synthesis inhibitor Drugs 0.000 description 1
- 229940123320 Cyclase inhibitor Drugs 0.000 description 1
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 102400001370 Galanin Human genes 0.000 description 1
- 101800002068 Galanin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 108010016122 Ghrelin Receptors Proteins 0.000 description 1
- 102100039256 Growth hormone secretagogue receptor type 1 Human genes 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 208000007353 Hip Osteoarthritis Diseases 0.000 description 1
- 101000928179 Homo sapiens Agouti-related protein Proteins 0.000 description 1
- 241001504226 Hoodia Species 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 108010000775 Hydroxymethylglutaryl-CoA synthase Proteins 0.000 description 1
- 102100028888 Hydroxymethylglutaryl-CoA synthase, cytoplasmic Human genes 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- 108010000410 MSH receptor Proteins 0.000 description 1
- 102400001132 Melanin-concentrating hormone Human genes 0.000 description 1
- 101800002739 Melanin-concentrating hormone Proteins 0.000 description 1
- 102100034216 Melanocyte-stimulating hormone receptor Human genes 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- AHLBNYSZXLDEJQ-UHFFFAOYSA-N N-formyl-L-leucylester Natural products CCCCCCCCCCCC(OC(=O)C(CC(C)C)NC=O)CC1OC(=O)C1CCCCCC AHLBNYSZXLDEJQ-UHFFFAOYSA-N 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- 102000030937 Neuromedin U receptor Human genes 0.000 description 1
- 108010002741 Neuromedin U receptor Proteins 0.000 description 1
- 102100029549 Neuropeptide Y receptor type 5 Human genes 0.000 description 1
- 108010046593 Neuropeptide Y5 receptor Proteins 0.000 description 1
- 101100221647 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cox-1 gene Proteins 0.000 description 1
- 229940123730 Orexin receptor antagonist Drugs 0.000 description 1
- 102000023984 PPAR alpha Human genes 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 102000000536 PPAR gamma Human genes 0.000 description 1
- 108010016731 PPAR gamma Proteins 0.000 description 1
- 101150062589 PTGS1 gene Proteins 0.000 description 1
- 101150000187 PTGS2 gene Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 244000019194 Sorbus aucuparia Species 0.000 description 1
- 229940123495 Squalene synthetase inhibitor Drugs 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- 229940121373 acetyl-coa carboxylase inhibitor Drugs 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229940125709 anorectic agent Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 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
- 239000003613 bile acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 1
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 229960003314 deracoxib Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000013367 dietary fats Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000008157 edible vegetable oil 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
- 239000000839 emulsion Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000006052 feed supplement Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000007160 gastrointestinal dysfunction Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 description 1
- 229940124750 glucocorticoid receptor agonist Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 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 1
- 230000007407 health benefit Effects 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000009097 homeostatic mechanism Effects 0.000 description 1
- 235000017277 hoodia Nutrition 0.000 description 1
- 239000003667 hormone antagonist Substances 0.000 description 1
- 102000055839 human AGRP Human genes 0.000 description 1
- 229940121380 ileal bile acid transporter inhibitor Drugs 0.000 description 1
- 229950005809 implitapide Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 208000030175 lameness Diseases 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 102000005861 leptin receptors Human genes 0.000 description 1
- 108010019813 leptin receptors Proteins 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 229960000994 lumiracoxib Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 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 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- SLZIZIJTGAYEKK-CIJSCKBQSA-N molport-023-220-247 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CN)[C@@H](C)O)C1=CNC=N1 SLZIZIJTGAYEKK-CIJSCKBQSA-N 0.000 description 1
- 230000000407 monoamine reuptake Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- HFQHREPTBMBXIA-UHFFFAOYSA-N n-(2-amino-2-oxo-1-phenylethyl)-1-methyl-5-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]indole-2-carboxamide Chemical compound C=1C=C2N(C)C(C(=O)NC(C(N)=O)C=3C=CC=CC=3)=CC2=CC=1NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 HFQHREPTBMBXIA-UHFFFAOYSA-N 0.000 description 1
- GMSCTAUKUATFHI-XIFFEERXSA-N n-[(1s)-2-oxo-2-(pentylamino)-1-phenylethyl]-2-[[2-[4-(trifluoromethyl)phenyl]benzoyl]amino]quinoline-6-carboxamide Chemical compound N([C@H](C(=O)NCCCCC)C=1C=CC=CC=1)C(=O)C(C=C1C=C2)=CC=C1N=C2NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 GMSCTAUKUATFHI-XIFFEERXSA-N 0.000 description 1
- 239000002660 neuropeptide Y receptor antagonist Substances 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 150000002814 niacins Chemical class 0.000 description 1
- 229940036132 norvasc Drugs 0.000 description 1
- 239000002417 nutraceutical Substances 0.000 description 1
- 235000021436 nutraceutical agent Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000013324 preserved food Nutrition 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000002469 receptor inverse agonist Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 1
- 229960003015 rimonabant Drugs 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- 235000006414 serbal de cazadores Nutrition 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 239000004550 soluble concentrate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940127230 sympathomimetic drug Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 239000003749 thyromimetic agent Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
- 230000037220 weight regain Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention generally relates to therapy for obesity or related eating disorders and/or reducing food consumption using low doses of MTP inhibitors optionally followed by dose escalation and optionally followed by a weight maint ⁇ nanc ⁇ /management or retraining phase.
- Obesity is a major public health concern because of its increasing prevalence and associated health risks. Moreover, obesity may affect a person's or animal's quality of life through limited mobility and decreased physical endurance as well as through social, academic and job discrimination.
