KR20190042775A - Protective effect of DMPC, DMPG, DMPC / DMPG, LysoPG and LysoPC on drugs causing channelopathy - Google Patents

Abstract

The present invention provides a method of reducing one or more cardiomyopathy or condition due to irregularity or alteration of a cardiac pattern caused by one or more sensory receptors, thixotropic agents, or both sensory receptors and thixotropic agents, and active agents or drugs. For the prevention of at least one cardiomyopathy or condition due to irregularity or alteration of a cardiac pattern caused by an active agent or drug in a human or animal subject, including the amount of phosphatidylglycerol adjusted for oral administration effective to prevent, Compositions and methods.

Description

Protective effect of DMPC, DMPG, DMPC / DMPG, LysoPG and LysoPC on drugs causing channelopathy

FIELD OF THE INVENTION The present invention relates generally to the field of drug therapy and more particularly to the use of one or more organoleptic agents, thixotropic agents, or both sensory receptors and thixotropic agents, 0002] The present invention relates to novel compositions and methods for reducing or eliminating the pathology or condition due to irregularities or alterations in the cardiac pattern caused by the heart.

Without limiting the scope of the present invention, it is contemplated that the background may be modified or functionalized by a therapeutic agent, or, if not modified, cardiomyocyte activity potential, torsade de points, and long QT syndrome, Controlling the duration of reperfusion of cardiac ventricular QT in the subject, comprising administering to a subject in need thereof a control of the duration of repolarization of the cardiac ventricular QT, with congenital defects capable of inducing an extension of the repolarization in the subject ≪ / RTI >

The heartbeat is due to precisely controlled regularly spaced waves of myocardial excitation and contraction. Currents during ion-based depolarization and repolarization can be measured by electrical leads placed at specific locations on the body measuring the electrical waves (electrocardiogram). The P-wave represents the depolarization of the atria. If the entire atrium is depolarized, the wave returns to zero. The ventricle is fully depolarized after 0.1 s, resulting in a QRS complex. The three peaks are due to the way current is spread in the ventricles. Followed by T-wave or repolarization of the ventricles. The QT interval, measured from the beginning of the QRS wave on the standard ECC to the end of the T wave, represents the time to completion of the cardiac muscle cell repolarization phase (or ventricular depolarization and repolarization). The duration of this interval can vary due to genetic variation, heart disease, electrolyte balance, toxic animal toxin poisoning, and drugs. Prolongation of the QT interval can result in ventricular arrhythmias and sudden death.

Drug-induced long QTc syndrome (LQTS), an extension of action potential duration, is a common cause of withdrawal from government legislation. QTc prolongation is an unforeseeable risk factor for Torsades de Pointes (TdP), a polymorphic ventricular tachycardia that causes ventricular fibrillation. Drug-induced LQTS contains about 3% of all prescriptions, which can constitute a fatal adverse reaction when TdP is followed. Patients who receive one or more than one QTc-prolonged drug incidentally have an increased risk of TdP. The overall incidence of TdP is statistically rare, but clinically relevant to the individual with the disease, and testing for this drug effect is a prerequisite before participating in the trial.

Structurally diverse drugs of common human ether-a-go-go- related gene (hERG or KCNH2) coded K ⁺ channels and cardiac delayed-and the results acquired LQTS by blocking rectifier potassium current I _K (KV11.1) . The drug-associated increased risk of LQTS is a major drug development hurdle and many drugs have been withdrawn during pre-clinical development, withdrawn from the market, or assigned black box warnings after approval. The autosomal recessive or dominant LQTS, based on 500 possible mutations in 10 different genes encoding the potassium channel, has an incidence of 1: 3000 or about 100,000 in the United States. The risk of an extended QT interval, or LQTS, occurs in 2.5% of the asymptomatic US population. If present, this syndrome can cause severe cardiac arrhythmias and sudden death in untreated patients. The likelihood of cardiac death increases in asymptomatic congenital LQTS patients receiving LQTS-induced drugs.

Most of the acquired LTQS drug withdrawal is due to occlusion of potassium ion channels coded by the human ether-a-go-go-related gene (hERG). High concentrations of hERG blocking drugs generally induce an extended QTc interval and increase the likelihood of TdP. Less than 10% of the cases of drug-induced TdP may be due to 13 major genetic mutations, 471 different mutations, and 124 polymorphisms (Chig, C 2006).

Systems and methods for detecting LQTS have been previously described. For example, U.S. Patent Publication No. 2010/0004549 (Kohls et al. 2010) describes a system and method for detecting LQTS in a patient by comparing a collected set of ECG data from a patient to a plurality of databases of collected ECG data . The plurality of databases will include a database containing previous ECG from the patient, a known acquired LQTS trait database, and a known genetic LQTS trait database. Comparing the patient's ECG with these databases will facilitate detection of occurrences such as changes in QT intervals, changes in T-wave morphology, changes in U-wave morphology from ECG success, and known genetic patterns of LQTS Can be matched. The system and method are sensitive to the patient's sex and ethnicity, and furthermore, the QT duration can be matched to the database of drug effects as these factors appear to have resulted in LQTS. The system and method are also easily integrated into current ECG management systems and storage devices.

Systems and methods for the diagnosis and treatment of LQTS are described in U.S. Patent Publication No. 2008/0255464 (Michael, 2008). The Michael invention describes a method for diagnosing a long QT syndrome (LQTS) that induces a QT / QS2 ratio from an electrical cardiac systolic (QT) and a mechanical heart systolic (QS2) to detect an extended QT interval in a patient's cardiac cycle System. The processor acquires the cardiac systolic from the microphone and chest electrodes, calculates the QT / QS2 ratio, and outputs the result to the display. The processor may compare the QT / QS2 ratio to a threshold stored in memory for diagnosing the LQTS in the patient. The user interface provides programming, set-up, and customization of the display. The mode selector allows the system to alternatively operate as a machine for diagnosing cardiac, 12 lead electrocardiograph, or LQTS. An associated method for diagnosing cardiac disorders such as LQTS involves measuring QT and QS2 during the same cardiac cycle, calculating the QT / QS2 ratio, and comparing the results to threshold values derived from the experimental data. The method may include measuring cardiac systolic at both rest and during exercise and may be used for drug efficacy, dose optimization, and acquired LQTS causality testing.

Methods of treating cardiac arrhythmias are provided in U.S. Patent Publication No. 2007/0048284 (Donahue and Marban, 2007). The method comprises administering an amount of at least one polynucleotide that modulates electrical characteristics of the heart. Polynucleotides of the invention can also be used in conjunction with micro-delivery vehicles, such as cationic liposomes and adenoviral vectors.

Methods, compositions, dosage regimens, and routes of administration for the treatment or prevention of arrhythmias are described in US Patent Publication No. 2001/00120890, Fedida et al. (2010). In the Fedida invention, an early depolarization and prolongation of the QT interval can be reduced or eliminated by administering an ion channel modulating compound to a subject in need thereof. The ion channel conditioning compound may be a cycloalkylamine ether compound, especially a cyclohexylamine ether compound. Also disclosed are compositions of ion channel conditioning compounds and medicaments which lead to depolarization, prolongation of the QT interval and / or torcadadpoint after premature administration. Non-limiting examples of antioxidants include vitamin C, vitamin E, beta-carotene, lutein, lycopene, vitamin B2, coenzyme Q10, Cysteine as well as herbs such as bilberry, turmeric (curcumin), grape seed or pine bark extract, and ginkgo.

In one embodiment, the invention provides a composition comprising one or more sensory receptors, a thixotropic agent, or both a sensory receptive agent and a thixotropic agent; And an amount of phosphatidylglycerol adjusted for oral administration effective to reduce or prevent one or more cardiac channelopathy or condition due to irregularity or alteration of a cardiac pattern caused by an active agent or drug. , Compositions for preventing at least one cardiomyopathy or condition due to irregularity or alteration of a cardiac pattern caused by an active agent or drug in a human or animal subject. In one aspect, the sensory receptive agent comprises one or more of a spice, a sweetener, a coolant, a dye, or combinations and mixtures thereof. In addition, it has been found that, even if unwanted sensory acceptance changes are caused in the dried powders according to the present invention, they are hardly effected and that the powders dried according to the present invention have sufficient solubility for various applications. In one aspect, thixotropic agents are selected from the group consisting of thixotropic matrices such as polysaccharides such as cellulose (e.g., carboxymethylcellulose) or gums (such as xanthan), collagen, gelatin, Amides, alkyd resins, and silica-lipids. In one aspect, the composition comprises both a sensory receptive agent and a thixotropic agent. In one aspect, the phosphatidylglycerol is an empty liposome having a diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM, (DMPC), 12-mysteroyl-2-hydroxy-sn-glycero-3- [phospho-rac- (glycerol)] (DMPG ), Or in the form of DMPC / DMPG liposomes. In one aspect, the lysophosphatidyl glycerol is selected from the group consisting of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidyl- lysophosphatidylcholine, oleoyl- , Linoleoyl-lysophosphatidylcholine, linoleenoyl-lysophosphatidylcholine or erucoyl-lysophosphatidylcholine; And at least one of at least one sensory receptive agent or thixotropic agent.

The process according to the invention is therefore suitable for producing a consumable product without any health risk, optionally after reconstitution in a suitable liquid. In another aspect, the lysophosphatidylglycerol is 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (DMPC), 12- (DMPG), DMPC / DMPG, 1-myristoyl-2-hydroxy- sn -glycero-3-phospho- (1'- rac -glycerol) ( LysoPG), or 1-myristoyl-2-hydroxy- sn -glycero-3-phosphocholine (LysoPC). In one aspect, the sensory receptive agent comprises one or more of a spice, a sweetener, a coolant, a dye, or combinations and mixtures thereof. In addition, it has been found that, even if unwanted sensory acceptance changes are caused in the dried powders according to the present invention, they are hardly effected and that the powders dried according to the present invention have sufficient solubility for various applications. In one aspect, thixotropic agents are selected from the group consisting of thixotropic matrices such as polysaccharides such as cellulose (e.g., carboxymethylcellulose) or gums (such as xanthan), collagen, gelatin, Amides, alkyd resins, and silica-lipids. In one aspect, the composition comprises both a sensory receptive agent and a thixotropic agent. In one aspect, the phosphatidylglycerol is an empty liposome having a diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM, (DMPC), 12-mysteroyl-2-hydroxy-sn-glycero-3- [phospho-rac- (glycerol)] (DMPG), or DMPC / DMPG liposomes.

