CA2672024C - Compositions for the reversal and detoxification of anesthetics and other compounds and methods of their use - Google Patents
Compositions for the reversal and detoxification of anesthetics and other compounds and methods of their use Download PDFInfo
- Publication number
- CA2672024C CA2672024C CA2672024A CA2672024A CA2672024C CA 2672024 C CA2672024 C CA 2672024C CA 2672024 A CA2672024 A CA 2672024A CA 2672024 A CA2672024 A CA 2672024A CA 2672024 C CA2672024 C CA 2672024C
- Authority
- CA
- Canada
- Prior art keywords
- particles
- toxin
- liquid composition
- compounds
- reversed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003193 general anesthetic agent Substances 0.000 title claims abstract description 27
- 239000000203 mixture Substances 0.000 title claims description 101
- 150000001875 compounds Chemical class 0.000 title claims description 72
- 229940035674 anesthetics Drugs 0.000 title claims description 9
- 238000000034 method Methods 0.000 title abstract description 28
- 238000001784 detoxification Methods 0.000 title description 9
- 239000002245 particle Substances 0.000 claims abstract description 203
- 239000003053 toxin Substances 0.000 claims abstract description 164
- 231100000765 toxin Toxicity 0.000 claims abstract description 161
- 239000006185 dispersion Substances 0.000 claims abstract description 85
- 239000003814 drug Substances 0.000 claims abstract description 67
- 229940079593 drug Drugs 0.000 claims abstract description 65
- 239000007788 liquid Substances 0.000 claims abstract description 48
- 239000003589 local anesthetic agent Substances 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 77
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 61
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 44
- 238000005192 partition Methods 0.000 claims description 43
- 229930003799 tocopherol Natural products 0.000 claims description 38
- 239000011732 tocopherol Substances 0.000 claims description 38
- 235000010384 tocopherol Nutrition 0.000 claims description 36
- 229960001295 tocopherol Drugs 0.000 claims description 36
- 239000000463 material Substances 0.000 claims description 35
- 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 35
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims description 34
- 229960003150 bupivacaine Drugs 0.000 claims description 34
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 31
- 150000002632 lipids Chemical class 0.000 claims description 29
- 229960004134 propofol Drugs 0.000 claims description 29
- 230000002209 hydrophobic effect Effects 0.000 claims description 28
- -1 opiates Substances 0.000 claims description 22
- 229940087168 alpha tocopherol Drugs 0.000 claims description 21
- 229960000984 tocofersolan Drugs 0.000 claims description 21
- 235000004835 α-tocopherol Nutrition 0.000 claims description 21
- 239000002076 α-tocopherol Substances 0.000 claims description 21
- ZPUCINDJVBIVPJ-LJISPDSOSA-N ***e Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 20
- 239000003833 bile salt Substances 0.000 claims description 17
- CDOSHBSSFJOMGT-UHFFFAOYSA-N linalool Chemical compound CC(C)=CCCC(C)(O)C=C CDOSHBSSFJOMGT-UHFFFAOYSA-N 0.000 claims description 16
- 239000004094 surface-active agent Substances 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 15
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims description 12
- 230000003444 anaesthetic effect Effects 0.000 claims description 10
- 229960003920 ***e Drugs 0.000 claims description 10
- HGASFNYMVGEKTF-UHFFFAOYSA-N octan-1-ol;hydrate Chemical compound O.CCCCCCCCO HGASFNYMVGEKTF-UHFFFAOYSA-N 0.000 claims description 10
- 239000001490 (3R)-3,7-dimethylocta-1,6-dien-3-ol Substances 0.000 claims description 9
- 239000000872 buffer Substances 0.000 claims description 9
- 229960001690 etomidate Drugs 0.000 claims description 9
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 9
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 claims description 8
- 229940093761 bile salts Drugs 0.000 claims description 8
- CDOSHBSSFJOMGT-JTQLQIEISA-N (R)-linalool Natural products CC(C)=CCC[C@@](C)(O)C=C CDOSHBSSFJOMGT-JTQLQIEISA-N 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 7
- 229930007744 linalool Natural products 0.000 claims description 7
- 239000002798 polar solvent Substances 0.000 claims description 7
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 6
- 229960002903 benzyl benzoate Drugs 0.000 claims description 6
- 229960004194 lidocaine Drugs 0.000 claims description 6
- 238000001179 sorption measurement Methods 0.000 claims description 6
- AURFZBICLPNKBZ-YZRLXODZSA-N 3alpha-hydroxy-5beta-pregnan-20-one Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-YZRLXODZSA-N 0.000 claims description 5
- AURFZBICLPNKBZ-UHFFFAOYSA-N Pregnanolone Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 AURFZBICLPNKBZ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 229940049706 benzodiazepine Drugs 0.000 claims description 5
- 229950007402 eltanolone Drugs 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 5
- DUHUCHOQIDJXAT-OLVMNOGESA-N 3-hydroxy-(3-α,5-α)-Pregnane-11,20-dione Chemical compound C([C@@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1=O DUHUCHOQIDJXAT-OLVMNOGESA-N 0.000 claims description 4
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 claims description 4
- 229960005274 benzocaine Drugs 0.000 claims description 4
- 229960003299 ketamine Drugs 0.000 claims description 4
- 229960003305 alfaxalone Drugs 0.000 claims description 3
- 229940125717 barbiturate Drugs 0.000 claims description 3
- 150000001557 benzodiazepines Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 230000000147 hypnotic effect Effects 0.000 claims description 3
- 229960002409 mepivacaine Drugs 0.000 claims description 3
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 claims description 3
- 229940127240 opiate Drugs 0.000 claims description 3
- 239000003381 stabilizer Substances 0.000 claims 6
- VTUSIVBDOCDNHS-UHFFFAOYSA-N Etidocaine Chemical compound CCCN(CC)C(CC)C(=O)NC1=C(C)C=CC=C1C VTUSIVBDOCDNHS-UHFFFAOYSA-N 0.000 claims 2
- KCLANYCVBBTKTO-UHFFFAOYSA-N Proparacaine Chemical compound CCCOC1=CC=C(C(=O)OCCN(CC)CC)C=C1N KCLANYCVBBTKTO-UHFFFAOYSA-N 0.000 claims 2
- XWYBFXIUISNTQG-VKMGZQQJSA-N alfadolone Chemical compound C1[C@H](O)CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CC[C@H]21 XWYBFXIUISNTQG-VKMGZQQJSA-N 0.000 claims 2
- 229940035676 analgesics Drugs 0.000 claims 2
- 239000000730 antalgic agent Substances 0.000 claims 2
- 229960002023 chloroprocaine Drugs 0.000 claims 2
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 claims 2
- 229960001747 cinchocaine Drugs 0.000 claims 2
- PUFQVTATUTYEAL-UHFFFAOYSA-N cinchocaine Chemical compound C1=CC=CC2=NC(OCCCC)=CC(C(=O)NCCN(CC)CC)=C21 PUFQVTATUTYEAL-UHFFFAOYSA-N 0.000 claims 2
- 229960003976 etidocaine Drugs 0.000 claims 2
- 239000003326 hypnotic agent Substances 0.000 claims 2
- 229960003502 oxybuprocaine Drugs 0.000 claims 2
- CMHHMUWAYWTMGS-UHFFFAOYSA-N oxybuprocaine Chemical compound CCCCOC1=CC(C(=O)OCCN(CC)CC)=CC=C1N CMHHMUWAYWTMGS-UHFFFAOYSA-N 0.000 claims 2
- 229960001807 prilocaine Drugs 0.000 claims 2
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 claims 2
- 229960004919 procaine Drugs 0.000 claims 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 claims 2
- KEJXLQUPYHWCNM-UHFFFAOYSA-N propanidid Chemical compound CCCOC(=O)CC1=CC=C(OCC(=O)N(CC)CC)C(OC)=C1 KEJXLQUPYHWCNM-UHFFFAOYSA-N 0.000 claims 2
- 229960004948 propanidid Drugs 0.000 claims 2
- 229960003981 proparacaine Drugs 0.000 claims 2
- 229960002372 tetracaine Drugs 0.000 claims 2
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 claims 2
- 108700012359 toxins Proteins 0.000 abstract description 157
- 230000000694 effects Effects 0.000 abstract description 65
- 231100000331 toxic Toxicity 0.000 abstract description 30
- 230000002588 toxic effect Effects 0.000 abstract description 27
- 241000282414 Homo sapiens Species 0.000 abstract description 18
- 230000001225 therapeutic effect Effects 0.000 abstract description 13
- 229960005015 local anesthetics Drugs 0.000 abstract description 12
- 238000011282 treatment Methods 0.000 abstract description 12
- 229940005494 general anesthetics Drugs 0.000 abstract description 8
- 238000011321 prophylaxis Methods 0.000 abstract description 6
- 239000002178 crystalline material Substances 0.000 abstract description 5
- 230000002411 adverse Effects 0.000 abstract description 3
- 239000007972 injectable composition Substances 0.000 abstract description 3
- 239000012313 reversal agent Substances 0.000 abstract description 3
- 230000002535 lyotropic effect Effects 0.000 abstract 1
- 239000012071 phase Substances 0.000 description 140
- 239000000839 emulsion Substances 0.000 description 36
- 239000003795 chemical substances by application Substances 0.000 description 22
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 22
- 229940028435 intralipid Drugs 0.000 description 22
- 241001465754 Metazoa Species 0.000 description 21
- 108010017384 Blood Proteins Proteins 0.000 description 20
- 102000004506 Blood Proteins Human genes 0.000 description 20
- 230000027455 binding Effects 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 230000009467 reduction Effects 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- 108010088751 Albumins Proteins 0.000 description 17
- 102000009027 Albumins Human genes 0.000 description 17
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 17
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 16
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[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 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 230000009471 action Effects 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 150000003904 phospholipids Chemical class 0.000 description 15
- 239000002270 dispersing agent Substances 0.000 description 14
- 238000001990 intravenous administration Methods 0.000 description 14
- 239000004973 liquid crystal related substance Substances 0.000 description 14
- 231100000419 toxicity Toxicity 0.000 description 14
- 230000001988 toxicity Effects 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 241000124008 Mammalia Species 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 229960003964 deoxycholic acid Drugs 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- 210000004185 liver Anatomy 0.000 description 12
- 239000008186 active pharmaceutical agent Substances 0.000 description 11
- 235000012000 cholesterol Nutrition 0.000 description 11
- 238000000576 coating method Methods 0.000 description 11
- 229940088679 drug related substance Drugs 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 230000001965 increasing effect Effects 0.000 description 10
- 230000003993 interaction Effects 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 239000003642 reactive oxygen metabolite Substances 0.000 description 10
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 9
- 229960003942 amphotericin b Drugs 0.000 description 9
- 239000000729 antidote Substances 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 206010002091 Anaesthesia Diseases 0.000 description 8
- 239000004471 Glycine Substances 0.000 description 8
- 230000037005 anaesthesia Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000002960 lipid emulsion Substances 0.000 description 8
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 8
- 230000000144 pharmacologic effect Effects 0.000 description 8
- 239000000523 sample Substances 0.000 description 8
- 150000003626 triacylglycerols Chemical class 0.000 description 8
- 229960003819 vecuronium Drugs 0.000 description 8
- BGSZAXLLHYERSY-XQIGCQGXSA-N vecuronium Chemical compound N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 BGSZAXLLHYERSY-XQIGCQGXSA-N 0.000 description 8
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 235000010469 Glycine max Nutrition 0.000 description 7
- 230000002238 attenuated effect Effects 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 229960004606 clomipramine Drugs 0.000 description 7
- 239000011248 coating agent Substances 0.000 description 7
- 230000002999 depolarising effect Effects 0.000 description 7
- 238000009792 diffusion process Methods 0.000 description 7
- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 description 7
- BPHQZTVXXXJVHI-AJQTZOPKSA-N ditetradecanoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-AJQTZOPKSA-N 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 238000000638 solvent extraction Methods 0.000 description 7
- 238000001356 surgical procedure Methods 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 108010007979 Glycocholic Acid Proteins 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound 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)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 210000000056 organ Anatomy 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 206010048610 Cardiotoxicity Diseases 0.000 description 5
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 231100000259 cardiotoxicity Toxicity 0.000 description 5
- 230000004087 circulation Effects 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 239000002158 endotoxin Substances 0.000 description 5
- 238000000265 homogenisation Methods 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 238000007726 management method Methods 0.000 description 5
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 5
- 229960000907 methylthioninium chloride Drugs 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000842 neuromuscular blocking agent Substances 0.000 description 5
- 230000001769 paralizing effect Effects 0.000 description 5
- 239000002356 single layer Substances 0.000 description 5
- 229940088594 vitamin Drugs 0.000 description 5
- 229930003231 vitamin Natural products 0.000 description 5
- 235000013343 vitamin Nutrition 0.000 description 5
- 239000011782 vitamin Substances 0.000 description 5
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 4
- 229930003427 Vitamin E Natural products 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 239000012062 aqueous buffer Substances 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 208000006218 bradycardia Diseases 0.000 description 4
- 230000036471 bradycardia Effects 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 230000000747 cardiac effect Effects 0.000 description 4
- 239000000544 cholinesterase inhibitor Substances 0.000 description 4
- 229940097362 cyclodextrins Drugs 0.000 description 4
- 229940099371 diacetylated monoglycerides Drugs 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 4
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 229960005181 morphine Drugs 0.000 description 4
- 239000003158 myorelaxant agent Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 229960004623 paraoxon Drugs 0.000 description 4
- WYMSBXTXOHUIGT-UHFFFAOYSA-N paraoxon Chemical compound CCOP(=O)(OCC)OC1=CC=C([N+]([O-])=O)C=C1 WYMSBXTXOHUIGT-UHFFFAOYSA-N 0.000 description 4
- 235000016236 parenteral nutrition Nutrition 0.000 description 4
- YXRDKMPIGHSVRX-OOJCLDBCSA-N rocuronium Chemical compound N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 YXRDKMPIGHSVRX-OOJCLDBCSA-N 0.000 description 4
- 229960000491 rocuronium Drugs 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005063 solubilization Methods 0.000 description 4
- 239000003549 soybean oil Substances 0.000 description 4
- 235000012424 soybean oil Nutrition 0.000 description 4
- 239000008223 sterile water Substances 0.000 description 4
- 239000008227 sterile water for injection Substances 0.000 description 4
- 229910001427 strontium ion Inorganic materials 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 229960004298 vecuronium bromide Drugs 0.000 description 4
- VEPSYABRBFXYIB-PWXDFCLTSA-M vecuronium bromide Chemical compound [Br-].N1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 VEPSYABRBFXYIB-PWXDFCLTSA-M 0.000 description 4
- 229940046009 vitamin E Drugs 0.000 description 4
- 235000019165 vitamin E Nutrition 0.000 description 4
- 239000011709 vitamin E Substances 0.000 description 4
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 3
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108090001090 Lectins Proteins 0.000 description 3
- 102000004856 Lectins Human genes 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 229960000836 amitriptyline Drugs 0.000 description 3
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 230000000890 antigenic effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 3
- 238000002680 cardiopulmonary resuscitation Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 229940009976 deoxycholate Drugs 0.000 description 3
- 230000000994 depressogenic effect Effects 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- 238000001962 electrophoresis Methods 0.000 description 3
- 230000009881 electrostatic interaction Effects 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 235000019197 fats Nutrition 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 229960000890 hydrocortisone Drugs 0.000 description 3
- 125000001165 hydrophobic group Chemical group 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 239000002523 lectin Substances 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 230000002232 neuromuscular Effects 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000006213 oxygenation reaction Methods 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 229920001993 poloxamer 188 Polymers 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000011552 rat model Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 210000002027 skeletal muscle Anatomy 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 230000003381 solubilizing effect Effects 0.000 description 3
- 229940031439 squalene Drugs 0.000 description 3
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 231100000057 systemic toxicity Toxicity 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 238000011287 therapeutic dose Methods 0.000 description 3
- 230000002110 toxicologic effect Effects 0.000 description 3
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 2
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 2
- YEDDVXZFXSHDIB-UHFFFAOYSA-N 1,1,2,2,3,3-hexafluoropropan-1-ol Chemical compound OC(F)(F)C(F)(F)C(F)F YEDDVXZFXSHDIB-UHFFFAOYSA-N 0.000 description 2
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- ITPDYQOUSLNIHG-UHFFFAOYSA-N Amiodarone hydrochloride Chemical compound [Cl-].CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCC[NH+](CC)CC)C(I)=C1 ITPDYQOUSLNIHG-UHFFFAOYSA-N 0.000 description 2
- 102100029470 Apolipoprotein E Human genes 0.000 description 2
- 101710095339 Apolipoprotein E Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108010009685 Cholinergic Receptors Proteins 0.000 description 2
- NMPOSNRHZIWLLL-XUWVNRHRSA-N Cocaethylene Chemical group O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OCC)C(=O)C1=CC=CC=C1 NMPOSNRHZIWLLL-XUWVNRHRSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 206010011951 Decompression Sickness Diseases 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 108010068370 Glutens Proteins 0.000 description 2
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010020844 Hyperthermia malignant Diseases 0.000 description 2
- 206010021118 Hypotonia Diseases 0.000 description 2
- 206010023126 Jaundice Diseases 0.000 description 2
- 239000000232 Lipid Bilayer Substances 0.000 description 2
- 239000004976 Lyotropic liquid crystal Substances 0.000 description 2
- 208000018717 Malignant hyperthermia of anesthesia Diseases 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 206010029315 Neuromuscular blockade Diseases 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 2
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 2
- 101710084578 Short neurotoxin 1 Proteins 0.000 description 2
- 108010052164 Sodium Channels Proteins 0.000 description 2
- 102000018674 Sodium Channels Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 2
- 208000018452 Torsade de pointes Diseases 0.000 description 2
- 208000002363 Torsades de Pointes Diseases 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 101710182532 Toxin a Proteins 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 102000034337 acetylcholine receptors Human genes 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 102000019997 adhesion receptor Human genes 0.000 description 2
- 108010013985 adhesion receptor Proteins 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- GYJHTGZQPKPEOT-SNVBAGLBSA-N alpha-Linalool Natural products O[C@](C=C)(CCCC(=C)C)C GYJHTGZQPKPEOT-SNVBAGLBSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229960005260 amiodarone Drugs 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000003466 anti-cipated effect Effects 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 230000010065 bacterial adhesion Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 150000001615 biotins Chemical class 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 229960002624 bretylium tosilate Drugs 0.000 description 2
- KVWNWTZZBKCOPM-UHFFFAOYSA-M bretylium tosylate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.CC[N+](C)(C)CC1=CC=CC=C1Br KVWNWTZZBKCOPM-UHFFFAOYSA-M 0.000 description 2
- 239000013590 bulk material Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 229940100084 cardioplegia solution Drugs 0.000 description 2
- 230000002612 cardiopulmonary effect Effects 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 229960002069 diamorphine Drugs 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 2
- 229940072271 diprivan Drugs 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229960000394 droperidol Drugs 0.000 description 2
- RMEDXOLNCUSCGS-UHFFFAOYSA-N droperidol Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CC=C(N2C(NC3=CC=CC=C32)=O)CC1 RMEDXOLNCUSCGS-UHFFFAOYSA-N 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- JPGQOUSTVILISH-UHFFFAOYSA-N enflurane Chemical compound FC(F)OC(F)(F)C(F)Cl JPGQOUSTVILISH-UHFFFAOYSA-N 0.000 description 2
- 229960000305 enflurane Drugs 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 235000021312 gluten Nutrition 0.000 description 2
- 150000003278 haem Chemical class 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 2
- 229960003132 halothane Drugs 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000005414 inactive ingredient Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940025708 injectable product Drugs 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 231100000636 lethal dose Toxicity 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 201000007004 malignant hyperthermia Diseases 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000028161 membrane depolarization Effects 0.000 description 2
- 239000001683 mentha spicata herb oil Substances 0.000 description 2
- RHCSKNNOAZULRK-UHFFFAOYSA-N mescaline Chemical compound COC1=CC(CCN)=CC(OC)=C1OC RHCSKNNOAZULRK-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 230000036640 muscle relaxation Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 230000002352 nonmutagenic effect Effects 0.000 description 2
- 230000014207 opsonization Effects 0.000 description 2
- 230000001151 other effect Effects 0.000 description 2
- 229940052293 other general anesthetics in atc Drugs 0.000 description 2
- 229940052264 other local anesthetics in atc Drugs 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 229960003147 reserpine Drugs 0.000 description 2
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 2
- 239000012465 retentate Substances 0.000 description 2
- 229960001549 ropivacaine Drugs 0.000 description 2
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000009919 sequestration Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019721 spearmint oil Nutrition 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052712 strontium Inorganic materials 0.000 description 2
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 239000002344 surface layer Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 229960003279 thiopental Drugs 0.000 description 2
- 235000019149 tocopherols Nutrition 0.000 description 2
- 231100000167 toxic agent Toxicity 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 231100000041 toxicology testing Toxicity 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 229960001722 verapamil Drugs 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LLSKXGRDUPMXLC-UHFFFAOYSA-N 1-phenylpiperidine Chemical class C1CCCCN1C1=CC=CC=C1 LLSKXGRDUPMXLC-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 description 1
- KISZTEOELCMZPY-UHFFFAOYSA-N 3,3-diphenylpropylamine Chemical class C=1C=CC=CC=1C(CCN)C1=CC=CC=C1 KISZTEOELCMZPY-UHFFFAOYSA-N 0.000 description 1
- SHXWCVYOXRDMCX-UHFFFAOYSA-N 3,4-methylenedioxymethamphetamine Chemical compound CNC(C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- WNWVKZTYMQWFHE-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound [CH2]CN1CCOCC1 WNWVKZTYMQWFHE-UHFFFAOYSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- JFFFKDHHNGBVFT-UHFFFAOYSA-N 7-phenylheptan-1-amine Chemical class NCCCCCCCC1=CC=CC=C1 JFFFKDHHNGBVFT-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102100033639 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 102000013918 Apolipoproteins E Human genes 0.000 description 1
- 108010025628 Apolipoproteins E Proteins 0.000 description 1
- 206010003671 Atrioventricular Block Diseases 0.000 description 1
- 206010003673 Atrioventricular block complete Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 208000001408 Carbon monoxide poisoning Diseases 0.000 description 1
- PCLITLDOTJTVDJ-UHFFFAOYSA-N Chlormethiazole Chemical compound CC=1N=CSC=1CCCl PCLITLDOTJTVDJ-UHFFFAOYSA-N 0.000 description 1
- 102000009016 Cholera Toxin Human genes 0.000 description 1
- 108010049048 Cholera Toxin Proteins 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- YVGGHNCTFXOJCH-UHFFFAOYSA-N DDT Chemical compound C1=CC(Cl)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(Cl)C=C1 YVGGHNCTFXOJCH-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- 229940123907 Disease modifying antirheumatic drug Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 101710146739 Enterotoxin Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010017999 Gastrointestinal pain Diseases 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- AIJTTZAVMXIJGM-UHFFFAOYSA-N Grepafloxacin Chemical compound C1CNC(C)CN1C(C(=C1C)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 AIJTTZAVMXIJGM-UHFFFAOYSA-N 0.000 description 1
- FOHHNHSLJDZUGQ-VWLOTQADSA-N Halofantrine Chemical compound FC(F)(F)C1=CC=C2C([C@@H](O)CCN(CCCC)CCCC)=CC3=C(Cl)C=C(Cl)C=C3C2=C1 FOHHNHSLJDZUGQ-VWLOTQADSA-N 0.000 description 1
- 208000010271 Heart Block Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 239000012741 Laemmli sample buffer Substances 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- VAYOSLLFUXYJDT-RDTXWAMCSA-N Lysergic acid diethylamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N(CC)CC)C2)=C3C2=CNC3=C1 VAYOSLLFUXYJDT-RDTXWAMCSA-N 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- NZXKDOXHBHYTKP-UHFFFAOYSA-N Metohexital Chemical compound CCC#CC(C)C1(CC=C)C(=O)NC(=O)N(C)C1=O NZXKDOXHBHYTKP-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZKLXUUYLEHCAMF-UUWFMWQGSA-N Oripavine Chemical class C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(O)C5=C4[C@@]21[C@H]3O5 ZKLXUUYLEHCAMF-UUWFMWQGSA-N 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- UQCNKQCJZOAFTQ-ISWURRPUSA-N Oxymorphone Chemical compound O([C@H]1C(CC[C@]23O)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O UQCNKQCJZOAFTQ-ISWURRPUSA-N 0.000 description 1
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical compound ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- IFFPICMESYHZPQ-UHFFFAOYSA-N Prenylamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)CCNC(C)CC1=CC=CC=C1 IFFPICMESYHZPQ-UHFFFAOYSA-N 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 208000004078 Snake Bites Diseases 0.000 description 1
- 239000004187 Spiramycin Substances 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 1
- 231100000644 Toxic injury Toxicity 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960002054 acenocoumarol Drugs 0.000 description 1
- VABCILAOYCMVPS-UHFFFAOYSA-N acenocoumarol Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=C([N+]([O-])=O)C=C1 VABCILAOYCMVPS-UHFFFAOYSA-N 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 231100001259 acute cardiotoxicity Toxicity 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 229960002105 amrinone Drugs 0.000 description 1
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 229940055075 anticholinesterase parasympathomimetics Drugs 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 229940033495 antimalarials Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 208000008784 apnea Diseases 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 150000001801 chenodeoxycholic acids Chemical class 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 1
- 229960005132 cisapride Drugs 0.000 description 1
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960004414 clomethiazole Drugs 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 229940047766 co-trimoxazole Drugs 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229940080861 demerol Drugs 0.000 description 1
- DPYMFVXJLLWWEU-UHFFFAOYSA-N desflurane Chemical compound FC(F)OC(F)C(F)(F)F DPYMFVXJLLWWEU-UHFFFAOYSA-N 0.000 description 1
- 229960003537 desflurane Drugs 0.000 description 1
- 229960003914 desipramine Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000000385 dialysis solution Substances 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 229960000920 dihydrocodeine Drugs 0.000 description 1
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229940051806 diphenylpropylamine derivative analgesics Drugs 0.000 description 1
- UVTNFZQICZKOEM-UHFFFAOYSA-N disopyramide Chemical compound C=1C=CC=NC=1C(C(N)=O)(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UVTNFZQICZKOEM-UHFFFAOYSA-N 0.000 description 1
- 229960001066 disopyramide Drugs 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000009189 diving Effects 0.000 description 1
- IXTMWRCNAAVVAI-UHFFFAOYSA-N dofetilide Chemical compound C=1C=C(NS(C)(=O)=O)C=CC=1CCN(C)CCOC1=CC=C(NS(C)(=O)=O)C=C1 IXTMWRCNAAVVAI-UHFFFAOYSA-N 0.000 description 1
- 229960002994 dofetilide Drugs 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000147 enterotoxin Substances 0.000 description 1
- 231100000655 enterotoxin Toxicity 0.000 description 1
- 230000005183 environmental health Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 231100000573 exposure to toxins Toxicity 0.000 description 1
- 230000004399 eye closure Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 210000000720 eyelash Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960000642 grepafloxacin Drugs 0.000 description 1
- 229960003242 halofantrine Drugs 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229940113601 irrigation solution Drugs 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 150000002643 lithocholic acids Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000003509 long acting drug Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229950002454 lysergide Drugs 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 229960004090 maprotiline Drugs 0.000 description 1
- QSLMDECMDJKHMQ-GSXCWMCISA-N maprotiline Chemical compound C12=CC=CC=C2[C@@]2(CCCNC)C3=CC=CC=C3[C@@H]1CC2 QSLMDECMDJKHMQ-GSXCWMCISA-N 0.000 description 1
- FQXXSQDCDRQNQE-UHFFFAOYSA-N markiertes Thebain Natural products COC1=CC=C2C(N(CC3)C)CC4=CC=C(OC)C5=C4C23C1O5 FQXXSQDCDRQNQE-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- 229960002683 methohexital Drugs 0.000 description 1
- RFKMCNOHBTXSMU-UHFFFAOYSA-N methoxyflurane Chemical compound COC(F)(F)C(Cl)Cl RFKMCNOHBTXSMU-UHFFFAOYSA-N 0.000 description 1
- 229960002455 methoxyflurane Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229960003574 milrinone Drugs 0.000 description 1
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 229960004798 minaxolone Drugs 0.000 description 1
- NCGLTZSBTFVVAW-KNXRZYMVSA-N minaxolone Chemical compound C1[C@@H](N(C)C)[C@@H]2[C@@]3(C)C[C@H](OCC)[C@@H](O)C[C@@H]3CC[C@H]2[C@@H]2CC[C@H](C(C)=O)[C@]21C NCGLTZSBTFVVAW-KNXRZYMVSA-N 0.000 description 1
- 229950007856 mofetil Drugs 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 229940014456 mycophenolate Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229960002362 neostigmine Drugs 0.000 description 1
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 210000000715 neuromuscular junction Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960004300 nicomorphine Drugs 0.000 description 1
- HNDXBGYRMHRUFN-CIVUWBIHSA-N nicomorphine Chemical compound O([C@H]1C=C[C@H]2[C@H]3CC=4C5=C(C(=CC=4)OC(=O)C=4C=NC=CC=4)O[C@@H]1[C@]52CCN3C)C(=O)C1=CC=CN=C1 HNDXBGYRMHRUFN-CIVUWBIHSA-N 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 229960001730 nitrous oxide Drugs 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229940051807 opiod analgesics morphinan derivative Drugs 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940051808 oripavine derivative analgesics Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 229960005118 oxymorphone Drugs 0.000 description 1
- GVEAYVLWDAFXET-XGHATYIMSA-N pancuronium Chemical compound C[N+]1([C@@H]2[C@@H](OC(C)=O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(C)CCCCC2)CCCCC1 GVEAYVLWDAFXET-XGHATYIMSA-N 0.000 description 1
- 229960005457 pancuronium Drugs 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000008251 pharmaceutical emulsion Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 229950010883 phencyclidine Drugs 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 229960000280 phenindione Drugs 0.000 description 1
- NFBAXHOPROOJAW-UHFFFAOYSA-N phenindione Chemical compound O=C1C2=CC=CC=C2C(=O)C1C1=CC=CC=C1 NFBAXHOPROOJAW-UHFFFAOYSA-N 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960003634 pimozide Drugs 0.000 description 1
- YVUQSNJEYSNKRX-UHFFFAOYSA-N pimozide Chemical compound C1=CC(F)=CC=C1C(C=1C=CC(F)=CC=1)CCCN1CCC(N2C(NC3=CC=CC=C32)=O)CC1 YVUQSNJEYSNKRX-UHFFFAOYSA-N 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 238000001907 polarising light microscopy Methods 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 235000021085 polyunsaturated fats Nutrition 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 229960001989 prenylamine Drugs 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 229960000244 procainamide Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000002694 regional anesthesia Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000012501 relaxation of skeletal muscle Effects 0.000 description 1
- 230000010410 reperfusion Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229960000652 sertindole Drugs 0.000 description 1
- GZKLJWGUPQBVJQ-UHFFFAOYSA-N sertindole Chemical compound C1=CC(F)=CC=C1N1C2=CC=C(Cl)C=C2C(C2CCN(CCN3C(NCC3)=O)CC2)=C1 GZKLJWGUPQBVJQ-UHFFFAOYSA-N 0.000 description 1
- DFEYYRMXOJXZRJ-UHFFFAOYSA-N sevoflurane Chemical compound FCOC(C(F)(F)F)C(F)(F)F DFEYYRMXOJXZRJ-UHFFFAOYSA-N 0.000 description 1
- 229960002078 sevoflurane Drugs 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].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)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 229960002370 sotalol Drugs 0.000 description 1
- ZBMZVLHSJCTVON-UHFFFAOYSA-N sotalol Chemical compound CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ZBMZVLHSJCTVON-UHFFFAOYSA-N 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229940124547 specific antidotes Drugs 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000002708 spider venom Substances 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229910001631 strontium chloride Inorganic materials 0.000 description 1
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 description 1
- PWYYWQHXAPXYMF-UHFFFAOYSA-N strontium(2+) Chemical compound [Sr+2] PWYYWQHXAPXYMF-UHFFFAOYSA-N 0.000 description 1
- AXOIZCJOOAYSMI-UHFFFAOYSA-N succinylcholine Chemical compound C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C AXOIZCJOOAYSMI-UHFFFAOYSA-N 0.000 description 1
- 229940032712 succinylcholine Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- UISARWKNNNHPGI-UHFFFAOYSA-N terodiline Chemical compound C=1C=CC=CC=1C(CC(C)NC(C)(C)C)C1=CC=CC=C1 UISARWKNNNHPGI-UHFFFAOYSA-N 0.000 description 1
- 229960005383 terodiline Drugs 0.000 description 1
- FQXXSQDCDRQNQE-VMDGZTHMSA-N thebaine Chemical compound C([C@@H](N(CC1)C)C2=CC=C3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 FQXXSQDCDRQNQE-VMDGZTHMSA-N 0.000 description 1
- 229930003945 thebaine Natural products 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960001166 thiamylal Drugs 0.000 description 1
- XLOMZPUITCYLMJ-UHFFFAOYSA-N thiamylal Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=S)NC1=O XLOMZPUITCYLMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 201000002931 third-degree atrioventricular block Diseases 0.000 description 1
- 229940042129 topical gel Drugs 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 239000010891 toxic waste Substances 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 150000003674 ursodeoxycholic acids Chemical class 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 229940019333 vitamin k antagonists Drugs 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dispersion Chemistry (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Methods of attenuating the toxic or medically undesirable effects of drugs and toxins in a human by administering to a human an injectable formulation comprised of a dispersion of particles comprised of reversed cubic or reversed hexagonal lyotropic liquid crystalline material. The particles absorb or adsorb or otherwise sequester and attenuate the effect of drugs and toxins, and may be used as a rescue or reversal agent, or as a prophylaxis. The invention is especially applicable in reversing adverse effects of local anesthetics inadvertently delivered systemically, and attenuating the therapeutic effects of general anesthetics in the course of treatment.
