MXPA99005262A - Treatment of equine laminitis - Google Patents
Treatment of equine laminitisInfo
- Publication number
- MXPA99005262A MXPA99005262A MXPA/A/1999/005262A MX9905262A MXPA99005262A MX PA99005262 A MXPA99005262 A MX PA99005262A MX 9905262 A MX9905262 A MX 9905262A MX PA99005262 A MXPA99005262 A MX PA99005262A
- Authority
- MX
- Mexico
- Prior art keywords
- donor
- equine
- acting
- acid
- nsaid
- Prior art date
Links
- 241000283073 Equus caballus Species 0.000 title claims abstract description 78
- 239000000203 mixture Substances 0.000 claims abstract description 137
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 116
- 150000002632 lipids Chemical class 0.000 claims abstract description 49
- 239000002840 nitric oxide donor Substances 0.000 claims abstract description 49
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 claims abstract description 48
- 230000000699 topical Effects 0.000 claims abstract description 37
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 36
- 230000002459 sustained Effects 0.000 claims abstract description 22
- 210000000003 Hoof Anatomy 0.000 claims abstract description 21
- 230000000694 effects Effects 0.000 claims abstract description 14
- 239000000969 carrier Substances 0.000 claims abstract description 11
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 100
- 235000014852 L-arginine Nutrition 0.000 claims description 49
- LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical compound CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 claims description 38
- SNIOPGDIGTZGOP-UHFFFAOYSA-N 1,2,3-propanetrioltrinitrate Chemical group [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims description 33
- 229960003711 glyceryl trinitrate Drugs 0.000 claims description 33
- 239000000006 Nitroglycerin Substances 0.000 claims description 32
- 229940014995 Nitroglycerin Drugs 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000003960 organic solvent Substances 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000000787 lecithin Substances 0.000 claims description 20
- 235000010445 lecithin Nutrition 0.000 claims description 20
- 239000003981 vehicle Substances 0.000 claims description 20
- 239000006071 cream Substances 0.000 claims description 19
- 239000004094 surface-active agent Substances 0.000 claims description 18
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 17
- 229940067606 Lecithin Drugs 0.000 claims description 17
- 239000002674 ointment Substances 0.000 claims description 15
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 11
- 125000001931 aliphatic group Chemical group 0.000 claims description 10
- 239000006260 foam Substances 0.000 claims description 10
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 9
- 230000002354 daily Effects 0.000 claims description 9
- 229960000991 ketoprofen Drugs 0.000 claims description 9
- 239000012528 membrane Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 210000003491 Skin Anatomy 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 239000003974 emollient agent Substances 0.000 claims description 6
- 239000000499 gel Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229960002009 naproxen Drugs 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 5
- 229960002460 Nitroprusside Drugs 0.000 claims description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- ASPOIVQEUUCDQT-UHFFFAOYSA-N nitroprusside Chemical compound O=N[Fe-2](C#N)(C#N)(C#N)(C#N)C#N ASPOIVQEUUCDQT-UHFFFAOYSA-N 0.000 claims description 5
- 238000011084 recovery Methods 0.000 claims description 5
- 239000002562 thickening agent Substances 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- 229940109239 Creatinine Drugs 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- 229940051880 analgesics and antipyretics Pyrazolones Drugs 0.000 claims description 4
- 230000036528 appetite Effects 0.000 claims description 4
- 235000019789 appetite Nutrition 0.000 claims description 4
- 238000009534 blood test Methods 0.000 claims description 4
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960001680 ibuprofen Drugs 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 claims description 4
- 150000003217 pyrazoles Chemical class 0.000 claims description 4
- 210000004369 Blood Anatomy 0.000 claims description 3
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 claims description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 229960004889 salicylic acid Drugs 0.000 claims description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 210000001519 tissues Anatomy 0.000 abstract description 12
- 239000004480 active ingredient Substances 0.000 description 22
- 229920001983 poloxamer Polymers 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 210000003414 Extremities Anatomy 0.000 description 8
- 229940079593 drugs Drugs 0.000 description 7
- 229940075495 isopropyl palmitate Drugs 0.000 description 7
- XUGNVMKQXJXZCD-UHFFFAOYSA-N Isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- -1 fenbufeno Chemical compound 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 239000008347 soybean phospholipid Substances 0.000 description 5
- 230000000261 vasodilator Effects 0.000 description 5
- 239000003071 vasodilator agent Substances 0.000 description 5
- CGIGDMFJXJATDK-UHFFFAOYSA-N Indometacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- AXISYYRBXTVTFY-UHFFFAOYSA-N Isopropyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OC(C)C AXISYYRBXTVTFY-UHFFFAOYSA-N 0.000 description 4
- 210000001364 Upper Extremity Anatomy 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 230000002500 effect on skin Effects 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229940074928 isopropyl myristate Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- ZOOGRGPOEVQQDX-KHLHZJAASA-N Cyclic Guanosine Monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 3
- WJTCGQSWYFHTAC-UHFFFAOYSA-N Cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 3
- 102000014469 EC 4.6.1.2 Human genes 0.000 description 3
- 108010078321 EC 4.6.1.2 Proteins 0.000 description 3
- 210000002889 Endothelial Cells Anatomy 0.000 description 3
- 241000283086 Equidae Species 0.000 description 3
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline zwitterion Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 230000001684 chronic Effects 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- 239000004914 cyclooctane Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- 150000003905 phosphatidylinositols Chemical class 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol 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 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 2
- 229940035676 ANALGESICS Drugs 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 2
- 210000004204 Blood Vessels Anatomy 0.000 description 2
- 240000000218 Cannabis sativa Species 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N Cholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 229960001231 Choline Drugs 0.000 description 2
- 208000002881 Colic Diseases 0.000 description 2
- 241000283074 Equus asinus Species 0.000 description 2
- 210000002683 Foot Anatomy 0.000 description 2
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 2
- 229960000905 Indomethacin Drugs 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- BMUKKTUHUDJSNZ-UHFFFAOYSA-N Isoxsuprine Chemical compound C=1C=C(O)C=CC=1C(O)C(C)NC(C)COC1=CC=CC=C1 BMUKKTUHUDJSNZ-UHFFFAOYSA-N 0.000 description 2
- 229960004819 Isoxsuprine Drugs 0.000 description 2
- 210000003141 Lower Extremity Anatomy 0.000 description 2
- 102100000871 NOS3 Human genes 0.000 description 2
- 229960002895 Phenylbutazone Drugs 0.000 description 2
- UNJJBGNPUUVVFQ-ZJUUUORDSA-N Phosphatidylserine Chemical compound CCCC(=O)O[C@H](COC(=O)CC)COP(O)(=O)OC[C@H](N)C(O)=O UNJJBGNPUUVVFQ-ZJUUUORDSA-N 0.000 description 2
- 229940067631 Phospholipids Drugs 0.000 description 2
- 102000014961 Protein Precursors Human genes 0.000 description 2
- 108010078762 Protein Precursors Proteins 0.000 description 2
- STECJAGHUSJQJN-FWXGHANASA-N Scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M Sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- WWUZIQQURGPMPG-KRWOKUGFSA-N Sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 2
- 230000001154 acute Effects 0.000 description 2
- 230000000202 analgesic Effects 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000037396 body weight Effects 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
- 238000006243 chemical reaction Methods 0.000 description 2
- RPKLZQLYODPWTM-KBMWBBLPSA-N cholanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 RPKLZQLYODPWTM-KBMWBBLPSA-N 0.000 description 2
- 229960002173 citrulline Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 239000004088 foaming agent Substances 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000002327 glycerophospholipids Chemical class 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003589 local anesthetic agent Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- 230000002829 reduced Effects 0.000 description 2
- 229960002646 scopolamine Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- XOZLRRYPUKAKMU-UHFFFAOYSA-N 1,5-dimethyl-2-phenyl-4-(propan-2-ylamino)pyrazol-3-one Chemical compound O=C1C(NC(C)C)=C(C)N(C)N1C1=CC=CC=C1 XOZLRRYPUKAKMU-UHFFFAOYSA-N 0.000 description 1
- BBMCTIGTTCKYKF-UHFFFAOYSA-N 1-Heptanol Chemical compound CCCCCCCO BBMCTIGTTCKYKF-UHFFFAOYSA-N 0.000 description 1
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N 1-Hexanol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N 2-(11-oxo-6H-benzo[c][1]benzoxepin-2-yl)acetic acid Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N 2-(2-Ethoxyethoxy)ethanol Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- IYEPZNKOJZOGJG-UHFFFAOYSA-N 2-(4-phenylphenyl)butanoic acid Chemical compound C1=CC(C(C(O)=O)CC)=CC=C1C1=CC=CC=C1 IYEPZNKOJZOGJG-UHFFFAOYSA-N 0.000 description 1
