KR20230110823A - Protective effect of dmpc, dmpg, dmpc/dmpg, lysopg and lysopc against drugs that cause channelopathies - Google Patents

Abstract

The present invention includes compositions and methods for preventing one or more cardiac channelopathy or conditions due to irregularities or alterations in cardiac patterns caused by an active agent or drug in a human or animal subject, comprising an amount of lysophosphatidylglycerol adapted for oral administration effective to reduce or prevent one or more cardiac channelopathy or conditions due to irregularities or alterations in cardiac patterns caused by an active agent or drug.

Description

Protective effect of DMPC, DMPG, DMPC/DMPG, LYSOPG and LYSOPC from drugs causing channelopathy {PROTECTIVE EFFECT OF DMPC, DMPG, DMPC/DMPG, LYSOPG AND LYSOPC AGAINST DRUGS THAT CAUSE CHANNELOPATHIES}

The present invention relates generally to the field of drug therapy, and more particularly to novel compositions and methods for reducing or eliminating channelopathy or conditions resulting from irregularities or alterations in cardiac patterns caused by active agents or drugs.

Without limiting the scope of the present invention, the duration of repolarization of cardiac ventricle QT in a subject in need of modification or functional interference by a therapeutic agent, or control of the duration of repolarization of cardiac ventricular QT, whose background is a congenital defect that, if not modified, can lead to prolongation of repolarization in cardiac myocyte action potential, torsade de points, and long QT syndrome, Compositions and methods for controlling are described.

The heart's beating is due to precisely controlled, regularly spaced waves of myocardial excitation and contraction. Current during ion-based depolarization and repolarization can be measured by electrical leads (electrocardiogram) placed at specific locations on the body that measure electrical waves. The P-wave represents a wave of atrial depolarization. When the entire atrium is depolarized, the wave returns to zero. After 0.1 seconds, the ventricle is completely depolarized, resulting in a QRS complex. The three peaks are due to the way the current spreads in the ventricles. This is followed by the T-wave or repolarization of the ventricles. The QT interval, measured from the beginning of the QRS wave on standard ECC to the end of the T wave, represents the duration of the cardiac myocyte repolarization phase (or ventricular depolarization and repolarization) to completion. The duration of this interval can vary due to genetic variation, heart disease, electrolyte balance, venom, and medications. Prolongation of the QT interval can result in ventricular arrhythmias and sudden death.

Drug-induced long QTc syndrome (LQTS), i.e. prolongation of action potential duration, is a common cause of government-legalized drug withdrawal. QTc prolongation is an unpredictable risk factor for Torsades de Pointes (TdP), a polymorphic ventricular tachycardia that causes ventricular fibrillation. Drug-induced LQTS comprises about 3% of all prescriptions, which can constitute a lethal adverse reaction when followed by TdP. Patients concomitantly taking one or more than one QTc-prolonging drug have an increased risk of TdP. The overall incidence of TdP is statistically rare but clinically significant in affected individuals, and testing for this drug's effectiveness is a prerequisite before entering a drug into clinical trials.

A common structurally diverse drug blocks the human ether-a-go-go-related gene (KCNH2 or hERG) encoded K ⁺ channels and the cardiac delayed-rectifier potassium current I _K (KV11.1) resulting in acquired LQTS. The drug-associated increased risk of LQTS is a major drug development obstacle and many drugs have been withdrawn during pre-clinical development, withdrawn from the market or assigned post-approval black box warnings. Autosomal recessive or dominant LQTS, based on 500 possible mutations in 10 different genes encoding potassium channels, has an incidence of 1:3000 or about 100,000 in the United States. The risk of prolonged QT interval, or LQTS, occurs in 2.5% of the asymptomatic US population. When manifested, this syndrome can cause severe cardiac arrhythmias and sudden death in untreated patients. The probability of cardiac death is increased in asymptomatic congenital LQTS patients receiving LQTS-inducing drugs.

Most of the acquired LTQS drug withdrawal is due to blockage of potassium ion channels encoded by the human ether-a-go-go-related gene (hERG). High concentrations of hERG blocking drugs generally induce a prolonged QTc interval and increase the probability of TdP. Up to 10% of cases of drug-induced TdP can be attributed 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, US Patent Publication No. 2010/0004549 (Kohls et al. 2010) discloses a system and method for detecting LQTS in a patient by comparing a collected set of ECG data from the patient to a plurality of databases of collected ECG data. The plurality of databases will include a database containing prior ECGs from patients, a database of known acquired LQTS traits, and a database of known genetic LQTS traits. Comparing a patient's ECG with these databases will facilitate the detection of occurrences such as changes in QT interval, changes in T-wave shape, changes in U-wave shape from the success of the ECG, and can match known genetic patterns of LQTS. The system and method are sensitive to the gender and ethnicity of the patient, as these factors have been shown to result in LQTS, and moreover, can match QT duration to a database of drug effects. The system and method are also easily integrated into existing ECG management systems and storage devices.

Systems and methods for diagnosis and treatment of LQTS are described in US Patent Publication No. 2008/0255464 (Michael, 2008). The Michael invention includes a system for diagnosing long QT syndrome (LQTS) that derives the QT/QS2 ratio from electrical cardiac systolic (QT) and mechanical cardiac systolic (QS2) to detect prolonged QT intervals in a patient's cardiac cycle. The processor obtains cardiac systole from the microphone and chest electrode, calculates the QT/QS2 ratio, and outputs the result to a display. The processor may compare the QT/QS2 ratio to a threshold stored in memory for diagnosing LQTS in the patient. The user interface provides for programming, set-up, and customization of the display. The mode selector allows the system to alternatively operate as a cardiometer, 12 lead electrocardiograph, or instrument for diagnosing LQTS. A related method for diagnosing cardiac disorders such as LQTS involves measuring QT and QS2 during the same cardiac cycle, calculating a QT/QS2 ratio, and comparing the results to threshold values derived from empirical data. The method may include measuring cardiac systolic both at rest and during exercise, and may be used for drug efficacy, dose optimization, and acquired LQTS causality testing.

A method for treating cardiac arrhythmias is provided in US Patent Publication No. 2007/0048284 (Donahue and Marban, 2007). The method comprises administering an amount of at least one polynucleotide that modulates the electrical properties of the heart. The polynucleotides of the present invention can also be used with microdelivery vehicles such as cationic liposomes and adenoviral vectors.

Methods, compositions, dosing 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, early postdepolarization 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 modulating compound may be a cycloalkylamine ether compound, particularly a cyclohexylamine ether compound. Also described are ion channel modulating compounds and compositions of drugs that induce early postdepolarization, prolongation of the QT interval and/or torsade de point. The Fedida invention also discloses antioxidants that can be provided with ion channel modulating compounds, 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 biloba.

The present invention relates to novel compositions and methods for reducing or eliminating channelopathy or conditions due to irregularities or alterations in cardiac patterns caused by active agents or drugs.

In one embodiment, the invention is a composition comprising one or more pharmacologically active agents that cause cardiac channelopathy or conditions due to irregularities or alterations in cardiac patterns in a subject and one or more lipids provided in an amount sufficient to prevent or reduce cardiac channelopathy or conditions due to irregularities or alterations in cardiac patterns caused by said one or more pharmacologically active agents, wherein the combination is dispersed in a pharmaceutically acceptable medium, solvent, or vehicle, wherein the active agents, lipids, or both are dissolved, dispersed, or suspended in a medium, solvent, or vehicle, wherein the pharmacological ratio of at least one active agent to lipid is from 10:1 to 1:10, from 1:5 to 5:1, from 3:1 to 1:3, wherein protection from cardiac channelopathy or condition due to irregularities or alterations in cardiac pattern lasts for 1 to 24 hours. In one aspect, the lipid is provided in an amount that eliminates the lipid from the bloodstream while preventing or reducing cardiac channelopathy or conditions due to irregularities or alterations in the cardiac pattern. In another aspect, the lipid prevents cardiac channelopathy or conditions due to irregularities or alterations in cardiac pattern for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In one aspect, the one or more pharmacologically active agents are selected from at least one of a 5-HT3 antagonist, a 5-HT4 receptor agonist, a histamine antagonist, a calcium channel blocker, an antimalarial agent, an antipsychotic agent, a halodol, an antibiotic, an antiarrhythmic agent, an anticancer agent, an opioid agent, or a lipid-lowering agent that blocks serotonin binding. In another aspect, the lipid comprises at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, cardiolipin, phosphatidylinositol or a precursor thereof. 또 다른 측면에서, 지질은 리소포스파티딜글리세롤, 리소포스파티딜콜린, 라우로일-리소포스파티딜콜린, 미리스토일-리소포스파티딜콜린, 팔미토일-리소포스파티딜콜린, 스테아로일-리소포스파티딜콜린, 아라키도일-리소포스파티딜콜린, 올레오일-리소포스파티딜콜린, 리놀레오일-리소포스파티딜콜린, 리놀레노일-리소포스파티딜콜린, 에루코일-리소포스파티딜콜린, 1-미리스토일-2-히드록시-sn-글리세로-3-포스포콜린 (DMPC), 12-미스테로일-2-히드록시-sn-글리세로-3-[포스포-rac-(글리세롤)] (DMPG), DMPC/DMPG, 1-미리스토일-2-히드록시- sn -글리세로-3-포스포-(1'- rac -글리세롤) (LysoPG), 또는 1-미리스토일-2-히드록시- sn -글리세로-3-포스포콜린 (LysoPC)을 포함한다. In another aspect, the lipid comprises both even and odd chain fatty acids, wherein short chain fatty acids are 5 carbons or fewer, medium chains are 6 to 12 carbons, long chains are 13 to 21 carbons, and very long chain fatty acids are lysophosphatidylglycerols, further defined as greater than 22 carbons. In another aspect, the lipid is saturated or unsaturated, 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, short chain fatty acids having 40, 45, 50, 55 or more carbons. In another aspect, the cardiac channelopathy or condition due to irregularities or alterations in cardiac pattern is inhibition of ion channels responsible for delayed rectifying K ⁺ currents in the heart, polymorphic ventricular tachycardia, prolongation of QTc, LQT2, LQTS, or Torsade de Point. In another aspect, the active drug is selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, grippafloxacin, terodylene, droperidol, lidoflazin, levometadil, sertindol, or cisapride. In another aspect, the composition is suitable for enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, pulmonary, rectal, vaginal, or oral administration.