Description
COMPOSITIONS FOR THE REVERSAL AND DETOXIFICATION
OF ANESTHETICS AND OTHER COMPOUNDS
AND METHODS OF THEIR USE
DESCRIPTION
BACKGROUND OF THE INVENTION
Field of the Invention This invention focuses on the administration of dispersions of certain lyotropic liquid crystal compositions to attenuate the toxic or medically undesirable effect of one or more compounds present in the body of a human or other mammal. The particles in dispersion comprise reversed cubic phase and/or reversed hexagonal phase liquid crystalline material in which a toxin or a drug substance is soluble and partitions substantially. The particle dispersions are suitable for administration to a human, and are given preferably by injection, most preferably intravenously, in an amount sufficient to be effective in attenuating the effects of a toxin or therapeutic drug in the body. The attenuation of the effects of toxins or drug substances in the body may result from sequestering the toxin or therapeutic drug from the plasma, displacing the toxin from the site of action, inducing redistribution of the toxin, or by other mechanisms.
Adjusting the composition by various means may increase or decrease the absorption or adsorption of a toxin or drug substance to the particles, the rate of uptake of the particles and associated toxins or drug substances by the liver, and otherwise impact attenuation of the effects of a toxin or drug substance. The invention is especially applicable in reversing adverse effects of local anesthetics delivered systemically, and attenuating the therapeutic effects of general anesthetics in the course of treatment.
Background of the Invention In most clinical applications, local anesthetics are typically injected or applied at or near a site intended to render an area or region of the body insensate to painful stimuli. Once applied or administered, systemic absorption of the local anesthetic occurs or, in some instances, a portion of the injectate may be inadvertently administered directly into the vascular system. In any case, local anesthetics may exert varying degrees of systemic toxicity.
Toxicity is usually directly proportional to the potency of the local anesthetic administered. It is widely believed that most local anesthetics exert their effects by binding to the alpha-subunit and blocking the voltage-gated sodium channel from an intracellular location, thereby conformationally inactivating the sodium channel and disrupting the influx of sodium ions preventing membrane depolarization. Local anesthetics are also known to block calcium, potassium and N-methyl-D-aspartate (NMDA) receptors to varying degrees. These differences are associated with the unique clinical profiles associated with each local anesthetic agent.
The unintentional intravascular administration of local anesthetics, bupivacaine in particular, which can occur during procedures designed to effect regional anesthesia can result in severe cardiac complications. These reactions include marked hypotension, atrioventricular dissociative heart block, idioventricular dysrhythmias as well as ventricular tachycardia and ventricular fibrillation. It is widely accepted that the R+ isomer of bupivacaine has a strong affinity to binding cardiac sodium channels and that its dissociation from this site is very slow.
At higher concentrations, calcium and potassium channels can also be blocked, further exacerbating the cardiotoxic effects.
Bupivacaine induced cardiac toxicity is a life-threatening emergency in which aggressive measures must be undertaken to preserve life. These measures frequently involve immediate and repeated administration of vasopressors to maintain normovascular tone as well as other agents to control the bradycardia, complete heart block and the various cardiac dysrhytmias which ensue. Cardiopulmonary resuscitation may be required to maintain oxygenation of vital organs while the myocardium is in arrest. It is not uncommon to attempt to emergently effect extracorporeal oxygenation via cardiopulmonary bypass with membrane oxygenation (or similar device) to await the return of a normalized cardiac cycle once the offending concentration of bupivacaine has been redistributed, metabolized or otherwise inactivated, and allow for the physiologic normalization of the myocardial cycle.
A number of specific therapies for local anesthetic toxicity have been proposed over the years including bretylium, glucose/insulin/potassium infusions, emergent resuscitative efforts (i.e. cardiopulmonary resuscitation CPR), and cardiopulmonary bypass.
Recently, attempts have been made to use fatty emulsions, typified by the product marketed under the name Intralipid , to scavenge bupivacaine and thereby reverse toxic effects. [See, e.g., Weinburg G, Ripper R, Feinstein DL, Hoffman W. RA&PM 2003; 28:198; Weinberg et al. (1998) Anesthesiology 88(4):10711. Similarly Intralipid has been investigated for use in ropivacaine toxicity. [Litz et al. (2006) Anaesthesia 61:8001. Tebbutt et al. found increased survival in a rat model of verapamil toxicity. [Tebbutt et al., Acac. Emerg. Med. (2006) 13:134]. Bania, Chu and Stolbach looked at the use of Intralipid to try to raise the LD50 in mice of an organophosphate compound, paraoxon. [Acad Emerg Med (2005) 12(5 Supplement 1):12]. The group of Bania and Chu has also looked at the use of Intralipid to treat toxicities from propanolol, VER, and amitriptyline. [Reported at the 2006 National SAEM Meeting, San Francisco CA].
Mathy-Hartert et al. investigated the use of Intralipid against reactive oxygen species produced by phorbol myristate acetate, but found only a weak effect. [Mathy-Hartert et al., Mediators Inflamm. (1998) 7:3271. Microemulsions made from Pluronic surfactant, ethyl butyrate, fatty acid sodium salts and water have been proposed for scavenging bupivacaine by the group of Dennis et al. [See Dennis et al., U.S. Patent Application Serial No. 10 /420,608, Varshney et al.
(2004) J. Am. Chem. Soc. 126:5108 and Renehan et al. (2005) Reg. Anes. Pain Med. 30(4):3801.
Dennis and coworkers have also proposed particles containing detoxifying enzymes, in U.S.
6,977,171.
Intralipid and related parenteral fatty emulsions have several disadvantages and limitations in the present context. Perhaps most importantly, they rely on triglycerides (soybean oil in Intralipid , other fats for the other fatty emulsions) for the solubilization and partitioning of compounds into the emulsion droplets, and as such they are strongly limited. Triglycerides are many-fold higher in molecular weight (on the order of 900Da) than most compounds that are known to be effective solubilizers, as the favorable entropies of mixing associated with low-MW
OF ANESTHETICS AND OTHER COMPOUNDS
AND METHODS OF THEIR USE
DESCRIPTION
BACKGROUND OF THE INVENTION
Field of the Invention This invention focuses on the administration of dispersions of certain lyotropic liquid crystal compositions to attenuate the toxic or medically undesirable effect of one or more compounds present in the body of a human or other mammal. The particles in dispersion comprise reversed cubic phase and/or reversed hexagonal phase liquid crystalline material in which a toxin or a drug substance is soluble and partitions substantially. The particle dispersions are suitable for administration to a human, and are given preferably by injection, most preferably intravenously, in an amount sufficient to be effective in attenuating the effects of a toxin or therapeutic drug in the body. The attenuation of the effects of toxins or drug substances in the body may result from sequestering the toxin or therapeutic drug from the plasma, displacing the toxin from the site of action, inducing redistribution of the toxin, or by other mechanisms.
Adjusting the composition by various means may increase or decrease the absorption or adsorption of a toxin or drug substance to the particles, the rate of uptake of the particles and associated toxins or drug substances by the liver, and otherwise impact attenuation of the effects of a toxin or drug substance. The invention is especially applicable in reversing adverse effects of local anesthetics delivered systemically, and attenuating the therapeutic effects of general anesthetics in the course of treatment.
Background of the Invention In most clinical applications, local anesthetics are typically injected or applied at or near a site intended to render an area or region of the body insensate to painful stimuli. Once applied or administered, systemic absorption of the local anesthetic occurs or, in some instances, a portion of the injectate may be inadvertently administered directly into the vascular system. In any case, local anesthetics may exert varying degrees of systemic toxicity.
Toxicity is usually directly proportional to the potency of the local anesthetic administered. It is widely believed that most local anesthetics exert their effects by binding to the alpha-subunit and blocking the voltage-gated sodium channel from an intracellular location, thereby conformationally inactivating the sodium channel and disrupting the influx of sodium ions preventing membrane depolarization. Local anesthetics are also known to block calcium, potassium and N-methyl-D-aspartate (NMDA) receptors to varying degrees. These differences are associated with the unique clinical profiles associated with each local anesthetic agent.
The unintentional intravascular administration of local anesthetics, bupivacaine in particular, which can occur during procedures designed to effect regional anesthesia can result in severe cardiac complications. These reactions include marked hypotension, atrioventricular dissociative heart block, idioventricular dysrhythmias as well as ventricular tachycardia and ventricular fibrillation. It is widely accepted that the R+ isomer of bupivacaine has a strong affinity to binding cardiac sodium channels and that its dissociation from this site is very slow.
At higher concentrations, calcium and potassium channels can also be blocked, further exacerbating the cardiotoxic effects.
Bupivacaine induced cardiac toxicity is a life-threatening emergency in which aggressive measures must be undertaken to preserve life. These measures frequently involve immediate and repeated administration of vasopressors to maintain normovascular tone as well as other agents to control the bradycardia, complete heart block and the various cardiac dysrhytmias which ensue. Cardiopulmonary resuscitation may be required to maintain oxygenation of vital organs while the myocardium is in arrest. It is not uncommon to attempt to emergently effect extracorporeal oxygenation via cardiopulmonary bypass with membrane oxygenation (or similar device) to await the return of a normalized cardiac cycle once the offending concentration of bupivacaine has been redistributed, metabolized or otherwise inactivated, and allow for the physiologic normalization of the myocardial cycle.
A number of specific therapies for local anesthetic toxicity have been proposed over the years including bretylium, glucose/insulin/potassium infusions, emergent resuscitative efforts (i.e. cardiopulmonary resuscitation CPR), and cardiopulmonary bypass.
Recently, attempts have been made to use fatty emulsions, typified by the product marketed under the name Intralipid , to scavenge bupivacaine and thereby reverse toxic effects. [See, e.g., Weinburg G, Ripper R, Feinstein DL, Hoffman W. RA&PM 2003; 28:198; Weinberg et al. (1998) Anesthesiology 88(4):10711. Similarly Intralipid has been investigated for use in ropivacaine toxicity. [Litz et al. (2006) Anaesthesia 61:8001. Tebbutt et al. found increased survival in a rat model of verapamil toxicity. [Tebbutt et al., Acac. Emerg. Med. (2006) 13:134]. Bania, Chu and Stolbach looked at the use of Intralipid to try to raise the LD50 in mice of an organophosphate compound, paraoxon. [Acad Emerg Med (2005) 12(5 Supplement 1):12]. The group of Bania and Chu has also looked at the use of Intralipid to treat toxicities from propanolol, VER, and amitriptyline. [Reported at the 2006 National SAEM Meeting, San Francisco CA].
Mathy-Hartert et al. investigated the use of Intralipid against reactive oxygen species produced by phorbol myristate acetate, but found only a weak effect. [Mathy-Hartert et al., Mediators Inflamm. (1998) 7:3271. Microemulsions made from Pluronic surfactant, ethyl butyrate, fatty acid sodium salts and water have been proposed for scavenging bupivacaine by the group of Dennis et al. [See Dennis et al., U.S. Patent Application Serial No. 10 /420,608, Varshney et al.
(2004) J. Am. Chem. Soc. 126:5108 and Renehan et al. (2005) Reg. Anes. Pain Med. 30(4):3801.
Dennis and coworkers have also proposed particles containing detoxifying enzymes, in U.S.
6,977,171.
Intralipid and related parenteral fatty emulsions have several disadvantages and limitations in the present context. Perhaps most importantly, they rely on triglycerides (soybean oil in Intralipid , other fats for the other fatty emulsions) for the solubilization and partitioning of compounds into the emulsion droplets, and as such they are strongly limited. Triglycerides are many-fold higher in molecular weight (on the order of 900Da) than most compounds that are known to be effective solubilizers, as the favorable entropies of mixing associated with low-MW
compounds is important for the functioning of most solvents. They are extremely hydrophobic, and thus very poor solvents for compounds that have one, or particularly more than one, polar group. Their propensity to support microbial contamination makes them poorly suited for field applications. And the high levels of polyunsaturated fats in lipid emulsions, combined with low levels of tocopherol to combat oxidation, lead to growing levels of peroxides and other free radical sources that can contribute to toxicities related to reactive oxygen species.
There is a need for a pharmaceutically acceptable composition and method for attenuating the effects of common drugs in circumstances in which they are toxic and in situations in which for other reasons, such as medical treatment or patient management, their attenuation is desirable which can work effectively, against a range of drugs and other toxins, and can be adjusted for different characteristics of action and different toxins.
SUMMARY OF THE INVENTION
In an exemplary embodiment of the invention, a method of attenuating the toxic effect of a toxin in a human or other mammal is achieved by administering to the human or other mammal in whom a toxin is or is suspected to be present an effective amount of a composition comprising particles which are formed from or include reversed cubic or reversed hexagonal phase material.
The particles are preferably present in a stable dispersion which includes a liquid comprising a polar solvent. The particles may be ionically charged (anionic or cationic).
The administration is preferably by injection (preferably i.v.) and results in the attenuation of the toxic effects of the toxin by the particles adsorbing or absorbing or otherwise sequestering the toxin from the site of toxic action.
It is another exemplary embodiment of this invention, a method of attenuating the therapeutic effect of a drug substance present in a human or other mammal is achieved by administering to the human or mammal in whom a drug substance is or is suspected to be present an effective amount of a composition comprising particles which are formed from or include reversed cubic or reversed hexagonal phase material. The particles are preferably present in a stable dispersion which includes a liquid comprising a polar solvent. The particles may be ionically charged (anionic or cationic). The administration is preferably by injection (preferably i.v.) and results in the attenuation of the therapeutic effects of the drug substance by the particles adsorbing or absorbing or otherwise sequestering the drug substance from the site of pharmacologic action.
A further exemplary embodiment of this invention is to provide a method of attenuating the effect of a chemical substance in a human comprising administering to the human a stabilized composition comprising lipid, tocopherol and a liquid comprising a polar solvent.
Whatever their specific therapeutic use, drugs are not always present at the most desired level in the body, and at times it may be necessary or beneficial to attenuate their effects. Some drugs of medical use, most notably the local anesthetics, can become life-threatening if they are inadvertently injected into a vein or artery, calling for removal or reduction to avoid or minimize neurotoxicity and cardiotoxicity. Other drugs used in medical practice, such as those associated with surgical procedures including general anesthetics like propofol and paralytic agents like vecuronium, can call for removal or reduction in a number of circumstances:
for example, after interruption or even completion of a surgical procedure, it may be desirable to attenuate the lingering effects of the general anesthetic or paralytic agent whose normal therapeutic effect has become, post-operatively, a nuisance, danger or impediment to optimum patient management. In other cases, a drug may have side effects on account of generating toxic metabolites in circulation, it may be debilitating to the patient, or it may be detrimental in terms of tolerance or addiction, and attenuation of the effects of the drug may be an important therapeutic need.
Certain compounds, such as ***e or morphine, for example, are of course used in medical practice, but also are used as drugs of abuse and as such may require removal or reduction in the course of detoxification and rehabilitation. Furthermore, metabolites of certain drugs, such as cocaethylene in the case of ***e and nor-meperedine in the case of meperedine (Demerol ), have considerable toxicity and their removal could be of importance in many settings. Finally, a toxin can be endogenous, such as an autoantibody or cortisol. In a particular embodiment of the invention, the invention permits attenuating the therapeutic effects of drugs on a selective basis, as well as in the removal of exogenous drug substances and endogenous toxins from the site of action.
Therapeutic agents such as propofol and other general anesthetics are selected for use and used, in part, on the basis of the duration and intensity of their therapeutic effect. In the course of their use, clinical circumstances may arise making it desirable to attenuate the therapeutic effects, for example, by reducing the time to emergence from the effect of a general anesthetic, or the duration of effect of the neuromuscular blocking agent. In an exemplary embodiment, the invention provides the ability to attenuate those effects and would provide an additional tool for optimum management of, for example, a course of surgery, as well as for the safety, comfort and convenience of the patient. In the case of an outpatient surgical procedure that proceeded successfully and more promptly than anticipated, for example, there may be benefits to patient and provider alike to accelerate the return of the patient to clear headedness, facilitating the discharge of the patient. In the case of a surgical procedure which has not proceeded according to plan and is being altered or terminated, there may be benefits to accelerating the patient's return to a state free from the therapeutic effects of a general anesthetic or a neuromuscular blocking agent.
In another setting, the course of delivering an anesthetic or securing an airway, it is of critical importance to relax skeletal muscles. This is most commonly accomplished with the use of neuromuscular blocking agents of either the depolarizing or non-depolarizing class.
Neuromuscular blocking agents are used to facilitate endotracheal intubation in securing and maintaining a patent airway, effecting relaxation of skeletal muscles to enable certain operative procedures and to ensure patient safety in certain clinical settings.
Depolarizing agents, i.e.
succinylcholine, act as acetylcholine (Ach) receptor agonists and quickly cause short lived muscle relaxation due to the rapid diffusion away from the neuromuscular junction and are hydrolyzed by nonspecific cholinesterases. In contrast, non-depolarizing agents, i.e.
vecuronium, function as competitive antagonists. The fact that non-depolarizers are neither metabolized by acetylcholinesterase nor eluted quickly from the Ach receptor predictably result in prolonged depolarization of the neuromuscular endplate, and yield longer duration of muscle relaxation. The best clinical practice and safest approach in the care of those paralyzed with neuromuscular blocker agents is to reverse, as completely as possible, the relaxant effects of these agents, especially non-depolarizing agents once relaxation is no longer required.
Typically, reversal of the non-depolarizing agents is augmented by the administration of cholinesterase inhibitors, also known as anticholinesterases, i.e., neostigmine. These agents reversibly bind to the enzyme that degrades Ach thereby indirectly increasing the amount of Ach available to competitively displace non-depolarizing agents from the Ach receptor by re-establishing normal neuromuscular function at the neuromuscular endplate.
Complications and other adverse reactions can occur with the administration cholinesterase inhibitors. These agents may be metabolized or administered in lower doses causing ineffective displacement of non-depolarizers from the receptor, yielding latent and unexpected return of paralysis. Administered in excessive doses, Achase inhibitors may paradoxically potentiate the effects of neuromuscular blockade. Other well known effects of increases in Ach associated with the use of Achase inhibitors include vagal mediated bradycardia, bronchospasm initiated by smooth muscle contraction, central nervous system effects including diffuse excitation, intestinal spasms, increased bladder tone and papillary constriction. Therefore, any strategy to minimize, supplement or preferably avoid the use of cholinesterase inhibitors in the reversal of neuromuscular blockade offers multiple advantages in the clinical setting. In an exemplary embodiment of the invention, this invention provides such a strategy.
Cyclodextrins are known to bind a number of drug molecules, such as rocuronium and vecuronium, and as such are being used as reversal agents for compounds like rocuronium. It should be noted that bradycardia is sometimes associated with the intravenous use of cyclodextrins, which is a distinct problem for the use of such compounds in connection with rescue from local anesthetic toxicity, where bradycardia is already a serious life-threatening complication. In another exemplary embodiment of the invention, an alternative to the use of cyclodextrins is provided.
Another embodiment of the invention relates to the management of the use of anesthetics in the clinical setting (e.g., hospital, doctor's office, clinic, nurses station, etc.). In practice, a patient will be provided with an anesthetic before, or after, or simultaneously with a composition containing particles that include reversed cubic phase or reverse hexagonal phase material. The patient will be subject to a medical or surgical procedure or will be simply observed. The anesthetizing effect of the anesthetic will be attenuated by the particles containing the reversed cubic phase or reverse hexagonal phase material. This allows control of the anesthetizing effect and may enhance a patient's recovery time. The type of anesthetics which may be managed in this way include both general anesthetics such as propofol, etomidate, ketamine, thiopental, a benzodiazepine, a barbiturate, an opioid, haloperidol, droperidol, and phencyclidine, and local anesthetics such as bupivacaine, lidocaine, ropivacaine, mepivacaine, and ***e. With respect to general anesthetics, the invention can be used for decreasing a duration of sedation, reducing a time to emergence, reducing a duration of apnea, and reducing a time to full cognition.
In another embodiment of the invention, pharmaceuticals in a wide range of drug classes can have their effects selectively attenuated by providing the patient with a composition including particles that have either reversed cubic phase or reversed hexagonal phase materials.
The methods of the invention can be used in conjunction with, for example, a patient that has or is suspected to have taken, or a patient that will be provided with a benzodiazepine, an opiate, a central venous system depressant, a respiratory depressant, a cardiovascular depressant, a psychomotor stimulant, a psychotropic, a sedative, a hypnotic, a muscle relaxant, and an organophosphate.
DETAILED DESCRIPTION OF THE PREFERRED
EMBODIMENTS OF THE INVENTION
A. Definitions.
"Attenuation" of a drug effect or toxic effect of a toxin means that one or more of the following occur (as compared to in the absence of treatment with the invention): substantial reduction in intensity of the effect, substantial reduction in the duration of the effect, substantial reduction in physiological insult and damage, substantially accelerated clearance of the drug or toxin from active or otherwise critical sites in the body, substantial reduction in symptoms of adverse reaction to the drug or toxin, substantial reduction in the concentrations of one or more toxic metabolites of the drug or toxin from critical sites in the body, or substantial reduction in pathological binding of exogenous or endogenous substance(s). In this definition, an effect, such as a reduction (e.g., in intensity), is considered substantial if it is clinically or medically useful or beneficial, or useful or beneficial in the management of a patient, to an extent that, in the view of one skilled in the art, it would warrant use of the invention in that situation. Also in the view of one skilled in the art, the effect of attenuating the drug or toxin should be preferential over other effects or side effects that would otherwise negate or render insignificant the desirable attenuating effect.
"Drug" means a compound consisting of or comprising an Active Pharmaceutical Ingredient (API).
"Toxin", in the context of this disclosure, is much broader than the connotation usually implied in day to day speech. In this disclosure "toxin" means any compound, or closely related group of compounds (such as different stereoisomers of a drug or different chain lengths of a particular lipid type), that pose a health risk or medical inconvenience to a mammal or human, and as such call for removal or reduction in the body, or for redistribution within the body (e.g., from tissues to blood, or from the blood to the liver, etc.). A toxin could be endogenous, such as an autoantibody or cortisol for example, though it will more often be an exogenous compound, and most typically an exogenous compound recognized to be toxic or antigenic at least under some circumstances (for purposes of this application, antigenic materials will be treated as toxins). Certain compounds, such as ***e or morphine, for example, are of course used in medical practice, but also are used as drugs of abuse and as such may require removal or reduction in the course of detoxification and rehabilitation, and thus can be toxins in the context of this invention; furthermore, metabolites of such compounds, such as cocaethylene in the case of ***e, have considerable toxicity and their removal by the present invention could be of importance in many settings. Other drugs of medical use, most notably the local anesthetics, can become life-threatening if they are inadvertently injected into a vein or artery, calling for removal or reduction, and in such cases become toxins in the context of this disclosure. Other drugs used in medical practice, such as those associated with anesthesia or pain control, including general anesthetics like propofol or paralytic agents like rocuronium or vecuronium, can call for removal or reduction in a number of circumstances, including overdosage, triggering of dangerous reactions such as malignant hyperthermia (MH) and respiratory depression. In addition, there are situations in which the treating physician or clinician may wish to attenuate the anesthetic effect for clinical reasons, for example, to allow a patient to be safely discharged from a hospital or clinic without having to wait for the entire length of time required for normal metabolism/excretion of the drug. Certain long-acting drugs of medical use, such as reserpine, or sustained-release formulations such as DepoMorphine, may call for removal or reduction if the duration of action needs to be cut, in which case the drug can be deemed a toxin in the context of this invention.
"Pharmaceutically-acceptable" generally designates compounds or compositions in which each excipient is approved by the Food and Drug Administration, or a similar body in another country, for use in a pharmaceutical or vaccine formulation, or belongs to a succinct class of compounds for which a Drug Master File is on file with a government regulatory agency, usually the FDA, or, less preferably, is known from extensive toxicity studies to be safe for the intended route of administration (which in the context of this invention is typically, though not always, intravenous). This also includes compounds that are major components of approved excipients. Listings of approved excipients, each with the various routes of administration for which they are approved, are published from time to time by the Division of Drug Information Resources of the FDA, as in January, 1996 and entitled "Inactive Ingredient Guide". The existence of a Drug Master File at the FDA is additional evidence that a given excipient is acceptable for pharmaceutical use, at least for certain routes of administration. For injectable products, a listing of approved excipients was published in 1997.
See Nema, Washkuhn and Brendel (1997) PDA J. of Phann. Sci. & Technol. 51(4):166. There are certain compounds, such as vitamins and amino acids, which are in injectable products (typically for parenteral nutrition) as "actives", and are thus known to be safe upon injection, and such compounds are considered herein as pharmaceutically-acceptable as excipients as well, for injection. There are also compounds which are not currently listed as an approved excipient, but which have been the subject of an extensive toxicity review and have been shown to be of very low toxicity, and non-mutagenic, and which, upon application to the proper authorities for a specific application, may be approved. A formulation pharmaceutically-acceptable for injection must be sterile.