- MTP microsomal triglyceride transfer protein
- Apo B secretion is useful in reducing food intake in mammals (European patent application publication No. 1 099 438 A2), reducing intestinal fat absorption (European patent application publication No. 1 099439 A2) and for treating obesity and associated diseases. See, for example, PCT patent application publication Nos. WO 03/002533, WO 2005/046644 and WO 2005/080373, and US 6,066, 653.
- the invention provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an initial amount of an MTP inhibitor effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor.
- the invention also provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an initial amount of an MTP inhibitor effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention also provides the use of an MTP inhibitor in the manufacture of a medicament for treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, wherein the initial amount of the MTP inhibitor is effective to ameliorate the obesity or related disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention also provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an initial low dose of an MTP inhibitor followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor wherein said initial low dose is effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of conventional doses of the MTP inhibitor and wherein said initial low dose reduces the side effects associated with administration of said step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention also provides a method of increasing the rate of weight loss in a subject suffering from obesity or related eating disorders, the method comprising administering to the subject an initial amount of an MTP inhibitor effective to ameliorate the obesity or disorder yet low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one stepwise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention further provides a method for inhibiting MTP in a subject in need thereof, the method comprising administering to the subject an amount of an MTP inhibitor effective to inhibit MTP, yet low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention also provides methods of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an MTP inhibitor at a dose at which the emesis associated with administration of the MTP inhibitor is reduced, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the invention further provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, or a method for inhibiting MTP in a subject in need thereof, the method comprising administering to the subject an amount of an MTP inhibitor effective to ameliorate the obesity or disorder, or effective to inhibit MTP, yet low enough to reduce the side effects associated with administration of the MTP inhibitor, and wherein said administration is in combination with at least one additional pharmaceutical agent, such as another anti-obesity agent, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor . and, optionally, followed by a weight maintenance/management or retraining phase.
- Also provided is a method of weight control in a subject comprising administering to the subject an effective weight-controlling amount of an MTP inhibitor which is low enough to reduce the side effects associated with administration of the MTP inhibitor, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- the MTP inhibitor may be used alone or in combination with at least one additional pharmaceutical agent, preferably an anti-obesity agent.
- the invention also provides a method of treating a subject suffering from obesity or related eating disorders and/or reducing food consumption, the method comprising administering to the subject an initial amount of an MTP inhibitor in the range of 0.025 to 0.30 mg/kg/day, optionally followed by administration of at least one step-wise, escalating dosage of the MTP inhibitor and, optionally, followed by a weight maintenance/management or retraining phase.
- a further aspect of the present invention pertains to a pharmaceutical kit for use by a consumer in the treatment or prevention of obesity or related eating disorders and/or reducing food consumption, or for inhibiting MTP in a subject in need thereof.
- the kit comprises (a) at least two sets of pharmaceutical dosage units comprising an MTP inhibitor; and (b) instructions describing a method of using the dosage form to treat or prevent obesity or related eating disorders and/or reducing food consumption, or for inhibiting MTP in a subject in need thereof.
- Another embodiment of the present invention relates to a pharmaceutical kit comprising: (a) a first pharmaceutical composition comprising at least two sets of pharmaceutical dosage units comprising an MTP inhibitor, (b) a second pharmaceutical composition comprising a second compound useful for the treatment or prevention of obesity or related eating disorders and/or reducing food consumption, or for inhibiting MTP in a subject in need thereof; and
- the MTP inhibitor is dirlotapide ((S)-N- ⁇ 2-[benzyl(methyl)amino]-2-oxo-1- phenylethylJ-i-methyl-S- ⁇ '-trifluoromethyOII .I'-biphenylj ⁇ -carboxamidol-I H-indole ⁇ -carboxamide).
- Obesity and overweight are generally defined by body mass index (BMI) in humans, which is correlated with total body fat and serves as a measure of the risk of certain diseases.
- BMI body mass index
- BMl is calculated by weight in kilograms divided by height in meters squared (kg/m 2 ).
- Overweight is typically defined as a BMI of 25-29.9 kg/m 2
- obesity is typically defined as a BMI of 30 kg/m 2 or higher.
- BCS Body Condition Score
- references to treating obesity included hereinbefore and hereinafter should also be taken to include treatment of overweight subjects.
- pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
- terapéuticaally effective amount means an amount of a compound that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein (e.g., reduces food intake or the desire to consume food).
- subject or "animal” means humans as well as all other warm-blooded members of the animal kingdom possessed of a homeostatic mechanism, including mammals (e.g., companion animals, zoo animals and food-source animals) and birds.
- mammals e.g., companion animals, zoo animals and food-source animals
- companion animals are all canine species (e.g., dogs), feline species (e.g., cats) and equine species (e.g., horses); some examples of food-source animals are pigs, cows, sheep, poultry and the like.
- the animal is a mammal.
- the mammal is a human, a companion animal or a food-source animal.
- the animal is a human or is a canine or feline (e.g., a cat or a dog).
- the animal is a canine (e.g., a dog).
- the terms "treating”, “treat”, or “treatment” embrace both preventative, i.e. prophylactic, and palliative treatment.
- the MTP inhibitors are preferably intestinal-acting MTP inhibitors and these are preferably intestinal selective.
- the term "selectivity" refers to a greater effect of a compound in a first assay, compared to the effect of the same compound in a second assay.
- the first assay is for the ability of the compound to inhibit intestinal fat absorption
- the second assay is for the ability of the compound to lower serum triglycerides.