In another aspect, the medicament is selected from the group consisting of albuterol (salbutamol), alfuzosin, amantadine, amiodarone, amargrafine, amitriptyline, amosulfine, amphetamine, anagrelide, apomorphine, , Arsenic trioxide, astemizole, atazanavir, aocomycetin, azithromycin, vedicillin, bepridil, bortezomib, curdinib, chloral hydrate, chloroqueen, chlorpromargin, ciprofloxacin, cisapride, citalop (D-amphetamine), dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, Dipronidone, Diphenhydramine, Dyspyrimide, Dobutamine, Dopetylide, Dolasitron, Dom Peridone, Dopamine, Doxepine, Dronedron, Droperidol, Ephedrine, Epinephrine ), Eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, pingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, (Glutamate), galantamine, gatifloxacin, gemifloxacin, granicetrone, halofantrine, haloperidol, hydrochlorothiazide, butylid, iloperidone, imipramine (Levalbutamol), levofloxacin, levomethalil, ricerodecamphetamine, lithium, mezoridazin, metaprozole, levodoprofen, levodextrin, (Methamphetamine), methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, nelfinavir, nikar The present invention relates to a pharmaceutical composition comprising at least one compound selected from the group consisting of dipeptide, nilotinib, norepinephrine (noradrenaline), norfloxacin, nortriptyline, oproxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, Lipid microspheres, pentermin, phenylpiperine, phenylpropanolamine, phimozide, posaconazole, probucol, procainamide, promethazine, protryptiline, pseudoephedrine, quetiapine, quinidine, quinine sulfate , Ranolavirin, rilpivirin, risperidone, ritodrine, ritonavir, roxithromycin, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, But are not limited to, thyroxine, thyroxine, thyroxine, thyroxine, thyroxine, thyroxine, thyroxine, thyroxine, Rodin, Torre Pen, trazodone, trimethoprim-sulfanyl, Plastic Tree US civil and van der tanip, Hvar Anywhere is selected from the peel, bay Village penip, venlafaxine, voriconazole, barley, no-start, or ziprasidone.

In one embodiment, the invention provides an active agent or drug that causes at least one adverse reaction resulting from administration of an active agent or drug in a human causing at least one of cardiomyopathy, I _Kr channel depression or QT prolongation A composition for preventing or treating a disease,

The amount of lysophosphatidylglycerol having the following basic structure, adjusted for oral administration effective to reduce or prevent said at least one cardiomyopathy, I _Kr channel inhibition or QT prolongation caused by said drug:

Wherein R ¹ or R ² is any even or odd chain fatty acid and R ³ can be H, acyl, alkyl, aryl, amino acid, alkene, or alkyne; And one or more active agents or drugs that result in at least one of I _Kr channel inhibition or QT prolongation, and a composition comprising at least one sensory receptive agent, a thixotropic agent, or both a sensory receptive agent and a thixotropic agent. In one aspect, the sensory receptive agent comprises one or more of a spice, a sweetener, a coolant, a dye, or combinations and mixtures thereof. In addition, it has been found that, even if unwanted sensory acceptance changes are caused in the dried powders according to the present invention, they are hardly effected and that the powders dried according to the present invention have sufficient solubility for various applications. In one aspect, thixotropic agents are selected from the group consisting of thixotropic matrices such as polysaccharides such as cellulose (e.g., carboxymethylcellulose) or gums (such as xanthan), collagen, gelatin, Amides, alkyd resins, and silica-lipids. In one aspect, the composition comprises both a sensory receptive agent and a thixotropic agent. In one aspect, the phosphatidylglycerol is an empty liposome having a diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM, (DMPC), 12-mysteroyl-2-hydroxy-sn-glycero-3- [phospho-rac- (glycerol)] (DMPG), or DMPC / DMPG liposomes. In one aspect, the lysophosphatidyl glycerol is selected from the group consisting of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidyl- lysophosphatidylcholine, oleoyl- , Linoleoyloyl-lysophosphatidylcholine, linolenolyl-lysophosphatidylcholine, or erucoyl-lysophosphatidylcholine. In another aspect, the liposome or liposome precursor is 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (DMPC), 12-mysteoyl-2-hydroxy-sn- DMPG / DMPG, 1-myristoyl-2-hydroxy- sn -glycero-3-phospho- (1'- rac -glycerol) (LysoPG), or 1-myristoyl-2-hydroxy- sn -glycero-3-phosphocholine (LysoPC). In yet another aspect, the short chain fatty acid has 5 or fewer carbons, the middle chain has 6 to 12 carbons, the long chain has 13 to 21 carbons, including both even and odd chain fatty acids, and the long long chain fatty acids have 22 Carbon. In yet another aspect, the short chain fatty acids are saturated or unsaturated fatty acids having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, , 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more carbons. In a further aspect, the heart due to the irregularity or change in heart pattern channel neuropathy or condition is delayed in a heart-inhibition of the ion channels that cause rectifier K ⁺ current (delayed-rectifier K + current), polymorphic ventricular tachycardia, QTc LQT2, LQTS, or Thorsad point. In another aspect, the composition is used for the treatment or prophylaxis of QT prolongation or prolongation of I _Kr channel inhibition caused by the administration of one or more drugs used in the treatment of heart, allergic, or cancer-related diseases. In yet another aspect, the at least one active agent is selected from the group consisting of chrysototipib, neilotinib, terfenadine, astemizole, gryfloxacin, terodilene, droperidol, lidoplagin, levomethal, sertindole, And is selected from at least one species. In yet another aspect, the active agent or drug is provided enterally, parenterally, intravenously, intraperitoneally, or orally. In another aspect, the liposome comprises a lipid or phospholipid wall wherein the lipid or phospholipid is selected from the group consisting of phosphatidylcholine (lecithin), lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, Phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, glycerol monostearate, glycerol monostearate, Hexadecyl stearate, isopropyl myristate, amphoteric acrylic polymer, fatty acid, fatty acid amide, cholesterol, cholesterol ester, diacylglycerol, and diacylglycerol succinate. In another aspect, the medicament is selected from the group consisting of albuterol (salbutamol), alfuzosin, amantadine, amiodarone, amargrafine, amitriptyline, amosulfine, amphetamine, anagrelide, apomorphine, , Arsenic trioxide, astemizole, atazanavir, aocomycetin, azithromycin, vedicillin, bepridil, bortezomib, curdinib, chloral hydrate, chloroqueen, chlorpromargin, ciprofloxacin, cisapride, citalop (D-amphetamine), dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, Dipronidone, Diphenhydramine, Dyspyrimide, Dobutamine, Dopetylide, Dolasitron, Dom Peridone, Dopamine, Doxepine, Dronedron, Droperidol, Ephedrine, Epinephrine ), Eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, pingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, (Glutamate), galantamine, gatifloxacin, gemifloxacin, granicetrone, halofantrine, haloperidol, hydrochlorothiazide, butylid, iloperidone, imipramine (Levalbutamol), levofloxacin, levomethalil, ricerodecamphetamine, lithium, mezoridazin, metaprozole, levodoprofen, levodextrin, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, terenol, methadone, methamphetamine (methamphetamine), methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, on But are not limited to, neprin (noradrenaline), norfloxacin, norptripyline, oproxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, fasciothione, pazopanib, pentamidine, Or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-methylpiperidine, N-phenylpiperine, phenylpropanolamine, phimozide, posaconazole, probucol, procainamide, promethazine, But are not limited to, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, , Sulpiride, sutinidip, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, Jodon, Trimeto Is selected from prima-sulfa, trimipramine, bandetanib, bardenafil, bemurafenib, venlafaxine, voriconazole, borinostat, or ziprasidone.