"Site of action of a toxin or drug" is defined herein to be a location, in molecular terms, where the toxin or drug manifests a clinically significant toxic or pharmacologic effect, which in the context of the invention is a harmful or otherwise undesirable effect motivating application of the invention. To be at the site of action in some cases may include being in the tissue, organ, blood and/or other body fluids. In some instances, the drug or toxin is in such proximity, at the level of molecular binding, to a molecular target as to be capable of exerting a toxic or pharmacologic effect at that moment in time, such as acting as agonist or antagonist at a receptor protein, or otherwise binding and affecting an enzyme, lipid, saccharide, lectin, nucleic acid, vitamin, metal ion, neurotransmitter, hormone, or other target. The site of action of a toxin or drug could itself be exogenous, such as in the case of an antibiotic or antifungal compound where the site of action is on or in a microbe, existing at the time within the body of a human "Recovery" of a toxin or drug by a multitude of particles means that the particles substantially (i.e., with clinically desirable effect) displace it from its site or sites of toxic or pharmacologic action, or prevent it from interacting with that site before it ever requires displacement through interactions between the particles and toxin or drug, including but not limited to adsorption or absorption of the toxin or drug by the particles. An example of recovery that is broadly illustrative is where a toxin molecule, existing at or in the vicinity of a receptor, enzyme, or other molecular target by virtue of interactions with the molecular target, is sequestered by a particle by virtue of interaction(s) with the particle (such as hydrophobic interaction), said toxin molecule therefore becoming less prone to interact with the molecular target due to its sequestration by the particle and, in some cases, by movement of the particle away from the molecular target with subsequent clearance of the toxin and/or particle-toxin combination.
"Reversed liquid crystalline phases" in the context of this disclosure includes reversed hexagonal phase and reversed cubic phase, which itself includes both reversed bicontinuous cubic phase and reversed discrete cubic phase. These phases are known in the art of surfactant self-association. All are understood to be as described in detail elsewhere (e.g. in U.S. Patent 6,638,621 B. Structure of the composition to be administered.
Reversed cubic and reversed hexagonal phase material particles have quite a distinct morphology and therefore characteristics in comparison with oil in water emulsions and liposomes. The following compares four different 200 nanometer diameter particles, each made of one of the four materials above. Particles are compared by morphology, phase, radius of monolayer curvature, specific surface area, hydrophobic volume fraction, farthest distance to polar or apolar domains, and loading capacity.
Reversed cubic phase material has an intricate long range nanometer-scale order, and may exist either in bulk material or particulate form. The fluid lipid bilayer is arranged with precise curvature in repeating cubic space groups, creating interlaced polar and apolar microdomains. It has a very high interfacial surface area. The radius of monolayer curvature of a typical cubic phase is on the order of 3 nanometers. The specific surface area is approximately 40 m2/mL. The hydrophobic volume fraction approximates 50-75%. The farthest distance to a polar or apolar domain from any point in or on the particle is only 3 nanometers. A reversed cubic phase particle can carry hydrophobic, hydrophilic and amphiphilic compounds in hydrophilic domains, in hydrophobic domains, and straddling both types of domains.
Similarly, reversed hexagonal phase material also has an intricate long range nanometer-scale order, and may be bulk material or particulate form. It also consists of a fluid lipid layer arranged with precise curvature creating polar microdomains, but in contrast to reversed cubic phase material, the structural units are cylinders arranged in a repeating pattern conforming to a hexagonal space group. Reversed hexagonal phase material also has a high interfacial surface area, though not as high as the reversed cubic phase. The radius of monolayer curvature of a reversed hexagonal phase is on the order of approximately 1.5 nanometers. The specific surface area is about 25m2/mL and the hydrophobic volume fraction is roughly 80%. As in the reversed cubic phase particle, the farthest distance to a polar or apolar domain is approximately 3 nanometers from any point in or on the particle. The reversed hexagonal phase particle, like the reversed cubic phase particle, can carry hydrophobic, hydrophilic and amphiphilic compounds in hydrophilic domains, in hydrophobic domains, and straddling both types of domains.
By contrast, an oil-in-water emulsion, such as Intralipid , has no long range nanometer-scale order. It consists of fat droplets of various sizes and shapes surrounded by a lipid-rich layer in an aqueous medium. A 200 nanometer emulsion oil droplet has the lowest interfacial surface area of all particles compared here. It is comprised of an oil-rich liquid phase surrounded by lipid-rich phase. For such an emulsion particle, the radius of monolayer curvature is 100 nanometers. The specific surface area is only 6m2/mL. The hydrophobic volume fraction is 95%, but the farthest distance to polar or apolar domain is 98 nanometers.
Liposomes, too, differ significantly in structure and characteristics from reversed cubic and reversed hexagonal phase material particles. As true of emulsions, liposomes have no long range nanometer scale order. They occur only in particulate form: the basic structure is one or more solid lipid (or less commonly, fluid) bilayers, generally spherical, encapsulating a large polar liquid phase (usually aqueous) compartment. Liposomes have a very low interfacial surface area. They are derived from lamellar phase material, with a liquid phase core. The radius of monolayer curvature of a 200 nanometer liposome is approximately 100 nanometers. The specific surface area is 12m2/mL. The hydrophobic volume fraction is a very small, e.g. 5%, and the farthest distance to polar or apolar domains, like the emulsion droplet, is very large, 96 nanometers.
Without wishing to be bound by theory, the reversal of toxin and drug effects by the invention can be at least partly, if not fully, understood as resulting directly from the action of the particles in absorbing toxin within the particle interior, or adsorbing toxin at the particle surface. The former, namely absorption, can occur by virtue of the ability of the liquid crystalline material to solubilize the toxin or drug (which is amply demonstrated by Example 7), whereas the latter, adsorption, can occur by virtue of particle surface charge, specific capture molecules (such as antibodies) at the surface, hydrophobic interaction, solubilization and partitioning of the toxin within a particle surface layer such as a PEG-rich layer, or a number of other interactions. It should be understood that there is a distinction between a particle surface layer, and a distinct surface phase. Once toxin molecules in the immediate vicinity of the particles are so taken up by the particles, then due to one or more equilibria between free toxin and tissue-bound toxin, tissue-bound toxin molecules may diffuse out of tissue to fill the void left by the departed, particle-sequestered toxin molecules, where they can be ab/adsorbed, and the cycle continues. A more complete description of the process would take into account particle uptake of protein-bound toxin, RES uptake of particles, and other effects, but in any case the key step in the process is absorption or adsorption of toxin by the particles. It is at that point that the particles provided to a human or other mammal patient according to the invention step in and manifest their effect on the pharmacokinetics of the toxin.
The preferred particle architecture is that of a charge-stabilized, uncoated particle, as specified in detail in U.S. Patent 7,713,440. The uncoated particle has the distinct advantage that no occlusive layer interferes with the direct absorption or adsorption of toxins from medium. Thus for example, in the case of a toxin that exhibits slow or limited diffusion across bilayers, lamellar coatings are advised against since they would interfere with the toxin-absorbing properties of the reversed liquid crystalline phase interior.
Indeed, a bicontinuous reversed cubic phase in particular, when uncoated, has a microstructure that allows bilayer-impermeable toxins to migrate directly into its pore space, where the toxin can be effectively maintained there by some combination of permselectivity, hydrophobic interactions with the bilayer, electrostatic interactions with the bilayer, van der Waals forces, or interaction with interior components of the cubic phase. Other particle architectures are possible as well provided that a substantial portion of the particle is a reversed cubic or reversed hexagonal phase.
Solid-coated particles are antithetical to the purpose of rapid toxin uptake and are thus inconsistent with the objects of the invention; this applies to both crystalline lamellar and solid (crystalline or amorphous) nonlamellar coatings. Preferably, most or nearly all of the particle is a reversed liquid crystalline phase, with reversed cubic being most preferred among these.
The reversed cubic or reversed hexagonal phase material in particulate form should be readily accessed by the diffusion of toxin molecules from a site in the body to the material when the particle is at the site. In particular, the particle should not be occluded by an impermeable coating. An impermeable coating would be one which is substantially crystalline (such as a lipid in the gel phase), or more generally in which the self-diffusion coefficient of the toxin within the coating is strongly reduced relative to the self-diffusion coefficient inside the liquid crystalline material; alternatively, the probe of permeability known as pyloPC (chemical name 1-palmitoy1-241'-pyrenedecanoyll phosphatidylcholine) can be used, and we take impermeable to mean that the self-diffusion coefficient of pyloPC in the coating material as measured by the fluorescence photobleaching recovery method as used by Vaz et al. is less than about 1 micron2/sec. [See Vaz, W. L. C., Z. I. Derzko, and K. A. Jacobson (1982) Cell Surf Rev. 8:83-136]. In that publication, Vaz et al. showed that pyloPC exhibits a high D in lipid bilayers above the gel to liquid crystalline temperature, and low D below this transition temperature when the bilayers are crystalline. The dividing point of 1 micron2/sec for this system is broadly indicative of coating fluidity in coated particles generally. The uncoated particles disclosed in U.S. Patent Application Ser. No. 10/889,313 are clearly accessible, as are, quite generally, reversed cubic and reversed hexagonal phase particles coated with coatings that are in liquid or liquid crystalline phases at body temperature (37 C for humans).
The ionically-charged (electrostatically-charged), bilayer-bound components discussed above, and described in detail in U.S. Patent 7,713.440 may bind toxin or pharmacological substances via electrostatic interactions, free of an impermeable coating, or coating of any sort.
In many applications, uncoated particles, particularly uncoated ionically charged particles, may be preferred to particles having reversed cubic or reversed hexagonal phase materials that are coated with solid coatings, such as those described in U.S.
Patent 6,482,517 and U.S. Patent 6,638,621 to Anderson.
Analysis of the toxins of focus in this disclosure reveals that most of them have at least one polar group on the molecule, and the vast majority have more than one polar group per molecule. In a 200 nrn emulsion droplet within Intralipid , for example, only a very small fraction of the droplet volume is within a typical molecular dimension, say 3 nanometers, of a strongly polar group of the phospholipid-triglyceride particle composition; by strongly polar group we mean a polar group that is, for example, operative as a surfactant head group as discussed in, e.g., U.S. Patent 6,638,621. By contrast, within a particle of the instant invention, virtually every point in the particle is within 3 nanometers of a polar group that is operative as a surfactant head group. Thus, even as hydrophobic groups of the toxin molecule localize in hydrophobic bilayer domains, any polar groups on the toxin can simultaneously localize in close proximity to such a surfactant polar group, and/or to water molecules (which hydrate the surfactant head groups), to experience energetically favorable polar interactions, without paying a large entropic price. This in turn leads to higher toxin solubilities, and higher partition coefficients, in particles of the instant invention over those of emulsion droplets, and this can translate directly into better performance of the instant invention over fat emulsions in terms of lower lipid doses (and thus less voluminous injections) required, and more rapid and complete removal of toxin from blood and/or tissue, and a wider range or toxins which can be effectively attenuated by treatment as described herein.
The surface area of accessible bilayer surface in a 200 nm particle of the bicontinuous cubic phase is an order of magnitude higher than that of an Intralipid emulsion droplet of the same size. This in itself makes the dispersions of the invention advantageous over emulsions in a number of cases: where the toxin adsorbs to the bilayer or binds to a bilayer component; where the toxin binds to a component (such as an antibody) which extends from the bilayer surface, perhaps with a spacer arm; where uptake of the toxin is limited by diffusion through a concentration gradient that extends the full particle radius in the case of an emulsion droplet (thus approximately 100 nm), but only half the bilayer thickness in a cubic phase particle (thus approximately 2 nm); where the toxin is a macromolecule that binds to the particle by inserting a hydrophobic moiety (such as an alpha-helix) into the bilayer; and where the toxin has a low partition coefficient and remains in the aqueous domain but interacts sufficiently with the bilayer as to remain substantially within any aqueous pores of the particle. As an example of the first case listed, Example 12 provides an instance where the toxin, an earth metal ion, actually binds to the head groups of the phosphatidylcholine molecule itself.
Particle size for intravenous embodiments of the invention will preferably have an average particle size between about 80 and 1,000 nm, most preferably between about 100 and 700 nm, and wherein 90% of the particle volume is in particles with size less than about 1,500 nm and most preferably less than about 1,000 nm. The full particle size distribution can be adjusted by manipulating the processing conditions (in particular, homogenization time and temperature, and microfluidization if desired), in particular to adjust the fraction of particles that are below about 80 nm in size, since evidence indicates that such particles are cleared more slowly than particles above 80 nm, and it might be desirable in a particular application to have a longer-circulating fraction of particles, so that toxin removal continues for a longer period than in the absence of particles smaller than 80 nm.
Dispersions of uncoated particles of the preferred embodiment bind to plasma protein much less strongly than do emulsion droplets. This is important because where a large volume of emulsion droplets or particles of the invention are given for detoxification, it is disadvantageous, if not dangerous, for the particles or droplets to remove proteins and other components naturally present in the bloodstream. Moreover, in analogy with liposome-disrupting effects of protein opsonization well known in the art, overt uptake of proteins by lipid-based particles¨particularly those such as emulsions which are already nonequilibrium structures¨can rapidly destabilize particles. Because they are weakly attracted to plasma proteins, it is unlikely that a targeting or toxin-capturing compound associated with the particle will be interfered with by interaction of the particle and plasma protein.
C. Toxins amenable to attenuation by the administration of the composition of the invention.
Toxins that are especially amenable to sequestration by particles of the instant invention are those that contain at least one hydrophobic group, and are thus considered either hydrophobic or amphiphilic. Compounds that are strictly hydrophilic, and contain no hydrophobic groups (compounds such as inorganic salts, glycine, and methanol), generally are not amenable to the invention since they will not partition preferentially into the particles of the invention. In the experience of the inventors, a compound is very likely to partition significantly into particles of the invention if one or more of the following criteria is met:
a) it has a contiguous string, or ring, of at least 6 carbon atoms in the molecule;
b) it has a solubility of at least 1% in alpha-tocopherol;
c) it has an octanol-water partition coefficient equal to or greater than about 100;
d) it lowers the surface tension of water to less than about 50 dynes/cm at low concentrations (e.g., less than 1%); or e) if a peptide or protein, it contains a contiguous sequence of at least 4 hydrophobic amino acids.
Bupivacaine and many other local anesthetics clearly fit one or more of these criteria. For example, the octanol-water coefficient of bupivacaine at pH 7.4 is greater than 1,000. It should be noted that the reference to the traditional octanol-water partition coefficient (Kow) is made here because this measure is often tabulated or otherwise available for a wide range of compounds. Nevertheless, in the context of this invention, it is the partition coefficient of the toxin in particles of the invention, as opposed to octanol, that is the most relevant measure. This disclosure will use the nomenclature KQw to indicate the partition coefficient in a cubic (Q) phase over water (or aqueous buffer more generally); that is, the ratio of concentration of the toxin in the cubic phase to the concentration in water, taken after the toxin has had time to equilibrate between contacting water and cubic phase volumes. It should be noted that this cubic phase-water partition coefficient, referred to in this paragraph, should be measured in the absence of albumin (unless the cubic phase in a particular formulation of the invention is, in fact, formulated with albumin as one ingredient) or other proteins. In the Examples below, a measurement is performed of partitioning into the cubic phase in the presence of albumin, in order to more closely mimic the situation where the invention is applied in the body, and this method of measurement is to be distinguished from measurement of the cubic phase-water partition coefficient per se. The term "effective partition coefficient" is used herein when the aqueous phase contains albumin,and typically this will be an albumin concentration of about 40 mg/mL..
In addition to these local anesthetics, propofol and other general anesthetics meet the above criteria. The invention could be used to attenuate the effects of the following intravenous general anesthetics, all of which have octanol-water partition coefficients greater than one hundred (100): eltanolone, minaxolone, methohexital, thiamylal, thiopental, ketamine, chlormethiazole, alphaxalone, and pentobarbital. As in the case of propofol, attenuation of these anesthetics by the invention could be performed either in cases of overdose, or simply to reverse anesthesia when it is no longer needed. Vecuronium bromide and other muscle relaxants also meet or more or these criteria (for example, by virtue of a steroidal backbone), and as shown in Example 15 below, although the octanol-water partition coefficient of vecuronium bromide is less than 100, its cubic phase-water partition coefficient is well above 100, and indeed above 1,000 for at least some cubic phases of use in the invention.
In addition to these drugs, other toxins that can be attenuated by the use of the instant invention include: (i) pharmaceutical compounds (some of which are also substances of abuse) such as propanolol, amitriptyline, verapamil, digoxin, reserpine, rocuronium, pancuronium, propofol, etomidate, halothane, enflurane, and methoxyflurane, benzodiazepines, N-methy1-3,4-methylenedioxyamphetamine, paracetamol, vitamin K antagonists (warfarin, acenocoumarol, phenindione), opioids (morphine, codeine, methadone, thebaine, heroin, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine), Clozapine, Risperidone and Olanzapine (antipsychotics), Paroxetine (antidepressant), Infliximab and Etanercept (anti-rheumatics), Paclitaxel (antineoplastic), Interferon beta (immunomodulator), phenylheptylamines, piperanilides, phenylpiperidines, diphenylpropylamine derivatives, benzomoiphan derivatives, oripavine derivatives, and volatile anesthetics such as nitrous oxide, halothane, enflurane, isoflurane, sevoflurane, and desflurane; (ii) vitamins, particularly the fat-soluble vitamins; (iii) other drugs of abuse such as ***e, heroin, LSD, "ecstasy", mescaline, amphetamines; (iv) compounds commonly known as poisons such as strychnine, carbon monoxide (a rather hydrophobic gas); (v) toxic compounds found in the environment such as pesticides, organophosphates, dichlorodiphenyltrichloroethane (DDT), morphinan derivatives, carbon tetrachloride, chloroform, trichloroethylene, tetrachloroethylene, dichloromethane, chlorofluorocarbons, benzene, toluene, xylene; (vi) toxins used in military and terrorist weapons such as VX; (vii) toxins from plant and animal sources such as snake venom, spider venom, insect toxins, ricin; allergens such as gluten, peanut oil; and (viii) substances of microbiological origin such as endotoxins, cholera toxin, E. coli enterotoxin, or indeed possibly even portions or whole bodies of viruses, prions, parasites, fungi, cryptosporidia, or even bacteria and other microorganisms. Lipopolysaccharide endotoxins such as Lipid A partition extremely strongly into lipid membranes such as those of the instant invention, and could be especially responsive to removal by the instant invention. The removal or attenuation of the effect of endotoxins in this manner could open up treatment to a variety of conditions, including, for example, sepsis.
D. Selection and composition of material administered As demonstrated below in Examples 17 and 18, the particle compositions can be used in viva to recover diverse pharmacologic agents from their site of action or the blood stream to attenuate the effects of those agents. These results combined with Examples 1-16 and discussions herein, and particularly Example 7, suggest a wide variety of toxins would also be able to be recovered or captured in vivo using a particle composition which includes a reversed cubic phase or reversed hexagonal phase material.
In some specific applications the ability to adsorb, absorb, sequester or otherwise recover a pharmaceutical or toxin may be enhanced by choosing particles of specific constitutions. This may be accomplished by selection of a reversed liquid crystal composition that more favorably solubilizes the toxin or pharmaceutical of interest, and which is pharmaceutically-acceptable, and preferably which achieves a high partition coefficient over aqueous buffer at the relevant pH
(typically about 7.4). Compositions for reversed liquid crystalline phases are discussed at length in U.S. Patent No. 6,482,517, filed September 8, 1998, U.S. published Application No. US
2002/0102280, filed November 28, 2001, and U.S. Patent Publication No. US
2004/0022820, as well as U.S. Patent 7,713,440.
In summary, the liquid crystal composition should solubilize the toxin (or toxins), at a level that provides for clinically significant recovery of the toxin.
Preferably the toxin is soluble in the reversed cubic or hexagonal phase liquid crystal to a level of at least 0.01%, more preferably equal to or greater than about 0.1%, and most preferably equal to or greater than about 1% by weight. The preferred solubility levels are reached by taking advantage of the inherent compound-solubilization properties of reversed liquid crystalline materials, discussed and demonstrated at length in the disclosures cited in the previous paragraph, and by further optimizing the liquid crystal composition through selection of the hydrophobe.
The reversed liquid crystal compositions typically are comprised of a lipid or surfactant, a hydrophobe and water. In the context of this invention, the term "hydrophobe"
means the third major [pseudo-komponent of a surfactant/water/third component liquid crystal composition even if this third component is, strictly speaking, amphiphilic by virtue of, e.g., a hydroxyl group, as in the case of linalool.
Liquid crystal compositions in which the main structural lipid (which is a surfactant, in accordance with the definition of the term "surfactant", see U.S. Patent No.
6,482,517) is phosphatidylcholine ("PC"), or a phosphatidylcholine-rich product such as a purified lecithin, are strongly preferred in the invention. The current invention makes advantageous use of naturally-occurring phospholipids, particularly phosphatidylcholine, and most preferably phosphatidylcholine that have a transition temperature below body temperature, or preferably below ambient temperature¨that is, the compositions employed are above the so-called Krafft line, temperatures below which crystalline phases appear and above which liquid crystalline and/or liquid phases appear. Phosphatidylcholine is put forth as uniquely well suited as the structural basis of injectable particles for toxin removal due to a constellation of favorable features, most importantly low toxicity, but including also the fact that it is endogenous, biocompatible, biodegradable, non-antigenic, cost-effective, and has a decades-long history of safe use in intravenous products at levels of 5 -25 grams per day. While other surfactants and lipids, such as poloxamers (e.g., Pluronics), Tweens, cremophors, mono- and di-glycerides for example, can be used in the invention, these compounds must be scrutinized for toxicities that, in the context of toxin reversal, could lead to dangerous and unpredictable effects. This is particularly true since in the practice of this invention, in the face of toxic challenges to the body, fairly high volumes of the dispersions may be used, typically on the order of 100-400 mL, which contain on the order of 5-20 grams of lipid.
Most preferably, the hydrophobe for an injectable product will be one or more of the following five hydrophobes: tocopherol, linalool, squalene, benzyl benzoate, and long-chain diacetylated monoglycerides.
For an injectable product, in the most preferred method, the solubility of the toxin is first determined, using methods well known in the art, in each of the five preferred hydrophobes identified above. If desired, pairwise combinations of these five solvents (numbering ten) can also be tested, preferably at a 50:50 cosolvent ratio, still keeping the number of solubility tests to a manageable number (viz., 15). Generally speaking, for the purposes of this invention, the hydrophobe mixture that best solubilizes the toxin will also yield the liquid crystalline particle that exhibits the greatest partition coefficient (measured between the liquid crystal and water).
Partitioning experiments can easily be performed by methods well known in the art, and as described in the Examples below. Based on these tests, and on the relative safety of these five hydrophobes themselves¨or rather, on their history of safe use in the intended route of administration¨a hydrophobe or hydrophobe mixture is selected. Tocopherol has the most extensive history of safe use particularly in intravenous products, as it has been used in parenteral nutrition for many decades, even in neonates, and thus it is the most preferred of the five hydrophobes from that perspective. Indeed, tocopherol is widely known to be of very low toxicity, with intravenous doses as high as 30 mg/Kg/day being essentially free from any adverse effects, and the excipient has a long history of safe use in intravenous products, both parenteral nutrition and in liposomal products. Diacetylated monoglycerides, in particular the brand Myvacet , which has been used as an excipient in regulatory-approved intravenous products.
Benzyl benzoate has been used in marketed injectable formulations, though not yet in intravenous formulations. Squalene has been used in vaccines as an adjuvant.
Care should be taken to avoid inclusion of squalene in products intended for use in indications where adjuvant stimulation of the immune system may be contraindicated. Linalool has been found to be safe in a battery of toxicity studies and nonmutagenic [U.S. National Institute of Environmental Health Sciences report, Technical Resources International, Contract No. NO2-CB-50511, June 19971, but has not been used in marketed injectable formulations, and could be a candidate for formal approval in an appropriate product.
Tocopherol can be included as part of the hydrophobe mixture in most cases, for a number of reasons: it helps protect phospholipids from rancidification; it helps with the formation and stability of reversed cubic phases; it is a surprisingly effective solvent for a wide range of hydrophobic and amphiphilic compounds; and its cleansing effect as a vitamin is well known and can serve a helpful role in the detoxification applications of the invention. It should be noted that while wax-like components such as ethyl butyrate have been investigated for use in injectable products, neither ethyl butyrate nor any of the waxes are on the FDA Inactive Ingredient Guide as injectable excipients nor, of course, has any ever been used as a parenteral active or component, and the present invention avoids the use of these waxes.
Once the hydrophobe has been selected, the composition of the reversed liquid crystalline phase is then found by a simple phase behavior mapping, as described in, e.g., U.S. Patent 6,638,821. Quantitative guidelines for determining the composition of a reversed cubic phase are given in U.S. Patent Publication No. US 2004/0022820. An examination of viscosity and appearance under polarizing optical microscopy are indicative of the phases of lyotropic liquid and liquid crystal material.
A dispersant is typically, though not necessarily, incorporated in order to maintain the particles dispersed, and stable as such over time, preferably at least two years without detrimental increase in effective particle size, and in particular without an increase in the fraction of particles larger than about 1.5 micron (and more preferably 1 micron), as this fraction should preferably remain less than 10% preferably, and more preferably less than 1%, by volume. The term "dispersant" will be used herein even in cases where the compound only aids in maintaining stably dispersed particles, and relies on other co-dispersants for achieving the desired effect; for example, in a DMPG-containing dispersion of the invention, Myvacet (a long-chain diacetylated monoglyceride product from Kerry Bioscience) was necessary as co-dispersant.
(DMPG is the abbreviation for dimyristoylphosphatidylglycerol). For most applications, the bile salts discussed herein are the preferred dispersants, with glycocholate being most preferred except possibly in situations where the danger posed by the toxin is low enough that a product with a high cost of materials, due to the high cost of glycocholate, is not justifiable. Bile salts are preferred for another reason, namely they promote uptake of particles by the liver, probably through binding of apolipoprotein E and/or related proteins, resulting in removal of the toxin from circulation; alternatively, cholesterol can be incorporated into the particles, and generally particles of the invention for intravenous use will contain either a bile salt or cholesterol, or both.
Other preferred dispersants are sodium oleate (preferably at 0.03% or less of the dispersion by weight), and other acidic diacyl phospholipids including phosphatidylglycerols, diphosphatidylinositol, and phosphatidic acid. For oral and topical products), other preferred dispersants are sodium docusate, and others given in U.S. Patent 7,713.440.
For intraveneous products with intended use in the United States, salts of fatty acids, including sodium oleate, should be avoided since they are not FDA approved as intravenous excipients, or in the case of caprylie acid, are approved only at extremely low levels, too low to be effective.
Preferred tonicity adjusters are neutral amino acids such as glycine or valine, and other standard, nonionic tonicity adjusters such as mannitol, glycerol, dextrose and xylitol.
E. Attenuation of effect from administration of composition.
The administration of an effective amount of the composition intravenously to a patient who is suffering neurotoxicity or cardiotoxicity due to the administration of a local anesthetic, as for example may occur from the inadvertent introduction directly into the bloodstream by injection of a toxic dose of the local anesthetic, would attenuate the severe neurological and cardiological toxicity caused by the local anesthetic. Administration of an effective amount of the composition under these circumstances would partially or entirely attenuate the toxicity, and mitigate or altogether end the toxic crisis for the patient.
The administration of an effective amount of the composition to a patient under the influence of a recently administered therapeutic dose of the general anesthetic propofol, would attenuate the effects of that drug, allowing the patient to emerge from anesthesia and return to clear headedness more quickly than without the administration of the composition. The ability to shorten the duration of effect can be of important medical value and become part of a standard of care from a point of view of safety and convenience. Similarly, the administration of an effective amount of the composition to a patient who has been treated with and is experiencing the therapeutic effects of a skeletal muscle relaxant such as vecuronium can attenuate the paralytic effects of that drug more quickly than in the absence of the administration of the composition. These and others can serve an important medical need in the surgical theater, and therefore facilitate safe use of optimal agents in these practices.
Prophylactic use of the invention is also possible. By administering an effective amount of the dispersion prior to or simultaneous with the anticipated ingestion, contact, or administration to a human of a drug or toxin, the effect of the toxin or drug can be attenuated from the beginning, and either mitigated in severity or duration or indeed attenuated to such an extent that clinical indications never appear. This is demonstrated in Example 16 below.
Clearly, in order to successfully attenuate the effect of the toxin (since the definition of "attenuate" requires substantial reduction in the effect of the insult), the dispersion must be administered fairly close in proximity to the time of the insult, preferably less than about 15 minutes before the ingestion or administration of the toxin, and more preferably less than about 5 minutes. However, for purposes of prophylaxis, the invention encompasses embodiments that can circulate for considerably longer time periods than minutes. In particular, by the incorporation of "stealth" lipids known by those skilled in the art, circulation times may be greatly increased. Such lipids, which are readily incorporated into particles of focus in the invention as demonstrated in Example 9 below, include PEGylated lipids such as polyethyleneglycol-2000-phosphatidylethanolamine, Vitamin E TPGS, and other lipids created by covalent attachment of hydrophilic polymer chains to hydrophobic lipids.
Settings where prophylaxis with the invention could be of medical importance include administration of local anesthetics at high-risk sites (guarding the patient against the toxic effect of a possible inadvertent injection into the blood stream), chemical or biological warfare arenas, clean-up operations at toxic waste sites, as well as other situations where exposure to toxins is probable or imminent.
The attenuation of a toxin by adsorbing or absorbing the toxin from the site of toxic action stands in contrast with other methods that rely on administering an antidote, provided that one is even available. While a competitive agonist or antagonist might preferentially displace a toxin from binding to a receptor or enzyme, the toxin can nonetheless remain at the site and continue to compete with the antidote for receptor binding, and in the case where the toxin and antidote bind to a common enzyme the competition continues as long as toxin remains in the organ of toxic insult, or in some cases as long as it remains in circulation.