In another aspect, the active agent is provided in a lipid formed into a liposome, wherein the lipid is phosphatidylcholine (lecithin), lysolecithin, lysophosphatidylethanol-amine, phosphatidylserine, phosphatidylinositol, sphingomyelin, phosphatidylethanolamine (cephalin), cardiolipin, phosphatidic acid, cerebroside, dicetylphosphate, phosphatidylcholine, and dipalmitoyl-phosphatidylglycerol. , stearylamine, dodecylamine, hexadecyl-amine, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, amphoteric acrylic polymers, fatty acids, fatty acid amides, cholesterol, cholesterol esters, diacylglycerols, or from at least one diacylglycerol succinate is chosen 또 다른 측면에서, 활성제는 알부테롤, 알푸조신, 아만타딘, 아미오다론, 아미술프리드, 아미트립틸린, 아목사핀, 암페타민, 아나그렐리드, 아포모르핀, 아르포르모테롤, 아리피프라졸, 삼산화비소, 아스테미졸, 아타자나비르, 아토목세틴, 아지트로마이신, 베다퀼린, 베프리딜, 보르테조밉, 보수티닙, 클로랄 수화물, 클로로퀸, 클로르프로마진, 시프로플록사신, 시사프리드, 시탈로프람, 클라리트로마이신, 클로미프라민, 클로자핀, 코카인, 쿠르쿠민, 크리조티닙, 다브라페닙, 다사티닙, 데시프라민, 덱스메데토미딘, 덱스메틸페니데이트, 덱스트로암페타민, d-암페타민, 디히드로아르테미시닌 및 피페라퀸, 디펜히드라민, 디소피라미드, 도부타민, 도페틸리드, 돌라세트론, 돔페리돈, 도파민, 독세핀, 드론다론, 드로페리돌, 에페드린, 에피네프린 , 아드레날린, 에리불린, 에리트로마이신, 에스시탈로프람, 파모티딘, 펠바메이트, 펜플루라민, 핑골리모드, 플레카이니드, 플루코나졸, 플루옥세틴, 포르모테롤, 포스카르네트, 포스페니토인, 푸로세미드, 프루세미드, 갈란타민, 가티플록사신, 게미플록사신, 그라니세트론, 할로판트린, 할로페리돌, 히드로클로로티아지드, 이부틸리드, 일로페리돈, 이미프라민, 멜리프라민, 인다파미드, 이소프로테레놀, 이스라디핀, 이트라코나졸, 이바브라딘, 케토코나졸, 라파티닙, 레발부테롤, 레보플록사신, 레보메타딜, 리스덱삼페타민, 리튬, 메조리다진, 메타프로테레놀, 메타돈, 메스암페타민(Methamphetamine) (메스암훼타민(methamfetamine)), 메틸페니데이트, 미도드린, 미페프리스톤, 미라베그론, 미르타자핀, 모엑시프릴/HCTZ, 목시플록사신, 넬피나비르, 니카르디핀, 닐로티닙, 노르에피네프린 (노르아드레날린), 노르플록사신, 노르트립틸린, 오플록사신, 올란자핀, 온단세트론, 옥시토신, 팔리페리돈, 파록세틴, 파시레오티드, 파조파닙, 펜타미딘, 퍼플루트렌 지질 미소구체, 펜테르민, 페닐에프린, 페닐프로판올아민, 피모지드, 포사코나졸, 프로부콜, 프로카인아미드, 프로메타진, 프로트립틸린, 슈도에페드린, 쿠에티아핀, 퀴니딘, 퀴닌 술페이트, 라놀라진, 릴피비린, 리스페리돈, 리토드린, 리토나비르, 록시트로마이신, 살부타몰, 살메테롤, 사퀴나비르, 세르틴돌, 세르트랄린, 세보플루란, 시부트라민, 솔리페나신, 소라페닙, 소탈롤, 스파르플록사신, 술피리드, 수니티닙, 타크롤리무스, 타목시펜, 텔라프레비르, 텔라반신, 텔리트로마이신, 테르부탈린, 테르페나딘, 테트라베나진, 티오리다진, 티자니딘, 톨테로딘, 토레미펜, 트라조돈, 트리메토프림-술파, 트리미프라민, 반데타닙, 바르데나필, 베무라페닙, 벤라팍신, 보리코나졸, 보리노스타트, 또는 지프라시돈으로부터 선택된다.

In another embodiment, the present invention provides a method for preventing or treating one or more cardiac channelopathy or conditions due to an irregularity or alteration of the heart pattern caused by a pharmacologically active agent used to treat a disease in a human or animal subject, comprising preparing a composition comprising the active agent and a lipid suitable for administration effective to reduce or prevent cardiac channelopathy or condition due to an irregularity or alteration of the heart pattern, wherein the amount of the lipid is attributable to irregularities or alterations in the heart pattern caused by the active agent. sufficient to reduce or eliminate cardiac channelopathy or condition caused by, wherein the pharmacological ratio of the at least one active agent to lipid is 10:1 to 1:10, 1:5 to 5:1, 3:1 to 1:3, wherein the protection from cardiac channelopathy or condition due to irregularities or alterations in cardiac pattern lasts for 1 to 24 hours; and methods comprising administering the composition to a human or animal subject in an amount sufficient to treat the condition. In one aspect, the lipid is provided in an amount that eliminates the lipid from the bloodstream while preventing or reducing cardiac channelopathy or conditions due to irregularities or alterations in the cardiac pattern. In another aspect, the lipid prevents cardiac channelopathy or conditions due to irregularities or alterations in cardiac pattern for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In one aspect, the one or more pharmacologically active agents are selected from at least one of a 5-HT3 antagonist, a 5-HT4 receptor agonist, a histamine antagonist, a calcium channel blocker, an antimalarial agent, an antipsychotic agent, a halodol, an antibiotic, an antiarrhythmic agent, an anticancer agent, an opioid agent, or a lipid-lowering agent that blocks serotonin binding. In another aspect, the lipid comprises at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, cardiolipin, phosphatidylinositol or a precursor thereof. 또 다른 측면에서, 지질은 리소포스파티딜글리세롤, 리소포스파티딜콜린, 라우로일-리소포스파티딜콜린, 미리스토일-리소포스파티딜콜린, 팔미토일-리소포스파티딜콜린, 스테아로일-리소포스파티딜콜린, 아라키도일-리소포스파티딜콜린, 올레오일-리소포스파티딜콜린, 리놀레오일-리소포스파티딜콜린, 리놀레노일-리소포스파티딜콜린, 에루코일-리소포스파티딜콜린, 1-미리스토일-2-히드록시-sn-글리세로-3-포스포콜린 (DMPC), 12-미스테로일-2-히드록시-sn-글리세로-3-[포스포-rac-(글리세롤)] (DMPG), DMPC/DMPG, 1-미리스토일-2-히드록시- sn -글리세로-3-포스포-(1'- rac -글리세롤) (LysoPG), 또는 1-미리스토일-2-히드록시- sn -글리세로-3-포스포콜린 (LysoPC) 중 적어도 1종을 포함한다. In another aspect, the lipid comprises both even and odd chain fatty acids, wherein short chain fatty acids are 5 carbons or fewer, medium chains are 6 to 12 carbons, long chains are 13 to 21 carbons, and very long chain fatty acids are lysophosphatidylglycerols, further defined as greater than 22 carbons. In another aspect, the lipid is saturated or unsaturated, 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, short chain fatty acids having 40, 45, 50, 55 or more carbons. In another aspect, the cardiac channelopathy or condition due to irregularities or alterations in cardiac pattern is inhibition of ion channels responsible for delayed rectifying K ⁺ currents in the heart, polymorphic ventricular tachycardia, prolongation of QTc, LQT2, LQTS, or Torsade de Point. In another aspect, the one or more active agents are selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, grippafloxacin, terodylene, droperidol, lidoflazin, levometadil, sertindol, or cisapride. In another aspect, the method further comprises adapting the composition for enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, pulmonary, rectal, vaginal, or oral administration. 또 다른 측면에서, 활성제는 알부테롤, 알푸조신, 아만타딘, 아미오다론, 아미술프리드, 아미트립틸린, 아목사핀, 암페타민, 아나그렐리드, 아포모르핀, 아르포르모테롤, 아리피프라졸, 삼산화비소, 아스테미졸, 아타자나비르, 아토목세틴, 아지트로마이신, 베다퀼린, 베프리딜, 보르테조밉, 보수티닙, 클로랄 수화물, 클로로퀸, 클로르프로마진, 시프로플록사신, 시사프리드, 시탈로프람, 클라리트로마이신, 클로미프라민, 클로자핀, 코카인, 쿠르쿠민, 크리조티닙, 다브라페닙, 다사티닙, 데시프라민, 덱스메데토미딘, 덱스메틸페니데이트, 덱스트로암페타민, d-암페타민, 디히드로아르테미시닌 및 피페라퀸, 디펜히드라민, 디소피라미드, 도부타민, 도페틸리드, 돌라세트론, 돔페리돈, 도파민, 독세핀, 드론다론, 드로페리돌, 에페드린, 에피네프린 , 아드레날린, 에리불린, 에리트로마이신, 에스시탈로프람, 파모티딘, 펠바메이트, 펜플루라민, 핑골리모드, 플레카이니드, 플루코나졸, 플루옥세틴, 포르모테롤, 포스카르네트, 포스페니토인, 푸로세미드, 프루세미드, 갈란타민, 가티플록사신, 게미플록사신, 그라니세트론, 할로판트린, 할로페리돌, 히드로클로로티아지드, 이부틸리드, 일로페리돈, 이미프라민, 멜리프라민, 인다파미드, 이소프로테레놀, 이스라디핀, 이트라코나졸, 이바브라딘, 케토코나졸, 라파티닙, 레발부테롤, 레보플록사신, 레보메타딜, 리스덱삼페타민, 리튬, 메조리다진, 메타프로테레놀, 메타돈, 메스암페타민 (메스암훼타민), 메틸페니데이트, 미도드린, 미페프리스톤, 미라베그론, 미르타자핀, 모엑시프릴/HCTZ, 목시플록사신, 넬피나비르, 니카르디핀, 닐로티닙, 노르에피네프린 (노르아드레날린), 노르플록사신, 노르트립틸린, 오플록사신, 올란자핀, 온단세트론, 옥시토신, 팔리페리돈, 파록세틴, 파시레오티드, 파조파닙, 펜타미딘, 퍼플루트렌 지질 미소구체, 펜테르민, 페닐에프린, 페닐프로판올아민, 피모지드, 포사코나졸, 프로부콜, 프로카인아미드, 프로메타진, 프로트립틸린, 슈도에페드린, 쿠에티아핀, 퀴니딘, 퀴닌 술페이트, 라놀라진, 릴피비린, 리스페리돈, 리토드린, 리토나비르, 록시트로마이신, 살부타몰, 살메테롤, 사퀴나비르, 세르틴돌, 세르트랄린, 세보플루란, 시부트라민, 솔리페나신, 소라페닙, 소탈롤, 스파르플록사신, 술피리드, 수니티닙, 타크롤리무스, 타목시펜, 텔라프레비르, 텔라반신, 텔리트로마이신, 테르부탈린, 테르페나딘, 테트라베나진, 티오리다진, 티자니딘, 톨테로딘, 토레미펜, 트라조돈, 트리메토프림-술파, 트리미프라민, 반데타닙, 바르데나필, 베무라페닙, 벤라팍신, 보리코나졸, 보리노스타트, 또는 지프라시돈으로부터 선택된다.