- the ability of the compound to inhibit intestinal fat absorption is measured by the ED 25 of the compound in an intestinal fat absorption assay, such that a greater effect of the compound results in the observation of a lower absolute (numerical) value for the ED 25 .
- the ability of the compound to lower serum triglycerides is measured by the ED 25 of the compound in a serum triglyceride assay. Again, a greater effect of a compound in the serum triglyceride lowering assay results in the observation of a lower absolute (numerical) value for the ED 25 . It is to be understood that any assay capable of measuring the effectiveness of a compound in inhibiting intestinal fat absorption, or capable of measuring the effectiveness of a compound in lowering serum triglycerides, is encompassed by the present invention. Examples of suitable assays are given in PCT Publication No. WO 03/002533.
- Intestinal selectivity may be achieved by controlling the solubility of the inhibitor in the intestinal tract and/or release of the inhibitor from the dosage form or by increasing lipid (fat) in the gut, i.e. administer with food and increase the dietary fat in the food.
- Another method for increasing intestinal selectivity may be rapid metabolism of the MTP inhibitor to an inactive form which in theory would decrease hepatic exposure.
- Figure 1 provides a summary of the incidence of the most frequent clinical signs identified as undesirable effects by dosing regimen and treatment over the weight loss phase of a study to assess the field efficacy and safety of three different dosing regimens of a commercial formulation of dirlotapide in the treatment of excessive body weight in adult overweight dogs (body condition score (BCS) greater than 5), in comparison with a placebo (Example 1).
- body condition score BCS
- Example 1 provides a summary of the incidence of the most frequent clinical signs identified as undesirable effects by dosing regimen and treatment over the weight loss phase of a study to assess the field efficacy and safety of three different dosing regimens of a commercial formulation of dirlotapide in the treatment of excessive body weight in adult overweight dogs (body condition score (BCS) greater than 5), in comparison with a placebo (Example 1).
- BCS body condition score
- Figure 2 provides a summary of the mean cumulative percentage body weight change, measured from day 0 to each scheduled visit for dogs treated with dirlotapide or placebo during studies A and B in Example 2.
- Figure 3 provides a summary of the mean weekly percentage weight change since the previous visit measured at each scheduled visit for dogs treated with dirlotapide or placebo during studies A and B in Example 2.
- MTP inhibitors for use in the present invention are known in the art.
- Suitable MTP inhibitors include compounds disclosed in U.S. Patent Nos. 4,453,913; 4,473,425; 4,491 ,589; 4,540,458; 4,962,115; 5,057,525; 5,137,896; 5,286,647; 5,521,186; 5,595,872; 5,646,162; 5,684,014; 5,693,650; 5,712,279;
- JP2002-220345(14220345) For a review of apo-B/MTP inhibitors, see, Williams, S.J. and J. D. Best, Expert Opin Ther Patents,
- MTP mobility transfer protein
- Preferred intestinal-acting MTP inhibitors for use in the instant invention include dirlotapide ((S)-N- ⁇ 2- [benzy ⁇ methyOaminol ⁇ -oxo-i-phenylethylJ-i-methyl- ⁇ - ⁇ '-thfluoromethyOCI .I'-biphenylJ ⁇ -carboxamidol-I H- indole-2-carboxamide) and 1-methyl-5-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-1 H-indole-2-carboxylic acid (carbamoyl- phenyl-methyl)-amide which can both be prepared using methods described in U.S. Patent No. 6,720,351 ;
- the methods further comprise the administration of at least one additional pharmaceutical agent.
- additional pharmaceutical agents include other anti-obesity agents such as cannabinoid-1 (CB-1 ) antagonists (such as rimonabant), 11 ⁇ -hydroxy steroid dehydrogenase-1 (11 ⁇ -HSD type 1) inhibitors, peptide YY (PYY) and PYY agonists (such as PYY 3-36 or analogs or derivatives thereof), MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, ⁇ 3 adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c receptor agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, lep
- anorectic agents such as a bombesin agonist
- neuropeptide-Y receptor antagonists e.g., NPY Y5 receptor antagonists
- thyromimetic agents dehydroepiandrosterone or an analog thereof
- glucocorticoid receptor agonists or antagonists orexin receptor antagonists
- glucagon-like peptide-1 receptor agonists ciliary neurotrophic factors (such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH)
- human agouti-related protein (AGRP) inhibitors such as AxokineTM available from Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH
- human agouti-related protein (AGRP) inhibitors ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like.
- lipid modifying compounds which include HMG CoA reductase inhibitors, cholesterol absorption inhibitors, ezetimide, squalene synthetase inhibitors, fibrates, bile acid sequestrants, statins, probucol and derivatives, niacin, niacin derivatives, PPAR alpha agonists, PPAR gamma agonists, thiazolidinediones, and cholesterol ester transfer protein (CETP) inhibitors.
- HMG CoA reductase inhibitors HMG CoA reductase inhibitors
- cholesterol absorption inhibitors ezetimide
- squalene synthetase inhibitors fibrates
- bile acid sequestrants statins
- statins probucol and derivatives
- niacin niacin derivatives
- PPAR alpha agonists PPAR alpha agonists
- PPAR gamma agonists thiazolidinediones
- LDL-cholesterol lowering agents include LDL-cholesterol lowering agents, triglyceride lowering agents, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitor of HMG-CoA reductase gene expression, a squalene synthetase inhibitor, a squaline epoxidase inhibitor, a squaline cyclase inhibitor, a combined squaline epoxidase/cydase inhibitor, a cholesterol synthesis inhibitor, a cholesterol absorption inhibitor such as ZetiaTM (ezetimibe), a CETP inhibitor, a PPAR modulator or other cholesterol lowering agent such as a fibrate, an ion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acid sequestrant.
