Liposomal Mitigation of Drug-Induced Inhibition of the Cardiac IKR Channel

Abstract

Compositions and methods are provided for preventing one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns, or both, in a human or animal subject comprising: one or more pharmacologically active agents that causes at least one of IKr channel inhibition or QT prolongation by inhibiting the activity of an ether-a-go-go-related gene (hERG); and one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the pharmacologically active agent.

What is claimed is: 
     
         1 . A composition for preventing one or more cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns, or both, in a human or animal subject comprising:
 one or more pharmacologically active agents that causes at least one of I Kr  channel inhibition or QT prolongation by inhibiting the activity of an ether-a-go-go-related gene (hERG); and   one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the pharmacologically active agent, wherein the empty liposomes are provided in an amount effective to reduce the cardiac channelopathies or conditions resulting from irregularities or alterations in cardiac patterns.   
     
     
         2 . The composition of  claim 1 , wherein the cardiac channelopathy or the condition resulting from the irregularity or alteration in the cardiac pattern is inhibition of an ion channel responsible for the delayed-rectifier K +  current in the heart, polymorphic ventricular tachycardia, prolongation of the QTc, LQT2, LQTS, or torsades de pointes. 
     
     
         3 . The composition of  claim 1 , wherein the composition is used for the treatment or prevention of prolongation of the I Kr  channel inhibition or QT prolongation induced by administration of one or more drugs used in the treatment of cardiac or non-cardiac related diseases. 
     
     
         4 . The composition of  claim 1 , wherein the one or more active agents is selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, gripafloxacin, terodilene, droperidole, lidoflazine, levomethadyl, sertindoyle or cisapride. 
     
     
         5 . The composition of  claim 1 , wherein the one or more active agents is selected from at least one of: Aloxi; Amiodarone; Arsenic trioxide; Astemizole; Bepridil; Chloroquine; Chlorpheniramine; Chlorpromazine (Thorazine); Cisapride; Celaxa; Citalopram; Clarithromycin; Erythromycin; Curcumin; Disopyramide; Dofetilide; Domperidone; Doxorubicin; Dronedarone; Droperidol; Grepafloxacin; Haldol; Haloperidol; Halofantrine; Ibutilide; Levomethadyl; Lidoflazine; Loratidine; Lovostatin; Mesoridazone; Methadone; Methanesulphonanilide; Moxifloxacin; Palonasitron; Pentamadine; Pimozide; Prenylamine; Probucol; Procainamide; Propafenone; Pyrilamine; Quinidine; Terfenidine; Sertindole; Sotalol; Sparfloxacin; Thioridazine; or Vandetanib. 
     
     
         6 . The composition of  claim 1 , wherein the composition is adapted for enteral, parenteral, intravenous, intraperitoneal, or oral administration. 
     
     
         7 . The composition of  claim 1 , wherein the active agent and the liposomes may be bound or conjugated together. 
     
     
         8 . The composition of  claim 1 , wherein the liposomes comprise anionic, cationic, or neutral liposomes. 
     
     
         9 . The composition of  claim 1 , wherein the liposomes comprises a lipid or a phospholipid wall, wherein the lipids or the phospholipids are selected from the group consisting of phosphatidylcholine (lecithin), lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine (cephalin), cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl sterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid, fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, and diacylglycerolsuccinate. 
     
     
         10 . The composition of  claim 1 , wherein the composition further comprises a pharmaceutically acceptable dispersion medium, solvent, or vehicle, wherein the active agent, the liposome or both are dissolved, dispersed, or suspended in the medium, the solvent, or the vehicle. 
     
     
         11 . The composition of  claim 1 , wherein the liposomes comprise DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]). 
     
     
         12 . The composition of  claim 1 , wherein the liposomes comprise a 9.7:1 ratio of DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]). 
     
     
         13 . A composition for preventing or treating one or more adverse reactions arising from administration of a therapeutically active agent or a drug in a human that causes at least one of I Kr  channel inhibition or QT prolongation by inhibiting the activity of an ether-a-go-go-related gene (hERG) comprising:
 one or more pharmacologically active agents that causes at least one of I Kr  channel inhibition or QT prolongation and one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the therapeutically active agent or the drug in an amount effective to reduce the adverse reactions arising from administration of the therapeutically active agent or drug.   
     