Another embodiment of the present invention is a method for preventing or treating cardiac channelopathy or condition due to an irregularity or alteration of cardiac pattern caused by an active agent in a human or animal subject, comprising the steps of identifying a subject in need of treatment for a disease treatable with said active agent causing said cardiac channelopathy; and an amount of a lipid effective to reduce or prevent cardiac channelopathy or conditions due to cardiac pattern irregularities or alterations, and an effective amount of said active agent sufficient to treat said diseases, wherein the pharmacological ratio of at least one active agent to lipid is from 10:1 to 1:10, 1:5 to 5:1, 3:1 to 1:3, and wherein protection from cardiac channelopathy or conditions due to irregularities or alterations in cardiac pattern is from 1 to 1:3. and lasting for 24 hours. In one aspect, the lipid is provided in an amount that eliminates the lipid from the bloodstream while preventing or reducing cardiac channelopathy or conditions due to irregularities or alterations in the cardiac pattern. In another aspect, the lipid prevents cardiac channelopathy or conditions due to irregularities or alterations in cardiac pattern for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In one aspect, the active agent has previously failed clinical trials due to cardiac channelopathy or conditions due to irregularities or alterations in cardiac patterns. In another aspect, the method further comprises identifying a drug in a clinical trial that has failed or has limited clinical use due to cardiac channelopathy or condition due to irregularity or alteration of cardiac pattern caused by the drug, and re-formulating the drug with a lipid to reduce or eliminate cardiac channelopathy or condition due to irregularity or alteration of cardiac pattern caused by the drug. 또 다른 측면에서, 활성제는 알부테롤, 알푸조신, 아만타딘, 아미오다론, 아미술프리드, 아미트립틸린, 아목사핀, 암페타민, 아나그렐리드, 아포모르핀, 아르포르모테롤, 아리피프라졸, 삼산화비소, 아스테미졸, 아타자나비르, 아토목세틴, 아지트로마이신, 베다퀼린, 베프리딜, 보르테조밉, 보수티닙, 클로랄 수화물, 클로로퀸, 클로르프로마진, 시프로플록사신, 시사프리드, 시탈로프람, 클라리트로마이신, 클로미프라민, 클로자핀, 코카인, 쿠르쿠민, 크리조티닙, 다브라페닙, 다사티닙, 데시프라민, 덱스메데토미딘, 덱스메틸페니데이트, 덱스트로암페타민, d-암페타민, 디히드로아르테미시닌 및 피페라퀸, 디펜히드라민, 디소피라미드, 도부타민, 도페틸리드, 돌라세트론, 돔페리돈, 도파민, 독세핀, 드론다론, 드로페리돌, 에페드린, 에피네프린 , 아드레날린, 에리불린, 에리트로마이신, 에스시탈로프람, 파모티딘, 펠바메이트, 펜플루라민, 핑골리모드, 플레카이니드, 플루코나졸, 플루옥세틴, 포르모테롤, 포스카르네트, 포스페니토인, 푸로세미드, 프루세미드, 갈란타민, 가티플록사신, 게미플록사신, 그라니세트론, 할로판트린, 할로페리돌, 히드로클로로티아지드, 이부틸리드, 일로페리돈, 이미프라민, 멜리프라민, 인다파미드, 이소프로테레놀, 이스라디핀, 이트라코나졸, 이바브라딘, 케토코나졸, 라파티닙, 레발부테롤, 레보플록사신, 레보메타딜, 리스덱삼페타민, 리튬, 메조리다진, 메타프로테레놀, 메타돈, 메스암페타민 (메스암훼타민), 메틸페니데이트, 미도드린, 미페프리스톤, 미라베그론, 미르타자핀, 모엑시프릴/HCTZ, 목시플록사신, 넬피나비르, 니카르디핀, 닐로티닙, 노르에피네프린 (노르아드레날린), 노르플록사신, 노르트립틸린, 오플록사신, 올란자핀, 온단세트론, 옥시토신, 팔리페리돈, 파록세틴, 파시레오티드, 파조파닙, 펜타미딘, 퍼플루트렌 지질 미소구체, 펜테르민, 페닐에프린, 페닐프로판올아민, 피모지드, 포사코나졸, 프로부콜, 프로카인아미드, 프로메타진, 프로트립틸린, 슈도에페드린, 쿠에티아핀, 퀴니딘, 퀴닌 술페이트, 라놀라진, 릴피비린, 리스페리돈, 리토드린, 리토나비르, 록시트로마이신, 살부타몰, 살메테롤, 사퀴나비르, 세르틴돌, 세르트랄린, 세보플루란, 시부트라민, 솔리페나신, 소라페닙, 소탈롤, 스파르플록사신, 술피리드, 수니티닙, 타크롤리무스, 타목시펜, 텔라프레비르, 텔라반신, 텔리트로마이신, 테르부탈린, 테르페나딘, 테트라베나진, 티오리다진, 티자니딘, 톨테로딘, 토레미펜, 트라조돈, 트리메토프림-술파, 트리미프라민, 반데타닙, 바르데나필, 베무라페닙, 벤라팍신, 보리코나졸, 보리노스타트, 또는 지프라시돈으로부터 선택된다.

Another embodiment of the invention is a method for evaluating a candidate drug for the treatment of a disease or condition, wherein the candidate drug causes cardiac channelopathy or condition due to an irregularity or alteration in the cardiac pattern caused by the candidate agent, (a) administering an amount of a lipid, liposome, or lipid precursor and the candidate drug to a first subset of patients, and administering a placebo to a second subset of patients, wherein the lipid, liposome, or lipid precursor causes a cardiac pattern caused by the candidate drug. provided in an amount effective to reduce or prevent one or more cardiac channelopathy or conditions due to irregularities or alterations, wherein the pharmacological ratio of the one or more active agents to lipids is from 10:1 to 1:10, 1:5 to 5:1, 3:1 to 1:3, wherein protection from cardiac channelopathy or conditions due to irregularities or alterations in cardiac pattern lasts for 1 to 24 hours; (b) determining the level of cardiac channelopathy or condition due to an irregularity or alteration in cardiac pattern from said first and second sets of patients; and (c) determining whether the combination of the lipid, liposome, or lipid precursor, and the candidate drug reduces the channelopathy or condition due to an irregularity or alteration of the cardiac pattern and the reduction is statistically significant compared to any reduction occurring in a subset of patients taking a placebo or to a known cardiac channelopathy or condition due to an irregularity or alteration in the cardiac pattern, wherein the statistically significant reduction is such that the combination of the lipid, liposome, or lipid precursor, and the candidate drug treats the disease state or condition. while also being useful for reducing or eliminating drug-induced cardiac channelopathy or conditions due to irregularities or alterations in cardiac patterns. In one aspect, the lipid is provided in an amount that eliminates the lipid from the bloodstream while preventing or reducing cardiac channelopathy or conditions due to irregularities or alterations in the cardiac pattern. In another aspect, the lipid prevents cardiac channelopathy or conditions due to irregularities or alterations in cardiac pattern for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In one aspect, the drug has previously failed clinical trials due to cardiac channelopathy or conditions due to irregularities or alterations in cardiac patterns. In another aspect, a drug has been withdrawn from the market due to cardiac channelopathy or a condition resulting from an irregularity or alteration of the heart pattern. In another aspect, the method further comprises repeating steps (a) to (c) after a period of time. 또 다른 측면에서, 활성제는 알부테롤, 알푸조신, 아만타딘, 아미오다론, 아미술프리드, 아미트립틸린, 아목사핀, 암페타민, 아나그렐리드, 아포모르핀, 아르포르모테롤, 아리피프라졸, 삼산화비소, 아스테미졸, 아타자나비르, 아토목세틴, 아지트로마이신, 베다퀼린, 베프리딜, 보르테조밉, 보수티닙, 클로랄 수화물, 클로로퀸, 클로르프로마진, 시프로플록사신, 시사프리드, 시탈로프람, 클라리트로마이신, 클로미프라민, 클로자핀, 코카인, 쿠르쿠민, 크리조티닙, 다브라페닙, 다사티닙, 데시프라민, 덱스메데토미딘, 덱스메틸페니데이트, 덱스트로암페타민, d-암페타민, 디히드로아르테미시닌 및 피페라퀸, 디펜히드라민, 디소피라미드, 도부타민, 도페틸리드, 돌라세트론, 돔페리돈, 도파민, 독세핀, 드론다론, 드로페리돌, 에페드린, 에피네프린 , 아드레날린, 에리불린, 에리트로마이신, 에스시탈로프람, 파모티딘, 펠바메이트, 펜플루라민, 핑골리모드, 플레카이니드, 플루코나졸, 플루옥세틴, 포르모테롤, 포스카르네트, 포스페니토인, 푸로세미드, 프루세미드, 갈란타민, 가티플록사신, 게미플록사신, 그라니세트론, 할로판트린, 할로페리돌, 히드로클로로티아지드, 이부틸리드, 일로페리돈, 이미프라민, 멜리프라민, 인다파미드, 이소프로테레놀, 이스라디핀, 이트라코나졸, 이바브라딘, 케토코나졸, 라파티닙, 레발부테롤, 레보플록사신, 레보메타딜, 리스덱삼페타민, 리튬, 메조리다진, 메타프로테레놀, 메타돈, 메스암페타민 (메스암훼타민), 메틸페니데이트, 미도드린, 미페프리스톤, 미라베그론, 미르타자핀, 모엑시프릴/HCTZ, 목시플록사신, 넬피나비르, 니카르디핀, 닐로티닙, 노르에피네프린 (노르아드레날린), 노르플록사신, 노르트립틸린, 오플록사신, 올란자핀, 온단세트론, 옥시토신, 팔리페리돈, 파록세틴, 파시레오티드, 파조파닙, 펜타미딘, 퍼플루트렌 지질 미소구체, 펜테르민, 페닐에프린, 페닐프로판올아민, 피모지드, 포사코나졸, 프로부콜, 프로카인아미드, 프로메타진, 프로트립틸린, 슈도에페드린, 쿠에티아핀, 퀴니딘, 퀴닌 술페이트, 라놀라진, 릴피비린, 리스페리돈, 리토드린, 리토나비르, 록시트로마이신, 살부타몰, 살메테롤, 사퀴나비르, 세르틴돌, 세르트랄린, 세보플루란, 시부트라민, 솔리페나신, 소라페닙, 소탈롤, 스파르플록사신, 술피리드, 수니티닙, 타크롤리무스, 타목시펜, 텔라프레비르, 텔라반신, 텔리트로마이신, 테르부탈린, 테르페나딘, 테트라베나진, 티오리다진, 티자니딘, 톨테로딘, 토레미펜, 트라조돈, 트리메토프림-술파, 트리미프라민, 반데타닙, 바르데나필, 베무라페닙, 벤라팍신, 보리코나졸, 보리노스타트, 또는 지프라시돈으로부터 선택된다.

According to the present invention, novel compositions and methods are provided for reducing or eliminating channelopathy or conditions due to irregularities or alterations in cardiac patterns caused by active agents or drugs.