This is particularly problematic in cases where the toxin is only slowly detoxified by an organ such as the liver, and in such a case, the current invention provides for liver uptake and detoxification by virtue of liver uptake of the particles, which can easily be one, or two, or more, orders of magnitude faster than liver uptake of individual molecules; lipidic particles in the 80-1000 nm range can be substantially taken up by the liver in under 10 minutes. Thus, even in cases where a toxin can be displaced from a receptor, it can still be advantageous to administer dispersions of the current invention in order to clear the displaced toxin, provided it can be established that the dispersion does not clear the antidote preferentially over the toxin; this is unlikely if the effective partition coefficient into the particles as measured in the Examples herein is significantly higher for the toxin as compared to the antidote, and becomes more and more effective as an approach the more strongly the antidote binds to the receptor. In many cases, including the important case of bupivacaine, no specific antidote exists, particularly no drug that will effectively, rapidly and safely remove the toxin from its molecular target such as receptor or enzyme, and drugs that might be administered represent an attempt to counteract the toxic effect, such as the administration of vasopressin, epinephrine, norepinephrine, amrinone, amiodarone, milrinone, lidocaine, calcium channel blockers, and phenytoin, none of which have been shown to be consistently safe and effective. [See Renehen EM et al. (2005) Reg. Anesth.
Pain Med.
30(4):3801. The latter is not surprising because in the application of a non-displacing antidote (one that does not exhibit competitive inhibition of the toxin at the receptor site), the toxic effect of the toxin continues in parallel with the counter-effect of the antidote, and as such the antidote does not get to the root of the problem, of the toxic insult. Furthermore, with many toxins the receptor site may not even be known, and in such cases the current invention might be found to be effective in attenuating the toxic effects even in the absence of this knowledge. The invention could, in fact, be used to detoxify the body of a mammal thought, but not known, to be suffering the effects of a toxin or toxins, such as in cases in man where the patient might be unconscious, delusional, or unwilling to admit the ingestion of toxic substances such as drugs of abuse.
F. Varying the composition Other methodologies that fit within the spirit of the invention include the following.
Targeting compounds, such as antibodies, lectins, ligands, bacterial adhesion receptors, complementary nucleic acids, bile salts, biotin derivatives, etc., can be incorporated (as described in U.S. Patent Application 10/889,313) so as to target particles of the invention to sites where toxins may accumulate and/or where they may do the most physiological damage, or to bind toxins directly, and/or to direct particles to elimination sites after toxin recovery. For example, a cholesterol- and/or bile salt-laden particle of the invention could be directed to, e.g., the liver by the ApoE mechanism discussed herein, where it could bring recovered toxin for detoxification, or where it could sequester toxin from the liver so as to, e.g., decrease the local concentration of free, unbound toxin. And glycolipid bacterial adhesion receptors, such as Forssman's antigen, are readily incorporated into the liquid crystalline particles of this invention, and such tagged particles could well bind bacteria with considerable specificity, so as to remove infectious bacteria, or to remove a bacterial by-product such as an endotoxin. Such capture could be coupled with proteases, nucleases, or antibiotics that could render the bound microbes noninfectious. Similarly, biospecific capture compounds, again including antibodies, lectins, ligands, complementary nucleic acids, bile salts, biotin derivatives, and also chelating agents, cyclodextrins, etc., can be incorporated into particles of the invention so as to amplify their ability to recover toxin.
Furthermore, the instant invention includes provisions for adjusting the rate of clearance, by the liver, of the particles, via a simple adjustment of the composition.
The uptake of these toxin or drug-laden particles by the liver constitutes a dominant mechanism for the removal of toxin or drug away from tissues in the body where it exerts its pharmacological effect.
Changing the dispersant from a bile salt, such as deoxycholate, to a charged phospholipid which is not recognized by Apolipoprotein E, can have a large effect on the circulation time of particles. Thus it is of significant importance that in the instant invention, the rate of clearance of the liquid crystalline particles can be increased by raising the concentration of cholesterol and/or bile salt in the particles, or decreased by lowering the concentration of these compounds.
If a bile salt is used for this adjustment, it must satisfy two structural requirements: first, it must have a hydroxyl (-OH) group at the 3-position, and second, it must have an alkyl side chain at the C17 position of the steroidal ring system. Some of the preferred compounds for use in the instant invention, which satisfy these requirements, are the acid and salt (e.g., sodium salt) forms of cholic, glycocholic, deoxycholic, and chenodeoxycholic acids most preferably, and less preferably glycochenodeoxycholic, glycodeoxycholic, lithocholic, and ursodeoxycholic acids.
Glycocholate and deoxycholate salts are especially preferred, as they are more hydrophobic, less toxic, and more reliably charged than others in the series. Deoxycholate has the additional advantage that it is inexpensive relative to glycocholate, although it is less reliably charged than glycocholate and the pH must remain above 7.2 to avoid precipitation.
In contrast, lipid emulsions such as Intralipid are poorly suited for addition of bile salt or cholesterol without undue experimentation. Addition of bile salt to a fat emulsion tends to create mixed micelles, as is well known in the art. And while a small amount of cholesterol could, at least in principle, be incorporated in a fat emulsion, this would be difficult to prepare due to the extremely low aqueous solubility of cholesterol in water, precluding the possibility of mixing the fat emulsion with an aqueous cholesterol solution. More broadly, the natural instability of fat emulsion makes them extraordinarily sensitive to changes in composition.
Also, since reactive oxygen species (ROS) can be detoxified by virtue of the high tocopherol concentrations in the particles of the preferred embodiment, the invention could be useful in pre- or post-treatment of humans or mammals exposed to hazardous radiation. It should be noted that phosphatidylcholine is also reputed to aid in detoxification of ROS taken internally, and the preferred embodiment of the invention offers a combination of tocopherol and phosphatidylcholine. Furthermore, particles of the invention can reasonably be expected to perform better at detoxifying reactive oxygen species than solution formulations of vitamin E, for example, because the ability of the particles to sequester ROS compounds through the solubilization and partitioning effects discussed herein will translate into a longer residence time of proximity between the toxic compound and tocopherol (and phosphatidylcholine as well).
Quite broadly, the sequestering effect of particles of the invention can be used to amplify the effect of detoxifying agents when those agents are embedded in the particles.
The toxin-attenuating aspect of the invention can be combined with other measures known in the medical arts to be of value in the treatment of the particular toxic insult. For example, particles of the invention, deliberately selected to attenuate the effects of a toxin A, could also be loaded with an Active Pharmaceutical Ingredient B, so as to deliver the agent B
while at the same time substantially recovering toxin A. For measures that involve delivery of a pharmaceutical agent that is hydrophobic or amphiphilic in accordance with the discussions above, it must be borne in mind that this pharmaceutical agent may itself be significantly sequestered by particles of the invention if co-administered close in time.
Thus it may be necessary to adjust dosages and dosing schedules of anesthetic agents, antibiotics, paralytic agents, and other agents used in the course of treatment when combined with treatment as per the instant invention.
G. Other applications.
As discussed above, the effects of anesthetics may be attenuated after performing a surgical procedure (e.g., elective or non-elective) or after an observation of a patient (e.g., simply observing a patients response to an anesthetic, etc.) by administration of a particles which include a reversed cubic phase or reversed cubic phase material. These methods can be applied to sequestering a wide variety of other drug substances and toxins. As discussed in more detail below, the methods may be employed in a number of other exemplary applications.
Decompression sickness, one instance of which is commonly called "the bends", is a condition in which nitrogen bubbles appear in the bloodstream and occurs in diving operations, pressurized mines, aircraft and spacecraft. Administration of dispersions of the invention, particularly embodiments in which fluorocarbons are incorporated, could substantially increase the solubility of nitrogen in the bloodstream by solubilizing diatomic nitrogen within the particle interior (that is, by absorbing nitrogen gas), and attenuate the noxious effects of nitrogen in decompression. This is an example of where a normally innocuous substance (N7) can, under certain circumstances, become a toxin in the sense of this disclosure. While the authors are not aware of any published value for the octanol-water partition coefficient of diatomic nitrogen, its extremely low solubility in water (about 17.3 ppm at 25 C) and its solubility in organic solvents indicates that Kow must be extremely high.
Similarly, carbon monoxide is sparingly soluble in water, but appreciably soluble in some organic solvents, again suggesting a high Kow, and thus the invention could potentially be used to attenuate the toxic effects of carbon monoxide poisoning. The effect of particles of the invention in sequestering carbon monoxide, particularly in a mammal already exposed to the toxin, might be further enhanced by incorporating hemoglobin or other heme-containing compound into the particles, and in contrast with red blood cells carrying heme-bound carbon monoxide, particles of the invention carrying CO would be rapidly cleared from the body.
A number of drugs are associated with QTc prolongation and/or torsade de pointes (TdP) including several that have been pulled off the market due to this toxicity problem, and the availability of a reversal agent such as provided by the instant invention could enable the safe use of these drugs. Some such drugs, potential toxins because of these effects, include disopyramide, procainamide, quinidine, amiodarone, bretylium, dofetilide, sotalol, astemizole, terfenadine, fluoroquinolone antibiotics such as grepafloxacin, levofloxacin, and sparfloxacin, macrolide antibiotics such as clarithromycin and erythromycin, imidazoline antifungals such as ketoconazole, antimalarials such as chloroquine, halofantrine and quinine, other antimicrobials such as cotrimoxazole, pentamidine and spiramycin, calcium antagonists such as prenylamine and terodiline, cisapride, and probucol, tricyclic and related antidepressant drugs such as amitriptyline, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, and antipsychotic drugs such as chlorpromazine, droperidol, thioridazine, ziprasidone, sertindole and pimozide.
High atomic weight earth metals, in particular strontium and barium, bind to phospholipid head groups, and have been found in the course of this work to bind rapidly and strongly to particles of the invention containing phospholipids (See Example 12). Thus the invention could be useful in removing such toxins from the body, pointing out yet another mechanism by which toxins can be bound by the invention. Similarly, the invention might be useful in removing leftover radioactive radionuclides following cancer therapy.
Bile salt accumulation in the blood causes jaundice, and since bile salts partition strongly into particles of the invention, another possible use for the invention is in the treatment of jaundice.
A number of compounds used in the operating room and emergency room are known to cause, in some people, allergic reactions such as anaphylaxis. Examples of such compounds, where the current invention could be used to remove such toxins, are salicylates, sulfonamides, cremophor, and penicillins, and to a lesser extent benzyl alcohol.
Due to the inclusion of significant levels of tocopherols in preferred embodiments of the invention, it is likely that the damaging effects of reactive oxygen species from a number of sources could be ameliorated with the invention. As discussed above, Intralipid0 has been tested against reactive oxygen species from produced by phorbol myristate acetate, but only a weak effect was found, which is not surprising since Intralipid does not contain significant levels of any strongly antioxidant compounds. In contrast, many preferred embodiments of the instant invention comprise both high levels of tocopherols and hydrophobic domains into which such species may preferentially partition, such domains typically being tocopherol-rich.
Ischemia and reperfusion are areas where the invention could be useful in a number of ways. The ability of tocopherol-containing embodiments of the invention to not only sequester, but also detoxify (by quenching radicals) reactive oxygen species is of course important in this potential application.
As another example, in organ transplants, the cardioplegia solution used to bring the heart to standstill (which typically includes local anesthetic among other toxins) can be mopped up with the methods and compositions of the invention administered, e.g., via the cardiotomy infusion site to deactivate the cardioplegia solution before attempting to restart the heart.
Injury also stems from biowaste in the donor organ from its prolonged lack of normal blood perfusion. These metabolites are "stunning" to the host upon reattachment of blood supply and the start of blood flow, and the current invention could be useful in removing these metabolites from the recipient's body.
In some embodiments of the instant invention, the reversed liquid crystalline phase material will contain, in its interior, a droplet of a hydrophobe-rich phase that is distinct from the reversed liquid crystalline phase; this is not to be confused with hydrophobic domains that are structural elements of the reversed liquid crystalline phase itself. This hydrophobe-rich droplet will be of a size between about 20 nm and 100 microns, that will contain as a major component a hydrophobe, thus a component of low solubility in water (less than about 3%), and/or of high octanol-water partition coefficient (Kow greater than or equal to about 10, more preferably greater than about 100), in which are solubilized the toxin and some fraction (perhaps very small) of each of the components of the second volume. The solubility of a given toxin in a mixture of hydrophobe and lipid is typically a very strongly increasing function of an increasing hydrophobe:lipid ratio, because the hydrophobe can generally be chosen specifically for its ability to solubilize the particular toxin whereas the choice of lipid has much more to do with its ability to form the desired liquid crystal (in the presence of the hydrophobe, in particular). Such "oil-core" reversed liquid crystalline particles are described in detail in U.S. Patent No.
6,991,809, filed June 21, 2002.
Besides intravenous injection, the preferred method for treating systemic toxicities of bupivacaine and other local anesthetics, and of general anesthetics quite broadly, the instant invention can be administered by a number of routes depending on the source and nature of the toxic challenge. Intraarticular injections could be particularly useful for insults within one or more joints of a mammal. Intramuscular, subcutaneous, and intraperitoneal administration may be used for insults that may be more local in nature. For example, if an intramuscular or subcutaneous administration of a drug has undesired consequences, local injection of dispersions of the invention could reverse, or at least attenuate, the undesirable effect.
For additional attenuation, removal of the dispersed particles laden with toxin could possibly be effected, by, e.g., removing the particle-containing fluid from the site with a syringe, or by applying local pressure or suction, or by using the dispersion of particles more along the lines of an irrigation solution in the first place. For toxins taken in by mouth, the preferred route might be oral, e.g., via pills, tablets, lozenges, capsules, troches, syrups and suspensions, but most preferably as a simple dispersion in most cases. Intrarectal administration might also be useful for toxins within the GI tract. For toxic insults to the eye, particles and particularly dispersions of this invention can be applied through a wide range of ophthalmic routes: periocular, intraocular, conjunctival, subconjunctival, transconjunctival, peribulbar, retrobulbar, subtenons, transscleral, topical eye drop, topical gel, topical dispersion, intraorbital, intrascleral, intravitreal, subretinal, transretinal, choroidal, uveal, intracameral, transcomeal, intracorneal, and intralenticular. And for toxic insults which may be systemic but also may have a local aspect as well (e.g., for a snake bite where local concentrations at the bite site could be very high and yet systemic application of the particles is of course crucial as well), the invention can be applied through an appropriately chosen non-oral route including but not limited to intrathecal, intramuscular, subcutaneous, intra-arterial, rectal, intravaginal, intranasal, via inhalation, and topical. For those applications which are "local" in nature, i.e., administration of the dispersion is done in such a way that the dispersion is primarily confined to a local area where toxin is removed, it will in some cases be advantageous to remove, or otherwise displace, the dispersion from the local site so as to clear the toxin. This could be accomplished by one of a number of means, such as removal by a syringe (pulling the plunger back), flushing with an aqueous buffer or solution, removal by suction or blotting, etc.
It should be noted that, in the spirit of this invention, one can in principle envision the possibility of emulsion formulations that would utilize the more powerful solubilizers (i.e., the preferred hydrophobes) of the instant invention in place of the triglycerides of emulsions, such as the soybean oil of Intralipida However, to begin with, such systems would be inherently inferior to the particles of the instant invention, due to the very intimate association of polar (hydrophilic) and apolar (hydrophobic) groups in the reversed liquid crystalline phases which, as discussed above, quite generally results in higher solubilities and partition coefficients in reversed liquid crystalline phases, as compared to emulsions. Furthermore, and perhaps even more importantly, most, in fact nearly all, of the preferred hydrophobes in the instant invention are at least partially miscible with phosphatidylcholine (the overwhelmingly preferred surfactant), and thus form water-saturated reversed liquid crystalline phases when combined with PC and water¨in sharp contrast with long-chain triglycerides, which due to near-complete immiscibility with PC form emulsions, rather than liquid crystals, at high water content.
EXAMPLES
The following Examples illustrate the present invention but are not to be construed as limiting the invention.
Example 1. An 800 mL batch of a dispersion of reversed cubic phase was prepared consisting of 862.83 mg/mL sterile water, 6.68 mg/mL sodium deoxycholate, 36.34 mg/mL
alpha-tocopherol, 71.17 mg/mL PC-90G (Phospholipon 90G, from Phospholipid GmbH), and 22.98 mg/mL glycine. First, a 14% sodium deoxycholate solution was prepared by sonicating 5.6 g of sodium deoxycholate in 34.4 g of deionized water. An amount 38.62 g of this solution was stirred with 64.84 g of the phosphatidylcholine product Phospholipon PC-90G (from Phospholipid GmbH), and 16.55 g of alpha-tocopherol until well-mixed. This was slowly added to 480 gm of deionized water, and the mixture homogenized for three hours and then allowed to sit overnight without agitation. Later, the sample was re-homogenized for 2 hours and 200 g of a 9.2% glycine solution was subsequently added. The sample was homogenized for another hour and 14.55 g of alpha-tocopherol was added over 10 minutes. The dispersion was homogenized for another 2 hours followed by addition of 0.6016 g of sodium deoxycholate and homogenization for 1 hour. The resulting dispersion consisted of submicron particles of reversed cubic phase material, at a volume concentration of approximately 5%, with a strongly negative zeta potential to the bilayer surface (both internal and external surfaces within the particle), making it well suited for uptake of bupivacaine, or other positively-charged toxins such as vecuronium and morphine.
Example 2. Two dispersions per the instant invention were first prepared, varying in the composition of the hydrophobe, and then tested in the next Example for their ability to sequester bupivacaine, as compared to Intralipid 20%. A 770 mL batch of a dispersion, hereafter called "RA5E", of the invention was prepared consisting of 937.38 mg/mL sterile water, 1.30 mg/mL
sodium deoxycholate, 18.67 mg/mL alpha-tocopherol, 21.85 mg/mL Phospholipon PC-90G, and 20.80 mg/mL glycine. 20.328 g of alpha-tocopherol and 23.802 g of PC-90G was stirred into 1.416 g of sodium deoxycholate dissolved in 14.520 g of sterile water. 42.7 g of this partial cubic phase was slowly added to 715.4 g of sterile water over 15 minutes. The mixture was homogenized at 5400 RPM for 5 hours to create a fine dispersion, followed by a 16.1 g addition of glycine. The dispersion was sparged, vialed and autoclaved.
In the second dispersion of this Example, hereinafter called "RA5EL", the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and linalool. In a 30mL beaker, added 0.3236 grams of sodium deoxycholate, 2.6621 grams of a 50:50 mixture of alpha-tocopherol and linalool, 2.3052 grams of deionized water, and 2.6682 grams of the phosphatidylcholine-rich product Phospholipon 90 (from Phospholipid GmbH).
This mixture was stirred until well-mixed. In a 25mL graduated cylinder, 1.6085 grams of this mixture and 8.3992 grams of deionized water were combined, and this wash homogenized until it formed a fine dispersion, which was vialed and autoclaved at 121 C for 15 minutes.
Example 3. In this Example the dispersions of Example 2 were tested for bupivacaine partitioning, as compared to Intralipid 20%. A 50 mL solution of Krebbs-Ringer buffer was prepared with 4% albumin and approximately 0.1 mg/mL bupivacaine. In a 150 mL
beaker, 2.0081 g bovine albumin was stirred until dissolved in 49.998g Krebbs-Ringer buffer. In a separate 100 mL beaker, 50.0252g of this Krebbs-Ringer Buffer with albumin was added to 0.0054 g of bupivacaine. 1 N HC1 solution was added to the beaker until pH
reached 2.0 and allowed to stir until bupivacaine dissolved. The pH was readjusted to 7.4 with 1 N NaOH
solution.
One mL of formulation (RA5E, RA5EL, as prepared above, or Intralipid 20%) was volumetrically added to a 15 cm length of 1,000 MW dialysis tubing wherein one end was tied shut. The bag was tied on the opposite ends and soaked in deionized water. The bag was then placed in a 10 mL graduated cylinders and 10 mL of Krebbs-Ringer buffer with 4% albumin and approximately 0.1 mg/mL bupivacaine was added volumetrically. The sample was allowed to sit without agitation until HPLC analysis was performed on the dialysis bath water.
In the following Table, the first number gives the percentage of total bupivacaine that was sequestered from the reservoir of spiked buffer; the second number gives the approximate amount sequestered per gram of lipid; this is a far more important measure;
and the third number is the approximate effective partition coefficient between the lipid phase and the buffer:
Dispersion % of bupivacaine Amount sequestered Effective partition sequestered per gram lipid coefficient Intralipid control 11% 0.5 mg/gm 6 RASE from Ex. 2 25% 3.7 mg/gm 58 RA5EL from Ex. 2 37% 2.5 mg/gm 46 Thus, the effective partition coefficient of bupivacaine ( in the presence of albumin, hence "effective" partition coefficient) into particles of the instant invention was measured to be an order of magnitude higher than that into Intralipid emulsion droplets.
Example 4. In this Example of the invention, the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and a diacetylated monoglyceride product marketed under the name Myvacet. A reversed cubic phase was prepared in a 12mL
test tube by combining 0.944gm of Phospholipon 90 (Phospholipid GmbH, Cologne, Germany) along with 0.733gm distilled water, and stifling until a homogenous consistency was reached. Then 0.272gm Myvacet (Kerry Bio-Science, Norwich, NY) and 0.273gm of alpha-tocopherol (ADM) were added, and after thorough mixing the material was optically isotropic and of high viscosity, indeed a reversed cubic phase. This was then dispersed by homogenizing the liquid crystal in an aqueous solution of sodium deoxycholate, where the deoxycholate constituted 5%
of the weight of the cubic phase, to create a dispersion of particles of the invention, which was then autoclaved. The Myvacet diacetylated monoglyceride behaves qualitatively very differently from long-chain triglycerides such as soybean oil when mixed with phosphatidylcholine and water: long-chain triglycerides are well known to form emulsions (Intralipid being an instance), whereas this Example shows that diacetylated monoglycerides, with the right compositions, forms reversed liquid crystalline phases. Furthermore, diacetylated monoglycerides are far better solvents in general that long-chain triglycerides.
Example 5. In this Example, the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and benzyl benzoate. A reversed cubic phase was prepared in a 12mL test tube by combining 0.950gm of Phospholipon 90, along with 0.750gm distilled water, and stirring until a homogenous consistency was reached. Then 0.276gm benzyl benzoate (Sigma Chemical Company) and 0.285gm of alpha-tocopherol were added, and after thorough mixing the material was optically isotropic and of high viscosity. This reversed cubic phase was then dispersed in a solution of sodium glycocholate, with the glycocholate being approximately 3.5% of the cubic phase by weight.
Example 6. In this Example, the partition coefficient of the compound methylene blue, an antimethemoglobinemic drug which is strongly colored, into particles of the invention was estimated using UV-Vis spectrometry. In a 10 mL syringe, 1 mL of an "RA5E"
dispersion of the invention prepared as in Example 2 was spiked with 5 mL water and 250 microliters of a methylene blue solution. A small portion of this dispersion was passed through a 0.1 micron filter every 30 seconds until 6 minutes, then every minute until 12 minutes, and then every 2 minutes until 24 minutes. UV/Vis spectrophotometry was used to determine the concentration of methylene blue in samples collected at 1 minute and 22 minutes. The one-minute sample gave an absorbance of 1.15 and the 22-minute sample gave an absorbance of 1.26, these being equal to within the error of the experiment due to idiosyncrasies of the filtration step. UV/Vis analysis of the methylene blue stock solution compared with the methylene blue concentration in test tubes yielded a log KQw>12 for the dispersion, and no significant difference of concentration or KQw at 1 minute and 22 minutes, where KQw stands for the partition coefficient measured between the cubic phase and water (or aqueous buffer).
Example 7. In this Example, selected drugs of considerable potency, and thus potential toxins, that are each of very low solubility in water and in soybean oil triglycerides (and thus in pharmaceutical emulsions such as Intralipid ) were tested for their solubilities in the preferred phosphatidylcholine / tocopherol / water cubic phase of the invention.
For a given compound X, the solubility in soy oil, and in tocopherol, was first determined as follows. Volatile organic solvents were first screened for the ability to dissolve both compound X and soy oil, or tocopherol. Methanol and dichloromethane were particularly effective for this purpose. After solubilizing the compound and soy oil or tocopherol together with the common solvent, the common solvent was then evaporated using a rotovap. At the resulting concentration of the compound in soy oil or tocopherol, the sample was monitored over approximately 4 weeks for any sign of precipitation, using centrifugation and microscopy; the microscopy was performed using a combination of Differential Interference Contrast (DIC), transmitted dark field, and polarizing modes. For the tocopherol cases, the solution of compound X in tocopherol was split into two parts, and phosphatidylcholine plus water added at the proper ratios to create a cubic phase (this composition is approximately 34%
phosphatidylcholine, 31%
tocopherol plus compound, and 35% water. This cubic phase was monitored for signs of crystallization of the compound. By repeating this process for a range of concentrations of compound X, the approximate solubility of the compound was determined to sufficient accuracy for the present purpose, in soy oil, tocopherol, and PC-tocopherol-water cubic phase. In the case of paclitaxel, the solubility was determined in both the PC-tocopherol-water cubic phase, and in another cubic phase with spearmint oil replacing tocopherol. The following table gives the final results of the work.
Solubility (mg/mL) in:
cubic phase with Drug soy oil Water tocopherol tocopherol Nimodipine -10 0.006 10 20 Paclitaxel <0.1 0.006 11 / 100* 42*
Mycophenolate 3 0.039 200 40 mofetil Cyclosporin 10 0.023 200 70 Alphaxolone <1 <0.005 120* 42*
Etomidate 80 0.000045 200 105 Hydrocortisone <0.1 0.28 30 3 Estradiol spar. sol. 0.05 10 Itraconazole <0.5 0.000001 60 20 Gluten <1 25*
*Spearmint oil used in place of tocopherol; tocopherol mixed 50:50 with linalool.
The results in the table clearly demonstrate the power of the preferred cubic phase composition in solubilizing drugs and toxins, and its vast superiority over triglyceride-based emulsions in this representative selection of compounds.
Example 8. Reversed cubic phase material was prepared in a 250mL beaker by combining 2.00gm sodium deoxycholate (Marcor Development), 44.15gm distilled water, 56.57gm phosphatidylcholine 90G (Phospholipid GmbH), 15.70gm linalool (Aldrich Chemical) and 20.39gm vitamin E (Archer Daniels Midland). The mixture was stirred thoroughly after the addition of each component and the resulting material was optically isotropic and of high viscosity. Of this, 128.5gm of cubic phase was added to a 3L stainless steel beaker into which had previously been added 631.0gm of distilled water. The cubic phase/aqueous solution was dispersed with a standard homogenizer (SiIverson AX-60) at 5174 rpm for approximately two hours, then 40.0gm mannitol (Sigma Chemical) was slowly added to the dispersion and homogenization continued for 15 minutes. The pH was measured at 7.6 (Hanna Instruments). A
portion was filtered through a 5-micron Nylon syringe filter and poured into 10mL sterile Hollister-Stier glass vials. The vials were capped and autoclaved at 121 C and 15 psi pressure for 20 minutes. After cooling, the zeta potential was measured at -58mV
(Beckman Coulter Delsa 440SX) and the particles were substantially submicron in size. The particle density in this formulation of the invention is approximately 16 vol%.
Example 9. This Example shows that particles of the instant invention can be produced which exhibit dramatically less plasma protein binding than emulsion droplets of the Intralipid type. A dispersion of particles loaded with the drug propofol was first prepared as described in US 10/889,313. Diprivan emulsion was obtained from the manufacturer. While these particles contain on the order of 10% propofol, the effect of the drug on protein binding is small compared to the effects of bile salts, surfactants, and cholesterol, as will be seen in the results below, so that the experiment is by and large a reasonable model of dispersions of the invention at least as far as plasma protein binding. A 10 microliter aliquot of dispersion, or emulsion, was diluted with 1000 microliters of deionized water, and also 30 microliters of human plasma was diluted with 3000 microliters of deionized water. In eight Nanosep Centrifugal devices with 300K MWCO, 200 microliters of dilute human plasma solution was incubated with 200 microliters of either a dispersion of the instant invention, or a marketed, Intralipid0-based propofol formulation.
Centrifugal devices were spun down on a microcentrifuge for 20 minutes to separate unbound plasma proteins from particle-bound plasma proteins. SDS solution was added to particle-bound plasma proteins and heated in a boiling water bath for 1 hour. Then 50 microliters of each sample was loaded on gel electrophoresis with 950 microliters of Laemmli Sample Buffer. After performing SDS-PAGE, gels were fixed, stained, and destained according to standard electrophoresis procedure, and photographed, and contained ten lanes. Samples corresponding to the ten lanes are as follows, with all samples containing approximately 1%
(10 mg/mL) propofol overall in the dispersion or emulsion (which would not be expected to qualitatively change the relative protein-binding properties of the dispersions or emulsions):
Lane 1: Long Range Protein Standard (control, i.e., no dispersion or emulsion involved);
Lane 2: Plasma proteins bound to Diprivan (marketed propofol emulsion, a 1%
propofol in Intralipid emulsion);
Lane 3: Plasma proteins bound to a dispersion of uncoated, reversed cubic phase particles containing propofol and stabilized with a bile salt;
Lane 4: Plasma proteins bound to a dispersion with DMPG
(dimyristoylphosphatidylglycerol) and Myvacet (a long-chain diacetylated monoglyceride) as dispersants;
Lane 5: Plasma proteins bound to a dispersion as in lane 3 but with 5%
cholesterol incorporated in the particles;
Lane 6: Plasma proteins bound to a dispersion of phosphatidylcholine /
tocopherol /
propofol / water reversed cubic phase particles with 5% cholesterol in the cubic phase and Pluronic F-68 as dispersant;
Lane 7: Plasma proteins bound to a dispersion of phosphatidylcholine /
tocopherol /
propofol / water reversed cubic phase particles with Pluronic F-68 as dispersant (no cholesterol);
Lane 8: Plasma proteins bound to a dispersion of phosphatidylcholine /
tocopherol /
propofol / water reversed cubic phase particles with sodium oleate as dispersant, where the oleate concentration is quite low (0.03%);
Lane 9: Plasma proteins bound to Baxter's marketed 1% Propofol emulsion based on a fat emulsion;
Lane 10: Plasma proteins (control, i.e., no dispersion or emulsion involved).