- VSQMKHNDXWGCDB-UHFFFAOYSA-N 2-(7-methoxy-10-methylphenothiazin-2-yl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C2SC3=CC(OC)=CC=C3N(C)C2=C1 VSQMKHNDXWGCDB-UHFFFAOYSA-N 0.000 description 1
- SJCRQMUYEQHNTC-UHFFFAOYSA-N 2-[1-(4-chlorophenyl)-2,5-dimethylpyrrol-3-yl]acetic acid Chemical compound CC1=CC(CC(O)=O)=C(C)N1C1=CC=C(Cl)C=C1 SJCRQMUYEQHNTC-UHFFFAOYSA-N 0.000 description 1
- MXCVHSXCXPHOLP-UHFFFAOYSA-N 4-oxo-6-propylchromene-2-carboxylic acid Chemical compound O1C(C(O)=O)=CC(=O)C2=CC(CCC)=CC=C21 MXCVHSXCXPHOLP-UHFFFAOYSA-N 0.000 description 1
- HIYAVKIYRIFSCZ-CYEMHPAKSA-N 5-(methylamino)-2-[[(2S,3R,5R,6S,8R,9R)-3,5,9-trimethyl-2-[(2S)-1-oxo-1-(1H-pyrrol-2-yl)propan-2-yl]-1,7-dioxaspiro[5.5]undecan-8-yl]methyl]-1,3-benzoxazole-4-carboxylic acid Chemical compound O=C([C@@H](C)[C@H]1O[C@@]2([C@@H](C[C@H]1C)C)O[C@@H]([C@@H](CC2)C)CC=1OC2=CC=C(C(=C2N=1)C(O)=O)NC)C1=CC=CN1 HIYAVKIYRIFSCZ-CYEMHPAKSA-N 0.000 description 1
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 description 1
- BWDBEAQIHAEVLV-UHFFFAOYSA-N 6-methylheptan-1-ol Chemical compound CC(C)CCCCCO BWDBEAQIHAEVLV-UHFFFAOYSA-N 0.000 description 1
- 229960004892 Acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N Acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N Alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 229940045714 Alkyl sulfonate alkylating agents Drugs 0.000 description 1
- 229950008930 Amfenac Drugs 0.000 description 1
- SOYCMDCMZDHQFP-UHFFFAOYSA-N Amfenac Chemical compound NC1=C(CC(O)=O)C=CC=C1C(=O)C1=CC=CC=C1 SOYCMDCMZDHQFP-UHFFFAOYSA-N 0.000 description 1
- 206010003119 Arrhythmia Diseases 0.000 description 1
- 108060001001 BRK1 Proteins 0.000 description 1
- UKMSUNONTOPOIO-UHFFFAOYSA-N Behenic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 1
- BYFMCKSPFYVMOU-UHFFFAOYSA-N Bendazac Chemical compound C12=CC=CC=C2C(OCC(=O)O)=NN1CC1=CC=CC=C1 BYFMCKSPFYVMOU-UHFFFAOYSA-N 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N Bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- JBRBWHCVRGURBA-UHFFFAOYSA-N Broxaterol Chemical compound CC(C)(C)NCC(O)C1=CC(Br)=NO1 JBRBWHCVRGURBA-UHFFFAOYSA-N 0.000 description 1
- 229950008847 Broxaterol Drugs 0.000 description 1
- FLWFHHFTIRLFPV-UHFFFAOYSA-N Bumadizone Chemical compound C=1C=CC=CC=1N(C(=O)C(C(O)=O)CCCC)NC1=CC=CC=C1 FLWFHHFTIRLFPV-UHFFFAOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N C[N+](C)(C)CCO Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 210000001736 Capillaries Anatomy 0.000 description 1
- 206010007521 Cardiac arrhythmias Diseases 0.000 description 1
- 241001456108 Castilla Species 0.000 description 1
- 229940107161 Cholesterol Drugs 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- GZCGUPFRVQAUEE-KCDKBNATSA-N D-(+)-Galactose Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-KCDKBNATSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- UUCMDZWCRNZCOY-UHFFFAOYSA-N Ditazole Chemical compound O1C(N(CCO)CCO)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 UUCMDZWCRNZCOY-UHFFFAOYSA-N 0.000 description 1
- KWKXNDCHNDYVRT-UHFFFAOYSA-N Dodecylbenzene Chemical compound CCCCCCCCCCCCC1=CC=CC=C1 KWKXNDCHNDYVRT-UHFFFAOYSA-N 0.000 description 1
- OEHFRZLKGRKFAS-UHFFFAOYSA-N Droxicam Chemical compound C12=CC=CC=C2S(=O)(=O)N(C)C(C2=O)=C1OC(=O)N2C1=CC=CC=N1 OEHFRZLKGRKFAS-UHFFFAOYSA-N 0.000 description 1
- 206010013709 Drug ineffective Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 210000003038 Endothelium Anatomy 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- RHAXSHUQNIEUEY-UHFFFAOYSA-N Epirizole Chemical compound COC1=CC(C)=NN1C1=NC(C)=CC(OC)=N1 RHAXSHUQNIEUEY-UHFFFAOYSA-N 0.000 description 1
- 241000283070 Equus zebra Species 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- XIRNKXNNONJFQO-UHFFFAOYSA-N Ethyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC XIRNKXNNONJFQO-UHFFFAOYSA-N 0.000 description 1
- QRZAKQDHEVVFRX-UHFFFAOYSA-N Felbinac Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 description 1
- 229950006236 Fenclofenac Drugs 0.000 description 1
- IDKAXRLETRCXKS-UHFFFAOYSA-N Fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 description 1
- RBBWCVQDXDFISW-UHFFFAOYSA-N Feprazone Chemical compound O=C1C(CC=C(C)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 RBBWCVQDXDFISW-UHFFFAOYSA-N 0.000 description 1
- 229960004369 Flufenamic Acid Drugs 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N Flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 description 1
- 229960002897 Heparin Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- BYPIURIATSUHDW-UHFFFAOYSA-N Ibuproxam Chemical compound CC(C)CC1=CC=C(C(C)C(=O)NO)C=C1 BYPIURIATSUHDW-UHFFFAOYSA-N 0.000 description 1
- RJMIEHBSYVWVIN-UHFFFAOYSA-N Indoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N Inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 Inositol Drugs 0.000 description 1
- 206010061255 Ischaemia Diseases 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N Isoamyl alcohol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- 229950000248 Isonixin Drugs 0.000 description 1
- 229950011455 Isoxepac Drugs 0.000 description 1
- 240000007049 Juglans regia Species 0.000 description 1
- 235000009496 Juglans regia Nutrition 0.000 description 1
- 102100011311 KNG1 Human genes 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N Ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 241001325354 Lamiinae Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 230000035633 Metabolized Effects 0.000 description 1
- 210000002464 Muscle, Smooth, Vascular Anatomy 0.000 description 1
- 229940105132 Myristate Drugs 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- WJDDCFNFNAHLAF-UHFFFAOYSA-N N-(2,6-dimethylphenyl)-2-oxo-1H-pyridine-3-carboxamide Chemical compound CC1=CC=CC(C)=C1NC(=O)C1=CC=CNC1=O WJDDCFNFNAHLAF-UHFFFAOYSA-N 0.000 description 1
- LKQLRGMMMAHREN-YJFXYUILSA-N N-stearoylsphingosine-1-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)[C@H](O)\C=C\CCCCCCCCCCCCC LKQLRGMMMAHREN-YJFXYUILSA-N 0.000 description 1
- 229960000916 Niflumic Acid Drugs 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- 102000008052 Nitric Oxide Synthase Type III Human genes 0.000 description 1
- 108010075520 Nitric Oxide Synthase Type III Proteins 0.000 description 1
- ODKSFYDXXFIFQN-SCSAIBSYSA-N OC(=O)[C@H](N)CCCNC(N)=N Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
- 229940049964 Oleate Drugs 0.000 description 1
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical group N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N Oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 102100018814 PCCA Human genes 0.000 description 1
- 101700074659 PCCA Proteins 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 229960001476 Pentoxifylline Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N Piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 229940069338 Potassium Sorbate Drugs 0.000 description 1
- CHHHXKFHOYLYRE-STWYSWDKSA-M Potassium sorbate Chemical compound [K+].C\C=C\C=C\C([O-])=O CHHHXKFHOYLYRE-STWYSWDKSA-M 0.000 description 1
- OLTAWOVKGWWERU-UHFFFAOYSA-N Proxazole Chemical compound C=1C=CC=CC=1C(CC)C1=NOC(CCN(CC)CC)=N1 OLTAWOVKGWWERU-UHFFFAOYSA-N 0.000 description 1
- 208000003142 Retained Placenta Diseases 0.000 description 1
- 206010038758 Retained placenta or membrane Diseases 0.000 description 1
- 229960000819 Sodium Nitrite Drugs 0.000 description 1
- 229940083618 Sodium Nitroprusside Drugs 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 229960000894 Sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N Sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- 229960004492 Suprofen Drugs 0.000 description 1
- MDKGKXOCJGEUJW-UHFFFAOYSA-N Suprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-UHFFFAOYSA-N 0.000 description 1
- 229940100611 Topical Cream Drugs 0.000 description 1
- 229940100615 Topical Ointment Drugs 0.000 description 1
- 230000036526 Transport Rate Effects 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N Zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- UFUVLHLTWXBHGZ-AVENPWRCSA-N [(2R,3R,4S,5R,6R)-6-[(1S,2R)-2-chloro-1-[[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-AVENPWRCSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002730 additional Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000001174 ascending Effects 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- 229960005149 bendazac Drugs 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 210000004027 cells Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 239000002812 cholic acid derivative Substances 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229950009185 clopirac Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- FHADSMKORVFYOS-UHFFFAOYSA-N cyclooctanol Chemical compound OC1CCCCCCC1 FHADSMKORVFYOS-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 231100000223 dermal penetration Toxicity 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000001079 digestive Effects 0.000 description 1
- 235000019961 diglycerides of fatty acid Nutrition 0.000 description 1
- 230000003292 diminished Effects 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- GIRZNGMZUXTPTL-UHFFFAOYSA-N disodium;iron(3+);nitroxyl;pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].O=N GIRZNGMZUXTPTL-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960005067 ditazole Drugs 0.000 description 1
- 229960001850 droxicam Drugs 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- MMKRHZKQPFCLLS-UHFFFAOYSA-N ethyl myristate Chemical compound CCCCCCCCCCCCCC(=O)OCC MMKRHZKQPFCLLS-UHFFFAOYSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229940067592 ethyl palmitate Drugs 0.000 description 1
- 229960000192 felbinac Drugs 0.000 description 1