For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the present invention in conjunction with the accompanying drawings, wherein:
1 is a graph showing the effect of DMPC, DMPC+nilotinib and nilotinib on hERG current density from transfected HEK293 cells.
2 is a graph showing the effect of DMPG, DMPG+nilotinib and nilotinib on hERG current density from transfected HEK293 cells.
3 is a graph showing the effect of DMPC/DMPG, DMPC/DMPG+nilotinib and nilotinib on hERG current density from transfected HEK293 cells.
Figure 4 is a graph showing the effect of LysoPC, LysoPC + nilotinib and nilotinib on 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.
6 is a graph showing the effect of DMPC, DMPC+nilotinib, DMPC+nilotinib (in DMSO) and nilotinib on hERG current density from transfected HEK293 cells.
7 is a graph showing the effect of DMPG, DMPG+nilotinib, DMPG+nilotinib (in DMSO) and nilotinib on hERG current density from transfected HEK293 cells.
8 depicts the structure of glycerophosphate-based lipids for use in the present invention.

Although the manufacture and use of various embodiments of the present invention are discussed in detail below, it should be recognized that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific methods for making and using the invention and do not limit the scope of the invention.

To facilitate understanding of the present invention, a number of terms are defined below. Terms defined herein have meanings commonly understood by one of ordinary skill in the field relevant to the present invention. Terms such as “a, an” and “the” are not intended to refer only to a singular entity, but include the general class of which specific examples may be used for illustration purposes. The terminology herein is used to describe specific embodiments of the invention, but their use does not delimit the invention, except as outlined in the claims .

Non-limiting exemplary lipids for use in the present invention include, for example, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, cardiolipin, phostadylinositol or a precursor thereof (in lipid, liposome, or lysoform). Non-limiting examples of lipids for use in the present invention include lysophosphatidylglycerol, lysophosphatidylcholine, lauroyl-lysophosphatidylcholine, myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine, oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine, linolenoyl-lysophosphatidylcholine or erucoil-lysophosphatidylcholine. Asymmetric phosphatidylcholines are referred to as 1-acyl, 2-acyl-sn-glycero-3-phosphocholines, where the acyl groups are different from each other. Symmetric 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-3-phosphocholine is abbreviated herein as "DPPC". Single fatty acid chain versions of these short or long chain fatty acids are referred to as "lyso" forms when only a single fatty acid chain is attached to the glyceryl backbone.

In one embodiment, lysophosphatidylglycerol has the basic structure:

In the formula, R ¹ or R ² may be any even or odd chain fatty acid, and R ³ may be H, acyl, alkyl, aryl, amino, alken, alken, where even numbers and odd chain fatty acids include carbon of 5 or less, heavy chains are 6 to 12 carbon, and long chains are 13 to 21 carbon, which are 13 to 21 carbon. Long chain fatty acids are over 22 carbon. In one example, the fatty acids are 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, which may be saturated or unsaturated. 40, 45, 50, 55 or more fatty acids.

The present invention can be used with any QT prolonging drug, including but not limited to those listed on www.crediblemeds.org, including: albuterol (salbutamol), alfuzosin, amantadine, amiodarone, amisulprid, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, arformoterol, aripiprazole, arsenic trioxide, astemi sol, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphe nidate, dextroamphetamine (d-amphetamine), dihydroartemisinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolacetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine (adrenaline), eribulin, erythromycin, escitalopram, Famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, phosphenytoin, furosemide (Frusemide), galantamine, gatifloxacin, gemifloxacin, granisetron, halopanthrin, haloperidol, hydrochlorothiazide, ibutylide, iloperidone, Imipramine (Mellipramine), indapamide, isoproterenol, isradipine, itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol (levsalbutamol), levofloxacin, levometadil, lisdexamphetamine, lithium, mezoridazine, metaproterenol, methadone, methamphetamine (methamphetamine), methylphenidate, Midodrine, mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, moxifloxacin, nelfinavir, nicardipine, nilotinib, norepinephrine (noradrenaline), norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasyreotide, pazo panib, pentamidine, perfluthrene lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide, posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salmete roll, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifenacin, sorafenib, sotalol, spafloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavansin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine , toremifene, trazodone, trimethoprim-sulfa, trimipramine, vandetanib, vardenafil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone.

The most common single cause for withdrawal or limitation of the use of marketed drugs has been QT-interval prolongation associated with the potentially fatal condition, torsade de point, or polymorphic ventricular tachycardia.

5-HT3 antagonists block serotonin binding. Aloxi (or palonasitron HCL) is an antiemetic, 5-HT3 antagonist for chemotherapy-induced nausea and vomiting, and blocks serotonin binding to 5-HT3. In the study, there was no significant difference in the QTc interval during the perioperative period with or without 0.075 mg palonosetron administered before or after sevoflurane anesthesia. Palonosetron may be safe in terms of QTc interval during sevoflurane anesthesia.

5-HT4 receptor agonists. Cisapride is a prokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Cisapride prolongs the QT interval in a dose-dependent manner. Neither Torsade de Point nor ventricular tachycardia were seen when monitoring 33 patients during the higher dose phase.

Histamine antagonists. Antihistamines used in the treatment of allergy act by competing with histamine for H1-receptor sites on effector cells. Thereby they prevent, but do not reverse, reactions mediated by histamine alone.

Relief of pain and premenstrual symptoms H1 antagonists are most useful in the acute exudative allergic type with symptoms of rhinitis, urticaria, and conjunctivitis. However, its effect is purely palliative and limited to suppression of symptoms due to the histamine-antibody response.

Pyrilamine is a diuretic first-generation histamine H1 antagonist. There is a case of an adolescent with a prolonged QT interval after an overdose of pyrilamine. Deaths due to ventricular tachyarrhythmias have been reported.

Terfenidine is an antihistamine used to treat allergies, hives (urticaria), and other allergic inflammatory conditions. The trade name Seldane has been discontinued in the United States. Rare reports of severe cardiovascular adverse effects including ventricular tachyarrhythmias (torsade de point, ventricular tachycardia, ventricular fibrillation, and cardiac arrest), hypotension, palpitations, and syncope have been received.

Loratidine is a first-line antihistamine and it is a second-generation peripheral histamine H1-receptor blocker. Structurally, it is closely related to tricyclic antidepressants such as imipramine and distantly related to the atypical antipsychotic quetiapine. Some antihistamines, such as mizolastine and ebastin, can prolong the QT interval and cause severe cardiac arrhythmias. As of mid-2009, little published clinical data has been published regarding the risk of QT prolongation with loratadine. The very rare reported cases of torsade de point related to loratadine seem to involve drug interactions primarily, especially with amiodarone and enzyme inhibitors. There are no reports of QT prolongation attributable to desloratadine, a major metabolite of loratadine. Loratadine should be avoided in patients with risk factors for Torsade de Point or who are taking certain enzyme inhibitors.

Astemizole is a long-acting, highly selective H1 antagonist that acts on the histamine H-1 and H-3 receptors. It has antipruritic and anticholinergic effects. It is also a functional inhibitor of acidic sphingomyelinase. An overdose of astemizole makes the myocardium susceptible to ventricular dysrhythmias, including torsade de point. However, dysrhythmias only occur in patients with a corrected QT interval greater than 500 ms.

Blocking calcium channels. Prenylamine is a calcium channel blocker of the amphetamine chemical class used as a vasodilator in the treatment of angina pectoris. Resting ECGs were recorded in 29 patients with angina pectoris before, during, and after daily treatment with prenilamine 180 mg. The QT interval was significantly prolonged after 1 week of treatment. Extension continued as long as therapy continued up to 6 months. After withdrawal of treatment, the QT interval returned to normal within 2 weeks.

Lidoflazine is a piperazine calcium channel blocker and it is a coronary vasodilator with some antiarrhythmic activity. As a tricyclic antihistamine, it acts as a selective inverse agonist of peripheral histamine H1-receptors. This carries a significant risk of QT interval prolongation and ventricular arrhythmias. Lidoflagine potently suppresses the HERG current (I(HERG)) recorded from HEK 293 cells stably expressing wild-type HERG (IC(50) of approximately 16 nM). It is approximately 13-fold more potent against HERG than verapamil under similar conditions in preferentially inhibiting activated/opened HERG channels. Lidoflazin causes high affinity blockade of the alpha subunit of the HERG channel by binding to aromatic amino acid residues in the channel pore, and secondly, likely represents the molecular mechanism of QT interval prolongation by this drug.

Bepridil is an antihypertensive drug that interferes with the movement of calcium (Ca2+) through calcium channels, while prolonging the QT interval. Bepridil prolongs QT and refractory, and a linear correlation between QTc and percent change in refractory duration prolongation can be demonstrated. In one patient, bepridil reduced the number of stimuli required to induce VT by one, but no spontaneous arrhythmias were noted. It has antiarrhythmic properties with minimal proarrhythmic effects.

antimalarial drugs.

Chloroquine-chloropheniramine, an antimalarial drug, chloroquine and chloroquine plus chloropheniramine, a histamine H1 receptor blocker that reverses chloroquine insensitivity in Plasmodium falciparum in vitro. Chloroquine/chloropheniramine results in a higher cure rate than chloroquine alone. Short QT Syndrome (SQTS) is a sporadic or autosomal dominant disorder characterized by markedly accelerated cardiac repolarization, ventricular arrhythmias, and sudden cardiac death. To date, mutations in five different ion channel genes (KCNH2, KCNQ1, KCNJ2, CACNA1C and CACNB2) have been identified to cause SQTS. The risk of ventricular arrhythmia and sudden death is significantly high in SQTS, and cardiac arrest is reported as a presenting symptom in 31% of SQTS subjects. Chloroquine blocks mutant Kir2.1 channels responsible for short QT syndrome and normalizes repolarization properties in silico.

Halofantrine is an antimalarial drug with a substituted phenanthrene and is related to the antimalarial drugs quinine and lumefantrin. This may be associated with cardiotoxicity. The most dangerous side effect is cardiac arrhythmias: Halofantrine causes significant QT prolongation, an effect seen even at standard doses. Therefore, the drug should not be given to patients with cardiac conduction defects and should not be used in combination with mefloquine. The mechanism of action of halopantrine is not known.

Quinidine is an antimalarial drug that acts as a class 1 antiarrhythmic (Ia) in the heart. It is a stereoisomer of quinine. This alkaloid attenuates the excitability of the heart and skeletal muscle by blocking sodium and potassium currents across cell membranes. This prolongs the cellular action potential and reduces automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission. Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may be one reason for the greater incidence of drug-induced torsade de point observed in women taking quinidine and may affect other cardiogenic and non-cardiac drugs that prolong the QTc interval.

antipsychotics. First-generation antipsychotics, known as classic antipsychotics, were discovered in the 1950's. Most second-generation drugs known as atypical antipsychotics have been developed more recently, but the first-generation atypical antipsychotic clozapine was discovered in the 1960s and entered clinical practice in the 1970s. Medications of both generations tend to block receptors in the brain's dopamine pathway, but atypical medications also tend to act at serotonin receptors. Medications of both generations tend to block receptors in the brain's dopamine pathway, but atypical medications also tend to act at serotonin receptors. QTc interval prolongation can occur as a result of treatment with both existing and novel antipsychotic medications and is of clinical concern because of its association with the potentially fatal ventricular arrhythmia Torsade de Pointe.