- LDL-cholesterol lowering agents include LDL-cholesterol lowering agents, triglyceride lowering agents, an HMG-CoA reduct
- bile acid reuptake inhibitors include bile acid reuptake inhibitors, ileal bile acid transporter inhibitors, ACC inhibitors, antihypertensive agents (such as Norvasc®), diuretics, garlic extract preparations, bile acid sequestrants, antibiotics, antidiabetics, and anti-inflammatory agents such as aspirin or, preferably, an anti-inflammatory agent that inhibits cyclooxygenase-2 (Cox-2) to a greater extent than it inhibits cyclooxygenase-1 (Cox-1) such as celecoxib (U.S. patent No. 5,466,823), valdecoxib (U.S. patent No.
- suitable additional pharmaceutical agents include naturally occurring substances that act to lower plasma cholesterol levels. These naturally occurring materials are commonly called nutraceuticals and include, for example, garlic extract, Hoodia plant extracts and niacin.
- the dosage of the additional pharmaceutical agent is generally dependent upon a number of factors including the health of the subject being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired.
- the dosage range of the additional pharmaceutical agent is in the range of from about 0.001 mg to about 100 mg per kilogram body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram body weight of the individual per day.
- some variability in the general dosage range may also be required depending upon the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered and the like.
- the determination of dosage ranges and optimal dosages for a particular patient is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.
- the MTP inhibitor is administered at escalating dosages.
- the escalating dosages comprise at least an initial first dose level and a second dose level.
- the escalating dosages comprise at least a first dose level, a second dose level and a third dose level.
- the escalating dosages further comprise a fourth dose level.
- the escalating dosages comprise at least a first dose level, a second dose level, a third dose level, a fourth dose level and a fifth dose level.
- six and further dose levels are contemplated. The original dose level may be increased by 10 %, 20%, 25%, 50%, 100% or 300% to produce the next dose level.
- the next dose level is double the original dose level.
- the next dose level is four times the original dose level.
- the original dose level is increased by 25%, 50% or 100%.
- the original dose level is increased by 50% or 100%, for example 100%.
- the first dose level is in the range of 0.025 to 0.30 mg/kg/day, for example in the range of 0.025 to 0.10 mg/kg/day, such as about 0.05 or 0.10 mg/kg/day, preferably about 0.05 mg/kg/day.
- the second dose level is 100% greater than the first, for example is in the range of 0.05 to 0.6 mg/kg/day, or for example is in the range of 0.05 to 0.2 mg/kg/day, such as about 0.10 or 0.2 mg/kg/day, preferably about 0.10 mg/kg/day.
- the third dose level is 100% greater than the second dose level, for example is in the range of 0.10 to 1.2 mg/kg/day, or for example is in the range of 0.10 to 0.4 mg/kg/day, for example about 0.2 or 0.4 mg/kg/day, preferably about 0.2 mg/kg/day.
- the fourth dose level is 50% greater than the third dose level, for example is in the range of 0.15 to 0.9 mg/kg/day, or for example is in the range of 0.15 to 0.6 mg/kg/day, for example about 0.3 or 0.6 , mg/kg/day, preferably about 0.3 mg/kg/day.
- the fourth dose level is increased by 50% thereafter to produce fifth, six and subsequent dose levels.
- the first dose level is in the range of 0.025 to 0.10 mg/kg/day, for example about 0.05 or 0.10 mg/kg/day, preferably about 0.05 mg/kg/day.
- the second dose level is 100% greater than the first, for example is in the range of 0.05 to 0.2 mg/kg/day, for example about 0.10 or 0.2 mg/kg/day, preferably about 0.10 mg/kg/day.
- the third dose level is 100% greater than the second dose level, for example is in the range of 0.10 to 0.4 mg/kg/day, for example about, 0.2 or 0.4 mg/kg/day, preferably about 0.2 mg/kg/day.
- the fourth dose level is 50% greater than the third dose level, for example is in the range of 0.15 to 0.6 mg/kg/day, for example about 0.3 or 0.6 mg/kg/day, preferably about 0.3 mg/kg/day.
- the fourth dose level is increased by 50% thereafter to produce fifth, six and subsequent dose levels.
- each dose level is administered to the subject for from about 1 to 4 weeks, for example, the dose levels may be increased after 1 week, 2 weeks, or monthly.
- the first dose level e.g. 0.05 mg/kg/day
- the second dose level e.g. 0.01 mg/kg/day
- the third dose level e.g. 0.2 mg/kg/day
- subsequent dose increases being made at, for example, monthly intervals.
- the initial dose when the MTP inhibitor is dirlotapide and the subject is a dog, the initial dose may be 0.05 mg/kg/day. After two weeks of therapy, the initial dose may be doubled to 0.10 mg/kg/day for two weeks. Following these initial 4 weeks of therapy, dogs may be weighed monthly and dose adjustments may be made monthly according to the following guidelines. At the end of each month of therapy, the percentage of body weight loss is determined. If the body weight loss since previous monthly weighing has been greater than or equal to 3% body weight per month (equivalent to 0.1 % body weight per day); the dose may be kept the same. If .the body weight loss since previous monthly weighing has been less than 3% body weight per month; the dose may be increased without adjusting for the dog's current body weight.