     
         14 . The composition of  claim 13 , wherein the therapeutically active agent or a drug is used in a prevention or a treatment of one or more cardiac or non-cardiac diseases in the human or animal subject. 
     
     
         15 . The composition of  claim 13 , wherein the cardiac channelopathy or the condition resulting from the irregularity or alteration in the cardiac pattern is inhibition of an ion channel responsible for the delayed-rectifier K +  current in the heart, polymorphic ventricular tachycardia, prolongation of the QTc, LQT2, LQTS, or torsades de pointes. 
     
     
         16 . The composition of  claim 13 , wherein the composition is used for the treatment or prevention of prolongation of the I Kr  channel inhibition or QT prolongation induced by administration of one or more drugs used in the treatment of cardiac or non-cardiac related diseases. 
     
     
         17 . The composition of  claim 13 , wherein the one or more active agents is selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, gripafloxacin, terodilene, droperidole, lidoflazine, levomethadyl, sertindoyle or cisapride. 
     
     
         18 . The composition of  claim 13 , wherein the composition is adapted for enteral, parenteral, intravenous, intraperitoneal, or oral administration. 
     
     
         19 . The composition of  claim 13 , wherein the active agent and the liposomes may be bound or conjugated together. 
     
     
         20 . The composition of  claim 13 , wherein the liposomes comprise anionic, cationic, or neutral liposomes. 
     
     
         21 . The composition of  claim 13 , wherein the liposomes comprises a lipid or a phospholipid wall, wherein the lipids or the phospholipids are selected from the group consisting of phosphatidylcholine (lecithin), lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine (cephalin), cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl sterate, isopropyl myristate, amphoteric acrylic polymers, fatty acid, fatty acid amides, cholesterol, cholesterol ester, diacylglycerol, and diacylglycerolsuccinate. 
     
     
         22 . The composition of  claim 13 , wherein the liposomes are spherical liposomes with a diameter ranging from 10 nm-200 nm. 
     
     
         23 . The composition of  claim 13 , wherein the liposomes comprise DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]). 
     
     
         24 . The composition of  claim 13 , wherein the liposomes comprise a 9.7:1 ratio of DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]). 
     
     
         25 . The composition of  claim 13 , wherein the one or more active agents is selected from at least one of: Aloxi; Amiodarone; Arsenic trioxide; Astemizole; Bepridil; Chloroquine; Chlorpheniramine; Chlorpromazine (Thorazine); Cisapride; Celaxa; Citalopram; Clarithromycin; Erythromycin; Curcumin; Disopyramide; Dofetilide; Domperidone; Doxorubicin; Dronedarone; Droperidol; Grepafloxacin; Haldol; Haloperidol; Halofantrine; Ibutilide; Levomethadyl; Lidoflazine; Loratidine; Lovostatin; Mesoridazone; Methadone; Methanesulphonanilide; Moxifloxacin; Palonasitron; Pentamadine; Pimozide; Prenylamine; Probucol; Procainamide; Propafenone; Pyrilamine; Quinidine; Terfenidine; Sertindole; Sotalol; Sparfloxacin; Thioridazine; or Vandetanib. 
     
     
         26 . A method for preventing or treating one or more cardiac channelopathies, irregularities or alterations in cardiac patterns, or both in a human or animal subject comprising the steps of:
 identifying the human or animal subject in need of prevention or treatment of the one or more cardiac channelopathies, irregularities or alterations in cardiac patterns, or both; and   administering to the human or animal subject a therapeutically effective amount of a composition comprising:   one or more pharmacologically active agents that causes at least one of I Kr  channel inhibition or QT prolongation by inhibiting the activity of an ether-a-go-go-related gene (hERG);   one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the pharmacologically active agent; and   an optional pharmaceutically acceptable dispersion medium, solvent, or vehicle, wherein the active agent, the liposome or both are dissolved, dispersed, or suspended in the medium, the solvent, or the vehicle.   
     
     
         27 . The method of  claim 26 , wherein the cardiac channelopathy or the condition resulting from the irregularity or alteration in the cardiac pattern is inhibition of an ion channel responsible for the delayed-rectifier K +  current in the heart, polymorphic ventricular tachycardia, prolongation of the QTc, LQT2, LQTS, or torsades de pointes. 
     