- 229960000489 feprazone Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- NOOCSNJCXJYGPE-UHFFFAOYSA-N flunixin Chemical compound C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O NOOCSNJCXJYGPE-UHFFFAOYSA-N 0.000 description 1
- 229960000588 flunixin Drugs 0.000 description 1
- 239000000576 food coloring agent Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229950009183 ibufenac Drugs 0.000 description 1
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 1
- 229960002595 ibuproxam Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-M myristate Chemical compound CCCCCCCCCCCCCC([O-])=O TUNFSRHWOTWDNC-UHFFFAOYSA-M 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960005113 oxaceprol Drugs 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000002085 persistent Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- PZQSQRCNMZGWFT-QXMHVHEDSA-N propan-2-yl (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(C)C PZQSQRCNMZGWFT-QXMHVHEDSA-N 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 229950001856 protizinic acid Drugs 0.000 description 1
- 229960001801 proxazole Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 229950000385 ramifenazone Drugs 0.000 description 1
- 230000000268 renotropic Effects 0.000 description 1
- 230000037335 skin penetration Effects 0.000 description 1
- 239000000050 smooth muscle relaxant Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 229960003676 tenidap Drugs 0.000 description 1
- LXIKEPCNDFVJKC-QXMHVHEDSA-N tenidap Chemical compound C12=CC(Cl)=CC=C2N(C(=O)N)C(=O)\C1=C(/O)C1=CC=CS1 LXIKEPCNDFVJKC-QXMHVHEDSA-N 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N trans-L-hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 230000000304 vasodilatating Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N α-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Abstract
Compositions and methods of the topical treatment of equine laminitis are disclosed. In particular,combinations of a fast acting nitric oxide (NO) donor, a sustained acting NO donor and an NSAID mixed in a lipid-based carrier are described. The application of such combinations to the affected areas, e.g., the hoofs and surrounding tissues, of an equine afflicted with laminitis provides relief from the debilitating effects of this painful, often life-threatening condition.
Description
TREATMENT OF EQUINE LAMINITIS
1. FIELD OF THE INVENTION This invention relates to the treatment 5 of equine laminitis, a very painful condition that affects the blades of an equine. Laminitis particularly affects the area where the hooves attach to the extremities and can lead to collapse or lameness. Without treatment, the condition may lead to the separation of the hoof from the bone and the deterioration of the general health of an equine, including insufficiency of the internal organs and subsequent infection. The invention relates, more particularly, to a composition that can be applied locally in the
hooves of an equine and in the surrounding tissue and which has an unusual curative effect on circulation throughout the area. Therefore, a composition and method is provided to alleviate the unfavorable or negative effects of laminitis
equine.
2. BACKGROUND OF THE INVENTION Equine laminitis, which is sometimes referred to as infosura, is a common disorder that has been
recognized and described even in the first books of veterinary medicine. In an article by Green, M.E. et al., which appeared in Equine Medicine and Surgery,
P13 9 / 99MX Fourth Edition, Vol. II, Colahan, P.T. et al. (Eds.), American Veterinary Publications, Inc. (1991), Chapter 12, p. 1354-1358, laminitis is described as an inflammation of the pedal blades that form the supporting junction between the hoof and the third phalanx. Laminitis is also described as a disorder of the hoof whose cause is varied. This is a multi-systemic, complex disease that affects the digestive, cardiovascular, hemic, renal, endocrine, musculoskeletal, integumentary and immunological systems. It is characterized by multi-systemic abnormalities that ultimately result in reduced capillary perfusion, ischemia and necrosis of the laminae. These results are accompanied by pain and loss of support function. Acute laminitis is described including the events that lead to lameness and its onset. Acute laminitis can progress to the chronic state. The chronic state results after persistent lameness (more than 48 hours) or when the distal phalanx deviates in a perceptible manner. Chronic laminitis is a consequence of some degree of loss of integrity of the digital support sheets. Figure 1 shows a photograph of a horse suffering from the effects of laminitis of the forelimbs. Observe that the horse assumes a recumbent position in which most of the weight is placed on the hind limbs and the pressure produced
P1349 / 99MX for low weight is exerted on the front limbs. There are reports that prove that equine laminitis is caused by the ingestion of too many grains; colic; retained placenta; exhaustion; swallowing castilla walnut shavings; ingestion of too much grass; excessive shaking and / or excessively cold water. Despite the accumulation of a large volume of information over a period of more than 300 years, equine laminitis remains to be fully understood. Although it is possible for an equine that has suffered from this condition. can recover without intervention treatment, during the course of the disease there is considerable pain, recumbent position, deformation of the wall of the hoof and even fall of the hooves. Several symptoms are shown, including: irregular digital pulse, hot feet, abnormal gait, weight variation or a combination of some or all of these. If the animal does not recover, after the lameness begins, the blades deteriorate, the legs of the animal are in extreme pain and the bolillo appears displaced. Sacrificing the animal is then the only humanitarian thing that can be done. Because of the serious consequences of this state, this has been the subject of many and varied treatments over the years. In almost all cases, since the state seems to be a function of a
P1349 / 99MX loss of circulation in the area of the hoof, treatments have been directed to increase the blood supply to the hoof and adjacent tissues and circulation in them. There are several different treatments that are currently used for the care of horses with laminitis. Several different vasodilators have been used in the past to treat this disorder and some of them are still in use. Many of them involve the use of nitroglycerin, which has been applied transdermally. Other methods employ isoxuprine administered orally, also a known vasodilator. Current therapy also includes the use of anticoagulants, such as heparin, aspirin and frental (pentoxifylline). All current therapies suffer from one or more disadvantages, among which - difficulty in the mode of administration of the active drug, lack of efficacy, lack of compliance and lack of simplicity in the proposed treatment regime are included. Katsuki, S. et al., In J. Cyclic Nucleotide
Res. (1977) 3: 23-35, notes that the activity of a variety of smooth muscle relaxants, including sodium nitroprusside, nitroglycerin, and sodium nitrite, may be related to their ability to increase tissue levels. of cyclic guanosine monophosphate (cGMP) or with the formation of nitric oxide (NO). Others
P13 9 / 99MX nitrogen-containing compounds that can also act in the same way, include hydroxylamine or sodium azide. These substances may also have vasodilating properties. These and other nitrogen-containing compounds can then be referred to as "donors" or "precursors" of nitric oxide. It has been shown that vascular endothelial cells synthesize nitric oxide from L-arginine (L-Arg) but not from D-arginine. See, Palmer R.M. J. et al., In Nature (1988) 333: 664-666. This article also describes how the release of NO from endothelial cells induced by bradykinin and the calcium ionophore A23187 is reversibly increased by infusions of L-Arg or L-citrulline. The release of NO through certain cells can be prolonged. Therefore, L-Arg can be considered as a donor or precursor of NO, but because the conversion of L-Arg may not be immediate and may occur over a prolonged period of time, L-Arg can be considered as a NO precursor of "slow action". In the sense in which it is used herein, a "slow-acting" NO precursor can maintain the release of NO in the tissues over the course of a few hours to several hours after the initial exposure to the NO precursor of "slow action" In contrast, a "fast acting" precursor of NO, such as
P13-49 / 99 X Nitroglycerin or nitroprusside, usually provides the almost instantaneous release of detectable f levels of NO in the plasma or tissue (eg, within a few minutes of exposure to the precursor of
NO "quick action" and it lasts several minutes). However, these "quick-acting" agents can quickly deplete. In this manner, a rapid-acting NO donor can be used to provide a burst of NO, whereas a slow-acting NO-NO donor can be used to provide a longer and sustained NO release level. A summary of Hinckley, K. A. et al. that appeared in J. Endocrinol. (1994) 143: P103, illustrates the complexity of the etiology of laminitis. These
authors conclude that the causes of laminitis are derived from multiple factors. These authors speak only of the intravenous administration of L-Arg. In a background editorial in the publication, Equine Vet. J. (1996) 28 (1): 1-2, Elliott, J. analyzes
the merits of the treatment of laminitis with nitric oxide. In this article, it is pointed out that NO was previously known as a relaxation factor derived from the endothelium, a tribute to the fact that this gas is produced continuously by the coating
of the blood vessels as a consequence of the action of an enzyme that is present in the endothelial cells, the endothelial nitric oxide-synthase eNOS.