- the dose may be increased by 100% (doubled). In subsequent required conditional increases, the dose may be increased by 50% up to a maximum dose of the product of 1 mg/kg current body weight. These adjustments may be continued until the weight targeted at the start of therapy is achieved.
- the dose may be reduced by 25%.
- a mean weight loss of about 18 to 20% after six months of weight loss therapy can be anticipated.
- the initial "weight loss" phase may last a number of months, for example about 4 months (i.e. about 16 weeks) to 6 months, or for example, about 112 to 196 days, or may last until the target weight loss is achieved, or may last until a particular Body Condition Score (BCS) is reached, for example a BCS of five.
- BCS Body Condition Score
- the weight maintenance/management or retraining phase may last for a period of months, for example about 3 months (i.e. about 12 weeks) or, for example, 84 days.
- the dose may be decreased, for example by 50%, or increased, for example by 100%, if the patient was losing or gaining too much weight (for example, more than 5%) from the start of the weight maintenance/management retraining phase, respectively.
- the weight maintenance/management or retraining phase can be commenced.
- the optimal level of food intake and physical activity needed should be established.
- Administration of the MTP inhibitor should be continued during the weight maintenance/management or retraining phase until the food intake and physical activity needed to stabilize body weight at the desired weight is established.
- the dose adjustment during the weight maintenance/management or retraining phase may be as follows: First dose adjustment If the dog lost greater than or equal to 1% body weight per week in the last month of the weight loss phase, the dose should be decreased by 50%.
- the dose should be increased by 50%. Subsequent dose adjustments In subsequent months the dose should be increased or decreased by 25% to maintain a constant weight.
- the dose should remain unchanged.
- the dose should be decreased by 25%. If the dog gained greater than 5% body weight, then the dose should be increased by 25%. Based on the dog's current body weight a daily dose of 1 mg/kg should not be exceeded.
- the additional pharmaceutically active agents are administered according to traditional treatment regimens. Jn some embodiments, the additional pharmaceutically active agents are administered at escalating dosages.
- the term "reduce the side effects associated with administration of the MTP inhibitor" or similar refers to an amelioration or elimination of one or more undesired side effects occurring as a result of administering MTP inhibitors according to traditional treatment regimens, for example at higher initial doses without dose escalation.
- Such side effects include emesis (vomiting), diarrhoea, lethargy, inappetence and anorexia, for example emesis (vomiting), diarrhea and lethargy and particularly include emesis.
- the present invention also pertains to a pharmaceutical kit for use by a consumer in the treatment or prevention of obesity or related eating disorders and/or reducing food consumption, or for inhibiting MTP in a subject in need thereof.
- the kit comprises (a) at least two sets of pharmaceutical dosage units comprising an MTP inhibitor wherein the first dose level is in the range of 0.025 to 0.30 mg/kg/day, for example in the range of 0.025 to 0.10 mg/kg/day, such as about 0.05 or 0.10 mg/kg/day, preferably about 0.05 mg/kg/day; and the second dose level is in the range of 0.05 to 0.6 mg/kg/day, or for example is in the range of 0.05 to 0.2 mg/kg/day, such as about 0.10 or 0.2 mg/kg/day, preferably about 0.10 mg/kg/day; and (b) instructions for use.
- the first dose level is in the range of 0.025 to 0.30 mg/kg/day, for example in the range of 0.025 to 0.10 mg/kg/day, such as about 0.05 or 0.10 mg/kg/day, preferably about 0.05 mg/kg/day
- the second dose level is in the range of 0.05 to 0.6 mg/kg/day, or for example is in the range of
- the MTP inhibitor and any additional pharmaceutical agent (referred to herein as a "combination") is administered to a subject in need of such treatment, preferably in the form of a pharmaceutical composition.
- the MTP inhibitor and the other pharmaceutical agent e.g., another anti-obesity agent,
- the agents may be administered in any order. It is generally preferred that such administration be oral. It is especially preferred that such administration be oral and simultaneous.
- the administration of each may be by the same or by different methods.
- the MTP inhibitor or a combination is preferably administered in the form of a pharmaceutical composition.
- Administration of the agents can be separately or together in any conventional oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular or subcutaneous), intracistemal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray or lotion), buccal or nasal dosage form (e.g., spray, drops or inhalant).
- the MTP inhibitors or combinations can be administered alone but will generally be administered in an admixture with one or more suitable pharmaceutical excipients, adjuvants, diluents or carriers known in the art and selected with regard to the intended route of administration and standard pharmaceutical practice.
- the MTP inhibitors or combination may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release dosage forms depending on the desired route of administration and the specificity of release profile, commensurate with therapeutic needs.
- the pharmaceutical composition comprises an MTP inhibitor or a combination in an amount generally in the range of from about 1% to about 75%, 80%, 85%, 90% or even 95% (by weight) of the composition, usually in the range of about 1%, 2% or 3% to about 50%, 60% or 70%, more frequently in the range of about 1 %, 2% or 3% to less than 50% such as about 25%, 30% or 35%.
- Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known to those skilled in this art. For examples, see Remington: The Practice of Pharmacy, Lippincott Williams and Wilkins, Baltimore MD, 20 th ed. 2000.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
- the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, sesame seed oil and the like), Miglyol ® (available from
- CONDEA Vista Co., Cranford, NJ. CONDEA Vista Co., Cranford, NJ.
- glycerol tetrahydrofurfuryl alcohol
- polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
- the composition may also include excipients, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- excipients such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Oral liquid forms of the MTP inhibitors or combinations include solutions, wherein the active compound is fully dissolved.