Visual analysis of the stained electrophoresis gel showed that plasma protein binding of the 8 formulations (lanes 2-9) could be ranked from most to least binding as follows:
lane 9> lane 2 >> lane 8 >> lane 6 > lane 3 > lane 4 = lane 5 > lane 7, with the last three showing almost no binding whatsoever.
It is clear from these data that emulsion droplets bound much more plasma protein than any of the dispersions of the instant invention. Furthermore, the most hydrophobic of the cubic phase particles, namely that with the low level of sodium oleate as the dispersant, binds the most among the cubic phase formulations, whereas the lowest binding is seen with the "stealth"
particle with a PEGylated surfactant (Pluronic F68) as the dispersant.
The propofol (1%) in each of these dispersions produces a reasonable representation of what the particle chemistry might look like after absorbing propofol, a potential application of the invention as exemplified in Example 18, and this electrophoresis measurement demonstrates that the plasma protein binding of reversed cubic phase particles of the invention in such an application can be modulated by manipulating the composition of the particle.
This can be used to influence the distribution and clearance of particles in the application of the invention, and may allow optimization of the particles with respect to opsonization, targeting, and minimal disruption of physiological processes.
Example 10. The uptake of 3 toxins¨paraoxon, etomidate, and clomipramine¨into particles of the invention, in the presence of albumin, was measured in this Example. Two dispersions, one at approximately 5.6 vol% particle concentration and the other approximately 15%, were prepared as follows. An amount 1.4195 gm of sodium deoxycholate was dissolved in 14.5705 gm of sterile water for injection, to which were added 10.1382 gm of alpha-tocopherol and 23.8061 gm of phosphatidylcholine (Phospholipon 90G from Phospholipid GmbH), and the mixture was stirred vigorously. From this, 35.66 gm were combined with 707.42 gm of sterile water for injection, and the mixture homogenized at 5200 RPM with a Silverson homogenizer at ambient temperature, with temperature maintained below 26 C by ice water jacketing. After 75 minutes, 7.237 gm of tocopherol were slowly dripped in to the dispersion.
Homogenization continued until the particle size was such that the dispersion could be filtered through a 2 micron depth filter, follow by a 1.2 micron membrane filter. This dispersion was then split in half, and to one half was added 8.07 gm of glycine, and sufficient NaOH to yield a pH of 7.6. The other half of the dispersion was placed in a round bottom flask and on a rotovap, whereupon the dispersion weight was reduced from 344.3 gm to 119.9 gm; 2.604 gm of glycine and sufficient NaOH were added to yield a final pH of 7.7. Twenty-milliliter vials were filled, sparged and autoclaved at 121 for 20 minutes, yielding two sterile dispersions, which will be referred to as "RA5-5E" and "RA5-15E" for the 5.6% and 15% particle concentrations, respectively. The zeta potentials were recorded as -46 mV and -32 mV, respectively.
Three toxin solutions were prepared. These were: 18 mg of etomidate in 9 mL of Krebbs-Ringer buffer with 40 mg/mL albumin, 20 microliters of paraoxon in 10 mL deionized water, and 15.1 mg of clomipramine in 30 mL of Krebbs-Ringer buffer with albumin.
Nanosep Omega centrifuge filters at 300,000 MWCO from Pall Filtron were used to separate particles from exterior phase. Thus, into each filter tube were placed 50 microliters of either RA5-5E or RA5-15E (also called LT-728(5E) and LT-728(15E) respectively), 100 microliters of toxin solution, and 150 microliters of distilled water. The loaded tubes were incubated at 40 C for 45 minutes, then centrifuged at 10,800 RPM in a Jouan high-speed centrifuge for approximately 1 hour.
For HPLC analysis, the bottom phase liquid (filtrate) was injected directly, and the top phase (retentate) dissolved in 500 microliters of methanol, then injected. The mobile phase in the HPLC was 30% pH 8.1 phosphate buffer, 35% acetonitrile and 35% methanol.
Standards were run for each of the toxins, and toxin concentrations determined in the exterior (bottom) phase and in the top phase retentate.
The following three tables show the data (assay values are in mg/mL) and the analysis thereof, for the three toxins. The analysis proceeded as follows. The top phase dilution factor was first computed by noting that either 5.6 or 14% liquid crystal was diluted into 500 microliters of methanol. From this and the top phase assay value, the concentration of toxin in the particles was back-calculated. This was then divided by the aqueous phase (bottom phase) concentration, since this was undiluted, in order to arrive at an effective partition coefficient. To check the validity of the calculation, a mass balance was performed by properly combining the two concentrations and respective volumes, and checking how close the result comes to the target, or theoretical, value, which is 50.3 in the clomipramine case and 200 in the other two cases (reflecting the 4-fold lower toxin concentration in the clomipramine toxin solution). One skilled in the art will recognize that this calculation is designed such that errors due to incomplete separation of exterior phase from the particles are minimized¨in particular, by using the known particle concentration rather than a measured top phase volume, the need for complete particle separation is circumvented.
CLOMIPRAMINE
Particle Top ph Eff part Drug acct Assay concn dilution coefficient (target=50.3) Bottom phase LT-728 (5E) 0.00562 0.056 179.6 3195.2 52.0 LT-728 (15E) 00288 0.15 67.7 2348.6 51.6 Top phase LT-728 (5E) 0.1 LT-728 (15E) 0.09996 PARAOXON
Particle Top ph Eff part Bup acct Assay concn dilution coefficient (target=200) Bottom phase LT-728 (5E) 0.462 0.056 179.6 81.6 242.9 LT-728(15E) 0.207 0.15 67.7 98.4 213.3 Top phase LT-728 (5E) 0.21 LT-728 (15E) 0.301 ETOMIDA I
Particle Top ph Eff part Etom acct Assay concn dilution coefficient (target=200) Bottom phase LT-728 (5E) 0.257 0.056 179.6 129.3 169.4 LT-728 (15E) 0.148 0.15 67.7 136.7 195.0 Top phase LT-728 (5E) 0.185 LT-728 (15E) 0.299 Thus the experiment demonstrates that etomidate and paraoxon, and particularly clomipramine, partitioned strongly into the particles of the invention in this experiment.
This is true even though the experiments were performed in the presence of albumin, which of course greatly increases the solubility of the toxins in water, and thus yields a much lower value for the effective partition coefficient than would be found for the true partition coefficient, that is, without albumin. Indeed, albumin was included in order to more closely simulate conditions under which the invention will be used. When the experiment was repeated with etomidate in the absence of albumin, an effective partition coefficient of 309 was recorded (with the mass balance within 5% of theoretical).
Example 11. Using the same dispersions and methods as in Example 10, the effective partition coefficients of lidocaine, benzocaine, and bupivacaine in the presence of albumin were measured. Lidocaine yielded a value of 57 (with the mass balance being within 3% of theoretical), benzocaine a value of 148 (with the mass balance being 84 whereas 95 was theoretical), in the case of the RA5-15E dispersion, and the value for bupivacaine was 62 (mass balance within 3% of theoretical).
Example 12. In this Example, strontium ions (Sr2+), which are known in the art to bind to phosphatidylcholine head groups, were shown to exhibit strong binding to the bilayer-rich cubic phase particles of the invention. To demonstrate this,18.9 mM of strontium chloride was added to an aliquot of the "RA5-15E" dispersion of the invention prepared in Example 10. A high degree of binding of strontium ions to the phosphatidylcholine in RA5-15E was evidenced by the immediate precipitation of the cubic phase, which centrifuged to the bottom of the dispersion.
Were the heavy strontium ions not bound, the cubic phase would be less dense than water and would have centrifuged to the top of the dispersion, as is the usual case with other methods of precipitating the particles. Radiostrontium, and to a lesser extent strontium, have known toxic effects, as do related phosphatidylcholine-binding metals. More broadly, this Example illustrates how the effect of large bilayer surface areas in cubic phase particles can result in effective uptake of toxins that bind to bilayer components.
Example 13. A 15% particle concentration dispersion of the invention was made in the Example without requiring rotovapping (as was used in Example 10). An amount 1.9093 gm of sodium deoxycholate was dissolved in 24.761 gm of sterile water for injection, to which were added 15.94 gm of alpha-tocopherol and 24.06 gm of phosphatidylcholine (Phospholipon 90G
from Phospholipid GmbH), and the mixture was stirred vigorously. From this, 60.01 gm were combined with 554.99 gm of sterile water for injection plus 2.00 mL of 1N
NaOH, and the mixture homogenized at 5200 RPM with a SiIverson AX60 1/2 HP homogenizer at ambient temperature, with temperature maintained between 19 and 28 C by ice water jacketing. After 3 hours, 3.6999 gm of tocopherol were slowly dripped in to the dispersion.
Homogenization continued for 2 hours and 20 minutes. Glycerol was added to a concentration of 2.3% for tonicity, the dispersion filtered through a 2 micron depth filter, and phosphate buffer added to a concentration of 20 mM, and the pH adjusted. Vials were loaded, sparged with nitrogen, capped and autoclaved at 121 C and 15 psi for 15 minutes. The final dispersion had a mean particle size, using unimodal analysis, of 193 nm, and a pH of 8Ø
Example 14. In this Example a fluorocarbon was incorporated into the particles, making the particles well suited for uptake of diatomic nitrogen, for potential treatment or prophylaxis of decompression sickness ("the bends" and related conditions). The specific fluorocarbon used was hexafluoropropanol. To start, 0.318 gm of sodium deoxycholate was dissolved in 4.127 gm of water. To this were added 4.01 gm of soy phosphatidylcholine (Lipoid E80), 1.96 gm of alpha-tocopherol, and 0.960 gm of hexafluoropropanol. Mixing this created a high-viscosity reversed cubic phase. An amount 10.16 gm of this liquid crystal was combined with 94.94 gm of water and 1.837 gm of glycerol (for tonicity), and the mixture homogenized with an Intron lab-scale homogenizer. The result was a fine dispersion of the invention, with approximately 10%
fluorocarbon in the cubic phase, or phrased otherwise, where approximately 17%
of the bilayer in the cubic phase was fluorocarbon.
Example 15 In this Example, the partitioning of the quaternary ammonium skeletal muscle relaxant vecuronium bromide, a water-soluble compound with a low octanol-water partition coefficient, between a phosphatidylcholine / tocopherol / water reversed cubic phase and water is measured, and found to be very high, sufficiently high as to enable the use of the invention in attenuating the effect of the drug in the body of a mammal. An amount 0.6169 gm of phosphatidylcholine (Phospholipon 90G, from Phospholipid GmbH) was mixed with 0.6730 gm of alpha-tocopherol and 0.2194 gm of a 10% vecuronium bromide solution in water. An amount 1.1226 gm of this mixture was smeared onto the inner wall of a test tube, and 6.4495 gm of water added to the tube so as to contact the mixture. Upon swelling with water, the mixture became a reversed cubic phase. After 3 days of contact between the cubic and aqueous phases to allow equilibration of the drug between the two phases, HPLC analysis showed that the concentration of vecuronium in the cubic phase was 10.0 mg/mL, while that in the aqueous phase was only 0.006 mg/mL. The partition coefficient between cubic phase and water was thus approximately 1,600 (or log KQw = 3.2). When the content of anionic lipid was increased significantly by incorporating a bile salt, this increased to log KQw approximately 4, which could reflect additional binding of drug due to electrostatic interactions with the bilayer-bound anion.
One with ordinary skill in the art will recognize that the vecuronium mass balance checks correctly if one assumes that the water content of the final cubic phase, after swelling to equilibrium, is approximately 40%, which is in perfect accord with the phase diagram derived in this laboratory for this cubic phase region.
Example 16. The RA5-5E and RA5-15E dispersions prepared in Example 10 were tested in vivo as prophylaxis, in a rat model incorporating a normally-lethal intravenous injection of bupivacaine. Sixteen adult male rats were randomly arranged into four groups of four animals each. Each group of animals were pre-treated with intravenous doses of either 4 ml/Kg normal physiologic saline (Group A), 4m1/Kg of dispersion RA5-15E of the instant invention with a 15 percent particle concentration (Group B), 6m1/Kg of dispersion RA5-5E of the instant invention with a 5.6 percent particle concentration (Group C) or 4m1/Kg Intralipid , a commercially available fat emulsion useful for parenteral nutrition. Animals in all four groups were then given intravenously a known lethal dose (12 mg/Kg) of the amide local anesthetic bupivacaine.
Animals from each group were then monitored for signs and symptoms of cardiotoxicity resulting from the administration of bupivacaine. All four animals in Group A
became pulseless within 10 seconds of the injection of bupivacaine while all of the animals in the remaining three groups survived without clinical signs of cardiotoxicity. This example demonstrates the use of the invention as prophylaxis to toxic injury.
Example 17. The RA5-5E and RA5-15E dispersions prepared in Example 10 were subsequently tested in vivo as a rescue agent in a rat model incorporating a normally-lethal intravenous injection of bupivacaine. Twelve adult male rats were randomly arranged into three groups of four animals each. Animals in each group were given a known lethal dose (12 mg/Kg) of the amide local anesthetic bupivacaine intravenously. Each animal was monitored for signs of acute cardiotoxicity. All animals became pulseless within 10 seconds of the injection of bupivacaine. When each animal became pulseless, it was treated immediately with mild chest compression and with one of the following: (i) 4 ml/Kg noimal physiologic saline (Group A);
(ii) 4m1/Kg of dispersion RA5-15E of the instant invention with a 15 percent particle concentration (Group B); or, (iii) 6m1/Kg of dispersion RA5-5E of the instant invention with a 5.6 percent particle concentration (Group C). All four animals in Group A
succumbed, while all four animals in Groups B and C recovered and exhibited normal pulse within minutes of administration of the dispersion of the instant invention. The administration of the dispersion according to the instant invention rescued the animals from death due to the systemic toxicity of an overdose of a common local anesthetic agent.
Example 18. Ten adult rats with previously inserted in-dwelling intra-jugular (U) venous cannulae were given 10 mg/kg of the intravenous anesthetic induction agent, propofol, via the indwelling U catheter. This constitutes a therapeutic dose. The Time to Emergence from anesthesia (defined as the elapsed time from the start of the propofol injection until the time of eye-closure and the loss of palpebral or eyelash reflex) was recorded for each of the animals.
Twenty four hours later, the same group of ten animals was again given the same dose of mg/kg of propofol via the indwelling U catheter. Immediately after induction of anesthesia, each animal was given an U injection of dispersion RA5-15E from Example 10, at 4 ml/Kg. The Time to Emergence from anesthesia was recorded as on Day 1 for each animal.
The differences in Time to Emergence from Day 1 to Day 2 calculated for each animal. The Time to Emergence from anesthesia was less for every one of the ten animals on Day 2 than on Day 1. The mean reduction in Time to Emergence from Day 1 to Day 2 was 23%, with a minimum reduction of 13% and a maximum reduction of 37%. The administration of the dispersion decreased the Time to Emergence, in this way attenuating the therapeutic effect of a therapeutic dose of the common general anesthetic propofol.
Example 19. Amphotericin B provides an example of an API with high toxicity which has a site of action in the interior of a fungal lipid biomembrane. In this Example the partition coefficient of amphotericin B between the preferred cubic phase of the invention (composition approximately 30% phosphatidylcholine, 30% alpha-tocopherol and 40% water) and water (both phases containing residual DMSO from the experiment) was measured using HPLC, and this partition coefficient was found to be approximately 1,000.
An amount 0.0082 g of Amphotericin B and 0.8 mL of DMSO (dimethylsulfoxide) were added to a 16 mL test tube. The test tube was heated to 60 C until the amphotericin B was completely dissolved. An amount 0.692 g of 2.5% DMPG in the phosphatidylcholine product Lipoid E80, 0.8 mL of DMSO, and 0.6mL of ethanol were added to a second 16 mL
test tube.
The mixture was heated to 60 C and vortexed until the Lipoid E80/DMPG was entirely dissolved. An amount 0.6873 g of vitamin E and 0.8 mL of DMSO were added to a third 16 mL
test tube. The mixture was heated to 60 C and vortexed until the vitamin E was completely dissolved. The contents of the second and third test tubes were added to the first test tube containing the amphotericin B and DMSO mixture. The test tube containing the entire mixture was heated to 60 C for 30 minutes to ensure that all components were completely dissolved.
An amount of 10 mL of deionized water was added to the test tube. The test tube was gently shaken at 40 RPM for 30 minutes on a Lab-Line Junior Orbit Shaker. The aqueous portion was decanted and filtered through Aldrich medium speed filter paper into a clean test tube and labeled "wash 1". This washing procedure was repeated three additional times to obtain "wash 2", "wash 3", and "wash 4".
HPLC analysis was then performed to determine the amphotericin B
concentrations in the 4 wash solutions and the final, quadruply-washed cubic phase. The latter concentration was found to be 1.76 mg/mL, and it was ascertained that the cubic phase contained entrapped pockets of water (as evidenced by an opaque appearance, for example), so that the true concentration in the cubic phase itself was estimated to be approximately 3 mg/mL. In contrast, the amphotericin B concentrations in the "wash 3" and "wash 4" solutions were both approximately 0.0035 mg/mL, thus making the partition coefficient on the order of 1,000.
It is known that amphotericin B partitions much more strongly into fungal cell membranes, the site of pharmacologic action, than into cell membranes of the human kidney, the site of toxic action. It is therefore possible that the application of the instant invention, using for example a phospholipid / tocopherol / water composition, could recover amphotericin B
from the site of toxic action preferentially over the site of desirable pharmacologic action, thus increasing the therapeutic index, or relieving a patient of toxic effects while maintaining antifungal activity.
There is a need for a pharmaceutically acceptable composition and method for attenuating the effects of common drugs in circumstances in which they are toxic and in situations in which for other reasons, such as medical treatment or patient management, their attenuation is desirable which can work effectively, against a range of drugs and other toxins, and can be adjusted for different characteristics of action and different toxins.
SUMMARY OF THE INVENTION
In an exemplary embodiment of the invention, a method of attenuating the toxic effect of a toxin in a human or other mammal is achieved by administering to the human or other mammal in whom a toxin is or is suspected to be present an effective amount of a composition comprising particles which are formed from or include reversed cubic or reversed hexagonal phase material.
The particles are preferably present in a stable dispersion which includes a liquid comprising a polar solvent. The particles may be ionically charged (anionic or cationic).
The administration is preferably by injection (preferably i.v.) and results in the attenuation of the toxic effects of the toxin by the particles adsorbing or absorbing or otherwise sequestering the toxin from the site of toxic action.
It is another exemplary embodiment of this invention, a method of attenuating the therapeutic effect of a drug substance present in a human or other mammal is achieved by administering to the human or mammal in whom a drug substance is or is suspected to be present an effective amount of a composition comprising particles which are formed from or include reversed cubic or reversed hexagonal phase material. The particles are preferably present in a stable dispersion which includes a liquid comprising a polar solvent. The particles may be ionically charged (anionic or cationic). The administration is preferably by injection (preferably i.v.) and results in the attenuation of the therapeutic effects of the drug substance by the particles adsorbing or absorbing or otherwise sequestering the drug substance from the site of pharmacologic action.
A further exemplary embodiment of this invention is to provide a method of attenuating the effect of a chemical substance in a human comprising administering to the human a stabilized composition comprising lipid, tocopherol and a liquid comprising a polar solvent.
Whatever their specific therapeutic use, drugs are not always present at the most desired level in the body, and at times it may be necessary or beneficial to attenuate their effects. Some drugs of medical use, most notably the local anesthetics, can become life-threatening if they are inadvertently injected into a vein or artery, calling for removal or reduction to avoid or minimize neurotoxicity and cardiotoxicity. Other drugs used in medical practice, such as those associated with surgical procedures including general anesthetics like propofol and paralytic agents like vecuronium, can call for removal or reduction in a number of circumstances:
for example, after interruption or even completion of a surgical procedure, it may be desirable to attenuate the lingering effects of the general anesthetic or paralytic agent whose normal therapeutic effect has become, post-operatively, a nuisance, danger or impediment to optimum patient management. In other cases, a drug may have side effects on account of generating toxic metabolites in circulation, it may be debilitating to the patient, or it may be detrimental in terms of tolerance or addiction, and attenuation of the effects of the drug may be an important therapeutic need.
Certain compounds, such as ***e or morphine, for example, are of course used in medical practice, but also are used as drugs of abuse and as such may require removal or reduction in the course of detoxification and rehabilitation. Furthermore, metabolites of certain drugs, such as cocaethylene in the case of ***e and nor-meperedine in the case of meperedine (Demerol ), have considerable toxicity and their removal could be of importance in many settings. Finally, a toxin can be endogenous, such as an autoantibody or cortisol. In a particular embodiment of the invention, the invention permits attenuating the therapeutic effects of drugs on a selective basis, as well as in the removal of exogenous drug substances and endogenous toxins from the site of action.
Therapeutic agents such as propofol and other general anesthetics are selected for use and used, in part, on the basis of the duration and intensity of their therapeutic effect. In the course of their use, clinical circumstances may arise making it desirable to attenuate the therapeutic effects, for example, by reducing the time to emergence from the effect of a general anesthetic, or the duration of effect of the neuromuscular blocking agent. In an exemplary embodiment, the invention provides the ability to attenuate those effects and would provide an additional tool for optimum management of, for example, a course of surgery, as well as for the safety, comfort and convenience of the patient. In the case of an outpatient surgical procedure that proceeded successfully and more promptly than anticipated, for example, there may be benefits to patient and provider alike to accelerate the return of the patient to clear headedness, facilitating the discharge of the patient. In the case of a surgical procedure which has not proceeded according to plan and is being altered or terminated, there may be benefits to accelerating the patient's return to a state free from the therapeutic effects of a general anesthetic or a neuromuscular blocking agent.
In another setting, the course of delivering an anesthetic or securing an airway, it is of critical importance to relax skeletal muscles. This is most commonly accomplished with the use of neuromuscular blocking agents of either the depolarizing or non-depolarizing class.
Neuromuscular blocking agents are used to facilitate endotracheal intubation in securing and maintaining a patent airway, effecting relaxation of skeletal muscles to enable certain operative procedures and to ensure patient safety in certain clinical settings.
Depolarizing agents, i.e.
succinylcholine, act as acetylcholine (Ach) receptor agonists and quickly cause short lived muscle relaxation due to the rapid diffusion away from the neuromuscular junction and are hydrolyzed by nonspecific cholinesterases. In contrast, non-depolarizing agents, i.e.
vecuronium, function as competitive antagonists. The fact that non-depolarizers are neither metabolized by acetylcholinesterase nor eluted quickly from the Ach receptor predictably result in prolonged depolarization of the neuromuscular endplate, and yield longer duration of muscle relaxation. The best clinical practice and safest approach in the care of those paralyzed with neuromuscular blocker agents is to reverse, as completely as possible, the relaxant effects of these agents, especially non-depolarizing agents once relaxation is no longer required.
Typically, reversal of the non-depolarizing agents is augmented by the administration of cholinesterase inhibitors, also known as anticholinesterases, i.e., neostigmine. These agents reversibly bind to the enzyme that degrades Ach thereby indirectly increasing the amount of Ach available to competitively displace non-depolarizing agents from the Ach receptor by re-establishing normal neuromuscular function at the neuromuscular endplate.
Complications and other adverse reactions can occur with the administration cholinesterase inhibitors. These agents may be metabolized or administered in lower doses causing ineffective displacement of non-depolarizers from the receptor, yielding latent and unexpected return of paralysis. Administered in excessive doses, Achase inhibitors may paradoxically potentiate the effects of neuromuscular blockade. Other well known effects of increases in Ach associated with the use of Achase inhibitors include vagal mediated bradycardia, bronchospasm initiated by smooth muscle contraction, central nervous system effects including diffuse excitation, intestinal spasms, increased bladder tone and papillary constriction. Therefore, any strategy to minimize, supplement or preferably avoid the use of cholinesterase inhibitors in the reversal of neuromuscular blockade offers multiple advantages in the clinical setting. In an exemplary embodiment of the invention, this invention provides such a strategy.
Cyclodextrins are known to bind a number of drug molecules, such as rocuronium and vecuronium, and as such are being used as reversal agents for compounds like rocuronium. It should be noted that bradycardia is sometimes associated with the intravenous use of cyclodextrins, which is a distinct problem for the use of such compounds in connection with rescue from local anesthetic toxicity, where bradycardia is already a serious life-threatening complication. In another exemplary embodiment of the invention, an alternative to the use of cyclodextrins is provided.
Another embodiment of the invention relates to the management of the use of anesthetics in the clinical setting (e.g., hospital, doctor's office, clinic, nurses station, etc.). In practice, a patient will be provided with an anesthetic before, or after, or simultaneously with a composition containing particles that include reversed cubic phase or reverse hexagonal phase material. The patient will be subject to a medical or surgical procedure or will be simply observed. The anesthetizing effect of the anesthetic will be attenuated by the particles containing the reversed cubic phase or reverse hexagonal phase material. This allows control of the anesthetizing effect and may enhance a patient's recovery time. The type of anesthetics which may be managed in this way include both general anesthetics such as propofol, etomidate, ketamine, thiopental, a benzodiazepine, a barbiturate, an opioid, haloperidol, droperidol, and phencyclidine, and local anesthetics such as bupivacaine, lidocaine, ropivacaine, mepivacaine, and ***e. With respect to general anesthetics, the invention can be used for decreasing a duration of sedation, reducing a time to emergence, reducing a duration of apnea, and reducing a time to full cognition.
In another embodiment of the invention, pharmaceuticals in a wide range of drug classes can have their effects selectively attenuated by providing the patient with a composition including particles that have either reversed cubic phase or reversed hexagonal phase materials.
The methods of the invention can be used in conjunction with, for example, a patient that has or is suspected to have taken, or a patient that will be provided with a benzodiazepine, an opiate, a central venous system depressant, a respiratory depressant, a cardiovascular depressant, a psychomotor stimulant, a psychotropic, a sedative, a hypnotic, a muscle relaxant, and an organophosphate.
DETAILED DESCRIPTION OF THE PREFERRED
EMBODIMENTS OF THE INVENTION
A. Definitions.
"Attenuation" of a drug effect or toxic effect of a toxin means that one or more of the following occur (as compared to in the absence of treatment with the invention): substantial reduction in intensity of the effect, substantial reduction in the duration of the effect, substantial reduction in physiological insult and damage, substantially accelerated clearance of the drug or toxin from active or otherwise critical sites in the body, substantial reduction in symptoms of adverse reaction to the drug or toxin, substantial reduction in the concentrations of one or more toxic metabolites of the drug or toxin from critical sites in the body, or substantial reduction in pathological binding of exogenous or endogenous substance(s). In this definition, an effect, such as a reduction (e.g., in intensity), is considered substantial if it is clinically or medically useful or beneficial, or useful or beneficial in the management of a patient, to an extent that, in the view of one skilled in the art, it would warrant use of the invention in that situation. Also in the view of one skilled in the art, the effect of attenuating the drug or toxin should be preferential over other effects or side effects that would otherwise negate or render insignificant the desirable attenuating effect.
"Drug" means a compound consisting of or comprising an Active Pharmaceutical Ingredient (API).
"Toxin", in the context of this disclosure, is much broader than the connotation usually implied in day to day speech. In this disclosure "toxin" means any compound, or closely related group of compounds (such as different stereoisomers of a drug or different chain lengths of a particular lipid type), that pose a health risk or medical inconvenience to a mammal or human, and as such call for removal or reduction in the body, or for redistribution within the body (e.g., from tissues to blood, or from the blood to the liver, etc.). A toxin could be endogenous, such as an autoantibody or cortisol for example, though it will more often be an exogenous compound, and most typically an exogenous compound recognized to be toxic or antigenic at least under some circumstances (for purposes of this application, antigenic materials will be treated as toxins). Certain compounds, such as ***e or morphine, for example, are of course used in medical practice, but also are used as drugs of abuse and as such may require removal or reduction in the course of detoxification and rehabilitation, and thus can be toxins in the context of this invention; furthermore, metabolites of such compounds, such as cocaethylene in the case of ***e, have considerable toxicity and their removal by the present invention could be of importance in many settings. Other drugs of medical use, most notably the local anesthetics, can become life-threatening if they are inadvertently injected into a vein or artery, calling for removal or reduction, and in such cases become toxins in the context of this disclosure. Other drugs used in medical practice, such as those associated with anesthesia or pain control, including general anesthetics like propofol or paralytic agents like rocuronium or vecuronium, can call for removal or reduction in a number of circumstances, including overdosage, triggering of dangerous reactions such as malignant hyperthermia (MH) and respiratory depression. In addition, there are situations in which the treating physician or clinician may wish to attenuate the anesthetic effect for clinical reasons, for example, to allow a patient to be safely discharged from a hospital or clinic without having to wait for the entire length of time required for normal metabolism/excretion of the drug. Certain long-acting drugs of medical use, such as reserpine, or sustained-release formulations such as DepoMorphine, may call for removal or reduction if the duration of action needs to be cut, in which case the drug can be deemed a toxin in the context of this invention.
"Pharmaceutically-acceptable" generally designates compounds or compositions in which each excipient is approved by the Food and Drug Administration, or a similar body in another country, for use in a pharmaceutical or vaccine formulation, or belongs to a succinct class of compounds for which a Drug Master File is on file with a government regulatory agency, usually the FDA, or, less preferably, is known from extensive toxicity studies to be safe for the intended route of administration (which in the context of this invention is typically, though not always, intravenous). This also includes compounds that are major components of approved excipients. Listings of approved excipients, each with the various routes of administration for which they are approved, are published from time to time by the Division of Drug Information Resources of the FDA, as in January, 1996 and entitled "Inactive Ingredient Guide". The existence of a Drug Master File at the FDA is additional evidence that a given excipient is acceptable for pharmaceutical use, at least for certain routes of administration. For injectable products, a listing of approved excipients was published in 1997.