In one embodiment, the invention provides a method of treating a disorder in a human or animal subject caused by an active agent or drug used to treat a disease in a human or animal subject, comprising the steps of: A method of preventing or treating an _IKr channel inhibition or QT prolongation comprising administering to said human or animal subject one or more of the cardiomyopathy, cardiac pattern irregularity or alteration, I _Kr channel inhibition caused by said activator or drug, or The amount of lysophosphatidylglycerol adjusted for oral administration effective to reduce or prevent QT prolongation; And an effective amount of said activator or drug sufficient to treat the disease wherein the orally provided lysophosphatidyl glycerol reduces or eliminates said at least one cardiomyopathy, irregularity or alteration of cardiac pattern, I _Kr channel inhibition or QT prolongation ) And one or more sensory receptors, thixotropic agents, or both sensory receptors and thixotropic agents. In one aspect, the sensory receptive agent comprises one or more of a spice, a sweetener, a coolant, a dye, or combinations and mixtures thereof. In addition, it has been found that, even if unwanted sensory acceptance changes are caused in the dried powders according to the present invention, they are hardly effected and that the powders dried according to the present invention have sufficient solubility for various applications. In one aspect, thixotropic agents are selected from the group consisting of thixotropic matrices such as polysaccharides such as cellulose (e.g., carboxymethylcellulose) or gums (such as xanthan), collagen, gelatin, Amides, alkyd resins, and silica-lipids. In one aspect, the composition comprises both a sensory receptive agent and a thixotropic agent. In one aspect, the phosphatidylglycerol is an empty liposome having a diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM, (DMPC), 12-mysteroyl-2-hydroxy-sn-glycero-3- [phospho-rac- (glycerol)] (DMPG), or DMPC / DMPG liposomes. In one aspect, the lysophosphatidyl glycerol is selected from the group consisting of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidyl- lysophosphatidylcholine, oleoyl- , Linoleoyloyl-lysophosphatidylcholine, linolenolyl-lysophosphatidylcholine, or erucoyl-lysophosphatidylcholine. In another aspect, the liposome or liposome precursor is 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (DMPC), 12-mysteoyl-2-hydroxy-sn- DMPG / DMPG, 1-myristoyl-2-hydroxy- sn -glycero-3-phospho- (1'- rac -glycerol) (LysoPG), or 1-myristoyl-2-hydroxy- sn -glycero-3-phosphocholine (LysoPC). In yet another aspect, the short chain fatty acid has 5 or fewer carbons, the middle chain has 6 to 12 carbons, the long chain has 13 to 21 carbons, including both even and odd chain fatty acids, and the long long chain fatty acids have 22 Carbon. In yet another aspect, the short chain fatty acids are saturated or unsaturated fatty acids having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, , 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more carbons. In another aspect, cardiomyopathy or condition due to cardiac pattern irregularity or alteration may be caused by inhibition of ion channels causing delayed-rectifier K ⁺ current in the heart, polymorphic ventricular tachycardia, prolongation of QTc, LQT2, LQTS, Or Thorsad de Point. In yet another aspect, the at least one active agent is selected from the group consisting of chrysototipib, neilotinib, terfenadine, astemizole, gryfloxacin, terodilene, droperidol, lidoplagin, levomethal, sertindole, And is selected from at least one species. In another aspect, the medicament is selected from the group consisting of albuterol (salbutamol), alfuzosin, amantadine, amiodarone, amargrafine, amitriptyline, amosulfine, amphetamine, anagrelide, apomorphine, , Arsenic trioxide, astemizole, atazanavir, aocomycetin, azithromycin, vedicillin, bepridil, bortezomib, curdinib, chloral hydrate, chloroqueen, chlorpromargin, ciprofloxacin, cisapride, citalop (D-amphetamine), dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, Dipronidone, Diphenhydramine, Dyspyrimide, Dobutamine, Dopetylide, Dolasitron, Dom Peridone, Dopamine, Doxepine, Dronedron, Droperidol, Ephedrine, Epinephrine ), Eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, pingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, (Glutamate), galantamine, gatifloxacin, gemifloxacin, granicetrone, halofantrine, haloperidol, hydrochlorothiazide, butylid, iloperidone, imipramine (Levalbutamol), levofloxacin, levomethalil, ricerodecamphetamine, lithium, mezoridazin, metaprozole, levodoprofen, levodextrin, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, terenol, methadone, methamphetamine (methamphetamine), methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, on But are not limited to, neprin (noradrenaline), norfloxacin, norptripyline, oproxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, fasciothione, pazopanib, pentamidine, Or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-methylpiperidine, N-phenylpiperine, phenylpropanolamine, phimozide, posaconazole, probucol, procainamide, promethazine, But are not limited to, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, , Sulpiride, sutinidip, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, Jodon, Trimeto Is selected from prima-sulfa, trimipramine, bandetanib, bardenafil, bemurafenib, venlafaxine, voriconazole, borinostat, or ziprasidone.

In one embodiment, the invention provides a method for preventing or treating one or more adverse reactions resulting from the administration of a therapeutically active agent or drug in a human or animal, comprising the step of administering to said human or animal subject Adapted for oral administration effective to reduce or prevent said at least one cardiomyopathy, I _Kr channel inhibition or QT prolongation caused; The amount of lysophosphatidylglycerol having the following basic structure adjusted for oral administration effective to reduce or prevent one or more cardiomyopathy or condition due to irregularity or alteration of the cardiac pattern caused by the drug:

Wherein R ¹ or R ² is any even or odd chain fatty acid and R ³ can be H, acyl, alkyl, aryl, amino acid, alkene, or alkyne; Measuring the effect of said lysophosphatidyl glycerol and said therapeutically active agent or drug on drug-induced channelopathy, wherein said composition comprises a therapeutically active agent or drug and one or more sensory receptors, thixotropic agents, Lt; RTI ID = 0.0 > and / or < / RTI > thrombocytopenia). In one aspect, the sensory receptive agent comprises one or more of a spice, a sweetener, a coolant, a dye, or combinations and mixtures thereof. In addition, it has been found that, even if unwanted sensory acceptance changes are caused in the dried powders according to the present invention, they are hardly effected and that the powders dried according to the present invention have sufficient solubility for various applications. In one aspect, thixotropic agents are selected from the group consisting of thixotropic matrices such as polysaccharides such as cellulose (e.g., carboxymethylcellulose) or gums (such as xanthan), collagen, gelatin, Amides, alkyd resins, and silica-lipids. In one aspect, the composition comprises both a sensory receptive agent and a thixotropic agent. In one aspect, the phosphatidylglycerol is an empty liposome having a diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM, (DMPC), 12-mysteroyl-2-hydroxy-sn-glycero-3- [phospho-rac- (glycerol)] (DMPG), or DMPC / DMPG liposomes.

For a fuller understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention taken in conjunction with the accompanying drawings, in which:
Figure 1 is a graph showing the effect of DMPC, DMPC + Nilotinib and Nilotinib on the hERG current density from transfected HEK293 cells.
Figure 2 is a graph showing the effect of DMPG, DMPG + Nilotinib and Nilotinib on the hERG current density from transfected HEK293 cells.
Figure 3 is a graph showing the effect of DMPC / DMPG, DMPC / DMPG + neurotinib and nilotinib on the hERG current density from transfected HEK293 cells.
Figure 4 is a graph showing the effect of LysoPC, LysoPC + Nilotinib and Nilotinib on the hERG current density from transfected HEK293 cells.
Figure 5 is a graph showing the effect of LysoPG, LysoPG + Nilotinib and Nilotinib on hERG current density from transfected HEK293 cells.
Figure 6 is a graph showing the effect of DMPC, DMPC + Nilotinib, DMPC + Nilotinib (in DMSO) and Nilotinib on the hERG current density from transfected HEK293 cells.
Figure 7 is a graph showing the effect of DMPG, DMPG + Nilotinib, DMPG + Nilotinib (in DMSO) and Nilotinib on the hERG current density from transfected HEK293 cells.

While the manufacture and use of various embodiments of the invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that may be embodied in many different specific contexts. The specific embodiments discussed herein are merely illustrative of specific methods for making and using the invention and are not intended to limit the scope of the invention.

In order to facilitate understanding of the present invention, a number of terms are defined below. The terms defined herein have meanings that are generally understood by those of ordinary skill in the art in the context of the present invention. The terms " a, " and " the " are not intended to refer to the singular entity but to a generic class for which specific examples may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but its use is not intended to be a limitation on the invention, except as outlined in the claims .

As used herein, the term " thixotropy " is used to describe one or more agonists, e.g., specific gels, that are liquefied when subjected to vibrational forces, such as simple shaking, and then solidify again when left to stand. Thixotropic behavior is observed when long chain molecules tend to orient themselves in the flow direction; As the applied force is increased, the resistance to flow is reduced. However, if the high shear stress is removed, the solution will quickly return to its original viscous state. Some celluloses exhibit thixotropic behavior in which the solution returns to its viscous state over a period of time. Examples of thixotropic agents for use with food, pharmaceuticals, for example, are described in the related art, for example, in the section entitled " A time-dependent for thixotropic areas. Application to Aerosil 200 hydrogels, " M. Dolz, F. Gonzalez, J. Delegido, MJ Hernandez, J. Pellicer, J. Pharm. Sci., Vol. 89, No. 6, pages 790-797 (2000). Many examples of thixotropic agents such as cellulose (e.g., carboxymethylcellulose), gums (e.g., xanthan), collagen, gelatin, aerogels and others are described in the related art, for example, U. S. Patent No. 6,709, 675, incorporated by reference; 6,838,449; 6,818,018, which is incorporated herein by reference.

As used herein, " sensory receptive " refers to an additive having a sensory attribute of a food or beverage, particularly an oral composition provided herein. Those of ordinary skill in the pertinent art will appreciate these characteristics and they can be quantified if necessary. Sensory receptive properties include, but are not limited to, taste, smell and / or appearance. The " preferred " sensory receptive properties are those sensory receptive properties such as desirable odor, taste and / or appearance, or undesirable odor, taste and / or appearance which make the food or beverage composition desirable for consumption by an average human subject Includes shortages. Undesirable sensory receptive properties may include, for example, the presence of an undesirable taste, odor or appearance attribute, such as " off-taste " or " off-odor " The presence of metal or iron, the presence of intense or flaming taste or odor, or the presence of undesirable appearance properties such as separation or precipitation. In one example, the beverage composition provided has the same or nearly the same taste, odor and / or appearance as the same beverage composition that does not contain the provided concentrate, i.e., the beverage composition provided has the desired sensory receptivity And retains the characteristics. Desirable and undesirable sensory receptive properties can be determined by conventional methods of the related art, including, for example, sensory acceptance evaluation methods in which undesirable properties can be detected by visual field, taste and / or odor and chemical tests. Can be measured by a variety of methods known to the skilled artisan as well as by chemical analysis methods. For example, the provided beverage composition may be administered over a period of time, for example, at least, or at least 1, 2, 3, 4, 5, 6, Over a period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months, or at least 1, 2, 3, 4 or more of the same beverage composition that does not contain the provided concentrate. As used herein, "possessing sensory receptive properties" refers to retention of these properties, typically at room temperature, during storage for the period mentioned.