P13 9 / 99MX It is thought that eNOS is activated by an increase in intracellular calcium concentration, which catalyzes the conversion of L-Arg to NO and citrulline. Nitric oxide passes through biological membranes, binds to heme iron in the soluble enzyme guanylate cyclase (GC). In this way the activity of the GC is stimulated, the cyclic guanosine monophosphate concentrations increase and the tone of the vascular smooth muscle is reduced. In this article there are speculations about the interruption of blood flow to the sensitive blades of the equine paw; that occurs in laminitis, could involve some disturbance in the route of the L-Arg-NO. The subject of the editorial, an article by Hinckley et al. in the > same number, Equine Vet. J. (1996) 28 (1): 17-28, describes a treatment using L-Arg administered intravenously and nitroglycerin (glyceryl trinitrate or GNT) applied locally. The L-Arg is administered intravenously as a 10% aqueous solution, while the GNT is administered as a 10% ointment through a patch that is placed over the digital vessels, using an adhesive strip. In particular, a laminitic poney, weighing 250 kg, received a total dose of 120 g of L-Arg or 0.48 g / kg of body weight in a proportion of approximately 40 mL / min (16 mg / kg body weight / min. for 30 min The GNT patches
P1349 / 99MX were also applied once a day to three limbs only, 12 hours after infusion of L-Arg. With the intravenous infusion, falls in the heart rate were observed, including hypotension and cardiac arrhythmia. Some ponies showed signs of pain, sweating and chills. The topical application of the GTN patches seemed to improve the lameness of some of the ponies that were treated. In others, no improvement was observed. Thus, it is evident that L-Arg administered intravenously is not a particularly effective treatment. The results of the balance of this study are contradictory. In this article there is no suggestion that L-Arg could be administered in a different way than intravenous or that some benefit could be obtained from the subsequent search for a combination treatment. The lecithin organogels are obtained by the addition of a minimum amount of water to a solution of lecithin in organic solvent. Normally, a minimal amount of water is added to lecithin dissolved in organic solvent. See,
Scartazzini, R. and Luisi, P. L., in J. Phys. Chem.
(1988) 92: 829-833. The results of an investigation on the transdermal transport of scopolamine and broxaterol through human skin using a soy lecithin organogel have been described. Willimann, H. et al., In J. Pharmaceutical Sci. (1992) 81 (9): 871-
P1349 / 99MX 874. The transdermal transport rate of scopolamine was found to be approximately one order of magnitude higher with the organogel relative to an aqueous solution of the drug at the same concentration. However, the rate of transport of the drug was not different with the organogel compared to a pre-gelation, microemulsion of the drug (lecithin, organic solvent and drug, but without added water). In the United States Patent No.
4,882,164 issued to Ferro, A. and Steffen, H. an aqueous solution of mixed micelles composed of salts of colic acid and lipids is used for the solubilization of non-steroidal anti-inflammatory drugs (NSAIDs). The salts of the colanic acid include cholates, glycocholates and taurocholates. The lipids include phosphatidylcholines, especially natural and synthetic lecithins. A formulation according to the invention is described as follows: carprofen (50 mg), L-Arg (30 mg), anhydrous glycolic acid (88.5 mg), 40% sodium hydroxide (19 microliters), lecithin for mixed micelles (169 mg), 2N HCl (up to pH 6.0) and injectable water (to complete 100 mL of final volume). The presence of the colanic acid is essential for the composition described. Furthermore, the presence of a NO precursor or a precursor is not considered, considered or suggested.
P13 9 / 99MX vasodilator. • NSAIDs are compounds that are structurally different from steroids and that show anti-inflammatory activity. NSAIDs usually contain a carboxylic acid group and are derivatives of acetic, propionic, butyric, salicylic acid and the like. Subcategories of NSAIDs include aminoarylcarboxylic acids (eg, enfenamine, flufenamic acid, isonixin, niflumic acid and the like), arylacetic acids (eg, acemetacin, alclofenac, amfenac, clopirac, felbinac, fenclofenac, ibufenac, indomethacin, isoxepac, sulindac, zomepirac and the like), arylbutyric acids (for example, bumadizona, fenbufeno, xenbucina and the like), arilcarboxílicos acids (for example, clinadac, ketorolac and the like), arilpropiónicos acids (for example, benoxaprofeno, carprofeno, ibuprofeno, ibuproxam, indoprofen, ketoprofen, naproxen, oxaprozin, protizinic acid, suprofen and the like), pyrazoles, pyrazolones and thiazinecarboxamides. Specific examples of NSAIDs include, but are not limited to, flunixin, epirizol, apazona, feprazone, ramifenazone, droxicam, aspirin, phenylbutazone,. piroxicam, bendazac, ditazol, guayazulene, oxaceprol, proxazole, tenidap and the like or the salts thereof. Therefore, there remains a strong need
P13 9/99 X of an effective treatment for equine laminitis.
3. SUMMARY OF THE INVENTION According to the invention, a topical composition for the treatment of equine laminitis is described comprising a nitric oxide (NO) donor of rapid action, preferably nitroglycerin and a sustained-acting NO donor, preferably L- arginine (L-Arg), dispersed in a vehicle with a lipid base. In a preferred embodiment of the invention, the topical composition further comprises a non-steroidal anti-inflammatory drug (NSAID). The lipid-based carrier preferably comprises a membrane-forming lipid, such as a phosphatidylcholine (for example, natural lecithin, derived from natural, synthetic or semi-synthetic). Preferably, the topical combination is in the form of an ointment, emulsion, cream, gel or foam that allows the supply of the active ingredients the fast-acting nitric oxide donor and the L-Arg via the hoof, skin or both of an affected equine. The invention also relates to a method for the improvement of the adverse effects of equine laminitis. The method, considered widely, consists of administering topically to the affected areas of an equine an effective amount of a nitric oxide (NO) donor of fast action
P1349 / 99MX dispersed in a vehicle with a lipid base. In a preferred embodiment, the method further comprises administering topically to the affected areas an effective amount of a sustained-acting NO donor. With superlative preference, the method even further consists in administering topically to the affected areas an effective amount of a non-steroidal anti-inflammatory drug (NSAID). The aforementioned active ingredients can be administered in any order (for example, successively) or practically in the same time period (i.e., simultaneously). Using the compositions and methods of the invention, it has been surprisingly discovered that topical application directly to the affected areas of an equine suffering from the adverse effects of equine laminitis, usually suffering from extreme pain, lameness, collapse, even partial separation of the hoof of the limb, decreased or inadequate organic function, little appetite and close death, provides amazing results. In particular, treated horses or ponies exhibit notable signs of recovery, including regaining ability to remain standing, improved posture, normal gait, improved appetite, improved and / or stabilized organic function and usually a return to normal activities
P1349 / 99MX The present invention also contemplates a process for the preparation of a combination that can be applied topically to alleviate the adverse effects of equine laminitis, which consists of (a) combining a first mixture comprising at least one alcohol solvent, at least one fast-acting nitric oxide (NO) donor, at least one sustained action NO donor and at least one NSAID with a second mixture comprising at least one membrane-forming lipid and at least one solvent biocompatible organic; (b) mixing with the mixture resulting from step (a) an amount of a third mixture comprising water and an effective surfactant to give a combination having a creamy texture. Therefore, it is a primary object of this invention to provide a new treatment for equine laminitis. It is another object of this invention to provide a novel composition that is suitable for topical application as a treatment for equine laminitis. It is another object of this invention to provide a method for treating laminitis consisting of topically applying an effective amount of a combination or composition that is effective for the treatment of equine laminitis. Other and additional objects will be evident
P1349 / 99MX for those with ordinary skill in the art from a consideration of the general and specific descriptions provided in this specification.