Pimozide is an antipsychotic drug of the diphenylbutylpiperidine class, which can cause prolongation of the QT interval. Pimozide is contraindicated in individuals with an acquired, congenital, or familial history of QT interval prolongation. Its use as an antagonist of D2, D3, D4 receptors and 5-HT7 receptors is not recommended in individuals and people with a personal or family history of arrhythmia or Torsade de Pointe. It is also an hERG blocker.

Sertindole is an antipsychotic drug. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. Abbott Labs first applied for US Food and Drug Administration (FDA) approval for sertindole in 1996, but withdrew this application in 1998 following concerns about the increased risk of sudden death from QTc prolongation. In a clinical trial involving 2000 patients taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths. The drug has not been approved by the FDA for use in the United States. In Europe, Sertindole has been approved and sold in 19 countries since 1996, but its marketing was suspended by the European Medicines Agency in 1998 and the drug was withdrawn from the market. In 2002, based on new data, the EMA's CHMP suggested that sertindole could be reintroduced for limited use in clinical trials, with strong safeguards, including extensive contraindications and warnings for patients at risk of cardiac arrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg with exceptional exceptions, and extensive ECG monitoring requirements before and during treatment.

Chlorpromazine, sold as thorazine and largactyl, is an antipsychotic drug of the classic class of antipsychotics. Its mechanism of action is not entirely clear, but is believed to be related to its ability as a dopamine antagonist. It also has antiserotonergic and antihistamine properties. Chlorpromazine is a very effective antagonist of the D2 dopamine receptor and similar receptors such as D3 and D5. Unlike most other drugs in this genre, it also has a high affinity for the D1 receptor. Electrocardiogram QT correction interval prolongation is reported by only a small number of people taking thorazine. In a study of 2,633 people with side effects while taking Thorazine from the FDA and social media, 5 had ECG QT correction interval prolongation.

Thioridazine was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias, but is a typical piperidine antipsychotic drug belonging to the branded phenothiazine drug product, for which a generic version is available in the United States. The drug was voluntarily discontinued by its worldwide manufacturer, Novartis, because it caused severe cardiac arrhythmias. Thioridazine dose-dependently prolongs the QTc interval. The ratio of 5-HT2A to D2 receptor binding is believed to indicate whether most antipsychotics are atypical or typical. In the case of thioridazine, its ratio of 5-HT2A to D2 receptor binding is actually lower than what is considered atypically required despite its relatively low extrapyramidal side effect liability.

Haldol, haloperidol. A typical antipsychotic drug QT interval prolongation is meperidine. It is on the WHO Model List of Essential Medicines. It is the most commonly used and typical antipsychotic agent. Special Precautions: Patients at special risk of developing QT prolongation (hypokalemia, concomitant use of amiodarone with other drugs causing QT: Q-Tc interval prolongation (potentially dangerous changes in heart rate prolongation)).

Mesoridazone is a piperidine neuroleptic drug belonging to a class of drugs called phenothiazines, used for the treatment of schizophrenia. It is a metabolite of thioridazine. In 2004, mesoridazine was withdrawn from the US market due to dangerous side effects, namely irregular heartbeat and QT-prolongation of the electrocardiogram.

Selective serotonin reuptake inhibitor. Cellaxa (citalopram) is an antidepressant in a class of drugs called selective serotonin reuptake inhibitors (SSRIs). The racemic bicyclic phthalan derivative, designated its chemical structure (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, is not related to other SSRIs, or other available antidepressants. Citalopram can cause conditions that affect heart rhythm (QT prolongation). QT prolongation.

Antibiotic. Moxifloxacin is a fourth-generation synthetic fluoroquinolone antibacterial agent. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV (an enzyme necessary to sequester bacterial DNA and thus inhibit cell replication) and can cause torsade de point. Coadministration of moxifloxacin with other drugs that also prolong the QT interval or cause bradycardia (eg beta-blockers, amiodarone) should be avoided. Careful consideration should be given to the use of moxifloxacin in patients with cardiovascular disease, including those with conduction abnormalities. Medications that prolong the QT interval may have additive effects on QT prolongation and increase the risk of ventricular arrhythmias.

Pentamadine is an antibacterial agent given to prevent and treat pneumocystis pneumonia. The exact mechanism of its anti-protozoal action is unknown (although it may involve a reaction with ubiquitin and mitochondrial function). Severe or fatal arrhythmias and heart failure are very frequent. Aromatic Diamidines Pentamidines act through inhibition of trafficking of hERG channels. Pentamidine has no acute effect on currents generated by hERG, KvLQT1/mink, Kv4.3, or SCNA5. However, after overnight exposure, pentamidine reduced hERG currents and inhibited hERG trafficking and maturation with IC50 values of 5-8 μM, similar to therapeutic concentrations.

Clarithromycin is an antibiotic prepared from erythromycin, chemically known as 6-O-methylerythromycin. It is in the macrolide class and works by stopping the production of proteins by some bacteria. This causes ventricular cardiac arrhythmias or QT prolongation, including torsade de point.

Erythromycin is an antibiotic with common side effects including arrhythmia, a serious side effect with prolonged QT interval including torsade de point.

Grepafloxacin is an oral broad-spectrum fluoroquinolone antibacterial drug used to treat bacterial infections. Grepafloxacin was withdrawn from the market in 1999 because of its side effect of prolonging the QT interval on the electrocardiogram, causing cardiac events and sudden death.

Sparfloxacin is a fluoroquinolone broad-spectrum antibiotic used in the treatment of bacterial infections. It has a debatable safety profile. The use of sparfloxacin is contraindicated in patients with known QTc prolongation and in patients treated concomitantly with class IA or III antiarrhythmic drugs. In one study, maximum plasma concentrations (Cmax) after doses of 1200 mg and 1600 mg were lower than expected from a linear dose relationship. This is also true for the mean increase and mean maximal increase in the QTc interval. Increase in QTc interval was strongly correlated with C _max but not with AUCo-infinity.

Curcumin (diferuloylmethane) is a bright yellow chemical produced by some plants. It is the major curcuminoid of turmeric ( Curcuma longa ) and exerts antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and antitumor activities. In whole-cell patch-clamp experiments, curcumin dose-dependently upregulated hERG K+ in HEK293 cells stably expressing the hERG channel. The current was suppressed with an IC50 value of 5.55 μM. Deactivation of hERG channels, inactivation, and recovery time from inactivation were significantly altered by acute treatment with 10 μM curcumin.

antiarrhythmic drugs. Antiarrhythmic agents are used to suppress abnormal heart rhythms (cardiac arrhythmias) such as atrial fibrillation, ventricular tachycardia, and ventricular fibrillation.

Procainamide is an antiarrhythmic agent used in the treatment of cardiac arrhythmias. Classified as Class Ia by the Vaughan Williams classification system, it is used for both supraventricular and ventricular arrhythmias. In addition, the antiarrhythmic drug procainamide has been found to interfere with pacemakers. Because toxic levels of procainamide cause a decrease in ventricular conduction velocity and an increase in ventricular refractory period. This results in disturbance of the artificial membrane potential and causes supraventricular empty bag, leading to pacemaker failure and death. It causes rapid blockage of the cardiac muscle's batrachotoxin (BTX)-activated sodium channels and acts as an antagonist to prolonged gating closure. Procainamide belongs to the aminobenzamides, which have similar cardiac effects to quinidine and have the same toxicity profile as quinidine.

Propafenone is a Class 1C antiarrhythmic drug that treats diseases associated with rapid heart beat, such as atrial and ventricular arrhythmias, and works by slowing the influx of sodium ions into cardiac muscle cells, causing a decrease in excitability of the cells. Propafenone is more selective for cells at a higher rate, but blocks more normal cells than Class Ia or Ib. Propafenone differs from the prototypical Class Ic antiarrhythmics in that it has additional activity as a beta-adrenergic blocker that can cause bradycardia.

Methanesulfonanilide (E-4031) is an experimental class III antiarrhythmic drug that blocks the potassium channel of class III antiarrhythmics. E-4031 acts on a specific class of voltage-dependent potassium channels found primarily in the heart, hERG channels. The hERG channel (Kv11.1) mediates IKr currents that repolarize cardiomyocytes. The hERG channel is encoded by the ether-a-go-go related gene (hERG). E-4031 blocks hERG-type potassium channels by binding to open channels. Its structural target within the hERG-channel is unclear, but some other methanesulfonanilide class III antiarrhythmics are known to bind to the S6 domain or C-terminus of the hERG-channel. Because E-4031 can prolong the QT-interval, it can cause fatal arrhythmias. To date, one clinical trial has been conducted to test the effect of E-4031 on prolongation of the QT-interval.

Amiodarone is a Class III antiarrhythmic agent for ventricular fibrillation or tachycardia, prolonging phase 3 of the cardiac action potential. Amiodarone is an antiarrhythmic agent known to cause a prolongation of the action potential duration reflected on the electrocardiogram as a prolongation of the QT. Amiodarone has several effects on myocardial depolarization and repolarization, making it a very effective antiarrhythmic drug. Its main effect is to block potassium channels, but it can also block sodium and calcium channels and beta and alpha adrenergic receptors. Amiodarone significantly prolongs the QT interval and QTc values.

Dronedarone is a benzofuran derivative related to amiodarone, and is a drug primarily used for cardiac arrhythmias (approved by the FDA in 2009). However, it is a “multichannel blocker” and it is not clear which channel(s) play a pivotal role in its success. The action of dronedarone at the cellular level has been controversial in most studies, suggesting inhibition of multiple outward potassium currents, including fast-lag rectifiers, slow-lag rectifiers and ACh-activated inward rectifiers. It is also believed to reduce inward rapid Na currents and L-type Ca channels. Some studies have shown that the decrease in K current is due to inhibition of K-ACh channels or associated GTP-binding proteins. A reduction of K+ current by 69% exhibits amiodarone-like Class III antiarrhythmic activity in vitro and in clinical trials, resulting in increased AP duration and increased effective refractory period. The drug also appears to be active in each of the four Von-Williams antiarrhythmic drug classes. Do not use concomitantly with drugs or herbal products that prolong the QT interval and may cause a torsade de point QTc Bazett interval ≥ 500 ms, or with drugs or herbal supplements that prolong the QT interval or increase the risk of torsade point (Class I or III antiarrhythmics, phenothiazines, tricyclic antidepressants, certain oral macrolides, ephedra).

Disopyramide is an antiarrhythmic medication used in the treatment of ventricular tachycardia. It is a sodium channel blocker and is therefore classified as a class 1a antiarrhythmic agent. The class 1a activity of disopyramide is similar to that of quinidine in that it targets sodium channels to inhibit conduction. Disopyramide reduces the increase in sodium permeability of cardiac myocytes during the zero phase of the cardiac action potential, which in turn reduces the inward sodium current. This results in an increased threshold for excitation and a decrease in upstroke rate. The disopyramid extends the PR interval by lengthening both the QRS and P wave durations. Concern about disopyramide has been the hypothetical possibility of inducing sudden death due to its type 1 antiarrhythmic effect.