- solvents include all pharmaceutically precedented solvents suitable for oral administration, particularly those in which the compounds of the invention show good solubility, e.g., polyethylene glycol, polypropylene glycol, edible oils and glyceryl- and glyceride- based systems.
- Glyceryl- and glyceride- based systems may include, for example, the following branded products (and corresponding generic products): CaptexTM 355 EP (glyceryl tricaprylate/caprate, from Abitec,
- CrodamolTM GTC/C medium chain triglyceride, from Croda, Cowick Hall, UK
- LabrafacTM CC medium chain triglyides, from Gattefosse
- CaptexTM 500P glyceryl triacetate i.e.
- medium chain (about C 8 to C 10 ) triglyceride oils are the medium chain (about C 8 to C 10 ) triglyceride oils. These solvents frequently make up the predominant portion of the composition, i.e., greater than about 50%, usually greater than about 80%, for example about 95% or 99%. Adjuvants and additives may also be included with the solvents principally as taste-mask agents, palatability and flavoring agents, antioxidants, stabilizers, texture and viscosity modifiers and solubilizers.
- Suspensions in addition to the MTP inhibitor or the combination, may further comprise carriers such as suspending agents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
- suspending agents e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
- the MTP inhibitor (or combination) can be carried in the drinking water so that a therapeutic dosage of the compound is ingested with the daily water supply.
- the compound can be directly metered into drinking water, preferably in the form of a liquid, water- soluble concentrate (such as an aqueous solution of a water-soluble salt).
- the MTP inhibitor (or combination) can also be added directly to the feed, as such, or in the form of an animal feed supplement.
- the present invention has several advantageous veterinary features.
- the instant invention provides the means by which this may be accomplished.
- utilization of the method of the present invention yields leaner animals that command higher sale prices from the meat industry.
- Example 1 Formulation: composition per mL - Dirlotapide: 5mg
- the study period was divided into three consecutive phases: a "weight loss phase”, extending from day 0 until the first scheduled visit where the patient reached a BCS of five or day 196 visit at the latest, followed by a 84-day “retraining phase” aimed at stabilizing body weight, then followed by a 28-day “post-treatment phase”, during which the patient did not receive any treatment.
- Patients were treated, during the weight loss and retraining phases, with a once daily dose of dirlotapide or placebo, prescribed by the Investigator and administered by the owner at the time of a meal.
- the percentage of weight loss was assessed and the dose had to be increased (generally by 100%) in case of insufficient weight loss (less than 1% per week since previous adjustment).
- the dose was decreased by 50% or increased by 100% if the patient was losing or gaining too much weight (more than 5%) from the start of the retraining phase, respectively.
- the dose could also be decreased (generally by 50%) at any time during the study, in case of severe reduction in food intake or of Suspected Adverse Drug Events (SADE).
- the dose to be administered was limited to a maximum allowed of 1 mg/kg of current body weight.
- the dirlotapide treatment induced undesirable digestive clinical signs (vomiting and diarrhoea), and lethargy and anorexia/inappetence, with incidences over the 10-month study which were substantially decreased by reducing the starting dose from 0.2 mg/kg to 0.05 mg/kg.
- the number of animals withdrawn for undesirable clinical signs over the whole study period decreased from 31.9% in the first regimen to 10.5% in the third dosing regimen.
- the percentage of animals vomiting at least once during the study decreased from 72% to 42% from the first to the last regimen.
- the third dosing regimen (starting dose of 0.05 mg/kg) appears therefore to be the regimen of choice as it provides the same efficacy as the other regimens but results in an enhanced tolerance profile.
- the dosage of dirlotapide was 0.53 mg/kg of initial body weight on average (approximately a 10 fold increase from start) and ranged from 0.10 mg/kg to 0.93 mg/kg of initial body weight.
- Dirlotapide administered at a starting dose of 0.05 mg/kg doubled after two weeks of treatment was as efficacious as the other dosing regimens, resulting in a weight loss of 20.9% after 28 weeks of weight loss therapy and only 10.5 % of the population experiencing a weight loss lower than 5% after 12 weeks of therapy .
- Table 1 provides a summary of the total percent weight change from study start at each scheduled visit of the weight loss phase;
- Table 2 provides a summary of the dose prescribed in mL/kg and in mg/kg at each scheduled visit of the weight loss phase; and
- Figure 1 provides a summary of the incidence of the most frequent clinical signs identified as undesirable effects by dosing regimen and treatment over the weight loss phase.
- Dirlotapide was evaluated in the management of obesity in dogs in two multicenter, clinical studies in North America (for more details see J. A. WREN, A. A. RAMUDO, S. L. CAMPBELL, V. L. KING, J. S. EAGLESON, J. GOSSELLIN, S. J. SUNDERLAND (2007); Efficacy and safety of dirlotapide in the management of obese dogs evaluated in two placebo-controlled, masked clinical studies in North America; Journal of Veterinary Pharmacology and Therapeutics 30 (s1), 81-89, incorporated herein by reference). A total of 335 obese dogs of various breeds were randomized to dirlotapide or placebo in a 2:1 ratio.
- Dirlotapide was administered orally once daily to dogs at an initial dose of 0.05 mg/kg, increased after 14 days to 0.1 (study B) or 0.2 mg/kg (study A) and then adjusted according to individual weight loss at 28-day intervals. Dogs were examined and weighed, and body condition scores (BCSs) were recorded every 28 days. Study A had three consecutive phases: weight loss (16 weeks, day 0-112); weight management (12 weeks); and post-treatment (8 weeks). Study B had a weight loss phase only.