4. BRIEF DESCRIPTION OF THE DRAWINGS OR FIGURES Figure 1 illustrates a poney that suffers from the adverse effects of equine laminitis (recumbent). Figure 2 illustrates the pony of Figure 1 after responding to treatment using the composition and method of the present invention (observe the straight front legs). Figure 3 illustrates the pony of Figure 2 recovered by doing normal activities, such as eating grass, while the weight is distributed in a normal manner on the forelimbs and hind limbs (at 12 weeks of Figure 1).
. DESCRIPTION OF THE PREFERRED MODALITIES 5.1 Glossary Nitric oxide donor (NO) - Any substance that is converted, degraded or metabolized in vivo to nitric oxide or NO or provides a source of it in vivo. A "fast acting" NO donor is a nitric oxide donor that causes in vivo production of NO in affected areas, tissues, hooves, limbs, etc. or around
P1349 / 99MX, of the diseased equine, approximately between one minute and ten minutes after the topical application of the rapid-acting NO donor on the affected areas, tissues, hooves, limbs, etc. of the sick equine A "sustained action" NO donor is a nitric oxide donor that causes the in vivo production of NO in affected areas, tissues, hooves, limbs, etc. or around them, from the diseased equine, approximately between thirty minutes and from a few to several hours (for example, two, four, six or eight hours) from the topical application of the sustained action NO donor on the areas affected, tissues, hooves, limbs, etc. of the sick equine Lipid Base Vehicle - Any vehicle, preferably a pharmacologically acceptable vehicle, which is comprised of lipid or fatty components, especially those having a hydrophobic part and a hydrophilic part and allowing the transdermal transport of an active ingredient from the surface of the body. the skin to the body areas under the skin. Once under the skin, the active ingredient (s) may remain localized in the region (s) or around the same (s) to the (s) that the combination or composition of interest has been applied, which is partially constituted by the base vehicle
Lipid P1349 / 99MX. Alternatively, the active ingredient (s) can be made systemically available. A preferred class of lipids, includes those that form membranes, bilayers, vesicles, liposomes and the like, in particular, biological membranes. Examples of these membrane-forming lipids include non-exclusively phospholipids, glycolipids and cholesterol-like lipids. Preferred lipids include phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, phosphatidyl inositol and the like. Biocompatible Organic Solvent - An organic solvent, typically constituted by fatty acid esters. The fatty acids contain aliphatic saturated or unsaturated long chain groups having about 8-50 carbon atoms, preferably about 12-30 atoms, more preferably about 14-24 carbon atoms, preferably superlative about between 16 and 18 carbon atoms. Examples of fatty acids include lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, palmitoleic, oleic, linoleic, linolenic, arachidonic and the like. The alcohol moiety of the ester group is usually a linear or branched lower alkyl group containing between about 1 and 8 carbon atoms. Examples of the alcohol portion
P1349 / 99MX include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, pentanol, isopentanol, hexanol, heptanol, octanol, isooctanol, cyclooctanol and the like. Accordingly, preferred esters include non-exclusive ethyl palmitate, ethyl myristate, ethyl oleate, isopropyl palmitate, isopropyl myristate, isopropyl oleate and the like. Other biocompatible organic solvents may include isooctane and cyclooctane. Second Aliphatic Organic Solvent Containing Hydroxy Group - An organic solvent containing a hydroxyl group, which includes in a non-exclusive manner those described in the previous paragraph in relation to the "alcohol portion of the ester group". Surfactant - Any surfactant or surfactant that decreases surface tension when dissolved in water or aqueous solutions or that decreases the interfacial tension between two liquids or between a liquid and a solid. Suitable surfactants for use in the present invention include ionic and nonionic detergents, dispersing agents, wetting agents, emulsifiers and the like. Examples of surfactants include, but are not limited to, the sodium salt of N- (alkylsulfonyl) glycine (EMULSIFIER STH), the salts of linear alkyl sulfonates (LAS),
P1349 / 99MX the alkyl benzene sulphonate salts (ABS), the sodium dodecyl sulfate salt (SDS), a nonionic series of 28 related difunctional block polymers terminating with primary hydroxyl groups with molecular weights ranging from about 1,000 to about 15,000, polyoxyalkylene derivatives of propylene glycol (PLURONIC) and the like. The surfactant employed in the present invention is preferably pharmaceutically acceptable and biodegradable.
. 2 Topical Composition As described above, the present invention is directed to a topical composition for the treatment of equine laminitis. In a particular embodiment of the invention, the topical composition comprises a fast-acting nitric oxide (NO) donor and a sustained-acting NO donor. In a preferred embodiment, the topical composition further comprises a non-steroidal anti-inflammatory drug (NSAID). To maximize the efficacy of the topical composition of the present invention, the active ingredients, such as nitroglycerin, L-Arg and ketoprofen (a fast-acting NO donor, a sustained-acting NO donor and an NSAID, respectively) are dispersed , optionally with other active and non-active ingredients, thickeners, emollients, fillers, etc., are dispersed in a vehicle
P1349 / 99MX
of lipid base. The lipid-based carrier is preferably a membrane-forming lipid, such as phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, phosphatidyl ethanolamine or the like. The preferred membrane lipid comprises lecithin as described above. Accordingly, in a particular embodiment of the invention, the lipid base carrier comprises at least one membrane-forming lipid, at least one first biocompatible aliphatic organic solvent, at least one second aliphatic organic solvent containing the hydroxyl group which it contains between 1 and 8 carbon atoms and at least one surfactant. Typically, phospholipids suitable for the present invention are derived from glycerol (eg, a phosphoglyceride), sphingosine or other simple or complex alcohols, among which non-exclusively include serine, glucose, galactose, ethanolamine, choline, inositol, Mannitol and the like. The fatty acid portion of the lipid may typically comprise between about 14 and 24 carbon atoms, more typically between about 16 and 18 carbon atoms, in particular, palmitate, oleate and myristate. Preferred lipids include sphingomyelin, cerebroside, cholesterol, cholic acid or phosphatidyl choline,
P1349 / 99MX phosphatidyl ethanolamine and the like. More preferably, the lipid base vehicle is constituted by lecithin either natural, derived from natural, synthetic or semi-synthetic. A pure lecithin is made up of phosphatidyl choline. For example, lecithins are mixtures of diglycerides of fatty acids attached to the choline ester and phosphoric acid. Lecithins can also be classified as phosphatides, as well as phosphoglycerides. A quick-acting NO donor according to the invention can be selected from nitroglycerin, hydroxylamine, a nitrite, a nitroprusside, an azide or a salt thereof The sustained-acting NO donor according to the invention can be selected in turn from L- Arg, derivatives thereof, analogs thereof and the like Particular NSAIDs suitable for use in the present invention include derivatives of acetic acid, propionic acid, butyric acid, salicylic acid and the like. an aminoarylcarboxylic acid, arylcarboxylic acid, arylacetic acid, arylpropionic acid, arylbutyric acid, pyrazoles, pyrazolones, thiazinecarboxyamides and the like, preferably superlatively, the selected NSAID is ketoprofen, ibuprofen or naproxen, additional NSAIDs described above in Section of Background.