Dofetilide is a class III antiarrhythmic drug. Due to dofetilide's arrhythmogenic potential, it is only available by prescription from a physician with special training in the risks of dofetilide treatment. Moreover, it is also only available by mail order or specially trained local pharmacies. Dofetilide works by selectively blocking the fast component outward potassium current of the lag rectifier. There is a dose-dependent increase in QT interval and corrected QT interval (QTc). Because of this, many physicians will only initiate dofetilide therapy in individuals undergoing telemetric monitoring or if they are able to perform continuous EKG measurements of QT and QTc.

Sotalol is a nonselective competitive beta-adrenergic receptor blocker that also exhibits class III antiarrhythmic properties. The US Food and Drug Administration advises that sotalol can only be used for severe arrhythmias because its prolongation of the QT interval carries a small risk of life-threatening torsade de point. Sotalol also acts on potassium channels and causes a delay in ventricular relaxation. By blocking these potassium channels, sotalol inhibits the efflux of K+ ions, resulting in an increase in ventricular muscle cells before another electrical signal can be generated. It increases in the period before a new signal for contraction is generated.

Ibutylide is a class III antiarrhythmic agent indicated for acute cardioconversion in atrial fibrillation and atrial flutter and prolongs the action potential and refractory period of cardiomyocytes. Because of its Class III antiarrhythmic activity, concomitant administration of Class Ia and Class III agents should be avoided. Unlike most other class III antiarrhythmic drugs, ibutylide neither prolongs the action potential through cardiac retardant rectifying blockade of potassium current nor does it possess the sodium-blocking, antiadrenergic, and calcium-blocking activity of other Class III agents. Therefore, it is often referred to as a "pure" Class III antiarrhythmic drug. Ibutylide, like other class III antiarrhythmics, blocks delayed rectifying potassium currents. It acts on slow sodium channels and promotes the influx of sodium through these slow channels. Like other antiarrhythmic drugs, ibutyride can cause abnormal heart rhythms due to its ability to prolong the QT interval, which can cause a potentially fatal abnormal heart rhythm known as torsade de point. The drug may be used in patients likely to develop abnormal heart rhythms; Contraindicated for use in persons with a past history of polymorphic ventricular tachycardia, long QT interval, sinus syndrome, or particularly recent myocardial infarction.

Dopamine receptor antagonists. Dopamine antagonists (anti-dopaminergic) are a type of drug that blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, so they have found use in the treatment of schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetic agents used in the treatment of nausea and vomiting.

Droperidol is an antidopaminergic butyrophenone used as an antiemetic and antipsychotic, and is a potent D2 (dopamine receptor) antagonist with some histamine and serotonin antagonist activity. There are concerns about QT prolongation and torsade de point. Evidence for this is disputed, with 9 reported cases of Torsad over 30 years, all of whom received doses greater than 5 mg. QT prolongation is a dose-related effect, and droperidol has no significant risk at low doses, but prolongation of the QT interval appears to cause a torsade de point.

Domperidone is a peripheral selective dopamine D2 receptor antagonist, a useful drug in Parkinson's disease, and caution is warranted due to cardiotoxic side effects of domperidone, especially when given intravenously, in the elderly, and in high doses (>30 mg/day). A clinical sign of potential cardiac toxicity of domperidone is prolongation (lengthening) of the QT interval (segments of the cardiac electrical pattern). Domperidone use is associated with an increased risk (by 70%) of sudden cardiac death, presumably through ventricular arrhythmias and its prolonging effect on the cardiac QT interval. The cause is thought to be blockage of hERG voltage-gated potassium channels. The risk is dose-dependent and appears greatest through intravenous administration at high/very high doses and in the elderly, as well as with drugs that interact with domperidone and increase its circulating concentrations (ie CYP3A4 inhibitors). However, there are conflicting reports. In neonates and infants, QT prolongation is controversial and uncertain.

anticancer drug. Doxorubicin and anthracyclines' QTc prolongation, increased QT spread, and development of late potentials are indicative of doxorubicin-induced aberrant ventricular depolarization and repolarization. Both QT dispersion and late potential are known to be associated with increased risk of sudden death and severe ventricular tachycardia in various heart diseases. Arsenic trioxide is an antileukemic agent that can prolong the QTc interval. Cardiac conduction abnormalities: Prior to initiation of therapy, a 12-lead ECG is performed, serum electrolytes and creatinine are assessed, pre-existing electrolyte abnormalities are corrected, and discontinuation of drugs known to prolong the QT interval is considered. Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to torsade de point-type ventricular arrhythmias, which can be fatal. The risk of Torsade de Point is related to the degree of QT prolongation, concomitant use of QT prolonging drugs, history of Torsade de Point, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-consuming diuretics, or other conditions resulting in hypokalemia or hypomagnesemia. One patient (also receiving amphotericin B) had a torsade de point during induction therapy for recurrent APL using arsenic trioxide. Arsenic trioxide (As ₂ O ₃ ), used in the treatment of acute promyelocytic leukemia, reduced the hERG/IKr current not by directly blocking it, but by inhibiting the processing of hERG protein in the endoplasmic reticulum (ER) and reducing the surface expression of hERG.

opioids. Levometadil is the levo isomer of α-methadyl acetate, a synthetic opioid similar in structure to methadone. It has a long duration of action due to its active metabolites. In 2001, levacetylmethadol was withdrawn from the European market due to reports of life-threatening ventricular rhythm disturbances. Methadone is an opioid used to treat pain and drug addiction. Serious risks include opioid abuse, and cardiac arrhythmias, including QT prolongation, can also occur. In the United States, methadone addiction-related deaths were 4,418 in 2011, accounting for 26% of all deaths due to opioid addiction.

Lipid lowering agent. Robostatin is a drug used to lower cholesterol, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyzes the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate. Mevalonate is an essential building block for cholesterol biosynthesis and lovastatin interferes with its production by acting as a reversible competitive inhibitor for HMG-CoA binding to HMG-CoA reductase. QTc prolongation associated with antipsychotic medications occurs in a dose-dependent manner. Addition of lovastatin causes an increase in plasma quetiapine levels through competitive inhibition of cytochrome P (450) (CYP) isoenzyme 3A4. This highlights the possibility that drug interactions between quetiapine and lovastatin cause QTc prolongation during the management of dyslipidemia in patients with schizophrenia.

Probucol is an antihyperlipidemic drug first developed in the treatment of coronary artery disease. Probucol has been associated with QT interval prolongation. Probucol exacerbates the long QT syndrome associated with the novel missmutation M124T at the N-terminus of HERG.

Human ether-a-go-go-related gene (hERG) potassium channel anti-blocking by liposomes and fragments. Potassium channels conduct the fast component of the delayed rectifying potassium current Kir, which is crucial for the repolarization of cardiac action potentials. Reduction of hERG currents, either due to genetic defects or adverse drug effects, can lead to hereditary or acquired long QT syndrome characterized by prolongation of action potentials, prolongation of the QT interval on surface ECG, and increased risk of "torsad de point" arrhythmias and sudden death. These undesirable side effects of non-antiarrhythmic compounds have prompted the drug's withdrawal from the market. Studies of mechanisms of hERG channel inhibition provide important insights into the molecular factors that determine the state-, voltage-, and use-dependence of hERG current blockade. Mutations that alter the nature of the high-affinity drug-binding site in hERG and its interaction with drug molecules cause hereditary short QT syndrome and increased currents with a high risk of life-threatening arrhythmias. (Thomas D1, 2006).

Another member of the inward-rectifier family of potassium channels is the prokaryotic KirBac1.1 channel. The structure of the Kir channel assembly in the closed state, when refined to a resolution of 3.65 angstroms, contains key active gates and structural elements involved in gating. Based on structural evidence, gating involves coupling between intracellular and membrane domains, suggesting that initiation of gating by membrane or intracellular signals represents a different entry point to a common mechanistic pathway. (Kuo, A 2003).

channelopathy

human ether- Mutations in the cardiac tetrameric potassium channel associated with the -go-go gene can sensitize patients to more than 163 drugs, inhibiting ion conduction and deregulating action potentials. Prolongation of the action potential follows effects on potassium channels. Ion channel active drugs can directly increase the QTc interval and increase the risk of Torsade de Pointe and sudden cardiac death. Deterioration of cardiomyocyte potassium channel sensitivity to drugs may also be associated with metabolic disease conditions including diabetes or may be of idiopathic origin.

For these reasons, evaluation of drug effects on cardiomyocyte potassium channel function is a critical step during drug development and, in severe cases, may hamper regulatory approval. In whole-cell patch-clamp experiments, curcumin dose-dependently upregulated hERG K ⁺ in HEK293 cells stably expressing hERG channels. The current was suppressed with an IC50 value of 5.55 μM. Deactivation of hERG channels, inactivation, and recovery time from inactivation were significantly altered by acute treatment with 10 μM curcumin. Incubation with 20 μM curcumin for 24 hours reduced HEK293 cell viability. Intravenous injection of 20 mg curcumin in rabbits did not affect cardiac repolarization as indicated by QTc values. (Hu CW 2012). These molecules are specific liposomes, or components of liposomes, that are initially bound to lipophilic drugs, enabling intravenous solubility under physiological conditions, and reducing adverse events. The site of action appears to be an important functional component of ion selectivity or gating site(s) within the channel that controls potassium ion transport: the regulation of the action potential that causes downstream myocyte contraction.

human ether- The mechanism of -go-go related gene channel blockade may be similar to the effect of externally applied quaternary ammonium derivatives, which may indirectly suggest a mechanism of action of the anti-blocking effect of DMPC/DMPG liposomes or their metabolites. The inhibition constants and relative binding energies for channel inhibition indicate that more hydrophobic quaternary ammoniums have higher affinity blocking, while cation-π interactions or size effects are not critical factors in channel inhibition by quaternary ammoniums. In addition, hydrophobic quaternary ammonium with either a larger head group or a longer tail group than tetraethylammonium penetrates the cell membrane, readily accesses the high-affinity internal binding sites of gene channels and exerts stronger blocking.

Although these data suggest that the basis for the improving effect liposomes, or components thereof, is a higher competitive affinity for the binding sites by DMPC and DMPG compared to QTc prolonging drugs, their constitutive lack of ion transport coordination, i.e., that liposomes or fragments thereof do not interfere with K+ ion transport, indicates that

By way of illustration, and by no means limiting these claims, these data suggest that the basis for the improving effect liposomes, or components thereof, is a higher competitive affinity for binding sites by the DMPC and DMPG compared to QTc prolonging drugs, and their constitutive lack of ion transport coordination, i.e., liposomes, or fragments thereof, do not interfere with K+ ion transport and indicate that the site of the mechanism of DMPC or DMPG protection may be in the selectivity segment of the channel or in hydration around the ions.