Examples of suitable liquid dosage forms include, but are not limited to, solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents (including esters), emulsions, syrups or elixirs, suspensions, reconstituted solutions from non- Suspensions and foamed formulations reconstituted from the foamed granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweetening agents, thickening agents, and melting agents. Oral dosage forms optionally contain a spice and a coloring agent. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system selected.

Non-limiting exemplary lysophosphatidylglycerols for use with the present invention include, but are not limited to, lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, Phosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenolyl-lysophosphatidylcholine or erucoyl-lysophosphatidylcholine. Asymmetric phosphatidylcholine is referred to as 1-acyl, 2-acyl-sn-glycero-3-phosphocholine, wherein the acyl groups are different from each other. Symmetrical phosphatidylcholine is referred to as 1,2-diacyl-sn-glycero-3-phosphocholine. As used herein, the abbreviation " PC " refers to phosphatidylcholine. Phosphatidylcholine 1,2-dimyristoyl-sn-glycero-3-phosphocholine is abbreviated herein as " DMPC ". Phosphatidylcholine 1,2-dioleoyl-sn-glycero-3-phosphocholine is abbreviated herein as "DOPC". Phosphatidylcholine 1,2-dipalmitoyl-sn-glycero- Quot; DPPC ". A single fatty acid chain version of these short or long chain fatty acids is referred to as a " lyso " form when only a single fatty acid chain is attached to the glyceryl backbone. In certain non-limiting examples, phosphatidylglycerol is empty and forms liposomes with diameters of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM.

As used herein, the term " additive " refers to a food that enhances one or more of its nutritional, medicinal, dietary, health, nutritional, health benefits, energy-providing, therapeutic, holistic, , Beverages, or other human consumables. In certain embodiments of the invention, a user of the composition will require one or more additional nutrients in conjunction with the present invention. For example, the additive may be an oil-based additive (e.g., a non-polar compound) such as a functional food; drugs; Vitamins such as fat soluble vitamins such as vitamin D, vitamin E and vitamin A; mineral; Fatty acids such as, for example, polyunsaturated fatty acids such as omega-3 fatty acids and omega-6 fatty acids such as alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), gamma-linolenic acid GLA, CLA, saw palmetto extract, flaxseed oil, fish oil and algae oil; Phytosterol; Coenzyme such as coenzyme Q10; And any other oily additive. Moreover, in certain embodiments, the composition may have decreased dosage compliance as a result of the taste or odor of the active agent and / or phosphatidylglycerol.

In one embodiment, the lysophosphatidyl glycerol has the following basic structure:

Wherein R ¹ or R ² can be any even or odd chain fatty acid and R ³ can be H, acyl, alkyl, aryl, amino acid, alkene, or alkyne, wherein both the even and odd chain fatty acids , The short chain fatty acids are 5 or less carbons, the heavy chains are 6 to 12 carbons, the long chains are 13 to 21 carbons, and the very long long chain fatty acids are more than 22 carbons. In one example, the fatty acid may be saturated or unsaturated, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more fatty acids.

The present invention relates to the use of any of the QT prolonging drugs, including but not limited to those listed in www.crediblemeds.org, including albuterol (salbutamol), alfuzosin, amantadine, amiodarone, Amphotericin, amphotericin, anagrelide, apomorphine, arformocetrol, aripiprazole, arsenic trioxide, astemizole, atazanavir, achomycetin, azithromycin, vedicillin, bepridil, bortezomib, maintenance The present invention relates to the use of a compound selected from the group consisting of tinib, chloral hydrate, chloroquine, chlorpromargin, ciprofloxacin, sisaflyte, citalopram, clarithromycin, clomipramine, clozapine, cocaine, Dexamethomidine, dexamethomidine, dexmedephenidate, dextroamphetamine (d-amphetamine), dihydroartemisinin + piperazquin, diphenhydramine, dyspyrimide, dobutamine, dofetilide, dolassetron, domperidone,The present invention relates to a pharmaceutical composition comprising at least one compound selected from the group consisting of at least one compound selected from the group consisting of at least one compound selected from the group consisting of at least one compound selected from the group consisting of atropine, But are not limited to, fluoxetine, formoterol, foscarnet, phosphenitol, furosemide (furcomide), galantamine, gatifloxacin, gemifloxacin, granicetrone, halofantrine, haloperidol, hydrochlorothiazide, (Levulabutamol), levofloxacin, levofloxacin, levodextrin, levodextrin, levodextrin, levodextrin, levofloxacin, (Methamphetamine), methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, mojecetinol, methamphetamine (methamphetamine) (Norepinephrine), norfloxacin, norfloxacin, norptrythrin, oproxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine , Fumarate, fasorotide, pazopanib, phentamidine, perfluorinated lipid microspheres, penttermine, phenyl ephrine, phenylpropanolamine, phimozide, posaconazole, probaccole, procainamide, But are not limited to, tryptamine, tryptamine, tryptamine, tryptyline, pseudoline, quadropine, quinidine, quinine sulfate, ranolin, rilpivirin, risperidone, ritodrine, ritonavir, roxithromycin, salmeterol, saquinavir, , Siboflulane, sibutramine, solifenacin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, Terfenadine, tetra But are not limited to, nadine, thiazolidinedine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfam, trimipramine, vandetanib, , ≪ / RTI > or ziprasidone.

Human ether-a-go-go-related gene (hERG) by liposomes and fragments Potassium channel anti-blockade.

The potassium channel conducts the fast component of the delayed rectifier potassium current Kir, which is crucial to the repolarization of the cardiac action potential. The reduction in hERG current due to either genetic defects or deleterious drug effects may be due to an increase in the activity potential, an extension of the QT interval on the surface ECG, and a < RTI ID = 0.0 > " torcadodep " arrhythmia & QT syndrome. This undesirable side effect of non-antiarrhythmic compounds triggered drug withdrawal from the market. Studies on the mechanisms of hERG channel suppression provide important insights into the molecular factors that determine the state-, voltage-, and use-dependence of hERG current interruption. High-affinity in hERG Mutations that alter the nature of the drug-binding site and its interaction with drug molecules cause hereditary short QT syndrome and increased currents that are at high risk for life-threatening arrhythmias. (Thomas D1, 2006).

Anatomical features of K + channels. The type and distribution of intrinsic rectified potassium (Kir) channels is one of the major determinants of electrophysiological characteristics of cardiomyocytes. The inward rectifier potassium (Kir) channel regulates cell excitability and the transport of K + ions across the cell membrane.

The potassium channel from Streptomyces lividans is an indispensable membrane protein with sequence similarity to all known K ⁺ channels, especially in the pore region. X-ray analysis with data on 3.2 angstroms showed that four identical subunits were cradling a selectivity filter of pores at its outer end, an inverted teepee, or a conical object . The narrow selectivity filter is only 12 angstroms long, while the remainder of the pore is wider and lined with hydrophobic amino acids. The large water filled cavities and helix dipoles are arranged to overcome the electrostatic destabilization of the ions in the pores at the center of the bilayer. The main chain carbonyl oxygen atom from the K ⁺ channel signature sequence is lined with a selectivity filter that is opened by structural constraints to coordinate the K ⁺ ion but not the smaller Na ⁺ ion. The selectivity filter contains two K ⁺ ions at about 7.5 angstroms apart. Ion channels represent ion selectivity through pore structures that conduct specific ions. This configuration facilitates ion conduction by utilizing electrostatic repulsion to overcome the attractive forces between the K ⁺ ions and the selectivity filter. The structure of the pore establishes a fundamental physical principle for selective K ⁺ conduction. (Doyle, 1998).

Another member of the inward-rectifier family of potassium channels is the prokaryotic KirBac 1.1 channel. The structure of the closed channel channel assembly, when purified at a resolution of 3.65 Angstroms, contains the main active gate and structural elements involved in gating. Based on structural evidence, gating involves coupling between intracellular and membrane domains, suggesting that the onset of gating by membrane or intracellular signals represents a different entry point to the general mechanistic path. (Kuo, A 2003).

Kirch channels in cardiac myocytes can be actively regulated by changes in the PIP (2) level rather than by downstream signaling pathways. Kir2.1, Kir6.2 / SUR2A (ATP-sensitive K (+) channel) and Kir3.1 / 3.4 (Muscarinic K (+) channel), the classic inward rectifier K Is typically produced by membrane lipid, phosphatidylinositol 4,5-bisphosphate (PIP (2)) Lt; / RTI > The PIP (2) interaction site appears to be conserved by the positively charged amino acid residues and the presumed alpha-helices at the C-terminus of the Kir channel. PIP (2) levels in the plasma membrane are regulated by agonist stimuli (Takano MI 2003).

The inward rectifier potassium channel is characterized by intracellular C-terminal domains that, in addition to two membrane perforations per subunit, control channel gating in response to concentration changes of the various ligands. Based on the crystal structure of the tetrameric C-terminal domain of Kir3.1 it is possible to construct a homology model of the ATP-binding C-terminal domain of Kir6.2. Molecular dynamics simulations are used to probe the kinetics of the Kir C-terminal domain and explore the relationship between its dynamics and possible mechanisms of channel gating. Multiple simulations were performed for both Kir3.1 (crystal structure) and Kir6.2 (homology model) for both their monomer and tetrameric forms, each with a duration of 10 ns. The Kir6.2 simulation was performed with and without conjugated ATP. The results of the simulations show comparable stereostructural stability to crystal structures and homology models. There is a reduction in stereostructural flexibility when comparing the monomer to the tetramer, which mainly corresponds to the subunit interface in the tetramer. The beta-phosphate of ATP interacts with the side chains of K185 in the Kir6.2 model and in the simulations. The flexibility of the Kir6.2 tetramer is not significantly changed by the presence of bound ATP, rather than in the two loop regions. The major component analysis of the simulated kinematics is the Kir3.1 and Kir6.2 tetramer, corresponding to the " dimer-of-dimers " motion of the subunits in the C-terminal domain of the corresponding Kir channel In both, it suggests the loss of symmetry. This suggests a precise tetragonal symmetry and a gating model in which the transitions between the dimers in the dimers are related to the channel gating and the change in coupled perforation helix packing. Among the dimers in C-terminal domain tetramers, dimer motion is also supported by the calculation of the ancillary (anisotropic network model) calculations. The loss of accurate rotational symmetry is suggested to play a role in gating in the bacterial Kir homologue, KirBac1.1, and the nicotinic acetylcholine receptor channel. (Haider SI, 2005).