P1349 / 99MX In a preferred embodiment of the invention, the topical composition comprises between about 0.5% and 3% by weight of nitroglycerin and about between 6 and 20% by weight of L-Arg, based on the weight of the total composition. More preferably, the topical composition comprises between about 1.0 and 2.4% by weight of nitroglycerin and about between 10 and 15% by weight of L-Arg, based on the weight of the total composition. In yet another embodiment, the topical composition comprises approximately between 5 and 16% by weight of nitroglycerin, based on the weight of L-Arg present in the total composition, more preferably between about 7 and 8% by weight of nitroglycerin, with based on the weight of L-Arg present in the total composition. When the topical combination includes an NSAID, the NSAID is preferably present in an amount of up to about 10% by weight, based on the weight of the total combination. Other active ingredients, which are also present in the topical combination, include analgesics, topical anesthetics and the like. As described above, the topical composition of the invention can come in any form, but preferably as an ointment, emulsion, cream, gel or foam. However, what is important is that the lipid-based vehicle allows the distribution of the fast-acting nitric oxide donor, from the L-
P1349 / 9-9MX Arg and other major active ingredients through the hoof, skin or both of an affected equine. In a specific embodiment of the invention, the lipid base carrier further comprises at least one pharmaceutically acceptable alcohol. Therefore, in a particular embodiment, a topical composition for the improvement of the negative effects of equine laminitis comprising at least one nitric oxide (NO) donor of rapid action, L-Arg and at least one dispersed NSAID is provided. in a lipid-based carrier comprising at least one membrane-forming lipid, at least one first biocompatible aliphatic organic solvent containing between 8 and 50 carbon atoms, at least one second aliphatic organic solvent containing the group hydroxyl containing between 1 and 8 carbon atoms.
. 3 TOPICAL ADMINISTRATION The present invention is directed to a method for alleviating or ameliorating the adverse or negative effects of equine laminitis. In general, the desired method comprises administering topically to the affected areas of an equine an effective amount of a fast-acting nitric oxide (NO) donor dispersed in a lipid base vehicle. Other methods, mentioned in ascending order of convenience,
P1349 / 99MX include topical administration to the affected areas of an effective amount of a sustained-acting NO donor and also topical administration to the affected areas of an effective amount of a nonsteroidal anti-inflammatory drug (NSAID). Preferably, a topical composition containing a fast acting NO donor, a sustained action NO donor and an NSAID is applied daily for a period of at least a few weeks (e.g., at least about a week, two weeks, three weeks or four weeks) and a few months (for example, at least approximately one month, two months or three months) to the affected areas of the equine. However, it is important to note that each of the main active ingredients can be administered topically in successive or more or less simultaneous manner. Also, the topical composition can be applied once a day or more than once, for example, twice a day or as many as necessary. The daily dose of the fast-acting NO donor ranges from about 0.165 to 0.7 mg / kg of the equine, preferably between about 0.2 and 0.5 mg / kg of the equine, preferably superlatively between about 0.3 and 0.4 mg / kg of the equine. In a specific embodiment of the invention, the dose of the rapid-acting NO donor is approximately 0.33 mg / kg of the equine. The daily dose
P1349 / 99MX of the sustained-acting NO donor varies between about 4 and 9 mg / kg of the equine, preferably between about 5 and 8 mg / kg of the equine, preferably superlatively between about 6 and 7 mg / kg of the equine. The daily dose of the NSAID varies between approximately 1.4 and 3.2 mg / kg of the equine, preferably between approximately 1.7 and 3.0 mg / kg of the equine and preferably superlative between approximately 2.0 and 2.8 mg / kg of the equine. When the fast-acting NO donor comprises nitroglycerin and the sustained-action NO donor comprises L-Arg, the preferred doses vary between about 0.3 and 0.4 mg / kg of the equine and between about 6.5 and 7 mg / kg of the equine, respectively . In a specific embodiment of the invention there is provided a method for improving the adverse effects of equine laminitis which consists in administering topically at least once a day to the affected areas of an equine an effective amount of a combination comprising at least a fast-acting NO donor, L-Arg and at least one NSAID in a lipid-based vehicle; and continue the administration of that combination until the equine shows signs of recovery. These signs of recovery include, but are not limited to: regaining the ability to stand, improved posture,
P1349 / 99MX normal pace, improved appetite or improved or stabilized organic function. Other signs can still be obtained from blood tests performed on the affected horse, which includes: horse, pony, donkey, donkey, zebra and the like. For example, the blood test could show normal levels of creatinine or blood urea nitrogen, where these levels would be elevated in diseased horses.
. 4. The Process of Preparing Composition
Topical The present invention is also directed to a process for the preparation of a combination, which can be applied topically to alleviate the adverse effects of equine laminitis. In particular, the combination or topical composition is first obtained by preparing a first mixture comprising at least one alcoholic solvent, at least one nitric oxide (NO) donor of rapid action, at least one NO donor of sustained action and at least one NSAID. A second mixture is then prepared, comprising at least one membrane-forming lipid and at least one bmpatible organic solvent. The first and second mixtures are then combined by mixing, preferably at or slightly below room temperature. To the resulting mixture, which contains
P1349 / 99MX main active ingredients (eg, fast acting NO donor, sustained action NO donor, optionally with an NSAID), an amount of a third mixture comprising water and a surfactant is added, such amount is effective for Provide a combination that has a creamy texture. The preferred surfactant is PLURONIC.
. 5 Most General Aspects of the Preferred Modalities As stated above, in general, the contemplated composition of this invention comprises a combination of L-Arg and nitroglycerin prepared in advance in a suitable form in the form of cream or ointment. This can also be used in the form of a foam. Suitable foams, ointments and creams of therapeutic compositions that are applied topically are available in the art. Specifically, the topically applied compositions of this invention comprise the above-mentioned active ingredients and further comprise non-active components, such as a suitable vehicle, which may be water-based or organic-based or a combination of both. An ingredient in compositions that are intended for topical application, can be a material that helps make the active ingredients
P1349 / 99 X pass through the dermal layer to allow subcutaneous attack of the condition that is sought to be improved. These dermal layer penetration aids, which have been found useful in this invention, include membrane-forming lipids and alcohols, in particular, water-soluble alcohols and other reciprocal solvents which make the active ingredients normally insoluble in water have solubility. in increased water and therefore increased skin penetration. Ethanol is one of those suitable materials and is the dermal penetration aid material of choice since it is readily available, inexpensive and pharmaceutically acceptable. Ethanol is also the preferred solvent for dissolving the main active ingredients of the present topical compositions for incorporation into the lipid base vehicle. Another common constituent of the topically applicable compositions is an emollient. Isopropyl palmitate is an example of these emollient materials. Other materials of these are well known in this technique and will be evident to those with ordinary skills. Surfactants are common ingredients in creams and ointments for
• transdermal medication supply. It is considered that the nonionic, cationic and anionic surfactants
P1349 / 99MX are suitable for use in the preparation of the topically applied composition of this invention. A suitable surfactant is a commercially available material marketed under the trade name PLURONIC. Others will be known to the person with ordinary skills in this field of technique. It is considered to be within the scope of this invention to provide additional therapeutic agents in the composition that is applied topically herein to treat specific conditions that often accompany equine laminitis. This state is painful. Therefore, it is appropriate to include topical anesthetics in the compositions of the invention. Topical analgesics are also suitable constituents. NSAIDs, such as ketoprofen and naproxen, are useful additions to the cream and / or ointment compositions of this invention. In addition, the thickening agents are a useful part of the compositions of this invention. Hydroxymethyl or hydroxyethyl cellulose can be used as thickening agents. It is known that creams and ointments require a combination of ingredients to balance the physical properties and act as an efficient vehicle and delivery system for the drugs that are incorporated herein. If the composition that is applied topically of this
P1349 / 99MX invention is prepared in the form of a foam, it is suitable to include conventional pharmaceutically acceptable foaming agents in the product. It has been found that butane, propane, pentane and mixtures thereof are suitably useful. These gases are relatively inert materials that have been used in the past to make foams and which will be useful in the invention. Suitably, the volatile compound, such as a light hydrocarbon or carbon dioxide, is incorporated into the composition of this invention in a pressurized container, such as a conventional aerosol can. When the composition is released, the light hydrocarbon foaming agent expands and converts the composition of this invention into a foam for topical application. The active ingredients of the topically applicable compositions of this invention, illustrated by nitroglycerin and L-Arg, are suitably used in amounts between about 0.5 and 3% by weight of nitroglycerin and between about 5 and 25% by weight of L-Arg, with base on the weight of the total composition. It is preferred to use between about 1 and 2.5% by weight of the nitroglycerin and between about 15 and 20% by weight of the L-Arg. The weight ratio of the fast acting NO donor to the sustained action NO donor ranges from about 1: 5 to 1:50 for the total composition. It is preferably used between
P1349 / 99MX approximately 2 and 10% by weight of NSAID, preferably between approximately 4 and 8%, based on I the weight of the total composition. Therefore, the weight ratio of the NSAID with respect to the 5 NO sustained action donor varies between approximately 1: 1.5 and 1: 5. The total amount of main active ingredients may vary between about 7.5 and 45% by weight, preferably between about 15 and 35%, preferably superlative between about
20 and 30%, based on the total composition. The ointment or ointment or lotion or foam to be applied topically, suitably contains up to about 23% by weight of the specific combination of nitroglycerin active ingredients and
L-Arg, based on the total weight of the completely formulated topical composition, preferably up to about 16% by weight, preferably superlative to about 14% by weight. As indicated above, the composition
The topically applicable Applicant of this invention comprises a combination of a fast-acting NO donor, such as nitroglycerin, azide, hydroxylamine and the like and a slower and more sustained NO donor, such as L-Arg, in the proportions stated.