- Dirlotapide (SlentrolTM; Pfizer Animal Health, New York, NY, USA) was administered in the commercial formulation with an oil vehicle containing 5 mg dirlotapide/mL Control dogs received food-grade corn oil. Treatments were indistinguishable by appearance and packaging. Doses were calculated to provide equal volumes of each treatment based on initial body weight and at subsequent monthly intervals the dose volume was adjusted individually based on body weight loss response.
- each dog was examined and weighed, and blood and urine samples were collected to determine suitability for enrollment. Animal information and medical history, including concomitant medications, were recorded, and BCS was assessed. The study period for each dog commenced on day 0 - the day participating animals began treatment with either dirlotapide or placebo. Treatments were administered by the owner at home.
- Study A comprised three consecutive phases: an initial weight loss phase from day 0 to day 112 (16 weeks), followed by weight management (12 weeks) and a post-treatment period (8 weeks); during this last period, body weight was monitored after cessation of treatment.
- the management phase the patient continued treatment with dirlotapide or placebo at a dose adjusted to maintain ⁇ 5% of the body weight achieved at the end of the weight loss phase.
- Dogs that had not lost sufficient body weight (minimum of 0.5% per week, equivalent to 8% over the whole phase) at the end of weight loss phase (day 112) completed the study and did not enter the management phase.
- Study B consisted of a 16-week (to day 112) weight loss phase only. Examination visits, at which dogs were weighed and BCS was assessed, were performed at 28- day intervals throughout each study. At the end of the weight loss phase, owners were asked to assess whether their dogs' level of physical activity had changed over the treatment period.
- blood samples were also collected at the end of eacHTstudy phase and at study completion (end of post-treatment phase in study A and end of weight loss phase in study B). Samples were analyzed for routine hematologic values and serum chemistry that included assessment of major organ function and lipid measurements (high-density lipoprotein, cholesterol, and triglyceride concentrations).
- the dose volume was increased by 50% at the first adjustment and by 25% thereafter if weight loss was ⁇ 1 % per week since the previous visit.
- the dose volume was increased by 50% if the dog had gained weight since the previous visit and the dose volume was reduced by 50% if the weekly weight loss was 1 % or more since the preceding visit.
- the dose volume was increased or decreased by 25% if weight gain or loss was >5% from the start of the management phase, respectively. The dose volume could only be increased 50% once during the weight management phase.
- dirlotapide doses were administered directly into the mouth to 77% of dirlotapide-treated dogs and 64% of placebo-treated dogs. Remaining animals were dosed by placing a small amount on the animal's food.
- the dose of dirlotapide was increased from 0.05 mg/kg for all dogs to a mean dose of 0.33 mg/kg (range, 0.14-0.52 mg/kg) in study A and 0.26 mg/kg (range, 0.11-0.53 mg/kg) in study B (Table 4).
- the range of doses during 112 days of weight loss was 0.045-0.53 mg/kg.
- dirlotapide doses decreased to a final mean of 0.26 mg/kg that varied widely (range, 0.07-0.54 mg/kg). Discussion
- Dirlotapide was found to be consistently effective in generating weight loss in obese dogs in the absence of dietary restriction.
- mean weight loss from day 0 was 19.3% by day 196 and 16.7% at the end of the post-treatment phase.
- weight loss of at least 13% of body weight was achieved by significantly more dirlotapide-treated dogs over 112 days than by dogs receiving placebo (39.1-50.0% vs. 5.3-5.6%).
- weight reduction of at least 11-12% has substantially improved clinical signs.
- the body weight measurement at the end of the first month post-treatment enabled the owner to further adjust the food offered for those dogs that gained weight. This implies that although some weight gain occurred, the mean weight loss of 16.7% in dogs receiving dirlotapide from day 0 could probably be maintained for a much longer period with minimal further weight gains, provided that the new feeding and exercise regimens were continued. Since approximately 10% of fat calories may be excreted in the feces during dirlotapide treatment it is also possible that feeding the amount of food that stabilized body weight may slightly overestimate the dog's calorie needs when dirlotapide is discontinued, illustrating the importance of maintaining veterinary supervision after dirlotapide is discontinued. In the present studies, dirlotapide was found to be safe in clinical use.
- the dose of dirlotapide was started at a low initial dose of 0.05 mg/kg and was subsequently increased incrementally to reach an optimal dose to produce weight loss for each dog and then adjusted to maintain weight loss.
- the first incremental increase was to 0.1 mg/kg in accordance with label recommendations (and in contrast to the increase to 0.2 mg/kg in study A), and this was found to further minimize emesis.
- the mean doses recorded had wide standard deviations and large range in dose volumes, confirming the need for individual titration and correction for differences in individual diet, exercise level, or metabolism which might affect rate of body weight loss.
- Table 3 provides a summary of the mean percentage weight changes [and 95% confidence intervals (Cl)] for dogs treated with dirlotapide or placebo during 112 days of weight loss in both studies;
- Table 4 provides a summary of the mean doses of dirlotapide and placebo administered to dogs at the end of each phase in both studies;
- Figure 2 provides a summary of the mean cumulative percentage body weight change, measured from day 0 to each scheduled visit for dogs treated with dirlotapide or placebo during studies A and B; and
- Figure 3 provides a summary of the mean weekly percentage weight change since the previous visit measured at each scheduled visit for dogs treated with dirlotapide or placebo during studies A and B.
- Table 1 Total Percent Weight Change from Study Start at each Scheduled Visit of the Weight Loss Phase.