A homotolenzomic model of the three mammalian Kir channels (Kir1.1, Kir3.1, and Kir6.2) was generated using the KirBac3.1 membrane penetration and rat Kir3.1 intracellular domain structure as template . All three models were explored by molecular dynamics simulations of 10 ns in the phospholipid bilayers. Analysis of the initial structure revealed the conservation of potential lipid interaction residues (lipid headgroup - Trp / Tyr and Arg / Lys branch near water interface). Investigation of the intracellular domain revealed major structural differences between Kir1.1 and Kir6.2, which could account for differences in channel inhibition by ATP. The behavior of all three models in the MD simulation has been found to have stereostructural stability similar to that exhibited in comparable simulations of structures derived from, for example, cold electron microscopy data. As observed in KirBac's previous simulation and KcsA's simulation and structure, local distortion of the selectivity filter was shown during the simulation. These may be related to the filter gating of the channel. Intracellular hydrophobic gates remain functionally closed because they do not undergo any substantial change during the simulation. Analysis of lipid-protein interactions in the Kir model emphasizes the key role of the M0 (or "slide") helix lying roughly parallel to the bilayer-water interface and forming a connection between the membrane perforations and intracellular domains of the channel Haider SI, 2007).

In the voltage-activated K + channel, potassium-selective membrane through pores are gated by changes in membrane potential. Activation gating (opening) occurs in milliseconds and involves gates on the cytoplasmic side of the pore. Substitution of cysteine at a particular site in the last membrane perforation (S6) of the homo-tetrameric Shaker K + channel creates a metal binding site that allows Cd2 + ions to bind with high affinity. The combined Cd2 + ions form a bridge between the cysteine introduced into one channel subunit and the native histidine of another subunit, and the bridge traps the gate in the open state. These results suggest that gating involves rearrangement of intersubunit contacts at the intracellular ends of S6. The structure of the bacterial K + channel shows that the S6 homologue intersects the bundle, leaving an aperture in the bundle crossing. In the context of this structure, the metal ion forms a bridge between the cysteine on the bundle crossing and the histidine below the bundle crossing in the adjacent subunit. The result suggests that gating occurs at the bundle intersection, possibly through a change in the conformation of the bundle itself (Holmgren ML 2002).

Activated gating in a voltage-activated K + channel is a potassium-selective membrane-penetrating pore gated by a change in membrane potential. This activation gating occurs in milliseconds and involves gates in the cytoplasmic side of the pore. Substitution of cysteine at a specific site in the last membrane perforation (S6) of the homoepitermic shaker K + channel creates a metal binding site that allows Cd2 + ions to bind with high affinity. The combined Cd2 + ions form a bridge between the cysteine introduced into one channel subunit and the native histidine of another subunit, and the bridge traps the gate in the open state. These results suggest that gating involves rearrangement of subunit contact at the intracellular end of S6. The structure of the bacterial K + channel shows that the S6 homologue intersects the bundle, leaving a hole in the bundle crossing. In the context of this structure, the metal ion forms a bridge between the cysteine on the bundle crossing and the histidine below the bundle crossing in the adjacent subunit. The result suggests that gating occurs at the bundle intersection, possibly through a change in the conformation of the bundle itself (Holmgren ML 2002).

Channelopathy

-go-go 유전자 관련 심장 사량체성 칼륨 채널은 돌연변이된 경우는 환자를 163종 초과의 약물에 민감하게 하여 이온 전도를 억제하고 활동 전위를 조절해제할 수 있다. (Credible Meds) 활동 전위의 연장은 칼륨 채널에서의 영향을 따른다. 이온 채널 활성 약물은 QTc 간격을 직접적으로 증가시키고, 토르사드 드 포인트 및 돌연 심장사의 위험을 증가시킬 수 있다. (표 1) 약물에 대한 심근세포 칼륨 채널 민감성의 악화는 또한 당뇨병을 포함한 대사성 질환 상태와 또한 연관될 수 있거나 (Veglio M, 2002) 특발성 기원일 수 있다.Human ether -

- go-go gene-related cardiac traumatic potassium channels can mutate, making patients more sensitive to over 163 drugs, inhibiting ion conduction and damping action potentials. (Credible Meds) The prolongation of the action potential follows the effects on the potassium channel. Ion channel activity drugs can directly increase the QTc interval and increase the risk of thoracic dots and sudden cardiac death. (Table 1) Aggravation of myocardial cell potassium channel sensitivity to drugs may also be associated with metabolic disease conditions, including diabetes (Veglio M, 2002) or idiopathic origin.

For these reasons, the assessment of drug effects on myocardial cell potassium channel function is a critical step during drug development and, in severe cases, may be an obstacle to regulatory approval. In whole-cell patch-clamp experiments, curcumin inhibited hERG K ⁺ current to an IC ₅₀ value of 5.55 μM in HEK293 cells stably expressing hERG channels dose-dependently. Recovery time from deactivation, inactivation, and inactivation of the hERG channel was significantly altered by acute treatment with 10 μM of curcumin. Incubation of 20 μM curcumin for 24 hours reduced HEK293 cell viability. Intravenous injection of 20 mg of curcumin in rabbits did not affect cardiac repolarization as evidenced by QTc values. (Hu CW 2012). However, SignPath Pharma found specific molecules that antagonize the QTc prolongation drug (Helson L, 2002 Ranjan A, 2014, Shopp G, 2014). These molecules are components of specific liposomes or liposomes that have been initially linked to lipophilic drugs to enable intravenous solubility under physiological conditions and reduce adverse events. The site of action appears to be an important functional component in the regulation of the action potentials that lead to myocyte contraction downstream to the ion selectivity or gating site (s) in the channel that controls potassium ion transport.

-go-go 관련 유전자 채널 봉쇄의 메커니즘은 간접적으로 DMPC/DMPG 리포솜 또는 그의 대사물질의 항-봉쇄 효과의 작용 메커니즘을 시사할 수 있는 외부적으로 적용된 4급 암모늄 유도체의 효과와 유사할 수 있다. 채널 억제에 대한 억제 상수 및 상대적 결합 에너지는 보다 소수성인 4급 암모늄이 보다 고친화도 봉쇄를 가지며 한편 양이온-π 상호작용 또는 크기 효과는 4급 암모늄에 의한 채널 억제에서 결정적인 요인이 아님을 나타내는 것이다. 또한, 테트라에틸암모늄보다 더 큰 헤드 기 또는 더 긴 꼬리 기 중 어느 하나를 가진 소수성 4급 암모늄은 세포막에 침투하여 유전자 채널의 고친화도 내부 결합 부위에 쉽게 접근하고 더 강한 봉쇄를 발휘한다. Human ether -

The mechanism of go-go related gene channel blockade may be similar to the effect of an externally applied quaternary ammonium derivative, which may indirectly suggest the mechanism of action of the anti-containment effect of DMPC / DMPG liposomes or their metabolites. Inhibitory constants and relative binding energies for channel inhibition indicate that the more hydrophobic quaternary ammonium has a higher affinity blockade while the cation-pi interaction or size effect is not a crucial factor in channel quenching by quaternary ammonium. In addition, the hydrophobic quaternary ammonium having either a larger head group or a longer tail group than tetraethylammonium penetrates into the cell membrane, so that the high affinity of the gene channel also easily approaches the internal binding site and exerts stronger blocking.

Although these data suggest a higher competitive affinity for the binding site by DMPC and DMPG as compared to the QTc prolongation drug () on the basis of the improvement effect liposomes or their components, its composition of ion transport regulation The absence of an antibody, i. E., That the liposome or fragment thereof does not interfere with K + ion transport,

By way of illustration and not by way of limitation, these claims are not to be construed as limiting the scope of the present invention to the extent that these data demonstrate that the basis for improving effect liposomes, or their components, is a higher competitive affinity for binding sites by the DMPC and DMPG Suggesting that the constitutive deficiency of ion transport regulation, that is, the liposomes, or fragments thereof, does not interfere with K + ion transport and that the site of the mechanism of DMPC or DMPG protection may be in the selectivity segment of the channel or in the hydration around the ion .

Furthermore, based on these hERG channel data, the structure of these liposome components can give information useful for the design or selection of other molecules to prevent drug induced cardiac arrhythmias.

This study provides additional information on QTc modulation effects mediated by the cardiomyocyte potassium channel, and mitigation by liposomal and liposomal components. The latter molecule presents an opportunity to probe the K ⁺ channel as a target for pharmacological relaxation of drug-induced channelopathy.

Evaluation of the protective effect of DMPC, DMPG, DMPC / DMPG, LysoPG and LysoPC from hERG inhibition by nilotinib.

Purpose: The purpose of this study was to investigate the effects of DMPC, DMPC, and DMPC on rapidly activating delayed-rectifier potassium selective current (I _Kr ) generated under normoxic conditions in stably transfected human embryonic kidney cells (HEK 293 cells) DMPG, DMPC / DMPG, LysoPG and LysoPC in vitro. This study was designed as a screen and does not require QA involvement (non-GLP-compliant).