above. When this effective composition is in the form of a cream or an ointment, the other conventional components of the cream or the ointment include a
P1349 / 99MX vehicle, such as water or petroleum solvents, which will be the main ingredient of the composition if considered based on weight or volume. This vehicle or solvent will be present in the composition in amounts between about 40 and 90 percent by weight of the entire composition, preferably between about 60 and 85 percent, more preferably between about 70 and 80 percent by weight. Emollients such as lecithin or the like are used in a proportion of up to about 10 weight percent based on the weight of the total composition. Conventional flavors such as perfumes and colorants, such as food colorants, may be used in their conventional proportions, for conventional purposes. The proportion of carrier materials, such as water or a mixture of water and an organic solvent, for example, an alcohol, will be in the conventional amount that will make a uniformly applied cream or ointment that remains on the dermal surface for a "sufficient time to allow that practically all the active ingredients leave the topical application composition and enter into an active relationship with the blood vessels of the horse's hooves.Nitroglycerin and L-Arg have been
P1349 / 99MX specified as the active ingredients of the compositions of this invention. It will be understood that nitroglycerin is a fast-acting NO donor, an immediate vasodilator, whereas L-Arg must first be converted to NO before it becomes effective. Therefore, L-Arg has a more sustained release. It is believed that other sources of immediate and sustained release NO are effective to combat equine laminitis by a topically applied composition comprising combinations described herein. Described herein are compounds that appear to be comparable with nitroglycerin and L-Arg, with respect to having a known tendency to release NO either rapidly / immediately or slowly / sustained, respectively. Others may be apparent to people with ordinary skills in this field of technology given the descriptions provided here. In this way, other vasodilators, such as isoxuprine or nitroprusside can replace nitroglycerin. Other NSAIDs can replace ketoprofen, such as phenylbutazone, aspirin, flurixin, ibuprofen, and naproxen. Considering the description presented here, the materials releasing slow / sustained NO, which have activity similar to L-Arg, will also be evident for those with ordinary skill in the art.
P1349 / 99MX It has been found and is another aspect of this invention that the transdermal transport of pharmaceutically active components, such as the NO donors of this invention, can be considerably improved. The active ingredients, which is nitroglycerin, L-Arg or any of them, plus NSAIDs, are first dissolved in ethanol or some other pharmaceutically acceptable solvent. Preferably this solvent is also compatible with water. This solution containing active ingredient is then converted to the topical cream or ointment by mixing or combining with a lipid, surfactant, biocompatible organic solvent, water, thickeners, emollients, surfactants and / or other conventional ingredients of a cream, an ointment or a foam. . The resulting topical composition is then applied to an affected part of the dermal layer, such as the hooves of a horse and the tissues surrounding them. The improving effect of the cream of the invention, prepared in this way, is completely dramatic and is further illustrated with the Examples given below.
6. Examples The following are illustrative of the compositions and methods contemplated by the present invention.
P1349 / 99MX 6.1. Preparation of PLURONIC Reserve Solution Potassium sorbate (NF, 0.3 g) and PLURONIC F127 (NF, 20 g and available from PCCA, Houston, TX) are combined with water (q.s., for a volume of 100 mL). The resulting 20% PLURONIC stock solution can be kept refrigerated. Reserve solutions can also be prepared at thirty percent (30%) and forty percent (40%) using 30 g and 40 g of PLURONIC F127, respectively.
6. 2. Preparation of Mixtures of
Lipid / Biocompatible solvent Soy lecithin (granular, 100 g) and sorbic acid (NF-FCC powder, 0.66 g) are dispersed in isopropyl palmitate (NF, 100 g or approximately 117 mL). The mixture is left to rest overnight to give a liquid with syrup consistency. Other organic solvents may be used in place of isopropyl palmitate while dissolving the lecithin (eg, commercial grade egg or soy lecithin). Examples of other suitable organic solvents include, in non-exclusive form, isopropyl myristate (preferably, cosmetic grade) or cyclooctane.
6. 3. Preparation of Lecithin PLURONIC Gel
P1349 / 99MX A pluronic lecithin gel can be prepared by combining soy lecithin (granular, 10 g) with acid
SORBIC (NF-FCC powder, 0.3 g) in isopropyl palmitate (NF, 10 g or 11.7 mL). The mixture is left
Rest overnight to give a syrup-like liquid. Sufficient amount of 20% pluronic stock solution is then added to the syrup to bring the final volume to 100 mL. L-Arg (25 g) is added to the resulting pluronic lecithin gel,
^^ 10 nitroglycerin (0.8 g) and indomethacin (10 g). The resulting mixture is mixed vigorously. Alternatively, 52 g of soy lecithin / isopropyl palmitate solution are mixed with 19 g of 20% pluronic stock solution. To this mixture is added ethoxy diglycol (2 g), purified water (27 g), L-Arg (15 f B), -OPIO (8 g) and nitroglycerin < _.- g,. The resulting mixture is mixed vigorously until a creamy consistency is obtained.
6.4. Preparation of Transdermal Cream Lecithin (10 g) dispersed in isopropyl myristate (10 g) is combined with a solution comprising L-Arg (15 g), ketoprofen (6 g) and nitroglycerin (1.2 g) dissolved in ethanol (10 mL) ). TO
This mixture is added an aqueous mixture of pluronic (20 g) in water (q.s., 120 g). The combined ingredients are mixed until a consistency is obtained
P1349 / 99MX creamy The resulting cream can be applied topically directly to the hoof and surrounding tissue of an equine, eg, a horse, to provide a treatment that alleviates the negative effects of equine laminitis: Other suitable formulations are provided below:
P1349 / 99MX Ingredients Quantities in grams Ex emp1o No 2 3 4 5 6
L-Arg 25 25 15 25 25 15 ketoprofen 10 5 6 5 10 6 ethanol (mL) 20 20 10 20 10 10 lecithin 10 10 10 10 10 10 pluronic 20 20 20 20 20 20 nitroglycerin 0.6 1.2 1.2 1.0 1.2 2.4 palmitate of 10 10 10 10 10 10 isopropyl water, qs (total g) 120 120 120 120 120 120
Other NSAIDs, such as naproxen, ibuprofen and the like, can be used instead of ketoprofen. Other fast-acting NO precursors, such as nitroprusside, hydroxylamine and the like, can be used instead of nitroglycerin. Instead of isopropyl palmitate, other biocompatible organic solvents can be used, such as isopropyl myristate, cyclooctane, isooctane and the like.
6. 5. Use of Transdermal Cream in a Laminating Pony A prostrate pony (lying down, unable to stand) is treated three times a day with approximately 5 g of transdermal cream of Example 3
P1349 / 99MX of Section 6.4, above. The third phalanx or P-3 is observed through the plant on both legs of the pony. The cream is applied daily to the coronary band and to the area at the tip of the P-3 for a period of three to four weeks. Approximately in week 3, the pony has the ability to accept nailed soles and stay upright. This improvement is remarkable given the initial broken position of the pony. At the end of the fourth week, the pony is walking freely and eating normally. A horse, shown in Figure 1, is showing a recumbent position because of pain associated with laminitis of the forelimbs. This horse is tested for liver and kidney function (eg, creatinine levels, blood urea nitrogen (BUN)). Blood tests show very diminished organic function (ie, high levels of creatinine and BUN). After one month of treatment using the transdermal cream of Example 3 of Section 6.4, the horse has the ability to stand upright (See, Figure 2) and move in a normal manner (See, Figure 3). Tests of organic function performed after the treatment period confirm that the horse's organs have returned to normal or near-normal function. It must be obvious to someone with skills
P1349 / 99MX ordinary in the art that can easily be contemplated other modalities considering the teachings of the present description. These other modalities, although not specifically set forth, however, fall within the scope and spirit of the present invention. Thus, the present invention should not be construed as limited to the specific embodiments described above, the invention is limited only by the claims below.