- Table 2 Summary of Dose Prescribed in mL/kg and in mg/kg at each Scheduled visit of the Weight Loss Phase.
- NB For each scheduled visit, doses are those prescribed from the scheduled visit day onwards. At each scheduled visit, summaries include only animals kept in the study beyond that point.
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US87001006P | 2006-12-14 | 2006-12-14 | |
US60/870,010 | 2006-12-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008072056A1 true WO2008072056A1 (en) | 2008-06-19 |
Family
ID=39321430
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2007/003842 WO2008072056A1 (en) | 2006-12-14 | 2007-12-03 | Use of mtp inhibitors for the treatment of obesity using low doses and dose-escalation |
Country Status (4)
Country | Link |
---|---|
JP (1) | JP2008150370A (ja) |
AR (1) | AR064344A1 (ja) |
TW (1) | TW200836718A (ja) |
WO (1) | WO2008072056A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11944602B2 (en) | 2015-02-26 | 2024-04-02 | Novartis Ag | Treatment of autoimmune disease in a patient receiving additionally a beta-blocker |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2538413T3 (es) * | 2008-12-22 | 2015-06-19 | Novartis Ag | Régimen de dosificación de un agonista del receptor S1P |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005087234A1 (en) * | 2004-03-05 | 2005-09-22 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
WO2005097131A2 (en) * | 2004-04-09 | 2005-10-20 | Janssen Pharmaceutica N.V. | Intermittent dosing regimen for the treatment of overweight with mtp-inhibitors |
WO2007047722A2 (en) * | 2005-10-18 | 2007-04-26 | Aegerion Pharmaceuticals | Methods for treating disorders associated with hyperlipidemia in a mammal |
-
2007
- 2007-12-03 WO PCT/IB2007/003842 patent/WO2008072056A1/en active Application Filing
- 2007-12-10 JP JP2007318836A patent/JP2008150370A/ja active Pending
- 2007-12-13 AR ARP070105612A patent/AR064344A1/es unknown
- 2007-12-13 TW TW096147654A patent/TW200836718A/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005087234A1 (en) * | 2004-03-05 | 2005-09-22 | The Trustees Of The University Of Pennsylvania | Methods for treating disorders or diseases associated with hyperlipidemia and hypercholesterolemia while minimizing side-effects |
WO2005097131A2 (en) * | 2004-04-09 | 2005-10-20 | Janssen Pharmaceutica N.V. | Intermittent dosing regimen for the treatment of overweight with mtp-inhibitors |
WO2007047722A2 (en) * | 2005-10-18 | 2007-04-26 | Aegerion Pharmaceuticals | Methods for treating disorders associated with hyperlipidemia in a mammal |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11944602B2 (en) | 2015-02-26 | 2024-04-02 | Novartis Ag | Treatment of autoimmune disease in a patient receiving additionally a beta-blocker |
Also Published As
Publication number | Publication date |
---|---|
JP2008150370A (ja) | 2008-07-03 |
AR064344A1 (es) | 2009-04-01 |
TW200836718A (en) | 2008-09-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Dossat et al. | Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake | |
US9427002B2 (en) | Isoflavone compositions for reducing accumulation of body fat in male mammals, and methods for their use | |
JP6779618B2 (ja) | 食欲不振制御化合物の組成物および使用方法 | |
ES2431085T3 (es) | Uso de glutamato, derivados o metabolitos de glutamato, análogos de glutamato o mezclas de los mismos para la fabricación de una composición para el tratamiento de osteoporosis | |
Wren et al. | Dirlotapide: a review of its properties and role in the management of obesity in dogs | |
Navarro et al. | Voluntary acceptance and consumption of two oral ciclosporin formulations in dogs: two randomised, controlled studies | |
US5972921A (en) | Use of an aromatase inhibitor in the treatment of decreased androgen to estrogen ratio and detrusor urethral sphincter dyssynergia in men | |
JP6419857B2 (ja) | グラピプラント組成物およびその使用方法 | |
WO2008072056A1 (en) | Use of mtp inhibitors for the treatment of obesity using low doses and dose-escalation | |
Fadel et al. | Synopsis of the pharmacokinetics, pharmacodynamics, applications, and safety of firocoxib in horses | |
WO1989005642A1 (en) | Dextrorphan potentiator for anticonvulsant composition and method | |
US20080090749A1 (en) | Prophylactic/therapeutic agent for stress-induced bowel disease | |
WO2008072061A1 (en) | Method of treatment of obesity with an mtp inhibitor in conjunction with an increased-fat diet | |
KR20010051558A (ko) | 아포 b분비/mtp억제제의 용도 | |
JPWO2004026296A1 (ja) | 抗ストレス性疾患組成物 | |
KR100439384B1 (ko) | 아포지단백질 비 분비/미소체 삼중글리세라이드 전이 단백질 저해제를 포함하는 약학 조성물 | |
WO2006046746A1 (ja) | 内臓痛予防・治療剤 | |
WO1983000624A1 (en) | Promotion of feed efficiency in animals | |
Dantas et al. | Pharmacologic intervention in behavioral therapy | |
US20090170900A1 (en) | Dosing regimen for weight loss | |
JPWO2020085179A1 (ja) | 抗肥満剤、頻尿改善剤、自律神経活動調節剤 | |
CA2461150A1 (en) | Amines with antialcoholic agents | |
JP2006232705A (ja) | 抗ポリグルタミン病剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07849004 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 07849004 Country of ref document: EP Kind code of ref document: A1 |