Test substance:

One- DMPC

2- DMPG

3- DMPC / DMPG 90: 9

4- 14: 0 LysoPC

5- 14: 0 LysoPG

6- DMPC + Nilotinib (0.1 [mu] M)

7- DMPG + Nilotinib (0.1 [mu] M)

8- DMPC / DMPG 90: 9 + Nilotinib (0.1 μM)

9- 14: 0 LysoPC + Nilotinib (0.1 [mu] M)

10- 14: 0 LysoPG + Nilotinib (0.1 [mu] M)

Test system: hERG-expressing HEK 293 transfected cell line. Performed Test: Whole Cell Patch - Clamp Current Acquisition and Analysis. Experiment temperature: 35 ± 2 ℃.

Application of test substance:

Five minutes exposure to each concentration in the presence of closed circuit perfusion (2 mL / min). 5 minutes for a washout period in the presence of closed-circuit perfusion (2 mL / min) plus flow-through perfusion (2 mL / min). A positive control (nilotinib, 0.05 μg / mL) was added to the same cell line and naive cells obtained from the same passage for 5 minutes in the presence of closed circuit perfusion (2 mL / min).

Cells were under continuous stimulation of the pulse protocol throughout the experiment and cell currents were recorded after 5 minutes exposure to each condition.

Original data acquisition design: acquisition rate (s): 1.0 kHz.

Design for acquisition in a compound or vehicle / solvent equivalent water test:

A recording made at the baseline condition (recording)

A single record made in the presence of concentration 1

Design for acquisition in positive control test:

One record made on baseline conditions

A single record made in the presence of a positive control

n = number of patched responsive cells to which the entire protocol can be applied.

Statistical analysis: Statistical comparisons were made using paired Student's t-tests. The recorded currents obtained on days 2, 3 and 4 were compared statistically with the currents recorded on day 1.

The recorded current after exposure to the positive control (nilotinib alone) was compared to the current recorded at baseline conditions.

The difference was considered significant when p ≤ 0.05.

By exclusion:

One. Time frame of unevaluated drug exposure

2. Seal instability

3. No tail currents generated by the patched cells

4. No significant effect of positive control group

5. Variability of more than 10% in capacitance transient amplitude over the duration of the study.

Effect of test substances on whole cell I _Kr hERG current. The total cell current derived during the voltage pulse was recorded at baseline conditions and after application of the selected concentration of test substance. Cells were depolarized for 1 s from the retention potential (-80 mV) to a maximum value of +40 mV, starting at -40 mV and proceeding in 10 mV increments. The membrane potential was then repolarized to -55 mV for 1 s and finally returned to -80 mV.

Total cell tail current amplitudes were measured at a retention potential of -55 mV after activation of currents from -40 mV to +40 mV. The current amplitude was measured at the maximum (peak) of this tail current. The current density was obtained by dividing the current amplitude by the measured cell capacitance before minimizing the capacitive transient.

Current run-down and solvent effect correction. All data points presented in this study report were calibrated for solvent effects and time-dependent current run-down. The current run-down and solvent effects were simultaneously measured by applying the experimental design in test-material free conditions over the same time frame as that made with the test material. The loss of current amplitude measured during these so-called vehicle experiments (indicating both solvent effect and time-dependent run-down) is subtracted from the loss of the measured amplitude in the presence of the test material, and the influence of the solvent and the current amplitude Apart from the inevitable run-down of the test substance, the influence of the test substance was isolated.

Effect of DMPC, DMPC + Nilotinib and Nilotinib on hERG current density from transfected HEK 293 cells. Normalized current density Calibrated normalized current density SEM p value n = base line 1,000 1,000 n / a n / a 3 DMPC 0.863 1.056 0.056 0.423 3 Nilotinib, 0.1 [mu] M 0.308 0.459 * 0.070 0.016 3 DMPC + Nilotinib, 0.1 [mu] M 0.836 1.029 0.023 0.328 3

Figure 1 is a graph showing the effect of DMPC, DMPC + Nilotinib and Nilotinib on the hERG current density from transfected HEK293 cells.

Effect of DMPG, DMPG + Nilotinib and Nilotinib on the hERG current density from transfected HEK 293 cells. Normalized current density Calibrated normalized current density SEM p value n = base line 1,000 1,000 n / a n / a 3 DMPC 0.800 0.994 0.044 0.901 3 Nilotinib, 0.1 [mu] M 0.308 0.459 * 0.070 0.016 3 DMPC + Nilotinib, 0.1 [mu] M 0.743 0.936 0.067 0.437 3

Figure 2 is a graph showing the effect of DMPG, DMPG + Nilotinib and Nilotinib on the hERG current density from transfected HEK293 cells.

Effect of DMPC / DMPG, DMPC / DMPG + Nilotinib and Nilotinib on hERG current density from transfected HEK293 cells. Normalized current density Calibrated normalized current density SEM p value n = base line 1,000 1,000 n / a n / a 3 DMPC-DMPG 0.871 1.064 0.127 0.647 4 Nilotinib, 0.1 [mu] M 0.308 0.459 * 0.070 0.016 3 DMPC / DMPG + Nilotinib, 0.1 [mu] M 0.773 0.966 0.098 0.754 4

Figure 3 is a graph showing the effect of DMPC / DMPG, DMPC / DMPG + neurotinib and nilotinib on the hERG current density from transfected HEK293 cells.

Effect of LysoPC, LysoPC + Nilotinib and Nilotinib on hERG current density from transfected HEK 293 cells. Normalized current density Calibrated normalized current density SEM p value n = base line 1,000 1,000 n / a n / a 3 LysoPC 0.647 0.840 * 0.040 0.028 4 Nilotinib, 0.1 [mu] M 0.308 0.459 * 0.070 0.016 3 LysoPC + Nilotinib, 0.1 [mu] M 0.865 1.097 0.055 0.553 3

Figure 4 is a graph showing the effect of LysoPC, LysoPC + Nilotinib and Nilotinib on the hERG current density from transfected HEK293 cells.

Effect of LysoPG, LysoPG + Nilotinib and Nilotinib on hERG current density from transfected HEK293 cells. Normalized current density Calibrated normalized current density SEM p value n = base line 1,000 1,000 n / a n / a 3 14: 0 LysoPG, 0.45 [mu] g / mL 0.930 1.124 0.128 0.435 3 Nilotinib, 0.1 [mu] M 0.308 0.459 * 0.070 0.016 3 14: 0 LysoPG + Nilotinib, 0.1 [mu] M 0.743 0.936 0.067 0.437 3

Figure 5 is a graph showing the effect of LysoPG, LysoPG + Nilotinib and Nilotinib on hERG current density from transfected HEK293 cells.

This study was performed to investigate the effects of DMPC, DMPG, DMPC / DMPG, and DMPC on the fast-activating delayed-rectifier potassium selective current (I _Kr ) generated under normoxic conditions in stably transfected human embryonic kidney (HEK) 293 cells induced by neuronotinib The aim was to quantify the protective effects of DMPG, LysoPG and LysoPC.

All data points presented in this study were calibrated for solvent effects and time-dependent current run-down. These two parameters were evaluated by applying exactly the same experimental design to the vehicle as done with the test material. The current was measured over the same period of time as was done in the presence of the test material. The effect of the test substance, if any, was corrected using the obtained values, indicating both the solvent effect and the time-dependent run-down. This ensures that changes due to time or solvent are not accidentally caused by the test substance.

DMPC, DMPG, DMPC / DMPG and LysoPG alone did not cause any inhibition of the hERG tail current density (n = 3). LysoPC alone caused 16% of inhibition of hERG tail current density (n = 4).

Nilotinib alone, formulated in DMSO at 0.1 μM, resulted in 54.1% of inhibition of hERG tail current (n = 3). The observed inhibition is consistent with previous data generated under the same conditions and is consistent with the inhibition value reported for this compound.

Neilotinib did not cause any inhibition of hERG tail current during formulation in aqueous solutions containing DMPC, DMPG, DMPC / DMPC, LysoPG or LysoPC (ratio 1: 9).

These data suggest that co-formulation of neurotinib with DMPC, DMPG, DMPC / DMPC, LysoPG and LysoPC protects against hERG inhibition caused by neilotinib.

In this study, DMPC + Nilotinib, DMPG + Nilotinib, DMPC / DMPC + Nilotinib, LysoPG + Nilotinib or LysoPC + Nilotinib were all formulated using the same method. The appropriate amount of the Nilotinib powder was dissolved in an aqueous solution containing DMPC, DMPG, DMPC / DMPC, LysoPG or LysoPC (ratio 9: 1). The solution was vortexed for 10 minutes before use in the patch-clamp assay.

In contrast, the neilotinib used in cells exposed to only nilotinib was dissolved in DMSO. Additional studies were performed to determine whether the differences in hERG inhibition between DMSO-formulated neurotinib and lipid-co-formulated neurotinib resulted from different formulations (aqueous or DMSO-based).

Steps for research:

* TA =

One- DMPC (in aqueous solution)

2- DMPG (in aqueous solution)

3- DMPC / DMPG 90: 9 (in aqueous solution)

4- 14: 0 LysoPC (in aqueous solution)

5- 14: 0 LysoPG (in aqueous solution)

6- DMPC + Nilotinib (0.1 [mu] M) (in aqueous solution)

7- DMPG + Nilotinib (0.1 [mu] M) (in aqueous solution)

8- DMPC / DMPG 90: 9 + Nilotinib (0.1 μM) (in aqueous solution)

9- 14: 0 LysoPC + Nilotinib (0.1 [mu] M) (in aqueous solution)

10- 14: 0 LysoPG + Nilotinib (0.1 [mu] M) (in aqueous solution)

11- Neilotinib alone (in DMSO)

Of the mechanisms deemed to account for the protection of the hERG current, it was possible that the DMPC / DMPG or Lyso-variants quenched the neilotinib at the moment of the formulation so that the neilotinib did not inherently enter the channel at its receptor site . Another possibility is that nilotinib is less soluble in aqueous solution and thus is poorly solubilized at 0.1 μM.