P1349 / 99MX
Claims (35)
- NOVELTY OF THE INVENTION Having described the present invention, it is considered a novelty and, therefore, the content of the following CLAIMS i 1. A topical composition for the treatment of equine laminitis comprising an oxide donor is claimed as property. fast-acting nitrate (NO) and L-arginine (L-Arg) dispersed in a lipid-based vehicle.
- 2. The composition according to claim 1, further comprising a non-steroidal anti-inflammatory drug (NSAID).
- 3. The composition according to claim 1, wherein the lipid base vehicle comprises a membrane forming lipid.
- 4. The composition according to claim 3, wherein the membrane forming lipid comprises phosphatidyl choline. The composition according to claim 4, wherein the phosphatidylcholine comprises a natural or synthetic lecithin. The composition according to claim 1, wherein the lipid base carrier comprises at least one membrane-forming lipid, at least one first biocompatible aliphatic organic solvent containing between 8 and 50 carbon atoms, at least P1349 / 99MX a second aliphatic organic solvent containing the hydroxyl group containing between 1 and 8 carbon atoms and at least one surfactant. The composition according to claim 1, wherein the rapid-acting NO donor is selected from the group consisting of nitroglycerin, hydroxylamine, a nitrite, a nitroprusside, an azide or salts thereof. The composition according to claim 2, wherein the NSAID is derived from acetic acid, propionic acid, butyric acid or salicylic acid. The composition according to claim 2, wherein the NSAID is derived from an aminoarylcarboxylic acid, arylcarboxylic acid, arylacetic acid, arylpropionic acid, arylbutyric acid, pyrazoles, pyrazolones or thiazinecarboxamides. The composition according to claim 2, wherein the NSAID is selected from the group consisting of ketoprofen, ibuprofen or naproxen. The composition according to claim 1, comprising between about 0.5 and 3% by weight of nitroglycerin and between about 5 and 25% by weight of L-Arg, based on the weight of the total composition. The composition according to claim 1, comprising between about 1 and 2.5% nitroglycerin and between about 15 and 20% by weight of L-Arg, based on the weight of the total composition. P1349 / 99MX 13. The composition according to claim 1, comprising a fast acting NO donor and a sustained acting NO donor in a weight ratio ranging from about 1: 5 to 1:50 for the total composition. The composition according to claim 2, which further comprises up to about 10% by weight of a non-steroidal anti-inflammatory drug (NSAID), based on the weight of the total composition. 15. The composition according to claim 2, comprising a NSAID and a sustained acting NO donor in a weight ratio between about 1: 1.5 and 1: 5 for the total composition. 16. The composition according to claim 1 which is an ointment, emulsion, cream, gel or foam. The composition according to claim 16 which allows the delivery of the fast-acting nitric oxide donor and the L-Arg via the hoof, skin or both of an affected equine. 18. A method for improving the adverse effects of equine laminitis comprising topically administering to the affected areas of an equine an effective amount of a fast-acting nitric oxide (NO) donor dispersed in a vehicle of lipid base. 19. The method according to claim 18 which further comprises topically administering to the P1349 / 99MX affected an effective amount of a sustained action NO donor. The method according to claim 19 further comprising topically administering to the affected areas an effective amount of a non-steroidal anti-inflammatory drug. (NSAID). 21. The method according to claim 19 wherein the donor. of NO of fast action and the donor of NO of sustained action are administered topically in successive way. 22. The method according to claim 19 wherein the fast acting NO donor and the sustained action NO donor are administered topically simultaneously. 23. The method according to claim 19 wherein the fast acting NO donor comprises nitroglycerin and the sustained acting NO donor comprises L-Arg. The method according to claim 20 wherein the NSAID is derived from an aminoarylcarboxylic acid, arylcarboxylic acid, arylacetic acid, arylpropionic acid, arylbutyric acid, pyrazoles, pyrazolones or thiazinecarboxamides. 25. The method according to claim 18 in which it is applied daily for at least about one week, two weeks, three weeks or four weeks. P1349 / 99MX 26. The method according to claim 18 in which it is applied daily for at least about one month. 27. The method according to claim 19 in which it is applied daily for at least about one month. 28. The method according to claim 20 in which it is applied daily for at least about one month. 29. The method according to claim 18 wherein the lipid base carrier comprises at least one membrane forming lipid, at least one thickening agent, at least one emollient and at least one surfactant. 30. The method according to claim 18 wherein the lipid base carrier further comprises at least one pharmaceutically acceptable alcohol. 31. A topical composition for improving the negative effects of equine laminitis comprising at least one fast-acting nitric oxide (NO) donor, L-Arg and at least one NSAID dispersed in a lipid-based carrier comprising at least one membrane-forming lipid, at least one first biocompatible aliphatic organic solvent containing between 8 and 50 carbon atoms, at least one second aliphatic organic solvent comprising the hydroxyl group containing between 1 and 7 carbon atoms; P1349 / 99MX carbon and at least one surfactant. 32. A method for improving the adverse effects of equine laminitis comprising administering topically at least once a day to the affected areas of an equine an effective amount of a combination comprising at least one fast acting NO donor, L-Arg and at least one NSAID in a vehicle of lipid base; and continue the administration of the combination until the equine shows signs of recovery. 33. The method according to claim 32, wherein the signs of recovery include regaining the ability to stand up, improved posture, normal pace, improved appetite, improved or stabilized organic function. 34. The method according to claim 33, wherein a blood test shows normal levels of creatinine and blood urea nitrogen. 35. A process for the preparation of a combination, which can be applied topically to alleviate the adverse effects of equine laminitis, comprising: (a) combining a first mixture comprising at least one alcohol solvent, at least one donor fast acting nitric oxide (NO), at least one sustained action NO donor and at least one NSAID with a second mixture comprising P1349 / 99 X at least one membrane forming lipid and at least one biocompatible organic solvent; (b) mixing with the mixture resulting from step (a) an amount of a third mixture comprising water and an effective surfactant to give a combination having a creamy texture. P1349 / 99MX
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08752415 | 1996-11-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99005262A true MXPA99005262A (en) | 2000-06-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5891472A (en) | Treatment of equine laminitis | |
US10898489B2 (en) | Treatment of erectile dysfunction and other indications | |
US6368618B1 (en) | Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs | |
EP0672422B1 (en) | Antiinflammatory and analgesic transdermal gel containing Ketoprofen | |
US5869529A (en) | Topical preparation for the prevention and treatment of lesions and sores associated with a herpes virus | |
AU765251B2 (en) | O/W emulsion comprising an hydroxylated oil | |
JPH0578241A (en) | Topical hydrophilic medicinal composition containing ketoprofen lysine salt | |
DK175621B1 (en) | Preparations with improved penetration | |
JP4387639B2 (en) | Transdermal absorption preparation | |
EP2515865A2 (en) | Cutaneous composition comprising vitamin d analogue and a mixture of solvent and surfactants | |
WO2011076209A2 (en) | Pharmaceutical composition comprising solvent mixture and a vitamin d derivative or analogue | |
CZ302649B6 (en) | Pharmaceutical formulation comprising cyclosporine and use thereof | |
Belgamwar et al. | Pluronic lecithin organogel | |
Usmania et al. | Minoxidil emulgel for androgenic alopecia: A literature review including patents | |
EP0853476B1 (en) | Pharmaceutical preparation containing nimesulide for topical use | |
AU2019306705A1 (en) | Medicinal preparation for external use | |
MXPA99005262A (en) | Treatment of equine laminitis | |
US20050002868A1 (en) | Method of treatment of a female suffering from androgen insufficiency | |
JP2001151668A (en) | Percutaneous absorbefacient | |
US20050159490A1 (en) | Method to treat chronic heart failure and/or elevated cholesterol levels | |
JP2022523208A (en) | Pharmaceutical composition for use in the treatment of pain | |
AU2012201048B2 (en) | Transdermal delivery of beneficial substances effected by a hostile biophysical environment | |
EP0787490A1 (en) | A topical preparation for the prevention and treatment of lesions and sores associated with a herpes virus | |
KR19980083942A (en) | Analgesic anti-inflammatory solution |