     
         28 . The method of  claim 26 , wherein the one or more active agents is selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, gripafloxacin, terodilene, droperidole, lidoflazine, levomethadyl, sertindoyle or cisapride. 
     
     
         29 . The method of  claim 26 , wherein the liposomes comprise DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]). 
     
     
         30 . The method of  claim 26 , wherein the liposomes comprise a 9.7:1 ratio of DMPC (1,2-dimyristoil-sn-glycero-3-phosphocholine) and DMPG (1,2-dimyristoyl-sn-glycero-3-phospho-rac-[1-glycerol]). 
     
     
         31 . The method of  claim 26 , wherein the one or more active agents is selected from at least one of: Aloxi; Amiodarone; Arsenic trioxide; Astemizole; Bepridil; Chloroquine; Chlorpheniramine; Chlorpromazine (Thorazine); Cisapride; Celaxa; Citalopram; Clarithromycin; Erythromycin; Curcumin; Disopyramide; Dofetilide; Domperidone; Doxorubicin; Dronedarone; Droperidol; Grepafloxacin; Haldol; Haloperidol; Halofantrine; Ibutilide; Levomethadyl; Lidoflazine; Loratidine; Lovostatin; Mesoridazone; Methadone; Methanesulphonanilide; Moxifloxacin; Palonasitron; Pentamadine; Pimozide; Prenylamine; Probucol; Procainamide; Propafenone; Pyrilamine; Quinidine; Terfenidine; Sertindole; Sotalol; Sparfloxacin; Thioridazine; or Vandetanib. 
     
     
         32 . A method for preventing or treating one or more adverse reactions arising from administration of a therapeutically active agent or a drug in a human or animal subject comprising the steps of:
 identifying the human or animal subject in need of prevention or treatment of the one or more adverse reactions arising from the administration of the therapeutically active agent or the drug that causes at least one of I Kr  channel inhibition or QT prolongation by inhibiting the activity of an ether-a-go-go-related gene (hERG);   administering to the human or animal subject a therapeutically effective amount of a composition comprising one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the therapeutically active agent or the drug or are liposomes loaded with the therapeutically active agent or the drug; and   measuring the effect of the combination of the liposomes and the therapeutically active agent or the drug on the drug-induced channelopathy, wherein the composition reduces or eliminated the channelopathy induced by the therapeutically active agent or the drug.   
     
     
         33 . A method for preventing or treating at least one of I Kr  channel inhibition or QT prolongation arising from administration of crizotinib, nilotinib, or any other active agent that causes a drug-induced channelopathy in a human or animal subject comprising the steps of:
 identifying the human or animal subject in need of prevention or treatment at least one of I Kr  channel inhibition or QT prolongation that results from the administration of crizotinib, nilotinib, or any other active agent that causes a drug-induced channelopathy; and   administering to the human or animal subject a therapeutically effective amount of a composition comprising one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the crizotinib, nilotinib, or any other active agent that causes a drug-induced channelopathy, wherein the composition reduces or eliminated the channelopathy induced by the therapeutically active agent or the drug.   
     
     
         34 . The method of  claim 33 , wherein the active agent has previously failed a clinical trial due to drug-induced IKr channel inhibition or QT prolongation. 
     
     
         35 . The method of  claim 33 , further comprising the step of identifying a drug in a clinical trial that failed or has limited clinical use due to drug-induced IKr channel inhibition or QT prolongation side-effects. 
     
     
         36 . A method of evaluating a candidate drug that reduces a channelopathy caused by a pharmacologically active agent, the method comprising:
 a) administering a candidate drug to a first subset of the patients, and a placebo to a second subset of the patients, wherein the composition is provided in conjunction with the pharmacologically active agent that causes at least one of I Kr  channel inhibition or QT prolongation and one or more liposomes, wherein the liposomes are empty liposomes and administered prior to, concomitantly, or after administration of the therapeutically active agent or the drug;   b) measuring the channelopathy from a suspected of having a drug-induced channelopathy from a set of patients;   c) repeating step a) after the administration of the candidate drug or the placebo; and   d) determining if the composition reduces the drug-induced channelopathy that is statistically significant as compared to any reduction occurring in the second subset of patients, wherein a statistically significant reduction indicates that the candidate drug is useful in treating said disease state.   
     
     
         37 . The method of  claim 36 , wherein the drug has previously failed a clinical trial due to drug-induced IKr channel inhibition or QT prolongation.