Moreover, based on these hERG channel data, the structures of these liposomal components can inform the design or selection of other molecules to prevent drug-induced cardiac arrhythmias.

This study provides additional information on the modulatory effect of QTc by drugs, induced in cardiac myocyte potassium channels, and on the alleviation by liposomes and liposomal components. The latter molecule presents an opportunity to probe K+ channels as targets for pharmacological alleviation of drug-induced channelopathy.

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

Study Objectives: The purpose of this study was to evaluate in vitro the protective effect of DMPC, DMPG, DMPC/DMPG, LysoPG and LysoPC against rapidly activating delayed rectifying potassium-selective currents (I _Kr ) generated under normoxic conditions in stably transfected human embryonic kidney cells (HEK 293 cells). 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 μM)

7- DMPG + nilotinib (0.1 μM)

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

9- 14:0 LysoPC + nilotinib (0.1 μM)

10- 14:0 LysoPG + Nilotinib (0.1 μM)

Test system: hERG-expressing HEK 293 transfected cell line. Tests performed: Whole-cell patch-clamp current acquisition and analysis. Experimental temperature: 35 ± 2 °C.

Application of test substance:

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

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

Design for obtaining when testing compounds or vehicle/solvent equivalents:

One recording made in baseline conditions

One recording made in the presence of concentration 1

Design for acquisition in positive control trials:

1 record made in baseline conditions

One recording 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. Recorded currents obtained on days 2, 3 and 4 were statistically compared to currents recorded on day 1.

Currents recorded after positive control (nilotinib alone) exposure were compared to currents recorded in baseline conditions.

Differences were considered significant when p ≤ 0.05.

Exclusion criteria:

One. Time frame of underappreciated drug exposure

2. Seal instability

3. No tail currents generated by patched cells

4. No significant effect of positive control

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

Effects of test substances on whole-cell IKr hERG currents. Whole-cell currents elicited during voltage pulses were recorded at baseline conditions and after application of selected concentrations of test substances. Cells were depolarized for 1 sec starting at -40 mV and progressing in 10 mV increments from a holding potential (-80 mV) to a maximum value of +40 mV. The membrane potential was then repolarized to -55 mV for 1 sec and finally returned to -80 mV.

Whole-cell tail current amplitude was measured at a holding potential of -55 mV after activation of the current from -40 mV to +40 mV. Current amplitude was measured at the maximum (peak) of this tail current. The current density was obtained by dividing the current amplitude by the cell capacitance measured before capacitive transient minimization.

Compensation for current run-down and solvent effects. All data points presented in this study report were corrected for solvent influence and time-dependent current run-down. Current run-down and solvent effects were measured simultaneously by applying the experimental design in test-material free conditions over the same time frame as was done with the test material. The loss of current amplitude measured during these so-called vehicle experiments (representing both solvent effect and time-dependent run-down) was subtracted from the loss of amplitude measured in the presence of the test substance, isolating the effect of the test substance apart from the influence of the solvent and the unavoidable run-down of the current amplitude over time.

Effect of DMPC, DMPC+nilotinib and nilotinib on hERG current density from transfected HEK 293 cells. normalized current density Corrected 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 μM 0.308 0.459* 0.070 0.016 3 DMPC + Nilotinib, 0.1 μM 0.836 1.029 0.023 0.328 3

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

Effect of DMPG, DMPG+nilotinib and nilotinib on hERG current density from transfected HEK 293 cells. normalized current density Corrected normalized current density SEM p value n = base line 1.000 1.000 n/a n/a 3 DMPG 0.800 0.994 0.044 0.901 3 Nilotinib, 0.1 μM 0.308 0.459* 0.070 0.016 3 DMPG + nilotinib, 0.1 μM 0.743 0.936 0.067 0.437 3

2 is a graph showing the effect of DMPG, DMPG+nilotinib and nilotinib on 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 Corrected 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 μM 0.308 0.459* 0.070 0.016 3 DMPC/DMPG + Nilotinib, 0.1 μM 0.773 0.966 0.098 0.754 4

3 is a graph showing the effect of DMPC/DMPG, DMPC/DMPG+nilotinib and nilotinib on 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 Corrected 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 μM 0.308 0.459* 0.070 0.016 3 LysoPC + nilotinib, 0.1 μM 0.865 1.097 0.055 0.553 3

Figure 4 is a graph showing the effect of LysoPC, LysoPC + nilotinib and nilotinib on 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 Corrected normalized current density SEM p value n = base line 1.000 1.000 n/a n/a 3 14:0 LysoPG, 0.45 µg/mL 0.930 1.124 0.128 0.435 3 Nilotinib, 0.1 μM 0.308 0.459* 0.070 0.016 3 14:0 LysoPG + Nilotinib, 0.1 μM 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 aimed to quantify the protective effect of DMPC, DMPG, DMPC/DMPG, LysoPG and LysoPC from nilotinib-induced inhibition of the rapidly activating delayed rectifying potassium-selective current (IKr) generated under normoxic conditions in stably transfected human embryonic kidney (HEK) 293 cells.

All data points presented in this study were corrected for solvent influence 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 substance. The current was measured over the same time course as was done in the presence of the test substance. The values obtained, which represent both solvent influence and time-dependent run-down, were used to correct for the influence, if any, of the test substance. This ensures that changes due to time or solvent are not inadvertently due to the test substance.

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

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

Nilotinib did not cause any inhibition of hERG tail currents when formulated in aqueous solutions containing DMPC, DMPG, DMPC/DMPC, LysoPG or LysoPC (ratio 1:9).

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

In this study, DMPC + nilotinib, DMPG + nilotinib, DMPC/DMPC + nilotinib, LysoPG + nilotinib or LysoPC + nilotinib were all formulated using the same method. An appropriate amount of 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 prior to use in the patch-clamp assay.

In contrast, nilotinib used for cells exposed only to nilotinib was dissolved in DMSO. Additional studies were conducted to determine whether differences in hERG inhibition between DMSO-formulated nilotinib and lipid-co-formulated nilotinib 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 μM) (in aqueous solution)

7- DMPG + nilotinib (0.1 μM) (in aqueous solution)

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

9- 14:0 LysoPC + nilotinib (0.1 μM) (in aqueous solution)

10- 14:0 LysoPG + nilotinib (0.1 μM) (in aqueous solution)

11- Nilotinib alone (in DMSO)

Among the mechanisms considered to account for the protection of hERG currents was the possibility that DMPC/DMPG or Lyso-variants quenched nilotinib at the moment of formulation, essentially preventing nilotinib from entering the channel at its receptor site. Another possibility is that nilotinib is less soluble in aqueous solution and therefore incompletely solubilized at 0.1 μM.

To test both hypotheses, nilotinib was formulated in DMSO and added into the experimental chamber after the addition of DMPC or DMPG. This indicates that 1- adding DMSO-formulated nilotinib after adding DMPC/DMPG alone would eliminate the possibility of initial quenching of nilotinib by lysosomes; 2- Based on the principle that DMSO will maintain the solubility of nilotinib (“nilotinib-only” inhibition of hERG was observed when DMSO-formulated nilotinib was added to cells).

steps for the data below

Effect of DMPC, DMPC+nilotinib, DMPC+nilotinib (in DMSO) and nilotinib on hERG current density from transfected HEK 293 cells. normalized current density Corrected 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 μM 0.308 0.459* 0.070 0.016 3 DMPC + nilotinib, 0.1 μM (aqueous) 0.836 1.029 0.023 0.328 3 DMPC + nilotinib (in DMSO), 0.1 μM 0.164 0.358 0.020 0.019 2

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

Effect of DMPG, DMPG+nilotinib, DMPG+nilotinib (in DMSO) and nilotinib on hERG current density from transfected HEK293 cells. normalized current density Corrected normalized current density SEM p value n = base line 1.000 1.000 n/a n/a 3 DMPG 0.800 0.994 0.044 0.901 3 Nilotinib, 0.1 μM 0.308 0.459* 0.070 0.016 3 DMPG + nilotinib, 0.1 μM 0.743 0.936 0.067 0.437 3 DMPG + nilotinib (in DMSO), 0.1 μM 0.630 0.823 0.290 0.651 2

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

8 shows the structure of glycerophosphate-based lipids for use in the present invention. The lipid structure shown is 1,2 distearoyl- sn -glycerol-3-phosphocholine or phosphatidylcholine (PC). Another phospholipid structure is formed by replacing the choline in the square with the head group shown on the right. Cardiolipin (CL) is also referred to as diphosphatidylglycerol because it contains two PAs linked by glycerol.

Table 8 shows examples of fatty acids for use in the present invention.

Examples of Unsaturated Fatty Acids common name chemical structure ^x C : D n - x myristoleic acid CH ₃ (CH ₂ ) ₃ CH=CH (CH ₂ ) ₇ COOH cis - ⁹ 14:1 n -5 palmitoleic acid CH ₃ (CH ₂ ) ₅ CH=CH (CH ₂ ) ₇ COOH cis - ⁹ 16:1 n -7 sapienoic acid CH ₃ (CH ₂ ) ₈ CH=CH (CH ₂ ) ₄ COOH cis - ⁶ 16:1 n -10 oleic acid CH ₃ (CH ₂ ) ₇ CH=CH (CH ₂ ) ₇ COOH cis - ⁹ 18:1 n -9 elaidic acid CH ₃ (CH ₂ ) ₇ CH=CH (CH ₂ ) ₇ COOH trans - ⁹ 18:1 n -9 Bacsenic acid CH ₃ (CH ₂ ) ₅ CH=CH (CH ₂ ) ₉ COOH trans - ¹¹ 18:1 n -7 linoleic acid CH ₃ (CH ₂ ) ₄ CH=CH CH ₂ CH=CH (CH ₂ ) ₇ COOH cis , cis - ⁹ , ¹² 18:2 n -6 linoleic acid CH ₃ (CH ₂ ) ₄ CH=CH CH ₂ CH=CH (CH ₂ ) ₇ COOH trans , trans - ⁹ , ¹² 18:2 n -6 α-linoleic acid CH ₃ CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH (CH ₂ ) ₇ COOH cis , cis , cis - ⁹ , ¹² , ¹⁵ 18:3 n -3 arachidonic acid CH ₃ (CH ₂ ) ₄ CH=CH CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH (CH ₂ ) ₃ COOH ^NIST cis , cis , cis , cis - ⁵ , ⁸ , ¹¹ , ¹⁴ 20:4 n -6 eicosapentaenoic acid CH ₃ CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH (CH ₂ ) ₃ COOH cis , cis , cis , cis , cis - ⁵ , ⁸ , ¹¹ , ¹⁴ , ¹⁷ 20:5 n -3 erucic acid CH ₃ (CH ₂ ) ₇ CH=CH (CH ₂ ) ₁₁ COOH cis - ¹³ 22:1 n -9 Docosahexaenoic acid CH ₃ CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH CH ₂ CH=CH (CH ₂ ) ₂ COOH cis , cis , cis , cis , cis , cis - ⁴ , ⁷ , ¹⁰ , ¹³ , ¹⁶ , ¹⁹ 22:6 n -3

For example, it has been found that the lipids of the present invention, such as those forming empty liposomes that may contain DMPG and DMPC, alone or in combination, can prevent drug-induced cardiac channelopathy over a wide range of ratios, i.e., lipids and liposomes of the present invention can operate over a wide range of ratios (weight-to-weight) of active agent or drug and lipid/liposome. For example, it has been found that the weight to weight of active agent to lipid/liposome can range from 10:1 to 1:10, 1:5 to 5:1, 3:1 to 1:3 without loss of effectiveness. Moreover, and surprisingly, the effect has been found to remain even after metabolic clearance of lipids/liposomes from the bloodstream, including from 1 to 24 hours, particularly more than 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, 20, 21, 22, 23 or 24 hours. . The lipid was provided in an amount that prevented or reduced cardiac channelopathy or conditions due to irregularities or alterations in the cardiac pattern but removed the lipid from the bloodstream. Protection continued despite the absence of lipids/liposomes in the bloodstream. The lipid/liposome prevents cardiac channelopathy or conditions due to irregularities or alterations in cardiac pattern for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In certain embodiments, the protection is 1 to 4, 2 to 6, 2 to 8, 1 to 5, 1 to 8, 4 to 6, 4 to 8, 4 to 12, 4 to 16, 4 to 20, 4 to 24, 6 to 8, 6 to 12, 6 to 18, 6 to 20 and 6 to 28, 8 to 12, 8 to 16, 8 to 18, 8 to 20, or even 8 to 24 hours.