See Nema, Washkuhn and Brendel (1997) PDA J. of Phann. Sci. & Technol. 51(4):166. There are certain compounds, such as vitamins and amino acids, which are in injectable products (typically for parenteral nutrition) as "actives", and are thus known to be safe upon injection, and such compounds are considered herein as pharmaceutically-acceptable as excipients as well, for injection. There are also compounds which are not currently listed as an approved excipient, but which have been the subject of an extensive toxicity review and have been shown to be of very low toxicity, and non-mutagenic, and which, upon application to the proper authorities for a specific application, may be approved. A formulation pharmaceutically-acceptable for injection must be sterile.
"Site of action of a toxin or drug" is defined herein to be a location, in molecular terms, where the toxin or drug manifests a clinically significant toxic or pharmacologic effect, which in the context of the invention is a harmful or otherwise undesirable effect motivating application of the invention. To be at the site of action in some cases may include being in the tissue, organ, blood and/or other body fluids. In some instances, the drug or toxin is in such proximity, at the level of molecular binding, to a molecular target as to be capable of exerting a toxic or pharmacologic effect at that moment in time, such as acting as agonist or antagonist at a receptor protein, or otherwise binding and affecting an enzyme, lipid, saccharide, lectin, nucleic acid, vitamin, metal ion, neurotransmitter, hormone, or other target. The site of action of a toxin or drug could itself be exogenous, such as in the case of an antibiotic or antifungal compound where the site of action is on or in a microbe, existing at the time within the body of a human "Recovery" of a toxin or drug by a multitude of particles means that the particles substantially (i.e., with clinically desirable effect) displace it from its site or sites of toxic or pharmacologic action, or prevent it from interacting with that site before it ever requires displacement through interactions between the particles and toxin or drug, including but not limited to adsorption or absorption of the toxin or drug by the particles. An example of recovery that is broadly illustrative is where a toxin molecule, existing at or in the vicinity of a receptor, enzyme, or other molecular target by virtue of interactions with the molecular target, is sequestered by a particle by virtue of interaction(s) with the particle (such as hydrophobic interaction), said toxin molecule therefore becoming less prone to interact with the molecular target due to its sequestration by the particle and, in some cases, by movement of the particle away from the molecular target with subsequent clearance of the toxin and/or particle-toxin combination.
"Reversed liquid crystalline phases" in the context of this disclosure includes reversed hexagonal phase and reversed cubic phase, which itself includes both reversed bicontinuous cubic phase and reversed discrete cubic phase. These phases are known in the art of surfactant self-association. All are understood to be as described in detail elsewhere (e.g. in U.S. Patent 6,638,621 B. Structure of the composition to be administered.
Reversed cubic and reversed hexagonal phase material particles have quite a distinct morphology and therefore characteristics in comparison with oil in water emulsions and liposomes. The following compares four different 200 nanometer diameter particles, each made of one of the four materials above. Particles are compared by morphology, phase, radius of monolayer curvature, specific surface area, hydrophobic volume fraction, farthest distance to polar or apolar domains, and loading capacity.
Reversed cubic phase material has an intricate long range nanometer-scale order, and may exist either in bulk material or particulate form. The fluid lipid bilayer is arranged with precise curvature in repeating cubic space groups, creating interlaced polar and apolar microdomains. It has a very high interfacial surface area. The radius of monolayer curvature of a typical cubic phase is on the order of 3 nanometers. The specific surface area is approximately 40 m2/mL. The hydrophobic volume fraction approximates 50-75%. The farthest distance to a polar or apolar domain from any point in or on the particle is only 3 nanometers. A reversed cubic phase particle can carry hydrophobic, hydrophilic and amphiphilic compounds in hydrophilic domains, in hydrophobic domains, and straddling both types of domains.
Similarly, reversed hexagonal phase material also has an intricate long range nanometer-scale order, and may be bulk material or particulate form. It also consists of a fluid lipid layer arranged with precise curvature creating polar microdomains, but in contrast to reversed cubic phase material, the structural units are cylinders arranged in a repeating pattern conforming to a hexagonal space group. Reversed hexagonal phase material also has a high interfacial surface area, though not as high as the reversed cubic phase. The radius of monolayer curvature of a reversed hexagonal phase is on the order of approximately 1.5 nanometers. The specific surface area is about 25m2/mL and the hydrophobic volume fraction is roughly 80%. As in the reversed cubic phase particle, the farthest distance to a polar or apolar domain is approximately 3 nanometers from any point in or on the particle. The reversed hexagonal phase particle, like the reversed cubic phase particle, can carry hydrophobic, hydrophilic and amphiphilic compounds in hydrophilic domains, in hydrophobic domains, and straddling both types of domains.
By contrast, an oil-in-water emulsion, such as Intralipid , has no long range nanometer-scale order. It consists of fat droplets of various sizes and shapes surrounded by a lipid-rich layer in an aqueous medium. A 200 nanometer emulsion oil droplet has the lowest interfacial surface area of all particles compared here. It is comprised of an oil-rich liquid phase surrounded by lipid-rich phase. For such an emulsion particle, the radius of monolayer curvature is 100 nanometers. The specific surface area is only 6m2/mL. The hydrophobic volume fraction is 95%, but the farthest distance to polar or apolar domain is 98 nanometers.
Liposomes, too, differ significantly in structure and characteristics from reversed cubic and reversed hexagonal phase material particles. As true of emulsions, liposomes have no long range nanometer scale order. They occur only in particulate form: the basic structure is one or more solid lipid (or less commonly, fluid) bilayers, generally spherical, encapsulating a large polar liquid phase (usually aqueous) compartment. Liposomes have a very low interfacial surface area. They are derived from lamellar phase material, with a liquid phase core. The radius of monolayer curvature of a 200 nanometer liposome is approximately 100 nanometers. The specific surface area is 12m2/mL. The hydrophobic volume fraction is a very small, e.g. 5%, and the farthest distance to polar or apolar domains, like the emulsion droplet, is very large, 96 nanometers.
Without wishing to be bound by theory, the reversal of toxin and drug effects by the invention can be at least partly, if not fully, understood as resulting directly from the action of the particles in absorbing toxin within the particle interior, or adsorbing toxin at the particle surface. The former, namely absorption, can occur by virtue of the ability of the liquid crystalline material to solubilize the toxin or drug (which is amply demonstrated by Example 7), whereas the latter, adsorption, can occur by virtue of particle surface charge, specific capture molecules (such as antibodies) at the surface, hydrophobic interaction, solubilization and partitioning of the toxin within a particle surface layer such as a PEG-rich layer, or a number of other interactions. It should be understood that there is a distinction between a particle surface layer, and a distinct surface phase. Once toxin molecules in the immediate vicinity of the particles are so taken up by the particles, then due to one or more equilibria between free toxin and tissue-bound toxin, tissue-bound toxin molecules may diffuse out of tissue to fill the void left by the departed, particle-sequestered toxin molecules, where they can be ab/adsorbed, and the cycle continues. A more complete description of the process would take into account particle uptake of protein-bound toxin, RES uptake of particles, and other effects, but in any case the key step in the process is absorption or adsorption of toxin by the particles. It is at that point that the particles provided to a human or other mammal patient according to the invention step in and manifest their effect on the pharmacokinetics of the toxin.
The preferred particle architecture is that of a charge-stabilized, uncoated particle, as specified in detail in U.S. Patent 7,713,440. The uncoated particle has the distinct advantage that no occlusive layer interferes with the direct absorption or adsorption of toxins from medium. Thus for example, in the case of a toxin that exhibits slow or limited diffusion across bilayers, lamellar coatings are advised against since they would interfere with the toxin-absorbing properties of the reversed liquid crystalline phase interior.
Indeed, a bicontinuous reversed cubic phase in particular, when uncoated, has a microstructure that allows bilayer-impermeable toxins to migrate directly into its pore space, where the toxin can be effectively maintained there by some combination of permselectivity, hydrophobic interactions with the bilayer, electrostatic interactions with the bilayer, van der Waals forces, or interaction with interior components of the cubic phase. Other particle architectures are possible as well provided that a substantial portion of the particle is a reversed cubic or reversed hexagonal phase.
Solid-coated particles are antithetical to the purpose of rapid toxin uptake and are thus inconsistent with the objects of the invention; this applies to both crystalline lamellar and solid (crystalline or amorphous) nonlamellar coatings. Preferably, most or nearly all of the particle is a reversed liquid crystalline phase, with reversed cubic being most preferred among these.
The reversed cubic or reversed hexagonal phase material in particulate form should be readily accessed by the diffusion of toxin molecules from a site in the body to the material when the particle is at the site. In particular, the particle should not be occluded by an impermeable coating. An impermeable coating would be one which is substantially crystalline (such as a lipid in the gel phase), or more generally in which the self-diffusion coefficient of the toxin within the coating is strongly reduced relative to the self-diffusion coefficient inside the liquid crystalline material; alternatively, the probe of permeability known as pyloPC (chemical name 1-palmitoy1-241'-pyrenedecanoyll phosphatidylcholine) can be used, and we take impermeable to mean that the self-diffusion coefficient of pyloPC in the coating material as measured by the fluorescence photobleaching recovery method as used by Vaz et al. is less than about 1 micron2/sec. [See Vaz, W. L. C., Z. I. Derzko, and K. A. Jacobson (1982) Cell Surf Rev. 8:83-136]. In that publication, Vaz et al. showed that pyloPC exhibits a high D in lipid bilayers above the gel to liquid crystalline temperature, and low D below this transition temperature when the bilayers are crystalline. The dividing point of 1 micron2/sec for this system is broadly indicative of coating fluidity in coated particles generally. The uncoated particles disclosed in U.S. Patent Application Ser. No. 10/889,313 are clearly accessible, as are, quite generally, reversed cubic and reversed hexagonal phase particles coated with coatings that are in liquid or liquid crystalline phases at body temperature (37 C for humans).
The ionically-charged (electrostatically-charged), bilayer-bound components discussed above, and described in detail in U.S. Patent 7,713.440 may bind toxin or pharmacological substances via electrostatic interactions, free of an impermeable coating, or coating of any sort.
In many applications, uncoated particles, particularly uncoated ionically charged particles, may be preferred to particles having reversed cubic or reversed hexagonal phase materials that are coated with solid coatings, such as those described in U.S.
Patent 6,482,517 and U.S. Patent 6,638,621 to Anderson.
Analysis of the toxins of focus in this disclosure reveals that most of them have at least one polar group on the molecule, and the vast majority have more than one polar group per molecule. In a 200 nrn emulsion droplet within Intralipid , for example, only a very small fraction of the droplet volume is within a typical molecular dimension, say 3 nanometers, of a strongly polar group of the phospholipid-triglyceride particle composition; by strongly polar group we mean a polar group that is, for example, operative as a surfactant head group as discussed in, e.g., U.S. Patent 6,638,621. By contrast, within a particle of the instant invention, virtually every point in the particle is within 3 nanometers of a polar group that is operative as a surfactant head group. Thus, even as hydrophobic groups of the toxin molecule localize in hydrophobic bilayer domains, any polar groups on the toxin can simultaneously localize in close proximity to such a surfactant polar group, and/or to water molecules (which hydrate the surfactant head groups), to experience energetically favorable polar interactions, without paying a large entropic price. This in turn leads to higher toxin solubilities, and higher partition coefficients, in particles of the instant invention over those of emulsion droplets, and this can translate directly into better performance of the instant invention over fat emulsions in terms of lower lipid doses (and thus less voluminous injections) required, and more rapid and complete removal of toxin from blood and/or tissue, and a wider range or toxins which can be effectively attenuated by treatment as described herein.
The surface area of accessible bilayer surface in a 200 nm particle of the bicontinuous cubic phase is an order of magnitude higher than that of an Intralipid emulsion droplet of the same size. This in itself makes the dispersions of the invention advantageous over emulsions in a number of cases: where the toxin adsorbs to the bilayer or binds to a bilayer component; where the toxin binds to a component (such as an antibody) which extends from the bilayer surface, perhaps with a spacer arm; where uptake of the toxin is limited by diffusion through a concentration gradient that extends the full particle radius in the case of an emulsion droplet (thus approximately 100 nm), but only half the bilayer thickness in a cubic phase particle (thus approximately 2 nm); where the toxin is a macromolecule that binds to the particle by inserting a hydrophobic moiety (such as an alpha-helix) into the bilayer; and where the toxin has a low partition coefficient and remains in the aqueous domain but interacts sufficiently with the bilayer as to remain substantially within any aqueous pores of the particle. As an example of the first case listed, Example 12 provides an instance where the toxin, an earth metal ion, actually binds to the head groups of the phosphatidylcholine molecule itself.
Particle size for intravenous embodiments of the invention will preferably have an average particle size between about 80 and 1,000 nm, most preferably between about 100 and 700 nm, and wherein 90% of the particle volume is in particles with size less than about 1,500 nm and most preferably less than about 1,000 nm. The full particle size distribution can be adjusted by manipulating the processing conditions (in particular, homogenization time and temperature, and microfluidization if desired), in particular to adjust the fraction of particles that are below about 80 nm in size, since evidence indicates that such particles are cleared more slowly than particles above 80 nm, and it might be desirable in a particular application to have a longer-circulating fraction of particles, so that toxin removal continues for a longer period than in the absence of particles smaller than 80 nm.
Dispersions of uncoated particles of the preferred embodiment bind to plasma protein much less strongly than do emulsion droplets. This is important because where a large volume of emulsion droplets or particles of the invention are given for detoxification, it is disadvantageous, if not dangerous, for the particles or droplets to remove proteins and other components naturally present in the bloodstream. Moreover, in analogy with liposome-disrupting effects of protein opsonization well known in the art, overt uptake of proteins by lipid-based particles¨particularly those such as emulsions which are already nonequilibrium structures¨can rapidly destabilize particles. Because they are weakly attracted to plasma proteins, it is unlikely that a targeting or toxin-capturing compound associated with the particle will be interfered with by interaction of the particle and plasma protein.
C. Toxins amenable to attenuation by the administration of the composition of the invention.
Toxins that are especially amenable to sequestration by particles of the instant invention are those that contain at least one hydrophobic group, and are thus considered either hydrophobic or amphiphilic. Compounds that are strictly hydrophilic, and contain no hydrophobic groups (compounds such as inorganic salts, glycine, and methanol), generally are not amenable to the invention since they will not partition preferentially into the particles of the invention. In the experience of the inventors, a compound is very likely to partition significantly into particles of the invention if one or more of the following criteria is met:
a) it has a contiguous string, or ring, of at least 6 carbon atoms in the molecule;
b) it has a solubility of at least 1% in alpha-tocopherol;
c) it has an octanol-water partition coefficient equal to or greater than about 100;
d) it lowers the surface tension of water to less than about 50 dynes/cm at low concentrations (e.g., less than 1%); or e) if a peptide or protein, it contains a contiguous sequence of at least 4 hydrophobic amino acids.
Bupivacaine and many other local anesthetics clearly fit one or more of these criteria. For example, the octanol-water coefficient of bupivacaine at pH 7.4 is greater than 1,000. It should be noted that the reference to the traditional octanol-water partition coefficient (Kow) is made here because this measure is often tabulated or otherwise available for a wide range of compounds. Nevertheless, in the context of this invention, it is the partition coefficient of the toxin in particles of the invention, as opposed to octanol, that is the most relevant measure. This disclosure will use the nomenclature KQw to indicate the partition coefficient in a cubic (Q) phase over water (or aqueous buffer more generally); that is, the ratio of concentration of the toxin in the cubic phase to the concentration in water, taken after the toxin has had time to equilibrate between contacting water and cubic phase volumes. It should be noted that this cubic phase-water partition coefficient, referred to in this paragraph, should be measured in the absence of albumin (unless the cubic phase in a particular formulation of the invention is, in fact, formulated with albumin as one ingredient) or other proteins. In the Examples below, a measurement is performed of partitioning into the cubic phase in the presence of albumin, in order to more closely mimic the situation where the invention is applied in the body, and this method of measurement is to be distinguished from measurement of the cubic phase-water partition coefficient per se. The term "effective partition coefficient" is used herein when the aqueous phase contains albumin,and typically this will be an albumin concentration of about 40 mg/mL..
In addition to these local anesthetics, propofol and other general anesthetics meet the above criteria. The invention could be used to attenuate the effects of the following intravenous general anesthetics, all of which have octanol-water partition coefficients greater than one hundred (100): eltanolone, minaxolone, methohexital, thiamylal, thiopental, ketamine, chlormethiazole, alphaxalone, and pentobarbital. As in the case of propofol, attenuation of these anesthetics by the invention could be performed either in cases of overdose, or simply to reverse anesthesia when it is no longer needed. Vecuronium bromide and other muscle relaxants also meet or more or these criteria (for example, by virtue of a steroidal backbone), and as shown in Example 15 below, although the octanol-water partition coefficient of vecuronium bromide is less than 100, its cubic phase-water partition coefficient is well above 100, and indeed above 1,000 for at least some cubic phases of use in the invention.
In addition to these drugs, other toxins that can be attenuated by the use of the instant invention include: (i) pharmaceutical compounds (some of which are also substances of abuse) such as propanolol, amitriptyline, verapamil, digoxin, reserpine, rocuronium, pancuronium, propofol, etomidate, halothane, enflurane, and methoxyflurane, benzodiazepines, N-methy1-3,4-methylenedioxyamphetamine, paracetamol, vitamin K antagonists (warfarin, acenocoumarol, phenindione), opioids (morphine, codeine, methadone, thebaine, heroin, oxycodone, hydrocodone, dihydrocodeine, hydromorphone, oxymorphone, nicomorphine), Clozapine, Risperidone and Olanzapine (antipsychotics), Paroxetine (antidepressant), Infliximab and Etanercept (anti-rheumatics), Paclitaxel (antineoplastic), Interferon beta (immunomodulator), phenylheptylamines, piperanilides, phenylpiperidines, diphenylpropylamine derivatives, benzomoiphan derivatives, oripavine derivatives, and volatile anesthetics such as nitrous oxide, halothane, enflurane, isoflurane, sevoflurane, and desflurane; (ii) vitamins, particularly the fat-soluble vitamins; (iii) other drugs of abuse such as ***e, heroin, LSD, "ecstasy", mescaline, amphetamines; (iv) compounds commonly known as poisons such as strychnine, carbon monoxide (a rather hydrophobic gas); (v) toxic compounds found in the environment such as pesticides, organophosphates, dichlorodiphenyltrichloroethane (DDT), morphinan derivatives, carbon tetrachloride, chloroform, trichloroethylene, tetrachloroethylene, dichloromethane, chlorofluorocarbons, benzene, toluene, xylene; (vi) toxins used in military and terrorist weapons such as VX; (vii) toxins from plant and animal sources such as snake venom, spider venom, insect toxins, ricin; allergens such as gluten, peanut oil; and (viii) substances of microbiological origin such as endotoxins, cholera toxin, E. coli enterotoxin, or indeed possibly even portions or whole bodies of viruses, prions, parasites, fungi, cryptosporidia, or even bacteria and other microorganisms. Lipopolysaccharide endotoxins such as Lipid A partition extremely strongly into lipid membranes such as those of the instant invention, and could be especially responsive to removal by the instant invention. The removal or attenuation of the effect of endotoxins in this manner could open up treatment to a variety of conditions, including, for example, sepsis.
D. Selection and composition of material administered As demonstrated below in Examples 17 and 18, the particle compositions can be used in viva to recover diverse pharmacologic agents from their site of action or the blood stream to attenuate the effects of those agents. These results combined with Examples 1-16 and discussions herein, and particularly Example 7, suggest a wide variety of toxins would also be able to be recovered or captured in vivo using a particle composition which includes a reversed cubic phase or reversed hexagonal phase material.
In some specific applications the ability to adsorb, absorb, sequester or otherwise recover a pharmaceutical or toxin may be enhanced by choosing particles of specific constitutions. This may be accomplished by selection of a reversed liquid crystal composition that more favorably solubilizes the toxin or pharmaceutical of interest, and which is pharmaceutically-acceptable, and preferably which achieves a high partition coefficient over aqueous buffer at the relevant pH
(typically about 7.4). Compositions for reversed liquid crystalline phases are discussed at length in U.S. Patent No. 6,482,517, filed September 8, 1998, U.S. published Application No. US
2002/0102280, filed November 28, 2001, and U.S. Patent Publication No. US
2004/0022820, as well as U.S. Patent 7,713,440.
In summary, the liquid crystal composition should solubilize the toxin (or toxins), at a level that provides for clinically significant recovery of the toxin.
Preferably the toxin is soluble in the reversed cubic or hexagonal phase liquid crystal to a level of at least 0.01%, more preferably equal to or greater than about 0.1%, and most preferably equal to or greater than about 1% by weight. The preferred solubility levels are reached by taking advantage of the inherent compound-solubilization properties of reversed liquid crystalline materials, discussed and demonstrated at length in the disclosures cited in the previous paragraph, and by further optimizing the liquid crystal composition through selection of the hydrophobe.
The reversed liquid crystal compositions typically are comprised of a lipid or surfactant, a hydrophobe and water. In the context of this invention, the term "hydrophobe"
means the third major [pseudo-komponent of a surfactant/water/third component liquid crystal composition even if this third component is, strictly speaking, amphiphilic by virtue of, e.g., a hydroxyl group, as in the case of linalool.
Liquid crystal compositions in which the main structural lipid (which is a surfactant, in accordance with the definition of the term "surfactant", see U.S. Patent No.
6,482,517) is phosphatidylcholine ("PC"), or a phosphatidylcholine-rich product such as a purified lecithin, are strongly preferred in the invention. The current invention makes advantageous use of naturally-occurring phospholipids, particularly phosphatidylcholine, and most preferably phosphatidylcholine that have a transition temperature below body temperature, or preferably below ambient temperature¨that is, the compositions employed are above the so-called Krafft line, temperatures below which crystalline phases appear and above which liquid crystalline and/or liquid phases appear. Phosphatidylcholine is put forth as uniquely well suited as the structural basis of injectable particles for toxin removal due to a constellation of favorable features, most importantly low toxicity, but including also the fact that it is endogenous, biocompatible, biodegradable, non-antigenic, cost-effective, and has a decades-long history of safe use in intravenous products at levels of 5 -25 grams per day. While other surfactants and lipids, such as poloxamers (e.g., Pluronics), Tweens, cremophors, mono- and di-glycerides for example, can be used in the invention, these compounds must be scrutinized for toxicities that, in the context of toxin reversal, could lead to dangerous and unpredictable effects. This is particularly true since in the practice of this invention, in the face of toxic challenges to the body, fairly high volumes of the dispersions may be used, typically on the order of 100-400 mL, which contain on the order of 5-20 grams of lipid.
Most preferably, the hydrophobe for an injectable product will be one or more of the following five hydrophobes: tocopherol, linalool, squalene, benzyl benzoate, and long-chain diacetylated monoglycerides.
For an injectable product, in the most preferred method, the solubility of the toxin is first determined, using methods well known in the art, in each of the five preferred hydrophobes identified above. If desired, pairwise combinations of these five solvents (numbering ten) can also be tested, preferably at a 50:50 cosolvent ratio, still keeping the number of solubility tests to a manageable number (viz., 15). Generally speaking, for the purposes of this invention, the hydrophobe mixture that best solubilizes the toxin will also yield the liquid crystalline particle that exhibits the greatest partition coefficient (measured between the liquid crystal and water).
Partitioning experiments can easily be performed by methods well known in the art, and as described in the Examples below. Based on these tests, and on the relative safety of these five hydrophobes themselves¨or rather, on their history of safe use in the intended route of administration¨a hydrophobe or hydrophobe mixture is selected. Tocopherol has the most extensive history of safe use particularly in intravenous products, as it has been used in parenteral nutrition for many decades, even in neonates, and thus it is the most preferred of the five hydrophobes from that perspective. Indeed, tocopherol is widely known to be of very low toxicity, with intravenous doses as high as 30 mg/Kg/day being essentially free from any adverse effects, and the excipient has a long history of safe use in intravenous products, both parenteral nutrition and in liposomal products. Diacetylated monoglycerides, in particular the brand Myvacet , which has been used as an excipient in regulatory-approved intravenous products.
Benzyl benzoate has been used in marketed injectable formulations, though not yet in intravenous formulations. Squalene has been used in vaccines as an adjuvant.
Care should be taken to avoid inclusion of squalene in products intended for use in indications where adjuvant stimulation of the immune system may be contraindicated. Linalool has been found to be safe in a battery of toxicity studies and nonmutagenic [U.S. National Institute of Environmental Health Sciences report, Technical Resources International, Contract No. NO2-CB-50511, June 19971, but has not been used in marketed injectable formulations, and could be a candidate for formal approval in an appropriate product.
Tocopherol can be included as part of the hydrophobe mixture in most cases, for a number of reasons: it helps protect phospholipids from rancidification; it helps with the formation and stability of reversed cubic phases; it is a surprisingly effective solvent for a wide range of hydrophobic and amphiphilic compounds; and its cleansing effect as a vitamin is well known and can serve a helpful role in the detoxification applications of the invention. It should be noted that while wax-like components such as ethyl butyrate have been investigated for use in injectable products, neither ethyl butyrate nor any of the waxes are on the FDA Inactive Ingredient Guide as injectable excipients nor, of course, has any ever been used as a parenteral active or component, and the present invention avoids the use of these waxes.
Once the hydrophobe has been selected, the composition of the reversed liquid crystalline phase is then found by a simple phase behavior mapping, as described in, e.g., U.S. Patent 6,638,821. Quantitative guidelines for determining the composition of a reversed cubic phase are given in U.S. Patent Publication No. US 2004/0022820. An examination of viscosity and appearance under polarizing optical microscopy are indicative of the phases of lyotropic liquid and liquid crystal material.
A dispersant is typically, though not necessarily, incorporated in order to maintain the particles dispersed, and stable as such over time, preferably at least two years without detrimental increase in effective particle size, and in particular without an increase in the fraction of particles larger than about 1.5 micron (and more preferably 1 micron), as this fraction should preferably remain less than 10% preferably, and more preferably less than 1%, by volume. The term "dispersant" will be used herein even in cases where the compound only aids in maintaining stably dispersed particles, and relies on other co-dispersants for achieving the desired effect; for example, in a DMPG-containing dispersion of the invention, Myvacet (a long-chain diacetylated monoglyceride product from Kerry Bioscience) was necessary as co-dispersant.
(DMPG is the abbreviation for dimyristoylphosphatidylglycerol). For most applications, the bile salts discussed herein are the preferred dispersants, with glycocholate being most preferred except possibly in situations where the danger posed by the toxin is low enough that a product with a high cost of materials, due to the high cost of glycocholate, is not justifiable. Bile salts are preferred for another reason, namely they promote uptake of particles by the liver, probably through binding of apolipoprotein E and/or related proteins, resulting in removal of the toxin from circulation; alternatively, cholesterol can be incorporated into the particles, and generally particles of the invention for intravenous use will contain either a bile salt or cholesterol, or both.
Other preferred dispersants are sodium oleate (preferably at 0.03% or less of the dispersion by weight), and other acidic diacyl phospholipids including phosphatidylglycerols, diphosphatidylinositol, and phosphatidic acid. For oral and topical products), other preferred dispersants are sodium docusate, and others given in U.S. Patent 7,713.440.
For intraveneous products with intended use in the United States, salts of fatty acids, including sodium oleate, should be avoided since they are not FDA approved as intravenous excipients, or in the case of caprylie acid, are approved only at extremely low levels, too low to be effective.
Preferred tonicity adjusters are neutral amino acids such as glycine or valine, and other standard, nonionic tonicity adjusters such as mannitol, glycerol, dextrose and xylitol.
E. Attenuation of effect from administration of composition.
The administration of an effective amount of the composition intravenously to a patient who is suffering neurotoxicity or cardiotoxicity due to the administration of a local anesthetic, as for example may occur from the inadvertent introduction directly into the bloodstream by injection of a toxic dose of the local anesthetic, would attenuate the severe neurological and cardiological toxicity caused by the local anesthetic. Administration of an effective amount of the composition under these circumstances would partially or entirely attenuate the toxicity, and mitigate or altogether end the toxic crisis for the patient.
The administration of an effective amount of the composition to a patient under the influence of a recently administered therapeutic dose of the general anesthetic propofol, would attenuate the effects of that drug, allowing the patient to emerge from anesthesia and return to clear headedness more quickly than without the administration of the composition. The ability to shorten the duration of effect can be of important medical value and become part of a standard of care from a point of view of safety and convenience. Similarly, the administration of an effective amount of the composition to a patient who has been treated with and is experiencing the therapeutic effects of a skeletal muscle relaxant such as vecuronium can attenuate the paralytic effects of that drug more quickly than in the absence of the administration of the composition. These and others can serve an important medical need in the surgical theater, and therefore facilitate safe use of optimal agents in these practices.
Prophylactic use of the invention is also possible. By administering an effective amount of the dispersion prior to or simultaneous with the anticipated ingestion, contact, or administration to a human of a drug or toxin, the effect of the toxin or drug can be attenuated from the beginning, and either mitigated in severity or duration or indeed attenuated to such an extent that clinical indications never appear. This is demonstrated in Example 16 below.
Clearly, in order to successfully attenuate the effect of the toxin (since the definition of "attenuate" requires substantial reduction in the effect of the insult), the dispersion must be administered fairly close in proximity to the time of the insult, preferably less than about 15 minutes before the ingestion or administration of the toxin, and more preferably less than about 5 minutes. However, for purposes of prophylaxis, the invention encompasses embodiments that can circulate for considerably longer time periods than minutes. In particular, by the incorporation of "stealth" lipids known by those skilled in the art, circulation times may be greatly increased. Such lipids, which are readily incorporated into particles of focus in the invention as demonstrated in Example 9 below, include PEGylated lipids such as polyethyleneglycol-2000-phosphatidylethanolamine, Vitamin E TPGS, and other lipids created by covalent attachment of hydrophilic polymer chains to hydrophobic lipids.