To test both hypotheses, Nilotinib was formulated in DMSO and added to the experimental chamber after addition of DMPC or DMPG. This suggests that adding DMSO-formulated < RTI ID = 0.0 > nilotinib < / RTI > after adding 1-DMPC / DMPG alone will eliminate the possibility of initial quenching of the nilotinib by lysosome; 2-DMSO was to maintain the solubility of the neilotinib ("neilotinib-only" inhibition of hERG was observed when DMSO-formulated neurotinib was added to the cells).

Steps for the following data

Effect of DMPC, DMPC + Nilotinib, DMPC + Nilotinib (in DMSO) and Nilotinib on the hERG current density from transfected HEK 293 cells. Normalized current density Calibrated normalized current density SEM p value n = base line 1,000 1,000 n / a n / a 3 DMPC 0.863 1.056 0.056 0.423 3 Nilotinib, 0.1 [mu] M 0.308 0.459 * 0.070 0.016 3 DMPC + Nilotinib, 0.1 [mu] M (aqueous) 0.836 1.029 0.023 0.328 3 DMPC + Nilotinib (in DMSO), 0.1 [mu] M 0.164 0.358 0.020 0.019 2

Figure 6 is a graph showing the effect of DMPC, DMPC + Nilotinib, DMPC + Nilotinib (in DMSO) and Nilotinib on the hERG current density from transfected HEK293 cells.

Effect of DMPG, DMPG + Nilotinib, DMPG + Nilotinib (in DMSO) and Nilotinib on the hERG current density from transfected HEK293 cells. Normalized current density Calibrated normalized current density SEM p value n = base line 1,000 1,000 n / a n / a 3 DMPG 0.800 1.994 0.044 0.901 3 Nilotinib, 0.1 [mu] M 0.308 0.459 * 0.070 0.016 3 DMPG + Nilotinib, 0.1 [mu] M 0.743 0.936 0.067 0.437 3 DMPG + Nilotinib (in DMSO), 0.1 [mu] M 0.630 0.823 0.290 0.651 2

Figure 7 is a graph showing the effect of DMPG, DMPG + Nilotinib, DMPG + Nilotinib (in DMSO) and Nilotinib on the hERG current density from transfected HEK293 cells.

Active Agent - Empty Liposome Suspension. Formulated suspensions with the capacity of the active agent, empty liposomes (e.g., DMPG, DMPC, or both DMOG and DMPC), and sensory receptive agents can be formed in suspension, and xantham gum Such as, for example, pigments, flavors, parabens (e.g., methylparaben and propylparaben) (preservatives), high fructose corn syrup Viscosity builders and sweeteners), propylene glycol (solvent and dispersant), and ascorbic acid (to adjust the pH of the suspension). The suspension can be studied for release profile in 0.1 N HCl at pH 1.2 using USP dissolution apparatus II using 900 ml of dissolution medium. Briefly, samples were taken at predetermined time intervals and the active agent content was analyzed using HPLC analysis. The release of the active agent over time can be plotted. Different amounts of thixotropic agents (and salts as required) can be added to the three suspensions to obtain suspensions with various thixotropic agents, e.g., 0.1, 0.3, and 0.5 wt%. The suspension may be mixed and maintained for 24 hours to achieve equilibrium.

In certain embodiments, the active agent can also be coated and formed into mini-capsules, mini-tablets, or only small particles (1.0 micrometer (uM), 10 uM, 100 uM, and 1 millimeter) May be mixed in solution with a sensory-receiving agent and / or a thixotropic agent.

It is contemplated that any of the embodiments discussed herein may be practiced with any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, the method of the present invention can be accomplished using the composition of the present invention.

It is to be understood that the particular embodiments described herein are not to be regarded as an easy limit by way of example of the invention. The main features of the invention may be used in various embodiments without departing from the scope of the invention. Those skilled in the relevant art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures set forth herein. Such equivalents are considered to be within the scope of the present invention and are covered by the claims.

All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

The use of the word " one " may mean " one " when used in conjunction with the term " comprising " It also coincides with the meaning of. The use of the term " or " in the claims is used to mean " and / or ", unless the context clearly dictates that the only alternative or alternative is mutually exclusive, . Throughout this application, the term " about " is used to specify that the value includes the intrinsic variation of the error for the device, the method used to determine the value, or the variation that exists between the study subjects.

(And any form of comprising, such as " comprises " and " comprising "), " having " (and any form of having (And any form of containing, e.g., " containing, " or " containing "Quot; and " contain ") are inclusive or open, and do not preclude additional, unrecited elements or method steps. In any of the embodiments of any of the compositions and methods provided herein, " comprising " may be replaced by " consisting essentially of " or " consisting of. &Quot; As used herein, the phrase " consisting essentially of " is intended to encompass the specified integer (s) or step (s) as well as those that do not materially affect the claimed feature or function of the claimed invention. As used herein, the term " comprising " is intended to encompass a set of integers (e.g., feature, element, feature, (S), feature (s), method / process step or limit (s)).

The term " or combination thereof " as used herein refers to all permutations and combinations of the listed items preceding the term. For example, " A, B, C, or a combination thereof " may be any combination of A, B, C, AB, AC, BC, or ABC, , ACB, BAC, or CAB. Continuing with this example, explicit combinations of one or more items or repeats of terms are included, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and the like. It will be understood by those of ordinary skill in the art that there is typically no limitation to the number of items or terms in any combination, unless the context clearly dictates otherwise.

As used herein, approximate words, such as, without limitation, " about ", " substantial " or " substantially " refer to a condition that is understood to be not necessarily absolute or complete, Will be deemed to be sufficiently close to the ordinary skilled artisan to ensure that the condition is specified as present. The extent to which the description can vary will depend on how large the change can be introduced and still be appreciated by those of ordinary skill in the art that the modified feature may still have the desired and unmodified capabilities . Generally, however, subject to the foregoing discussion, the numerical values herein modified by approximate words such as " about " refer to values of at least +/- 1, 2, 3, 4, 5, 6, 7, 10, 12 Or 15%.

All of the compositions and / or methods disclosed and claimed herein may be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in terms of preferred embodiments, variations may be applied to the compositions and / or methods and in the steps of the methods described herein or in the order of steps without departing from the concept, spirit and scope of the present invention Will be apparent to one of ordinary skill in the art. All such similar substitutions and modifications apparent to those of ordinary skill in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

references

U.S.A. Patent Publication No. 2010/0004549: System and Method of Serial Comparison for Detection of Long QT Syndrome (LQTS).

U.S.A. Patent Publication No. 2008/0255464: System and Method for Diagnosing and Treating Long QT Syndrome.

U.S.A. Patent Publication No. 2007/0048284: Cardiac Arrhythmia Treatment Methods.

U.S.A. Patent Publication No. 2001/00120890: Ion Channel Modulating Activity I.

Claims (26)

One or more cardiomyopathies due to irregularity or alteration of a cardiac pattern caused by one or more organoleptic agents, thixotropic agents, or both sensory receptors and thixotropic agents and active agents or drugs the amount of phosphatidylglycerol adjusted for oral administration effective to reduce or prevent cardiac channelopathy or condition
Comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of < RTI ID = 0.0 > 1, < / RTI > The method of claim 1, wherein the phosphatidyl glycerol is selected from the group consisting of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidyl- Wherein the composition comprises at least one of phosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenolyl-lysophosphatidylcholine, or erucoyl-lysophosphatidylcholine. The composition of claim 1, wherein the at least one sensory receptive agent comprises one or more of a spice, a sweetener, a coolant, a dye, or a combination and mixtures thereof. The method of claim 1, wherein the at least one thixotropic agent forms a thixotropic matrix and is selected from the group consisting of polysaccharides, cellulose, carboxymethyl cellulose, gum, xanthan gum, collagen, gelatin, aerogels, polyacrylamides, alkyd resins, ≪ / RTI > lipid. The composition of claim 1, wherein the phosphatidylglycerol is formed of an empty liposome and has an average diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM. 7. The composition of claim 1 wherein the phosphatidylglycerol is formed from liposomes having an average diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, (DMPC), 12-mysteroyl-2-hydroxy-sn-glycero-3- [phospho-rac- (glycerol)] (DMPG), or DMPC / DMPG. The method of claim 1, wherein the phosphatidylglycerol is 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (DMPC), 12- (DMPG), DMPC / DMPG, 1-myristoyl-2-hydroxy- sn -glycero-3-phospho- (1'- rac -glycerol) ( LysoPG), or 1-myristoyl-2-hydroxy- sn -glycero-3-phosphocholine (LysoPC). The method of claim 1, wherein the phosphatidylglycerol comprises both even and odd chain fatty acids, wherein the short chain fatty acid has no more than 5 carbons, the heavy chain has 6 to 12 carbons, the long chain is 13 to 21 carbons, Wherein the fatty acid is further defined as more than 22 carbons. The method of claim 1, wherein the phosphatidylglycerol is saturated or unsaturated at 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55 or more carbons. The method of claim 1, wherein the cardiomyopathy or condition due to irregularity or alteration of the cardiac pattern is selected from the group consisting of suppression of the ion channel causing polymorphic ventricular tachycardia, QTc Or prolongation of QT prolongation or IKr channel inhibition caused by the administration of an active agent or drug used in the treatment of heart, allergic or cancer-related disorders, or a prolongation of IQr channel inhibition, LQT2, LQTS, or torsades de pointes, Or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein the drug is selected from the group consisting of albuterol (salbutamol), alfuzosin, amantadine, amiodarone, artfreep, amitriptyline, amoxifene, amphetamine, anagrelide, apomorphine, Azithromycin, azithromycin, vedicillin, bepridil, bortezomib, curdinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, sissafrid, catechin, atorvastatin, (D-amphetamine), dexamethasone, dexamethomidine, dexamphetamine, dextroamphetamine (d-amphetamine), diclofenac, (Adrenaline), dihydroartemisinin + piperazin, diphenhydramine, dyspyrimide, dobutamine, dofetilide, dolassetron, domperidone, dopamine, doxepin, dronedron, droperidol, ephedrine, , Eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, phosphenitol, furosemide Glucopyranoside, lucamide, galantamine, gatifloxacin, gemifloxacin, glanisetron, halofantrine, haloperidol, hydrochlorothiazide, butylid, iloperidone, imipramine (melipramine), indapamide , Isoproterenol, isoproterenol, isradipine, itraconazole, ibabradine, ketoconazole, lapatinib, levbaluterol (lev resbutarol), levofloxacin, levomadyl, lysedecampetamine, lithium, The present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment and / or prophylaxis of diabetes mellitus, nausea, methadone, methamphetamine (methamphetamine), methylphenidate, midodrine, mifepristone, mirabegron, (Norepinephrine), norfloxacin, norfloxilin, oproxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, fasciothione, pazopanib, pentamidine, , Phenylephrine, phenylpropanolamine, phimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, , Sulforadone, sitorapenib, sotalol, sparfloxacin, sulforadone, risperidone, ritodrine, ritonavir, roxithromycin, salmeterol, saquinavir, A medicament for the treatment and / or prophylaxis of a disease or condition selected from the group consisting of sulpiride, sutinidip, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, , Trimethov Wherein the composition is selected from rim-sulfa, trimipramine, bandetanib, bardenapil, bemula penip, venlafaxine, voriconazole, borinostat, or ziprasidone. An agent or agent which causes at least one adverse reaction resulting from the administration of an active agent or drug in a human causing at least one of cardiomyopathy, I _Kr channel depression or QT prolongation As a composition,
The amount of lysophosphatidylglycerol having the following basic structure, adjusted for oral administration effective to reduce or prevent said at least one cardiomyopathy, I _Kr channel inhibition or QT prolongation induced by said drug:

Wherein R ¹ or R ² is any even or odd chain fatty acid and R ³ can be H, acyl, alkyl, aryl, amino acid, alkene, or alkyne;
At least one activator or drug that causes at least one of I _Kr channel inhibition or QT prolongation; And
A composition comprising at least one sensory receptive agent, a thixotropic agent, or both a sensory receptive agent and a thixotropic agent. 13. The composition of claim 12, wherein the at least one sensory receptive agent comprises one or more of a spice, a sweetener, a coolant, a dye, or a combination and mixtures thereof. 13. The composition of claim 12, wherein the at least one thixotropic agent forms a thixotropic matrix and is selected from the group consisting of polysaccharides, cellulose, carboxymethylcellulose, gum, xanthan gum, collagen, gelatin, aerogels, polyacrylamides, alkyd resins, ≪ / RTI > lipid. 13. The composition of claim 12, wherein the phosphatidylglycerol is formed of an empty liposome and has an average diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, or 100 nM. 13. The method of claim 12, wherein the phosphatidylglycerol is formed from liposomes having an average diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90, (DMPC), 12-mysteroyl-2-hydroxy-sn-glycero-3- [phospho-rac- (glycerol)] (DMPG), or DMPC / DMPG. 13. The method of claim 12, wherein the cardiomyopathy or condition due to cardiac pattern irregularity or alteration is selected from the group consisting of inhibition of ion channels causing delayed-rectifier K ⁺ current in the heart, polymorphic ventricular tachycardia, prolongation of QTc, LQT2, LQTS , Or torcadadone, or the composition is used for the treatment or prophylaxis of prolonged QT prolongation or I _Kr channel inhibition caused by the administration of one or more drugs used in the treatment of heart, allergic, or cancer-related disorders ≪ / RTI > 13. The composition of claim 12, wherein the liposome comprises a lipid or phospholipid wall wherein the lipid or phospholipid comprises phosphatidylcholine (lecithin), lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine Phosphatidylglycerol, stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, glycerol monostearate, glycerol monostearate, , Hexadecyl stearate, isopropyl myristate, amphoteric acrylic polymer, fatty acid, fatty acid amide, cholesterol, cholesterol ester, diacylglycerol, and diacylglycerol succinate. 13. The method according to claim 12, wherein the drug is selected from the group consisting of albuterol (salbutamol), alfuzosin, amantadine, amiodarone, araffrid, amitriptyline, amoxifene, amphetamine, anagrelide, apomorphine, Azithromycin, azithromycin, vedicillin, bepridil, bortezomib, curdinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, sissafrid, catechin, atorvastatin, (D-amphetamine), dexamethasone, dexamethomidine, dexamphetamine, dextroamphetamine (d-amphetamine), diclofenac, , Dihydroartemisinin + piperazin, diphenhydramine, dyspyrimide, dobutamine, dofetilide, dolassetron, domperidone, dopamine, doxepin, dronedron, droperidol, ephedrine, epinephrine ), Eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, pingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, (Glutamate), galantamine, gatifloxacin, gemifloxacin, granicetrone, halofantrine, haloperidol, hydrochlorothiazide, butylid, iloperidone, imipramine (Levalbutamol), levofloxacin, levomethalil, ricerodecamphetamine, lithium, mezoridazin, metaprozole, levodoprofen, levodextrin, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, terenol, methadone, methamphetamine (methamphetamine), methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, Epi (Norepinephrine), norfloxacin, norfloxilin, oproxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, fasciothione, pazopanib, pentamidine, , Phenylephrine, phenylpropanolamine, phimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, , Sulforadone, sitorapenib, sotalol, sparfloxacin, sulforadone, risperidone, ritodrine, ritonavir, roxithromycin, salmeterol, saquinavir, A medicament for the treatment and / or prophylaxis of a disease or condition selected from the group consisting of sulpiride, sutinidip, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, , Trimetho Rim-sulfanyl, tri US plastic min, van der tanip, would fill Bar Gardena, chopping mura penip, venlafaxine, voriconazole, barley furnace start, or if selected from ziprasidone composition. In a human or animal subject caused by the active agent or drug used to treat diseases in the human or animal subject, comprising the steps, at least one cardiac channel neuropathy, irregularities or changes in the heart pattern, I _Kr channel inhibition or QT How to prevent or treat prolongation:
Or a pharmaceutically _acceptable salt or solvate thereof, is administered to the human or animal subject in an amount effective to reduce or prevent one or more cardiomyopathy, cardiac pattern irregularity or alteration, I _Kr channel inhibition, or QT prolongation caused by the active agent or drug The amount of glycerol;
Wherein the orally administered lysophosphatidyl glycerol reduces or eliminates the at least one cardiomyopathy, cardiac pattern irregularity or alteration, I _Kr channel inhibition or QT prolongation, wherein the effective amount of the activator or drug is sufficient to treat the disease ); And
Administering one or more sensory receptors, thixotropic agents, or both sensory receptors and thixotropic agents. 21. The method of claim 20, wherein the phosphatidyl glycerol is selected from the group consisting of lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidyl- Phospholipids, phosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenolyl-lysophosphatidylcholine or erucoyl-lysophosphatidylcholine. 21. The method of claim 20, wherein the at least one sensory receptive agent comprises one or more of a spice, a sweetener, a coolant, a dye, or a combination and mixtures thereof. 21. The composition of claim 20, wherein the at least one thixotropic agent forms a thixotropic matrix and is selected from the group consisting of polysaccharides, cellulose, carboxymethylcellulose, gum, xanthan gum, collagen, gelatin, aerogels, polyacrylamide, alkyd resins, ≪ RTI ID = 0.0 > lipid. ≪ / RTI > 21. The method of claim 20, wherein the phosphatidylglycerol is formed of an empty liposome and has an average diameter of 10, 20, 25, 30, 40, 50, 60, 75, 80, 90 or 100 nM. 21. The method of claim 20, wherein the cardiomyopathy or condition due to cardiac pattern irregularity or alteration is selected from the group consisting of suppression of ion channels causing delayed-rectifier K ⁺ current in the heart, polymorphic ventricular tachycardia, prolongation of QTc, LQT2, LQTS , Or Thorsad de Point. 21. The pharmaceutical composition according to claim 20, wherein the drug is selected from the group consisting of albuterol (salbutamol), alfuzosin, amantadine, amiodarone, artfreep, amitriptyline, amoxifene, amphetamine, anagrelide, apomorphine, Azithromycin, azithromycin, vedicillin, bepridil, bortezomib, curdinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, sissafrid, catechin, atorvastatin, (D-amphetamine), dexamethasone, dexamethomidine, dexamphetamine, dextroamphetamine (d-amphetamine), diclofenac, , Dihydroartemisinin + piperazin, diphenhydramine, dyspyrimide, dobutamine, dofetilide, dolassetron, domperidone, dopamine, doxepin, dronedron, droperidol, ephedrine, epinephrine ), Eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, pingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, (Glutamate), galantamine, gatifloxacin, gemifloxacin, granicetrone, halofantrine, haloperidol, hydrochlorothiazide, butylid, iloperidone, imipramine (Levalbutamol), levofloxacin, levomethalil, ricerodecamphetamine, lithium, mezoridazin, metaprozole, levodoprofen, levodextrin, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, terenol, methadone, methamphetamine (methamphetamine), methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril / HCTZ, moxifloxacin, Epi (Norepinephrine), norfloxacin, norfloxilin, oproxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, fasciothione, pazopanib, pentamidine, , Phenylephrine, phenylpropanolamine, phimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, , Sulforadone, sitorapenib, sotalol, sparfloxacin, sulforadone, risperidone, ritodrine, ritonavir, roxithromycin, salmeterol, saquinavir, A medicament for the treatment and / or prophylaxis of a disease or condition selected from the group consisting of sulpiride, sutinidip, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, , Trimetho The method sulfamic, Plastic Tree US civil and van der tanip, Dana Barr, Phil Vespa Village penip, venlafaxine, voriconazole, barley, no-start or not is selected from ziprasidone-rim.

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