It is contemplated that any embodiment discussed herein may be practiced for any method, kit, reagent, or composition of the invention, and vice versa. Moreover, the compositions of the present invention may be used to achieve the methods of the present invention.

It will be understood that the specific embodiments described herein are presented by way of illustration and not as limitation of the invention. The main features of the present invention can be used in various embodiments without departing from the scope of the present invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.

All publications and patent applications mentioned herein 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 was specifically and individually indicated to be incorporated by reference.

The use of the word "a" when used in connection with the term "comprising" in the claims and/or specification may mean "one," but is also consistent with the meaning of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and/or" unless it is expressly stated that the only alternative or alternatives are mutually exclusive, but this disclosure supports definitions that refer to only alternatives and "and/or". Throughout this application, the term "about" is used to indicate that a value includes the inherent variability in error for a device, the method used to determine that value, or the variability that exists among study subjects.

As used in this specification and claim(s), the word "comprising" (and any form of including, such as "comprises" and "includes"), "having" (and any form of having, such as "has" and "has"), "comprising" (and any form of inclusion, such as "comprises" and "comprises") or containing (and any form of containing, such as "contains" and "contains") is inclusive or open-ended and additional, recitations It does not exclude elements or method steps that have not been identified. In any one embodiment of any of the compositions and methods provided herein, “comprising” may be replaced with “consisting essentially of” or “consisting of”. As used herein, the phrase “consisting essentially of” requires the specified integer(s) or steps as well as those that do not materially affect the features or functions of the claimed invention. As used herein, the term "consisting of" is used to indicate the presence of only a recited integer (e.g., feature, element, characteristic, characteristic, method/process step or limitation) or group of integers (e.g., feature(s), element(s), feature(s), characteristic(s), method/process step or limitation(s)).

As used herein, the term “or combinations thereof” refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of A, B, C, AB, AC, BC, or ABC, and, where order is important in certain circumstances, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing this example, combinations containing repetitions of one or more items or terms, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, etc., are explicitly included. Skilled artisans will understand that there is typically no limit to the number of items or terms in any combination, unless otherwise apparent from the context.

As used herein, words of approximation such as, without limitation, "about," "substantially," or "substantially" refer to a condition that, when so modified, is understood to be not necessarily absolute or complete, but will be considered close enough to warrant designating the condition as existing by those skilled in the art. The extent to which the description can be varied will depend on how large a change can be introduced, and will still allow one skilled in the art to recognize the modified feature as still possessing the required feature and the capabilities of the unmodified feature. In general, but subject to the foregoing discussion, numerical values herein modified by an approximate word such as "about" may vary by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12 or 15% from the stated value.

All compositions and/or methods disclosed and claimed herein can be prepared and practiced without undue experimentation in light of the present disclosure. Although the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and/or methods and to the steps or sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. All such similar substitutions and modifications obvious to those skilled in the art are considered to be within the spirit, scope and concept of the present invention as defined by the appended claims.

references

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

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

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

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

Claims (10)

A composition for preventing or treating one or more cardiac channelopathy or conditions due to irregularities or alterations in cardiac patterns, the composition comprising:
In a subject, at least one pharmacologically active agent selected from QTc, LQT2, LQTS, or torsades de pointes, which induces cardiac channelopathy or condition due to irregularities or alterations in the cardiac pattern induced by the active agent, and
상기 1종 이상의 약리학상 활성제에 의해 야기된, 심장 패턴의 불규칙성 또는 변경으로 인한 심장 채널병증 또는 병태를 예방하거나 감소시키기에 충분한 양으로 제공되는 1종 이상의 지질을 포함하고, 여기서 상기 지질은 포스파티딜콜린 (레시틴), 리소레시틴, 리소포스파티딜에탄올-아민, 포스파티딜세린, 포스파티딜이노시톨, 스핑고미엘린, 포스파티딜에탄올아민(세팔린), 카르디오리핀, 포스파티드산, 세레브로시드, 디세틸포스페이트, 포스파티딜콜린, 디팔미토일-포스파티딜글리세롤, 스테아릴아민, 도데실아민, 헥사데실-아민, 아세틸 팔미테이트, 글리세롤 리시놀레에이트, 헥사데실 스테아레이트, 이소프로필 미리스테이트, 양쪽성 아크릴계 중합체, 지방산, 지방산 아미드, 콜레스테롤, 콜레스테롤 에스테르, 디아실글리세롤, 디아실글리세롤숙시네이트, 1-미리스토일-2-히드록시-sn-글리세로-3-포스포콜린 (DMPC), 12-미스테로일-2-히드록시-sn-글리세로-3-[포스포-rac-(글리세롤)] (DMPG), DMPC/DMPG, 1-미리스토일-2-히드록시- sn -글리세로-3-포스포-(1'- rac -글리세롤) (LysoPG), 또는 1-미리스토일-2-히드록시- sn -글리세로-3-포스포콜린 (LysoPC) 중 적어도 1종으로부터 선택되고,
wherein the composition is dispersed in a pharmaceutically acceptable medium, solvent, or vehicle, wherein the active agent, lipid, or both are dissolved, dispersed, or suspended in the medium, solvent, or vehicle, wherein the weight-to-weight ratio of active agent to lipid is from 10:1 to 1:10, wherein the protection against cardiac channelopathy or condition due to irregularities or alterations in cardiac pattern lasts for 1 to 24 hours. 2. The composition of claim 1 wherein the ratio of active agent to lipid is from 1:5 to 5:1. The composition of claim 1 wherein the ratio of active agent to lipid is from 3:1 to 1:3. 4. The composition according to any one of claims 1 to 3, wherein the lipid is provided in an amount that prevents or reduces cardiac channelopathy or conditions due to irregularities or alterations in the heart pattern even after the lipid has been removed from the bloodstream. The composition according to any one of claims 1 to 4, wherein the lipid comprises at least one of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, cardiolipin, phosphatidylinositol or a precursor thereof. 6. The method according to any one of claims 1 to 5, wherein the lipid is DMPG, DMPG, LysoPg or LysoPC, 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (DMPC), 12-mysteroyl-2-hydroxy-sn-glycero-3-[phospho-rac-(glycerol)] (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). 7. The composition of any one of claims 1 to 6, wherein the active agent is selected from at least one of crizotinib, nilotinib, terfenadine, astemizole, grippafloxacin, terodylene, droperidol, lidoflazin, levometadil, sertindol or cisapride. 8. The composition according to any one of claims 1 to 7, wherein the composition is suitable for enteral, parenteral, intravenous, intraperitoneal, dermal, subcutaneous, pulmonary, rectal, vaginal, or oral administration. 9. The method of any one of claims 1 to 8, wherein the active agent is albuterol, alfuzosin, amantadine, amiodarone, amisulprid, amitriptyline, amoxapine, amphetamine, anagrelide, apomorphine, aformoterol, aripiprazole, arsenic trioxide, astemizole, atazanavir, atomoxetine, azithromycin, bedaquiline, bepridil, Bortezomib, bosutinib, chloral hydrate, chloroquine, chlorpromazine, ciprofloxacin, cisapride, citalopram, clarithromycin, clomipramine, clozapine, cocaine, curcumin, crizotinib, dabrafenib, dasatinib, desipramine, dexmedetomidine, dexmethylphenidate, dextroamphetamine, d-amphetamine, dihydroartemi Sinin and piperaquine, diphenhydramine, disopyramide, dobutamine, dofetilide, dolasetron, domperidone, dopamine, doxepin, dronedarone, droperidol, ephedrine, epinephrine, adrenaline, eribulin, erythromycin, escitalopram, famotidine, felbamate, fenfluramine, fingolimod, flecainide, fluconazole, fluoxetine, formoterol, foscarnet, phosphenytoin, furosemide, prusemide, galantamine, gatifloxacin, gemifloxacin, granisetron, halophanthrine, haloperidol, hydrochlorothiazide, ibutylide, iloperidone, imipramine, melipramine, indapamide, isoproterenol, isradipine, Itraconazole, ivabradine, ketoconazole, lapatinib, levalbuterol, levofloxacin, levometadil, lisdexamfetamine, lithium, mesoridazine, metaproterenol, methadone, methamphetamine (methamphetamine), methylphenidate, midodrine, mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, moxifloxacin , nelfinavir, nicardipine, nilotinib, norepinephrine (noradrenaline), norfloxacin, nortriptyline, ofloxacin, olanzapine, ondansetron, oxytocin, paliperidone, paroxetine, pasireotide, pazopanib, pentamidine, perfluthrene lipid microspheres, phentermine, phenylephrine, phenylpropanolamine, pimozide , posaconazole, probucol, procainamide, promethazine, protriptyline, pseudoephedrine, quetiapine, quinidine, quinine sulfate, ranolazine, rilpivirine, risperidone, ritodrine, ritonavir, roxithromycin, salbutamol, salmeterol, saquinavir, sertindole, sertraline, sevoflurane, sibutramine, solifena Sin, sorafenib, sotalol, sparfloxacin, sulpiride, sunitinib, tacrolimus, tamoxifen, telaprevir, telavancin, telithromycin, terbutaline, terfenadine, tetrabenazine, thioridazine, tizanidine, tolterodine, toremifene, trazodone, trimethoprim-sulfa, trimipramine, vandetanib, barde A composition selected from napil, vemurafenib, venlafaxine, voriconazole, vorinostat, or ziprasidone. 10. The method of any one of claims 1 to 9, wherein the lipid prevents cardiac channelopathy or conditions due to irregularities or alterations in cardiac pattern for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 hours phosphorus composition.