Settings where prophylaxis with the invention could be of medical importance include administration of local anesthetics at high-risk sites (guarding the patient against the toxic effect of a possible inadvertent injection into the blood stream), chemical or biological warfare arenas, clean-up operations at toxic waste sites, as well as other situations where exposure to toxins is probable or imminent.
The attenuation of a toxin by adsorbing or absorbing the toxin from the site of toxic action stands in contrast with other methods that rely on administering an antidote, provided that one is even available. While a competitive agonist or antagonist might preferentially displace a toxin from binding to a receptor or enzyme, the toxin can nonetheless remain at the site and continue to compete with the antidote for receptor binding, and in the case where the toxin and antidote bind to a common enzyme the competition continues as long as toxin remains in the organ of toxic insult, or in some cases as long as it remains in circulation.
This is particularly problematic in cases where the toxin is only slowly detoxified by an organ such as the liver, and in such a case, the current invention provides for liver uptake and detoxification by virtue of liver uptake of the particles, which can easily be one, or two, or more, orders of magnitude faster than liver uptake of individual molecules; lipidic particles in the 80-1000 nm range can be substantially taken up by the liver in under 10 minutes. Thus, even in cases where a toxin can be displaced from a receptor, it can still be advantageous to administer dispersions of the current invention in order to clear the displaced toxin, provided it can be established that the dispersion does not clear the antidote preferentially over the toxin; this is unlikely if the effective partition coefficient into the particles as measured in the Examples herein is significantly higher for the toxin as compared to the antidote, and becomes more and more effective as an approach the more strongly the antidote binds to the receptor. In many cases, including the important case of bupivacaine, no specific antidote exists, particularly no drug that will effectively, rapidly and safely remove the toxin from its molecular target such as receptor or enzyme, and drugs that might be administered represent an attempt to counteract the toxic effect, such as the administration of vasopressin, epinephrine, norepinephrine, amrinone, amiodarone, milrinone, lidocaine, calcium channel blockers, and phenytoin, none of which have been shown to be consistently safe and effective. [See Renehen EM et al. (2005) Reg. Anesth.
Pain Med.
30(4):3801. The latter is not surprising because in the application of a non-displacing antidote (one that does not exhibit competitive inhibition of the toxin at the receptor site), the toxic effect of the toxin continues in parallel with the counter-effect of the antidote, and as such the antidote does not get to the root of the problem, of the toxic insult. Furthermore, with many toxins the receptor site may not even be known, and in such cases the current invention might be found to be effective in attenuating the toxic effects even in the absence of this knowledge. The invention could, in fact, be used to detoxify the body of a mammal thought, but not known, to be suffering the effects of a toxin or toxins, such as in cases in man where the patient might be unconscious, delusional, or unwilling to admit the ingestion of toxic substances such as drugs of abuse.
F. Varying the composition Other methodologies that fit within the spirit of the invention include the following.
Targeting compounds, such as antibodies, lectins, ligands, bacterial adhesion receptors, complementary nucleic acids, bile salts, biotin derivatives, etc., can be incorporated (as described in U.S. Patent Application 10/889,313) so as to target particles of the invention to sites where toxins may accumulate and/or where they may do the most physiological damage, or to bind toxins directly, and/or to direct particles to elimination sites after toxin recovery. For example, a cholesterol- and/or bile salt-laden particle of the invention could be directed to, e.g., the liver by the ApoE mechanism discussed herein, where it could bring recovered toxin for detoxification, or where it could sequester toxin from the liver so as to, e.g., decrease the local concentration of free, unbound toxin. And glycolipid bacterial adhesion receptors, such as Forssman's antigen, are readily incorporated into the liquid crystalline particles of this invention, and such tagged particles could well bind bacteria with considerable specificity, so as to remove infectious bacteria, or to remove a bacterial by-product such as an endotoxin. Such capture could be coupled with proteases, nucleases, or antibiotics that could render the bound microbes noninfectious. Similarly, biospecific capture compounds, again including antibodies, lectins, ligands, complementary nucleic acids, bile salts, biotin derivatives, and also chelating agents, cyclodextrins, etc., can be incorporated into particles of the invention so as to amplify their ability to recover toxin.
Furthermore, the instant invention includes provisions for adjusting the rate of clearance, by the liver, of the particles, via a simple adjustment of the composition.
The uptake of these toxin or drug-laden particles by the liver constitutes a dominant mechanism for the removal of toxin or drug away from tissues in the body where it exerts its pharmacological effect.
Changing the dispersant from a bile salt, such as deoxycholate, to a charged phospholipid which is not recognized by Apolipoprotein E, can have a large effect on the circulation time of particles. Thus it is of significant importance that in the instant invention, the rate of clearance of the liquid crystalline particles can be increased by raising the concentration of cholesterol and/or bile salt in the particles, or decreased by lowering the concentration of these compounds.
If a bile salt is used for this adjustment, it must satisfy two structural requirements: first, it must have a hydroxyl (-OH) group at the 3-position, and second, it must have an alkyl side chain at the C17 position of the steroidal ring system. Some of the preferred compounds for use in the instant invention, which satisfy these requirements, are the acid and salt (e.g., sodium salt) forms of cholic, glycocholic, deoxycholic, and chenodeoxycholic acids most preferably, and less preferably glycochenodeoxycholic, glycodeoxycholic, lithocholic, and ursodeoxycholic acids.
Glycocholate and deoxycholate salts are especially preferred, as they are more hydrophobic, less toxic, and more reliably charged than others in the series. Deoxycholate has the additional advantage that it is inexpensive relative to glycocholate, although it is less reliably charged than glycocholate and the pH must remain above 7.2 to avoid precipitation.
In contrast, lipid emulsions such as Intralipid are poorly suited for addition of bile salt or cholesterol without undue experimentation. Addition of bile salt to a fat emulsion tends to create mixed micelles, as is well known in the art. And while a small amount of cholesterol could, at least in principle, be incorporated in a fat emulsion, this would be difficult to prepare due to the extremely low aqueous solubility of cholesterol in water, precluding the possibility of mixing the fat emulsion with an aqueous cholesterol solution. More broadly, the natural instability of fat emulsion makes them extraordinarily sensitive to changes in composition.
Also, since reactive oxygen species (ROS) can be detoxified by virtue of the high tocopherol concentrations in the particles of the preferred embodiment, the invention could be useful in pre- or post-treatment of humans or mammals exposed to hazardous radiation. It should be noted that phosphatidylcholine is also reputed to aid in detoxification of ROS taken internally, and the preferred embodiment of the invention offers a combination of tocopherol and phosphatidylcholine. Furthermore, particles of the invention can reasonably be expected to perform better at detoxifying reactive oxygen species than solution formulations of vitamin E, for example, because the ability of the particles to sequester ROS compounds through the solubilization and partitioning effects discussed herein will translate into a longer residence time of proximity between the toxic compound and tocopherol (and phosphatidylcholine as well).
Quite broadly, the sequestering effect of particles of the invention can be used to amplify the effect of detoxifying agents when those agents are embedded in the particles.
The toxin-attenuating aspect of the invention can be combined with other measures known in the medical arts to be of value in the treatment of the particular toxic insult. For example, particles of the invention, deliberately selected to attenuate the effects of a toxin A, could also be loaded with an Active Pharmaceutical Ingredient B, so as to deliver the agent B
while at the same time substantially recovering toxin A. For measures that involve delivery of a pharmaceutical agent that is hydrophobic or amphiphilic in accordance with the discussions above, it must be borne in mind that this pharmaceutical agent may itself be significantly sequestered by particles of the invention if co-administered close in time.
Thus it may be necessary to adjust dosages and dosing schedules of anesthetic agents, antibiotics, paralytic agents, and other agents used in the course of treatment when combined with treatment as per the instant invention.
G. Other applications.
As discussed above, the effects of anesthetics may be attenuated after performing a surgical procedure (e.g., elective or non-elective) or after an observation of a patient (e.g., simply observing a patients response to an anesthetic, etc.) by administration of a particles which include a reversed cubic phase or reversed cubic phase material. These methods can be applied to sequestering a wide variety of other drug substances and toxins. As discussed in more detail below, the methods may be employed in a number of other exemplary applications.
Decompression sickness, one instance of which is commonly called "the bends", is a condition in which nitrogen bubbles appear in the bloodstream and occurs in diving operations, pressurized mines, aircraft and spacecraft. Administration of dispersions of the invention, particularly embodiments in which fluorocarbons are incorporated, could substantially increase the solubility of nitrogen in the bloodstream by solubilizing diatomic nitrogen within the particle interior (that is, by absorbing nitrogen gas), and attenuate the noxious effects of nitrogen in decompression. This is an example of where a normally innocuous substance (N7) can, under certain circumstances, become a toxin in the sense of this disclosure. While the authors are not aware of any published value for the octanol-water partition coefficient of diatomic nitrogen, its extremely low solubility in water (about 17.3 ppm at 25 C) and its solubility in organic solvents indicates that Kow must be extremely high.
Similarly, carbon monoxide is sparingly soluble in water, but appreciably soluble in some organic solvents, again suggesting a high Kow, and thus the invention could potentially be used to attenuate the toxic effects of carbon monoxide poisoning. The effect of particles of the invention in sequestering carbon monoxide, particularly in a mammal already exposed to the toxin, might be further enhanced by incorporating hemoglobin or other heme-containing compound into the particles, and in contrast with red blood cells carrying heme-bound carbon monoxide, particles of the invention carrying CO would be rapidly cleared from the body.
A number of drugs are associated with QTc prolongation and/or torsade de pointes (TdP) including several that have been pulled off the market due to this toxicity problem, and the availability of a reversal agent such as provided by the instant invention could enable the safe use of these drugs. Some such drugs, potential toxins because of these effects, include disopyramide, procainamide, quinidine, amiodarone, bretylium, dofetilide, sotalol, astemizole, terfenadine, fluoroquinolone antibiotics such as grepafloxacin, levofloxacin, and sparfloxacin, macrolide antibiotics such as clarithromycin and erythromycin, imidazoline antifungals such as ketoconazole, antimalarials such as chloroquine, halofantrine and quinine, other antimicrobials such as cotrimoxazole, pentamidine and spiramycin, calcium antagonists such as prenylamine and terodiline, cisapride, and probucol, tricyclic and related antidepressant drugs such as amitriptyline, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, and antipsychotic drugs such as chlorpromazine, droperidol, thioridazine, ziprasidone, sertindole and pimozide.
High atomic weight earth metals, in particular strontium and barium, bind to phospholipid head groups, and have been found in the course of this work to bind rapidly and strongly to particles of the invention containing phospholipids (See Example 12). Thus the invention could be useful in removing such toxins from the body, pointing out yet another mechanism by which toxins can be bound by the invention. Similarly, the invention might be useful in removing leftover radioactive radionuclides following cancer therapy.
Bile salt accumulation in the blood causes jaundice, and since bile salts partition strongly into particles of the invention, another possible use for the invention is in the treatment of jaundice.
A number of compounds used in the operating room and emergency room are known to cause, in some people, allergic reactions such as anaphylaxis. Examples of such compounds, where the current invention could be used to remove such toxins, are salicylates, sulfonamides, cremophor, and penicillins, and to a lesser extent benzyl alcohol.
Due to the inclusion of significant levels of tocopherols in preferred embodiments of the invention, it is likely that the damaging effects of reactive oxygen species from a number of sources could be ameliorated with the invention. As discussed above, Intralipid0 has been tested against reactive oxygen species from produced by phorbol myristate acetate, but only a weak effect was found, which is not surprising since Intralipid does not contain significant levels of any strongly antioxidant compounds. In contrast, many preferred embodiments of the instant invention comprise both high levels of tocopherols and hydrophobic domains into which such species may preferentially partition, such domains typically being tocopherol-rich.
Ischemia and reperfusion are areas where the invention could be useful in a number of ways. The ability of tocopherol-containing embodiments of the invention to not only sequester, but also detoxify (by quenching radicals) reactive oxygen species is of course important in this potential application.
As another example, in organ transplants, the cardioplegia solution used to bring the heart to standstill (which typically includes local anesthetic among other toxins) can be mopped up with the methods and compositions of the invention administered, e.g., via the cardiotomy infusion site to deactivate the cardioplegia solution before attempting to restart the heart.
Injury also stems from biowaste in the donor organ from its prolonged lack of normal blood perfusion. These metabolites are "stunning" to the host upon reattachment of blood supply and the start of blood flow, and the current invention could be useful in removing these metabolites from the recipient's body.
In some embodiments of the instant invention, the reversed liquid crystalline phase material will contain, in its interior, a droplet of a hydrophobe-rich phase that is distinct from the reversed liquid crystalline phase; this is not to be confused with hydrophobic domains that are structural elements of the reversed liquid crystalline phase itself. This hydrophobe-rich droplet will be of a size between about 20 nm and 100 microns, that will contain as a major component a hydrophobe, thus a component of low solubility in water (less than about 3%), and/or of high octanol-water partition coefficient (Kow greater than or equal to about 10, more preferably greater than about 100), in which are solubilized the toxin and some fraction (perhaps very small) of each of the components of the second volume. The solubility of a given toxin in a mixture of hydrophobe and lipid is typically a very strongly increasing function of an increasing hydrophobe:lipid ratio, because the hydrophobe can generally be chosen specifically for its ability to solubilize the particular toxin whereas the choice of lipid has much more to do with its ability to form the desired liquid crystal (in the presence of the hydrophobe, in particular). Such "oil-core" reversed liquid crystalline particles are described in detail in U.S. Patent No.
6,991,809, filed June 21, 2002.
Besides intravenous injection, the preferred method for treating systemic toxicities of bupivacaine and other local anesthetics, and of general anesthetics quite broadly, the instant invention can be administered by a number of routes depending on the source and nature of the toxic challenge. Intraarticular injections could be particularly useful for insults within one or more joints of a mammal. Intramuscular, subcutaneous, and intraperitoneal administration may be used for insults that may be more local in nature. For example, if an intramuscular or subcutaneous administration of a drug has undesired consequences, local injection of dispersions of the invention could reverse, or at least attenuate, the undesirable effect.
For additional attenuation, removal of the dispersed particles laden with toxin could possibly be effected, by, e.g., removing the particle-containing fluid from the site with a syringe, or by applying local pressure or suction, or by using the dispersion of particles more along the lines of an irrigation solution in the first place. For toxins taken in by mouth, the preferred route might be oral, e.g., via pills, tablets, lozenges, capsules, troches, syrups and suspensions, but most preferably as a simple dispersion in most cases. Intrarectal administration might also be useful for toxins within the GI tract. For toxic insults to the eye, particles and particularly dispersions of this invention can be applied through a wide range of ophthalmic routes: periocular, intraocular, conjunctival, subconjunctival, transconjunctival, peribulbar, retrobulbar, subtenons, transscleral, topical eye drop, topical gel, topical dispersion, intraorbital, intrascleral, intravitreal, subretinal, transretinal, choroidal, uveal, intracameral, transcomeal, intracorneal, and intralenticular. And for toxic insults which may be systemic but also may have a local aspect as well (e.g., for a snake bite where local concentrations at the bite site could be very high and yet systemic application of the particles is of course crucial as well), the invention can be applied through an appropriately chosen non-oral route including but not limited to intrathecal, intramuscular, subcutaneous, intra-arterial, rectal, intravaginal, intranasal, via inhalation, and topical. For those applications which are "local" in nature, i.e., administration of the dispersion is done in such a way that the dispersion is primarily confined to a local area where toxin is removed, it will in some cases be advantageous to remove, or otherwise displace, the dispersion from the local site so as to clear the toxin. This could be accomplished by one of a number of means, such as removal by a syringe (pulling the plunger back), flushing with an aqueous buffer or solution, removal by suction or blotting, etc.
It should be noted that, in the spirit of this invention, one can in principle envision the possibility of emulsion formulations that would utilize the more powerful solubilizers (i.e., the preferred hydrophobes) of the instant invention in place of the triglycerides of emulsions, such as the soybean oil of Intralipida However, to begin with, such systems would be inherently inferior to the particles of the instant invention, due to the very intimate association of polar (hydrophilic) and apolar (hydrophobic) groups in the reversed liquid crystalline phases which, as discussed above, quite generally results in higher solubilities and partition coefficients in reversed liquid crystalline phases, as compared to emulsions. Furthermore, and perhaps even more importantly, most, in fact nearly all, of the preferred hydrophobes in the instant invention are at least partially miscible with phosphatidylcholine (the overwhelmingly preferred surfactant), and thus form water-saturated reversed liquid crystalline phases when combined with PC and water¨in sharp contrast with long-chain triglycerides, which due to near-complete immiscibility with PC form emulsions, rather than liquid crystals, at high water content.
EXAMPLES
The following Examples illustrate the present invention but are not to be construed as limiting the invention.
Example 1. An 800 mL batch of a dispersion of reversed cubic phase was prepared consisting of 862.83 mg/mL sterile water, 6.68 mg/mL sodium deoxycholate, 36.34 mg/mL
alpha-tocopherol, 71.17 mg/mL PC-90G (Phospholipon 90G, from Phospholipid GmbH), and 22.98 mg/mL glycine. First, a 14% sodium deoxycholate solution was prepared by sonicating 5.6 g of sodium deoxycholate in 34.4 g of deionized water. An amount 38.62 g of this solution was stirred with 64.84 g of the phosphatidylcholine product Phospholipon PC-90G (from Phospholipid GmbH), and 16.55 g of alpha-tocopherol until well-mixed. This was slowly added to 480 gm of deionized water, and the mixture homogenized for three hours and then allowed to sit overnight without agitation. Later, the sample was re-homogenized for 2 hours and 200 g of a 9.2% glycine solution was subsequently added. The sample was homogenized for another hour and 14.55 g of alpha-tocopherol was added over 10 minutes. The dispersion was homogenized for another 2 hours followed by addition of 0.6016 g of sodium deoxycholate and homogenization for 1 hour. The resulting dispersion consisted of submicron particles of reversed cubic phase material, at a volume concentration of approximately 5%, with a strongly negative zeta potential to the bilayer surface (both internal and external surfaces within the particle), making it well suited for uptake of bupivacaine, or other positively-charged toxins such as vecuronium and morphine.
Example 2. Two dispersions per the instant invention were first prepared, varying in the composition of the hydrophobe, and then tested in the next Example for their ability to sequester bupivacaine, as compared to Intralipid 20%. A 770 mL batch of a dispersion, hereafter called "RA5E", of the invention was prepared consisting of 937.38 mg/mL sterile water, 1.30 mg/mL
sodium deoxycholate, 18.67 mg/mL alpha-tocopherol, 21.85 mg/mL Phospholipon PC-90G, and 20.80 mg/mL glycine. 20.328 g of alpha-tocopherol and 23.802 g of PC-90G was stirred into 1.416 g of sodium deoxycholate dissolved in 14.520 g of sterile water. 42.7 g of this partial cubic phase was slowly added to 715.4 g of sterile water over 15 minutes. The mixture was homogenized at 5400 RPM for 5 hours to create a fine dispersion, followed by a 16.1 g addition of glycine. The dispersion was sparged, vialed and autoclaved.
In the second dispersion of this Example, hereinafter called "RA5EL", the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and linalool. In a 30mL beaker, added 0.3236 grams of sodium deoxycholate, 2.6621 grams of a 50:50 mixture of alpha-tocopherol and linalool, 2.3052 grams of deionized water, and 2.6682 grams of the phosphatidylcholine-rich product Phospholipon 90 (from Phospholipid GmbH).
This mixture was stirred until well-mixed. In a 25mL graduated cylinder, 1.6085 grams of this mixture and 8.3992 grams of deionized water were combined, and this wash homogenized until it formed a fine dispersion, which was vialed and autoclaved at 121 C for 15 minutes.
Example 3. In this Example the dispersions of Example 2 were tested for bupivacaine partitioning, as compared to Intralipid 20%. A 50 mL solution of Krebbs-Ringer buffer was prepared with 4% albumin and approximately 0.1 mg/mL bupivacaine. In a 150 mL
beaker, 2.0081 g bovine albumin was stirred until dissolved in 49.998g Krebbs-Ringer buffer. In a separate 100 mL beaker, 50.0252g of this Krebbs-Ringer Buffer with albumin was added to 0.0054 g of bupivacaine. 1 N HC1 solution was added to the beaker until pH
reached 2.0 and allowed to stir until bupivacaine dissolved. The pH was readjusted to 7.4 with 1 N NaOH
solution.
One mL of formulation (RA5E, RA5EL, as prepared above, or Intralipid 20%) was volumetrically added to a 15 cm length of 1,000 MW dialysis tubing wherein one end was tied shut. The bag was tied on the opposite ends and soaked in deionized water. The bag was then placed in a 10 mL graduated cylinders and 10 mL of Krebbs-Ringer buffer with 4% albumin and approximately 0.1 mg/mL bupivacaine was added volumetrically. The sample was allowed to sit without agitation until HPLC analysis was performed on the dialysis bath water.
In the following Table, the first number gives the percentage of total bupivacaine that was sequestered from the reservoir of spiked buffer; the second number gives the approximate amount sequestered per gram of lipid; this is a far more important measure;
and the third number is the approximate effective partition coefficient between the lipid phase and the buffer:
Dispersion % of bupivacaine Amount sequestered Effective partition sequestered per gram lipid coefficient Intralipid control 11% 0.5 mg/gm 6 RASE from Ex. 2 25% 3.7 mg/gm 58 RA5EL from Ex. 2 37% 2.5 mg/gm 46 Thus, the effective partition coefficient of bupivacaine ( in the presence of albumin, hence "effective" partition coefficient) into particles of the instant invention was measured to be an order of magnitude higher than that into Intralipid emulsion droplets.
Example 4. In this Example of the invention, the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and a diacetylated monoglyceride product marketed under the name Myvacet. A reversed cubic phase was prepared in a 12mL
test tube by combining 0.944gm of Phospholipon 90 (Phospholipid GmbH, Cologne, Germany) along with 0.733gm distilled water, and stifling until a homogenous consistency was reached. Then 0.272gm Myvacet (Kerry Bio-Science, Norwich, NY) and 0.273gm of alpha-tocopherol (ADM) were added, and after thorough mixing the material was optically isotropic and of high viscosity, indeed a reversed cubic phase. This was then dispersed by homogenizing the liquid crystal in an aqueous solution of sodium deoxycholate, where the deoxycholate constituted 5%
of the weight of the cubic phase, to create a dispersion of particles of the invention, which was then autoclaved. The Myvacet diacetylated monoglyceride behaves qualitatively very differently from long-chain triglycerides such as soybean oil when mixed with phosphatidylcholine and water: long-chain triglycerides are well known to form emulsions (Intralipid being an instance), whereas this Example shows that diacetylated monoglycerides, with the right compositions, forms reversed liquid crystalline phases. Furthermore, diacetylated monoglycerides are far better solvents in general that long-chain triglycerides.
Example 5. In this Example, the hydrophobe in the reversed cubic phase consisted of a 50:50 mixture of alpha-tocopherol and benzyl benzoate. A reversed cubic phase was prepared in a 12mL test tube by combining 0.950gm of Phospholipon 90, along with 0.750gm distilled water, and stirring until a homogenous consistency was reached. Then 0.276gm benzyl benzoate (Sigma Chemical Company) and 0.285gm of alpha-tocopherol were added, and after thorough mixing the material was optically isotropic and of high viscosity. This reversed cubic phase was then dispersed in a solution of sodium glycocholate, with the glycocholate being approximately 3.5% of the cubic phase by weight.
Example 6. In this Example, the partition coefficient of the compound methylene blue, an antimethemoglobinemic drug which is strongly colored, into particles of the invention was estimated using UV-Vis spectrometry. In a 10 mL syringe, 1 mL of an "RA5E"
dispersion of the invention prepared as in Example 2 was spiked with 5 mL water and 250 microliters of a methylene blue solution. A small portion of this dispersion was passed through a 0.1 micron filter every 30 seconds until 6 minutes, then every minute until 12 minutes, and then every 2 minutes until 24 minutes. UV/Vis spectrophotometry was used to determine the concentration of methylene blue in samples collected at 1 minute and 22 minutes. The one-minute sample gave an absorbance of 1.15 and the 22-minute sample gave an absorbance of 1.26, these being equal to within the error of the experiment due to idiosyncrasies of the filtration step. UV/Vis analysis of the methylene blue stock solution compared with the methylene blue concentration in test tubes yielded a log KQw>12 for the dispersion, and no significant difference of concentration or KQw at 1 minute and 22 minutes, where KQw stands for the partition coefficient measured between the cubic phase and water (or aqueous buffer).
Example 7. In this Example, selected drugs of considerable potency, and thus potential toxins, that are each of very low solubility in water and in soybean oil triglycerides (and thus in pharmaceutical emulsions such as Intralipid ) were tested for their solubilities in the preferred phosphatidylcholine / tocopherol / water cubic phase of the invention.
For a given compound X, the solubility in soy oil, and in tocopherol, was first determined as follows. Volatile organic solvents were first screened for the ability to dissolve both compound X and soy oil, or tocopherol. Methanol and dichloromethane were particularly effective for this purpose. After solubilizing the compound and soy oil or tocopherol together with the common solvent, the common solvent was then evaporated using a rotovap. At the resulting concentration of the compound in soy oil or tocopherol, the sample was monitored over approximately 4 weeks for any sign of precipitation, using centrifugation and microscopy; the microscopy was performed using a combination of Differential Interference Contrast (DIC), transmitted dark field, and polarizing modes. For the tocopherol cases, the solution of compound X in tocopherol was split into two parts, and phosphatidylcholine plus water added at the proper ratios to create a cubic phase (this composition is approximately 34%
phosphatidylcholine, 31%
tocopherol plus compound, and 35% water. This cubic phase was monitored for signs of crystallization of the compound. By repeating this process for a range of concentrations of compound X, the approximate solubility of the compound was determined to sufficient accuracy for the present purpose, in soy oil, tocopherol, and PC-tocopherol-water cubic phase. In the case of paclitaxel, the solubility was determined in both the PC-tocopherol-water cubic phase, and in another cubic phase with spearmint oil replacing tocopherol. The following table gives the final results of the work.
Solubility (mg/mL) in:
cubic phase with Drug soy oil Water tocopherol tocopherol Nimodipine -10 0.006 10 20 Paclitaxel <0.1 0.006 11 / 100* 42*
Mycophenolate 3 0.039 200 40 mofetil Cyclosporin 10 0.023 200 70 Alphaxolone <1 <0.005 120* 42*
Etomidate 80 0.000045 200 105 Hydrocortisone <0.1 0.28 30 3 Estradiol spar. sol. 0.05 10 Itraconazole <0.5 0.000001 60 20 Gluten <1 25*
*Spearmint oil used in place of tocopherol; tocopherol mixed 50:50 with linalool.
The results in the table clearly demonstrate the power of the preferred cubic phase composition in solubilizing drugs and toxins, and its vast superiority over triglyceride-based emulsions in this representative selection of compounds.
Example 8. Reversed cubic phase material was prepared in a 250mL beaker by combining 2.00gm sodium deoxycholate (Marcor Development), 44.15gm distilled water, 56.57gm phosphatidylcholine 90G (Phospholipid GmbH), 15.70gm linalool (Aldrich Chemical) and 20.39gm vitamin E (Archer Daniels Midland). The mixture was stirred thoroughly after the addition of each component and the resulting material was optically isotropic and of high viscosity. Of this, 128.5gm of cubic phase was added to a 3L stainless steel beaker into which had previously been added 631.0gm of distilled water. The cubic phase/aqueous solution was dispersed with a standard homogenizer (SiIverson AX-60) at 5174 rpm for approximately two hours, then 40.0gm mannitol (Sigma Chemical) was slowly added to the dispersion and homogenization continued for 15 minutes. The pH was measured at 7.6 (Hanna Instruments). A
portion was filtered through a 5-micron Nylon syringe filter and poured into 10mL sterile Hollister-Stier glass vials. The vials were capped and autoclaved at 121 C and 15 psi pressure for 20 minutes. After cooling, the zeta potential was measured at -58mV
(Beckman Coulter Delsa 440SX) and the particles were substantially submicron in size. The particle density in this formulation of the invention is approximately 16 vol%.
Example 9. This Example shows that particles of the instant invention can be produced which exhibit dramatically less plasma protein binding than emulsion droplets of the Intralipid type. A dispersion of particles loaded with the drug propofol was first prepared as described in US 10/889,313. Diprivan emulsion was obtained from the manufacturer. While these particles contain on the order of 10% propofol, the effect of the drug on protein binding is small compared to the effects of bile salts, surfactants, and cholesterol, as will be seen in the results below, so that the experiment is by and large a reasonable model of dispersions of the invention at least as far as plasma protein binding. A 10 microliter aliquot of dispersion, or emulsion, was diluted with 1000 microliters of deionized water, and also 30 microliters of human plasma was diluted with 3000 microliters of deionized water. In eight Nanosep Centrifugal devices with 300K MWCO, 200 microliters of dilute human plasma solution was incubated with 200 microliters of either a dispersion of the instant invention, or a marketed, Intralipid0-based propofol formulation.
Centrifugal devices were spun down on a microcentrifuge for 20 minutes to separate unbound plasma proteins from particle-bound plasma proteins. SDS solution was added to particle-bound plasma proteins and heated in a boiling water bath for 1 hour. Then 50 microliters of each sample was loaded on gel electrophoresis with 950 microliters of Laemmli Sample Buffer. After performing SDS-PAGE, gels were fixed, stained, and destained according to standard electrophoresis procedure, and photographed, and contained ten lanes. Samples corresponding to the ten lanes are as follows, with all samples containing approximately 1%
(10 mg/mL) propofol overall in the dispersion or emulsion (which would not be expected to qualitatively change the relative protein-binding properties of the dispersions or emulsions):
Lane 1: Long Range Protein Standard (control, i.e., no dispersion or emulsion involved);
Lane 2: Plasma proteins bound to Diprivan (marketed propofol emulsion, a 1%
propofol in Intralipid emulsion);
Lane 3: Plasma proteins bound to a dispersion of uncoated, reversed cubic phase particles containing propofol and stabilized with a bile salt;
Lane 4: Plasma proteins bound to a dispersion with DMPG
(dimyristoylphosphatidylglycerol) and Myvacet (a long-chain diacetylated monoglyceride) as dispersants;
Lane 5: Plasma proteins bound to a dispersion as in lane 3 but with 5%
cholesterol incorporated in the particles;
Lane 6: Plasma proteins bound to a dispersion of phosphatidylcholine /
tocopherol /
propofol / water reversed cubic phase particles with 5% cholesterol in the cubic phase and Pluronic F-68 as dispersant;
Lane 7: Plasma proteins bound to a dispersion of phosphatidylcholine /
tocopherol /
propofol / water reversed cubic phase particles with Pluronic F-68 as dispersant (no cholesterol);
Lane 8: Plasma proteins bound to a dispersion of phosphatidylcholine /
tocopherol /
propofol / water reversed cubic phase particles with sodium oleate as dispersant, where the oleate concentration is quite low (0.03%);
Lane 9: Plasma proteins bound to Baxter's marketed 1% Propofol emulsion based on a fat emulsion;
Lane 10: Plasma proteins (control, i.e., no dispersion or emulsion involved).
Visual analysis of the stained electrophoresis gel showed that plasma protein binding of the 8 formulations (lanes 2-9) could be ranked from most to least binding as follows:
lane 9> lane 2 >> lane 8 >> lane 6 > lane 3 > lane 4 = lane 5 > lane 7, with the last three showing almost no binding whatsoever.
It is clear from these data that emulsion droplets bound much more plasma protein than any of the dispersions of the instant invention. Furthermore, the most hydrophobic of the cubic phase particles, namely that with the low level of sodium oleate as the dispersant, binds the most among the cubic phase formulations, whereas the lowest binding is seen with the "stealth"
particle with a PEGylated surfactant (Pluronic F68) as the dispersant.
The propofol (1%) in each of these dispersions produces a reasonable representation of what the particle chemistry might look like after absorbing propofol, a potential application of the invention as exemplified in Example 18, and this electrophoresis measurement demonstrates that the plasma protein binding of reversed cubic phase particles of the invention in such an application can be modulated by manipulating the composition of the particle.
This can be used to influence the distribution and clearance of particles in the application of the invention, and may allow optimization of the particles with respect to opsonization, targeting, and minimal disruption of physiological processes.
Example 10. The uptake of 3 toxins¨paraoxon, etomidate, and clomipramine¨into particles of the invention, in the presence of albumin, was measured in this Example. Two dispersions, one at approximately 5.6 vol% particle concentration and the other approximately 15%, were prepared as follows. An amount 1.4195 gm of sodium deoxycholate was dissolved in 14.5705 gm of sterile water for injection, to which were added 10.1382 gm of alpha-tocopherol and 23.8061 gm of phosphatidylcholine (Phospholipon 90G from Phospholipid GmbH), and the mixture was stirred vigorously. From this, 35.66 gm were combined with 707.42 gm of sterile water for injection, and the mixture homogenized at 5200 RPM with a Silverson homogenizer at ambient temperature, with temperature maintained below 26 C by ice water jacketing. After 75 minutes, 7.237 gm of tocopherol were slowly dripped in to the dispersion.
Homogenization continued until the particle size was such that the dispersion could be filtered through a 2 micron depth filter, follow by a 1.2 micron membrane filter. This dispersion was then split in half, and to one half was added 8.07 gm of glycine, and sufficient NaOH to yield a pH of 7.6. The other half of the dispersion was placed in a round bottom flask and on a rotovap, whereupon the dispersion weight was reduced from 344.3 gm to 119.9 gm; 2.604 gm of glycine and sufficient NaOH were added to yield a final pH of 7.7. Twenty-milliliter vials were filled, sparged and autoclaved at 121 for 20 minutes, yielding two sterile dispersions, which will be referred to as "RA5-5E" and "RA5-15E" for the 5.6% and 15% particle concentrations, respectively. The zeta potentials were recorded as -46 mV and -32 mV, respectively.
Three toxin solutions were prepared. These were: 18 mg of etomidate in 9 mL of Krebbs-Ringer buffer with 40 mg/mL albumin, 20 microliters of paraoxon in 10 mL deionized water, and 15.1 mg of clomipramine in 30 mL of Krebbs-Ringer buffer with albumin.
Nanosep Omega centrifuge filters at 300,000 MWCO from Pall Filtron were used to separate particles from exterior phase. Thus, into each filter tube were placed 50 microliters of either RA5-5E or RA5-15E (also called LT-728(5E) and LT-728(15E) respectively), 100 microliters of toxin solution, and 150 microliters of distilled water. The loaded tubes were incubated at 40 C for 45 minutes, then centrifuged at 10,800 RPM in a Jouan high-speed centrifuge for approximately 1 hour.
For HPLC analysis, the bottom phase liquid (filtrate) was injected directly, and the top phase (retentate) dissolved in 500 microliters of methanol, then injected. The mobile phase in the HPLC was 30% pH 8.1 phosphate buffer, 35% acetonitrile and 35% methanol.
Standards were run for each of the toxins, and toxin concentrations determined in the exterior (bottom) phase and in the top phase retentate.
The following three tables show the data (assay values are in mg/mL) and the analysis thereof, for the three toxins. The analysis proceeded as follows. The top phase dilution factor was first computed by noting that either 5.6 or 14% liquid crystal was diluted into 500 microliters of methanol. From this and the top phase assay value, the concentration of toxin in the particles was back-calculated. This was then divided by the aqueous phase (bottom phase) concentration, since this was undiluted, in order to arrive at an effective partition coefficient. To check the validity of the calculation, a mass balance was performed by properly combining the two concentrations and respective volumes, and checking how close the result comes to the target, or theoretical, value, which is 50.3 in the clomipramine case and 200 in the other two cases (reflecting the 4-fold lower toxin concentration in the clomipramine toxin solution). One skilled in the art will recognize that this calculation is designed such that errors due to incomplete separation of exterior phase from the particles are minimized¨in particular, by using the known particle concentration rather than a measured top phase volume, the need for complete particle separation is circumvented.
CLOMIPRAMINE
Particle Top ph Eff part Drug acct Assay concn dilution coefficient (target=50.3) Bottom phase LT-728 (5E) 0.00562 0.056 179.6 3195.2 52.0 LT-728 (15E) 00288 0.15 67.7 2348.6 51.6 Top phase LT-728 (5E) 0.1 LT-728 (15E) 0.09996 PARAOXON
Particle Top ph Eff part Bup acct Assay concn dilution coefficient (target=200) Bottom phase LT-728 (5E) 0.462 0.056 179.6 81.6 242.9 LT-728(15E) 0.207 0.15 67.7 98.4 213.3 Top phase LT-728 (5E) 0.21 LT-728 (15E) 0.301 ETOMIDA I
Particle Top ph Eff part Etom acct Assay concn dilution coefficient (target=200) Bottom phase LT-728 (5E) 0.257 0.056 179.6 129.3 169.4 LT-728 (15E) 0.148 0.15 67.7 136.7 195.0 Top phase LT-728 (5E) 0.185 LT-728 (15E) 0.299 Thus the experiment demonstrates that etomidate and paraoxon, and particularly clomipramine, partitioned strongly into the particles of the invention in this experiment.
This is true even though the experiments were performed in the presence of albumin, which of course greatly increases the solubility of the toxins in water, and thus yields a much lower value for the effective partition coefficient than would be found for the true partition coefficient, that is, without albumin. Indeed, albumin was included in order to more closely simulate conditions under which the invention will be used. When the experiment was repeated with etomidate in the absence of albumin, an effective partition coefficient of 309 was recorded (with the mass balance within 5% of theoretical).
Example 11. Using the same dispersions and methods as in Example 10, the effective partition coefficients of lidocaine, benzocaine, and bupivacaine in the presence of albumin were measured. Lidocaine yielded a value of 57 (with the mass balance being within 3% of theoretical), benzocaine a value of 148 (with the mass balance being 84 whereas 95 was theoretical), in the case of the RA5-15E dispersion, and the value for bupivacaine was 62 (mass balance within 3% of theoretical).
Example 12. In this Example, strontium ions (Sr2+), which are known in the art to bind to phosphatidylcholine head groups, were shown to exhibit strong binding to the bilayer-rich cubic phase particles of the invention. To demonstrate this,18.9 mM of strontium chloride was added to an aliquot of the "RA5-15E" dispersion of the invention prepared in Example 10. A high degree of binding of strontium ions to the phosphatidylcholine in RA5-15E was evidenced by the immediate precipitation of the cubic phase, which centrifuged to the bottom of the dispersion.
Were the heavy strontium ions not bound, the cubic phase would be less dense than water and would have centrifuged to the top of the dispersion, as is the usual case with other methods of precipitating the particles. Radiostrontium, and to a lesser extent strontium, have known toxic effects, as do related phosphatidylcholine-binding metals. More broadly, this Example illustrates how the effect of large bilayer surface areas in cubic phase particles can result in effective uptake of toxins that bind to bilayer components.
Example 13. A 15% particle concentration dispersion of the invention was made in the Example without requiring rotovapping (as was used in Example 10). An amount 1.9093 gm of sodium deoxycholate was dissolved in 24.761 gm of sterile water for injection, to which were added 15.94 gm of alpha-tocopherol and 24.06 gm of phosphatidylcholine (Phospholipon 90G
from Phospholipid GmbH), and the mixture was stirred vigorously. From this, 60.01 gm were combined with 554.99 gm of sterile water for injection plus 2.00 mL of 1N
NaOH, and the mixture homogenized at 5200 RPM with a SiIverson AX60 1/2 HP homogenizer at ambient temperature, with temperature maintained between 19 and 28 C by ice water jacketing. After 3 hours, 3.6999 gm of tocopherol were slowly dripped in to the dispersion.
Homogenization continued for 2 hours and 20 minutes. Glycerol was added to a concentration of 2.3% for tonicity, the dispersion filtered through a 2 micron depth filter, and phosphate buffer added to a concentration of 20 mM, and the pH adjusted. Vials were loaded, sparged with nitrogen, capped and autoclaved at 121 C and 15 psi for 15 minutes. The final dispersion had a mean particle size, using unimodal analysis, of 193 nm, and a pH of 8Ø
Example 14. In this Example a fluorocarbon was incorporated into the particles, making the particles well suited for uptake of diatomic nitrogen, for potential treatment or prophylaxis of decompression sickness ("the bends" and related conditions). The specific fluorocarbon used was hexafluoropropanol. To start, 0.318 gm of sodium deoxycholate was dissolved in 4.127 gm of water. To this were added 4.01 gm of soy phosphatidylcholine (Lipoid E80), 1.96 gm of alpha-tocopherol, and 0.960 gm of hexafluoropropanol. Mixing this created a high-viscosity reversed cubic phase. An amount 10.16 gm of this liquid crystal was combined with 94.94 gm of water and 1.837 gm of glycerol (for tonicity), and the mixture homogenized with an Intron lab-scale homogenizer. The result was a fine dispersion of the invention, with approximately 10%
fluorocarbon in the cubic phase, or phrased otherwise, where approximately 17%
of the bilayer in the cubic phase was fluorocarbon.
Example 15 In this Example, the partitioning of the quaternary ammonium skeletal muscle relaxant vecuronium bromide, a water-soluble compound with a low octanol-water partition coefficient, between a phosphatidylcholine / tocopherol / water reversed cubic phase and water is measured, and found to be very high, sufficiently high as to enable the use of the invention in attenuating the effect of the drug in the body of a mammal. An amount 0.6169 gm of phosphatidylcholine (Phospholipon 90G, from Phospholipid GmbH) was mixed with 0.6730 gm of alpha-tocopherol and 0.2194 gm of a 10% vecuronium bromide solution in water. An amount 1.1226 gm of this mixture was smeared onto the inner wall of a test tube, and 6.4495 gm of water added to the tube so as to contact the mixture. Upon swelling with water, the mixture became a reversed cubic phase. After 3 days of contact between the cubic and aqueous phases to allow equilibration of the drug between the two phases, HPLC analysis showed that the concentration of vecuronium in the cubic phase was 10.0 mg/mL, while that in the aqueous phase was only 0.006 mg/mL. The partition coefficient between cubic phase and water was thus approximately 1,600 (or log KQw = 3.2). When the content of anionic lipid was increased significantly by incorporating a bile salt, this increased to log KQw approximately 4, which could reflect additional binding of drug due to electrostatic interactions with the bilayer-bound anion.
One with ordinary skill in the art will recognize that the vecuronium mass balance checks correctly if one assumes that the water content of the final cubic phase, after swelling to equilibrium, is approximately 40%, which is in perfect accord with the phase diagram derived in this laboratory for this cubic phase region.
Example 16. The RA5-5E and RA5-15E dispersions prepared in Example 10 were tested in vivo as prophylaxis, in a rat model incorporating a normally-lethal intravenous injection of bupivacaine. Sixteen adult male rats were randomly arranged into four groups of four animals each. Each group of animals were pre-treated with intravenous doses of either 4 ml/Kg normal physiologic saline (Group A), 4m1/Kg of dispersion RA5-15E of the instant invention with a 15 percent particle concentration (Group B), 6m1/Kg of dispersion RA5-5E of the instant invention with a 5.6 percent particle concentration (Group C) or 4m1/Kg Intralipid , a commercially available fat emulsion useful for parenteral nutrition. Animals in all four groups were then given intravenously a known lethal dose (12 mg/Kg) of the amide local anesthetic bupivacaine.
Animals from each group were then monitored for signs and symptoms of cardiotoxicity resulting from the administration of bupivacaine. All four animals in Group A
became pulseless within 10 seconds of the injection of bupivacaine while all of the animals in the remaining three groups survived without clinical signs of cardiotoxicity. This example demonstrates the use of the invention as prophylaxis to toxic injury.
Example 17. The RA5-5E and RA5-15E dispersions prepared in Example 10 were subsequently tested in vivo as a rescue agent in a rat model incorporating a normally-lethal intravenous injection of bupivacaine. Twelve adult male rats were randomly arranged into three groups of four animals each. Animals in each group were given a known lethal dose (12 mg/Kg) of the amide local anesthetic bupivacaine intravenously. Each animal was monitored for signs of acute cardiotoxicity. All animals became pulseless within 10 seconds of the injection of bupivacaine. When each animal became pulseless, it was treated immediately with mild chest compression and with one of the following: (i) 4 ml/Kg noimal physiologic saline (Group A);
(ii) 4m1/Kg of dispersion RA5-15E of the instant invention with a 15 percent particle concentration (Group B); or, (iii) 6m1/Kg of dispersion RA5-5E of the instant invention with a 5.6 percent particle concentration (Group C). All four animals in Group A
succumbed, while all four animals in Groups B and C recovered and exhibited normal pulse within minutes of administration of the dispersion of the instant invention. The administration of the dispersion according to the instant invention rescued the animals from death due to the systemic toxicity of an overdose of a common local anesthetic agent.
Example 18. Ten adult rats with previously inserted in-dwelling intra-jugular (U) venous cannulae were given 10 mg/kg of the intravenous anesthetic induction agent, propofol, via the indwelling U catheter. This constitutes a therapeutic dose. The Time to Emergence from anesthesia (defined as the elapsed time from the start of the propofol injection until the time of eye-closure and the loss of palpebral or eyelash reflex) was recorded for each of the animals.
Twenty four hours later, the same group of ten animals was again given the same dose of mg/kg of propofol via the indwelling U catheter. Immediately after induction of anesthesia, each animal was given an U injection of dispersion RA5-15E from Example 10, at 4 ml/Kg. The Time to Emergence from anesthesia was recorded as on Day 1 for each animal.
The differences in Time to Emergence from Day 1 to Day 2 calculated for each animal. The Time to Emergence from anesthesia was less for every one of the ten animals on Day 2 than on Day 1. The mean reduction in Time to Emergence from Day 1 to Day 2 was 23%, with a minimum reduction of 13% and a maximum reduction of 37%. The administration of the dispersion decreased the Time to Emergence, in this way attenuating the therapeutic effect of a therapeutic dose of the common general anesthetic propofol.
Example 19. Amphotericin B provides an example of an API with high toxicity which has a site of action in the interior of a fungal lipid biomembrane. In this Example the partition coefficient of amphotericin B between the preferred cubic phase of the invention (composition approximately 30% phosphatidylcholine, 30% alpha-tocopherol and 40% water) and water (both phases containing residual DMSO from the experiment) was measured using HPLC, and this partition coefficient was found to be approximately 1,000.
An amount 0.0082 g of Amphotericin B and 0.8 mL of DMSO (dimethylsulfoxide) were added to a 16 mL test tube. The test tube was heated to 60 C until the amphotericin B was completely dissolved. An amount 0.692 g of 2.5% DMPG in the phosphatidylcholine product Lipoid E80, 0.8 mL of DMSO, and 0.6mL of ethanol were added to a second 16 mL
test tube.
The mixture was heated to 60 C and vortexed until the Lipoid E80/DMPG was entirely dissolved. An amount 0.6873 g of vitamin E and 0.8 mL of DMSO were added to a third 16 mL
test tube. The mixture was heated to 60 C and vortexed until the vitamin E was completely dissolved. The contents of the second and third test tubes were added to the first test tube containing the amphotericin B and DMSO mixture. The test tube containing the entire mixture was heated to 60 C for 30 minutes to ensure that all components were completely dissolved.
An amount of 10 mL of deionized water was added to the test tube. The test tube was gently shaken at 40 RPM for 30 minutes on a Lab-Line Junior Orbit Shaker. The aqueous portion was decanted and filtered through Aldrich medium speed filter paper into a clean test tube and labeled "wash 1". This washing procedure was repeated three additional times to obtain "wash 2", "wash 3", and "wash 4".
HPLC analysis was then performed to determine the amphotericin B
concentrations in the 4 wash solutions and the final, quadruply-washed cubic phase. The latter concentration was found to be 1.76 mg/mL, and it was ascertained that the cubic phase contained entrapped pockets of water (as evidenced by an opaque appearance, for example), so that the true concentration in the cubic phase itself was estimated to be approximately 3 mg/mL. In contrast, the amphotericin B concentrations in the "wash 3" and "wash 4" solutions were both approximately 0.0035 mg/mL, thus making the partition coefficient on the order of 1,000.
It is known that amphotericin B partitions much more strongly into fungal cell membranes, the site of pharmacologic action, than into cell membranes of the human kidney, the site of toxic action. It is therefore possible that the application of the instant invention, using for example a phospholipid / tocopherol / water composition, could recover amphotericin B
from the site of toxic action preferentially over the site of desirable pharmacologic action, thus increasing the therapeutic index, or relieving a patient of toxic effects while maintaining antifungal activity.
Claims (32)
1. Use of a liquid composition comprising particles stabilized in dispersion in a polar solvent to absorb or adsorb one or more compounds in vivo, wherein said particles consists essentially of reversed cubic phase or reversed hexagonal phase material, and wherein said one or more compounds are selected from a drug, a toxin, an exogenous substance, and an endogenous substance which satisfies one or more of the following criteria:
a) contiguous string or ring of at least six carbon atoms, b) solubility of at least 1% in alpha-tocopherol, c) an octanol-water partition coefficient equal to or greater than 100, d) lowers surface tension of water to less than 50 dynes/cm at concentrations of 1% or less, or e) contains a contiguous sequence of at least four hydrophobic amino acids.
a) contiguous string or ring of at least six carbon atoms, b) solubility of at least 1% in alpha-tocopherol, c) an octanol-water partition coefficient equal to or greater than 100, d) lowers surface tension of water to less than 50 dynes/cm at concentrations of 1% or less, or e) contains a contiguous sequence of at least four hydrophobic amino acids.
2. The use of claim 1 wherein said particles are uncoated and ionically charged.
3. The use of claim 1 wherein said reversed cubic phase or reversed hexagonal phase material is comprised of (i) a lipid or surfactant, (ii) a polar solvent, and (iii) one or more hydrophobes selected from the group consisting of tocopherol, linalool, and benzyl benzoate.
4. The use of claim 1 wherein said reversed cubic phase or reversed hexagonal phase material comprises phosphatidylcholine and tocopherol.
5. The use of claim 1 wherein said particles have an average particle size ranging from 40 nm to 1000 nm in size.
6. The use of claim 1, wherein said one or more compounds is selected from:
anesthetics, opiates, analgesics, benzodiazepines, hypnotics and barbiturates.
anesthetics, opiates, analgesics, benzodiazepines, hypnotics and barbiturates.
7. The use of claim 1, wherein said one or more compounds includes at least one anesthetic that is a local anesthetic selected from bupivacaine, lidocaine, procaine, tetracaine, mepivacaine, etidocaine, oxybuprocaine, ***e, benzocaine, pramixinine, prilocaine, proparacaine, ropivicaines, chloroprocaine, and dibucaine.
8. The use of claim 7, wherein said local anesthetic is bupivacaine.
9. The use of claim 7, wherein said local anesthetic is ***e.
10. The use of claim 1, wherein said one or more compounds includes at least one anesthetic that is a general anesthetic selected from propofol, alphaxalone, alfatalone, alphadolone, eltanolone, propanidid, ketamine, pregnanolone, and etomidate.
11. The use of claim 10, wherein said general anesthetic is propofol.
12. The use of claim 1, wherein said one or more compounds includes at least one toxin.
13. The use of claim 4 wherein the particles further comprise water and one or more stabilizers.
14. The use of claim 13 wherein said one or more stabilizers include bile salts.
15. The use of claim 1 wherein the liquid composition consists essentially of phosphatidylcholine, alpha tocopherol, water, one or more stabilizers, one or more tonicity adjustors, and one or more buffers.
16. The use of claim 1 wherein said one or more compounds is a drug.
17. A liquid composition comprising particles stabilized in dispersion in a polar solvent for use in the absorption or adsorption of one or more compounds in vivo, wherein said particles consists essentially of reversed cubic phase or reversed hexagonal phase material, and wherein said one or more compounds are selected from a drug, a toxin, an exogenous substance, and an endogenous substance which satisfies one or more of the following criteria:
a) contiguous string or ring of at least six carbon atoms, b) solubility of at least 1% in alpha-tocopherol, c) an octanol-water partition coefficient equal to or greater than 100, d) lowers surface tension of water to less than 50 dynes/cm at concentrations of 1% or less, or e) contains a contiguous sequence of at least four hydrophobic amino acids.
a) contiguous string or ring of at least six carbon atoms, b) solubility of at least 1% in alpha-tocopherol, c) an octanol-water partition coefficient equal to or greater than 100, d) lowers surface tension of water to less than 50 dynes/cm at concentrations of 1% or less, or e) contains a contiguous sequence of at least four hydrophobic amino acids.
18. The liquid composition of claim 17 wherein said particles are uncoated and ionically charged.
19. The liquid composition of claim 17 wherein said reversed cubic phase or reversed hexagonal phase material is comprised of (i) a lipid or surfactant, (ii) a polar solvent, and (iii) one or more hydrophobes selected from the group consisting of tocopherol, linalool, and benzyl benzoate.
20. The liquid composition of claim 17 wherein said reversed cubic phase or reversed hexagonal phase material comprises phosphatidylcholine and tocopherol.
21. The liquid composition of claim 17 wherein said particles have an average particle size ranging from 40 nm to 1000 nm in size.
22. The liquid composition of claim 17, wherein said one or more compounds is selected from: anesthetics, opiates, analgesics, benzodiazepines, hypnotics and barbiturates.
23. The liquid composition of claim 17, wherein said one or more compounds includes at least one anesthetic that is a local anesthetic selected from bupivacaine, lidocaine, procaine, tetracaine, mepivacaine, etidocaine, oxybuprocaine, ***e, benzocaine, pramixinine, prilocaine, proparacaine, ropivicaines, chloroprocaine, and dibucaine.
24. The liquid composition of claim 23, wherein said local anesthetic is bupivacaine.
25. The liquid composition of claim 23, wherein said local anesthetic is ***e.
26. The liquid composition of claim 17, wherein said one or more compounds includes at least one anesthetic that is a general anesthetic selected from propofol, alphaxalone, alfatalone, alphadolone, eltanolone, propanidid, ketamine, pregnanolone, and etomidate.
27. The liquid composition of claim 26, wherein said general anesthetic is propofol.
28. The liquid composition of claim 17, wherein said one or more compounds includes at least one toxin.
29. The liquid composition of claim 20 wherein the particles further comprise water and one or more stabilizers.
30. The liquid composition of claim 29 wherein said one or more stabilizers include bile salts.
31. The liquid composition of claim 17 wherein the liquid composition consists essentially of phosphatidylcholine, alpha tocopherol, water, one or more stabilizers, one or more tonicity adjustors, and one or more buffers.
32. The liquid composition of claim 17 wherein said one or more compounds is a drug.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US86895006P | 2006-12-07 | 2006-12-07 | |
US60/868,950 | 2006-12-07 | ||
PCT/US2007/086642 WO2008127456A2 (en) | 2006-12-07 | 2007-12-06 | Compositions for the reversal and detoxification of anesthetics and other compounds and methods of their use |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2672024A1 CA2672024A1 (en) | 2008-10-23 |
CA2672024C true CA2672024C (en) | 2014-07-08 |
Family
ID=39864561
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2672024A Active CA2672024C (en) | 2006-12-07 | 2007-12-06 | Compositions for the reversal and detoxification of anesthetics and other compounds and methods of their use |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP2107904A4 (en) |
JP (1) | JP2010512341A (en) |
AU (1) | AU2007351338B2 (en) |
CA (1) | CA2672024C (en) |
WO (1) | WO2008127456A2 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013168167A1 (en) * | 2012-05-10 | 2013-11-14 | Painreform Ltd. | Depot formulations of a hydrophobic active ingredient and methods for preparation thereof |
JP6255975B2 (en) * | 2012-12-27 | 2018-01-10 | Jnc株式会社 | Liquid crystal composition, antioxidant and liquid crystal display element |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5630410A (en) * | 1996-01-04 | 1997-05-20 | Us Navy | Accelerated gas removal from divers' tissues utilizing gas metabolizing bacteria |
US7799337B2 (en) * | 1997-07-21 | 2010-09-21 | Levin Bruce H | Method for directed intranasal administration of a composition |
JP4792149B2 (en) * | 1997-09-09 | 2011-10-12 | リオトロピック セラピュティックス アイエヌシー. | Coated particles and their production and use |
WO2001022960A1 (en) * | 1999-09-30 | 2001-04-05 | Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center | Treatment of carbon monoxide poisoning |
CA2488705A1 (en) * | 2002-06-13 | 2003-12-24 | Lyotropic Therapeutics, Inc. | A nanoporous particle with a retained target |
US20030232340A1 (en) * | 2002-06-13 | 2003-12-18 | David Anderson | Nanoporous particle with a retained target |
US7528172B2 (en) * | 2003-01-21 | 2009-05-05 | The Cooper Health System, Inc. | Compositions and methods for improving recovery after general anesthesia |
US20050119340A1 (en) * | 2003-06-13 | 2005-06-02 | David Anderson | Treatment methods with low-dose, longer-acting formulations of local anesthetics and other agents |
US7713440B2 (en) * | 2003-10-08 | 2010-05-11 | Lyotropic Therapeutics, Inc. | Stabilized uncoated particles of reversed liquid crystalline phase materials |
US20050101621A1 (en) * | 2003-11-12 | 2005-05-12 | Richard Lipsky | Method for rapid detoxification of addiction |
-
2007
- 2007-12-06 JP JP2009540476A patent/JP2010512341A/en active Pending
- 2007-12-06 EP EP07873662A patent/EP2107904A4/en not_active Withdrawn
- 2007-12-06 CA CA2672024A patent/CA2672024C/en active Active
- 2007-12-06 AU AU2007351338A patent/AU2007351338B2/en not_active Ceased
- 2007-12-06 WO PCT/US2007/086642 patent/WO2008127456A2/en active Application Filing
Also Published As
Publication number | Publication date |
---|---|
CA2672024A1 (en) | 2008-10-23 |
WO2008127456A3 (en) | 2008-12-11 |
WO2008127456A2 (en) | 2008-10-23 |
AU2007351338B2 (en) | 2013-04-04 |
EP2107904A4 (en) | 2010-06-02 |
EP2107904A2 (en) | 2009-10-14 |
AU2007351338A1 (en) | 2008-10-23 |
JP2010512341A (en) | 2010-04-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10912772B2 (en) | Opioid formulations | |
JP5764792B2 (en) | Novel pharmaceutical composition comprising a macrolide immunosuppressant | |
US8834921B2 (en) | Sustained-release liposomal anesthetic compositions | |
US5389373A (en) | Preparation of oil-in-water emulsions of drugs | |
JP2007520555A (en) | Dispersants prepared by use of self-stabilizing agents | |
Golenser et al. | New formulations and derivatives of amphotericin B for treatment of leishmaniasis | |
US20240131021A1 (en) | Opioid formulations | |
CA2672024C (en) | Compositions for the reversal and detoxification of anesthetics and other compounds and methods of their use | |
JP2002504505A (en) | Butorphanol sustained release formulation | |
US7968124B2 (en) | Compositions for the reversal and detoxification of anesthetics and other compounds and methods of their use | |
WO2020033195A1 (en) | Sustained-release pharmaceutical compositions comprising an antipsychotic drug and uses thereof | |
CN112654345A (en) | Sustained-release ophthalmic pharmaceutical composition and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |