Compositions and methods to ameliorate drug-induced long QT syndrome

Abstract

Compositions comprising a therapeutic agent that induces a long QT interval and a cardioprotective agent are provided. Use of the compositions in managing risk of or actual QT prolongation are described, where the cardioprotective agent is administered before, during and / or after the therapeutic agent that induces a long QT interval.

Description

COMPOSITIONS AND METHODS TO AMELIORATE DRUG-INDUCED LONG QTSYNDROMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The current application claims priority to U.S. Provisional Patent Application Serial No. 63 / 604,106, entitled “Compositions and Methods to Ameliorate Drug-Induced Long QT Syndrome'’, filed November 29, 2023. The disclosure of U.S. Provisional Patent Application No. 63 / 604,106 is hereby incorporated by reference in its entirety for all purposes.TECHNICAL FIELD

[0002] The subject matter described herein relates to compositions and methods of treatment to ameliorate, reduce or manage drug-induced long QT syndrome. In embodiments, a cardioprotective agent is administered in conjunction with a drug that induces a prolonged QT interval.BACKGROUND

[0003] Long QT syndrome is characterized by inherited or acquired prolonged QT interval on a surface electrocardiogram. A prolonged QT interval can lead to torsade de pointes ventricular tachycardia and ventricular fibrillation. In the acquired form of the disease, medications from several classes of drugs can cause torsade de pointes ventricular tachycardia or potentiate the electrocardiographic findings. These include class IA and III antiarrhythmics, antibiotics (macrolides and quinolones), antidepressants (tricyclics and selective serotonin reuptake inhibitors), antipsychotics (haloperidol and phenothiazines), and antiemetics (ondansetron and prochlorperazine). The present disclosure provides compositions and methods to prophylactically manage this problem.

[0004] The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive.BRIEF SUMMARY

[0005] The following aspects and embodiments thereof described and illustrated below are meant to be exemplary and illustrative, not limiting in scope.

[0006] In an embodiment, a method for reducing risk of drug-induced long QT syndrome is provided. In another embodiment, a method for administering a drug that induces long QT syndrome is provided. The methods comprise administering, or instructing to administer, to a subject in need a cardioprotective agent in an amount effective to achieve aphysiologic effect to reduce risk of long QT syndrome and / or to reduce risk of complications due to a long QT syndrome; and administering, or instructing to administer, a therapeutic agent or salt thereof that causes a prolonged QT interval. In other embodiments, the method comprises administering, or instructing to administer, to a subject in need a cardioprotective agent in an amount effective to achieve a physiologic effect to attenuate or to ameliorate complications arising from a prolonged QT interval; and administering, or instructing to administer, a therapeutic agent or salt thereof that causes a prolonged QT interval.

[0007] In an embodiment, administering or instructing to administer the cardioprotective agent occurs before, simultaneous with, or after the administering, or instructing to administer, the therapeutic agent or salt thereof that causes, is know n to cause, is likely to cause and / or is at risk of causing a prolonged QT interval.

[0008] In another embodiment, a method for administering a drug that induces long QT syndrome is provided. The method comprises providing a device comprising a plurality of unit doses of a cardioprotective agent and a plurality of unit doses of a therapeutic agent or salt thereof that causes a prolonged QT interval or salt thereof; instructing a subject to selfadminister one or more unit doses from the plurality of unit doses of the cardioprotective agent, the unit dose of the cardioprotective agent effective to achieve a physiologic effect to reduce risk of long QT syndrome; and instructing a subject to self-administer a unit dose from the plurality of unit doses of a therapeutic agent or salt thereof that causes a prolonged QT interval to the subject.

[0009] In another embodiment, a composition is provided that is comprised of a dosage form comprising a therapeutic agent or salt thereof that causes a prolonged QT interval and a salt of magnesium, potassium and / or calcium, the salt of magnesium, potassium and / or calcium present in the dosage form in an amount effective to achieve a physiologic effect to reduce risk of a drug-induced long QT syndrome.

[0010] In an embodiment, the dosage form is orally administrable.

[0011] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is an antibiotic, such as a fluoroquinolone or a macrolide.

[0012] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is methadone.

[0013] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is an antiarrhythmic agent.

[0014] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is an antipsychotic agent.

[0015] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is an antiemetic agent.

[0016] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is an antidepressant agent.

[0017] In embodiments, the therapeutic agent of salt thereof is one known to cause, likely to cause and / or is at risk of causing a long QT interval.

[0018] In embodiments, the physiologic effect is achieved when the cardioprotective agent is at a threshold concentration in the blood for a period of time, and the therapeutic agent or salt thereof that causes a prolonged QT interval is administered during the period of time.

[0019] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is at a therapeutic concentration in the blood for a treatment period, and the method further comprises administering to the subject a further amount of the cardioprotective agent to achieve a physiologic effect to reduce risk of a long QT syndrome.

[0020] In embodiments, the further amount of the cardioprotective agent is administered parenterally or orally.

[0021] In embodiments, the methods comprise assessing a baseline QT interval, or receiving information on a baseline QT interval, of the subj ect prior to administering the cardioprotective agent, after administering the cardioprotective agent, and / or after administering the therapeutic agent or salt thereof that causes or is likely to cause a prolonged QT interval.

[0022] In embodiments, the cardioprotective agent is administered in an amount effective to achieve a physiologic effect to reduce risk of a drug-induced or acquired long QT syndrome.

[0023] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is not an iboga alkaloid, such as ibogaine.

[0024] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interval is not an antiarrhythmic agent.

[0025] In embodiments, the therapeutic agent or salt thereof that causes a prolonged QT interv al is administered orally, parenterally or intrathecally.

[0026] In embodiments, the administering, or instructing to administer, the cardioprotective agent comprises orally administering or instructing to orally administer.

[0027] In one embodiment, the cardioprotective agent is selected from the group consisting of a mineral, a sodium channel blocker (a class IB antiarrhythmic), a potassium channel blocker, an hERG (human ether -a-go-go-related gene) channel agonist, and beta adrenoceptor agonists.

[0028] In one embodiment, the sodium channel blocker is selected from the group consisting of mexiletine, tocainide, lidocaine, flecainide, and R-56865 (2- benzothiazolamine, N-(l-(4-(4-fluorophenoxy)butyl)-4-piperidinyl)-N-methyl).

[0029] In one embodiment, the potassium channel blocker is selected from the group consisting of amiodarone and ranolazine.

[0030] In one embodiment, the mineral is selected from the group consisting of magnesium, calcium and potassium.

[0031] In one embodiment, the mineral is in the form a salt, and wherein said administering or instructing to administer the cardioprotective agent comprises administering or instructing to administer prior to said administering the therapeutic agent or salt thereof that causes a prolonged QT interval.

[0032] In one embodiment, the mineral is in the form of a salt, and wherein the administering or instructing to administer the cardioprotective agent comprises administering or instructing to administer concurrent with and / or subsequent to said administering the therapeutic agent or salt thereof that causes a prolonged QT interval.

[0033] In one embodiment, wherein the hERG channel agonist is selected from the group consisting of RPR260243 ([(37?,47?)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-l-[3- (2,3,5 trifluorophenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid]), PD-118057 ([2-(4-[2- (3,4-dichloro-phenyl)-ethyl]-phenylamino)-benzoic acid]), and NS1643 (N,N'-bis[2- hydroxy-5-(trifluoromethyl)phenyl]-urea).

[0034] In one embodiment, the beta adrenoceptor agonist is isoproterenol.

[0035] In one embodiment, the cardioprotective agent is (i) not a CYP2D6 inhibitor or (ii) a CYP2D6 inhibitor administered at a dose ineffective to inhibit CYP2D6 or (iii) not amiodarone.

[0036] In one embodiment, the cardioprotective agent is a magnesium salt, which is administered in an amount of between about 50-8000 mg per day.

[0037] In one embodiment, the therapeutic agent or salt thereof that causes a prolonged QT interval is administered at a dose in the recommended dosage range. In an embodiment,the therapeutic agent or salt thereof that causes a prolonged QT interval is administered in an amount between about 50-5000 mg per day or between about 100-3000 mg.

[0038] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following descriptions.

[0039] Additional embodiments of the present methods and compositions, and the like, will be apparent from the following description, drawings, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present disclosure. Additional aspects and advantages of the present disclosure are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIGS. 1A-1B are illustrative electrocardiographs of a subject showing a prolonged QT interval and a restored QT interval.

[0041] FIGS. 2A-2B are illustrative electrocardiographs of a subject showing a prolonged QT interval and a restored QT interval.DETAILED DESCRIPTIONI. Definitions

[0042] Various aspects now will be described more fully hereinafter. Such aspects may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0043] Where a range of values is provided, it is intended that each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. For example, if a range of 1 pm to 8 pm is stated, it is intended that 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, and 7 pm are alsoexplicitly disclosed, as well as the range of values greater than or equal to 1 pm and the range of values less than or equal to 8 pm.

[0044] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "polymer" includes a single polymer as well as two or more of the same or different polymers, reference to an "excipient" includes a single excipient as well as two or more of the same or different excipients, and the like.

[0045] The word "about" when immediately preceding a numerical value means a range of plus or minus 10% of that value, e.g., "about 50" means 45 to 55, "about 25,000" means 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as "about 49. about 50. about 55, "about 50" means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases "less than about" a value or "greater than about" a value should be understood in view of the definition of the term "about" provided herein.

[0046] The compositions of the present disclosure can comprise, consist essentially of, or consist of, the components disclosed.

[0047] All percentages, parts and ratios are based upon the total weight of the composition and all measurements made are at about 25 °C, unless otherwise specified.

[0048] "Administration" refers to introducing an agent into a subject or patient. Typically, an effective amount is administered, which amount can be determined by the treating physician or the like. Any route of administration, such as oral, topical, subcutaneous, peritoneal, intraarterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used. The agent may be administered by direct blood stream delivery, e.g., sublingual, buccal, intranasal, or intrapulmonary administration.

[0049] The related terms and phrases "administering" and "administration of, when used in connection with a compound or pharmaceutical composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and / or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to selfadminister a drug and / or provides a patient with a prescription for a drug is administering the drug to the patient.

[0050] As used herein, the term "patient" or “subject” refers to mammals and includes humans and non-human mammals.

[0051] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, salts, compositions, dosage forms, etc., which are within the scope of sound medical judgment-suitable for use in contact with the tissues of human beings and / or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some aspects, "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals (e.g., animals), and more particularly, in humans.

[0052] "Pharmaceutically acceptable salt" refers to salts, including pharmaceutically acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and when the molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.

[0053] "Therapeutically effective amount" or "therapeutic amount" refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount may vary depending upon the patient and the condition being treated, the gender, weight and age of the subject, the severity of the condition, presence of co-morbidities, the salt, solvate, or derivative of the active drug portion chosen, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. The full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of an agent, in the context of treating a neurodegenerative disease or a movement disorder and / or symptoms thereof, refers to an amount of the agent that attenuates the disease or disorder; attenuates, reverses, or reduces the severity of a symptom or symptomsthereof; and / or prevents, delays, or reduces the severity of progression of the disease or disorder.

[0054] A "therapeutic level" of a drug is an amount that is sufficient to treat or prevent the disease or disorder and / or symptoms thereof, but not high enough to pose any significant risk to the patient. Therapeutic levels of drugs can be determined by tests that measure the actual concentration of the compound in the blood of the patient. This concentration is referred to as the "serum concentration."

[0055] The term "treating" is used herein, for instance, in reference to methods of treating a neuropsychiatric disorder, and generally includes the administration of a compound or composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition (e.g., a neuropsychiatric disorder or a neurological disorder or a neurodegenerative disorder) in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the symptoms, clinical signs, biological signed, and / or underlying pathology of a condition in a manner to improve or stabilize a subject's condition.

[0056] The term "unit dose" refers to a dose of drug provided to a patient to provide a therapeutic result, independent of the weight of the patient. The unit dose can be a standard form (e.g., a tablet or capsule). The unit dose may be administered as a single dose or a series of subdoses that collectively equal the single dose.

[0057] By reserving the right to proviso out or exclude any individual members of any such group, including any sub-ranges or combinations of sub-ranges within the group, that can be claimed according to a range or in any similar manner, less than the full measure of this disclosure can be claimed for any reason. Further, by reserving the right to proviso out or exclude any individual substituents, analogs, compounds, ligands, structures, or groups thereof, or any members of a claimed group, less than the full measure of this disclosure can be claimed for any reason.

[0058] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0059] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in thisdisclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.II. Compositions for Treatment

[0060] The acquired form or dmg-induced form of long QT syndrome is a potentially fatal medical condition. More than 50 medications can affect the QT interval. Potent QT- prolonging medications include antiarrhythmic agents, such as amiodarone, dofetilide, quinidine, and sotalol. Other QT-prolonging medications that are not cardiac medications include antibiotics, such as macrolides and quinolones, antidepressants, such as tricyclics and selective serotonin reuptake inhibitors, antipsychotics, such as haloperidol and phenothiazines, and antiemetics such as ondansetron. An online list of medications that can prolong the QT interval is maintained by The Arizona Center for Research and Education on Therapeutics. Exemplary agents that cause, are known to cause, are likely to cause and / or at risk of causing QT prolongation are set forth in Table 1.Table 1: Examples of therapeutic agents that prolong the QT interval

[0061] The QT interval is a measurement made on an electrocardiogram used to assess electrical properties of the heart. It corresponds to the time from the start of the Q wave to the end of the T wave, and approximates to the time taken from when the cardiac ventricles start to contract to when they finish relaxing. Measurement of the QT interval is done by several methods, as the end of the T wave is not always clearly defined and usually merges gradually with the baseline. Common methods to measure the QT interval in an ECG complex include the threshold method, in which the end of the T wave is determined by the point at which the component of the T wave merges with the isoelectric baseline, and the tangent method, in which the end of the T wave is determined by the intersection of atangent line extrapolated from the T wave at the point of maximum downslope to the isoelectric baseline. Another method is to use a digital ECG with simultaneous 12-channel recording, where QT measurement is determined by the 'superimposed median beat' method. In the superimposed median beat method, a median ECG complex is constructed for each of the 12 leads. The 12 median beats are superimposed on each other, and the QT interval is measured either from the earliest onset of the Q wave to the latest offset of the T wave or from the point of maximum convergence for the Q wave onset to the T wave offset.

[0062] The QT interval changes in response to the heart rate - as heart rate increases the QT interval shortens. To compare QT intervals measured at different heart rates, and improve the reliability of QT measurement, the QT interval can be corrected for heart rate (QTc) using a variety of mathematical formula, a process often performed automatically by modem ECG recorders.

[0063] In an embodiment, the therapeutic agent that induces a long QT interval is one that induces or causes a QT or a QTc value of above about 450 ms for an adult male or above about 460 ms for an adult female. In other embodiments, the therapeutic agent that induces a long QT interval is one that induces or causes a QT or a QTc value of above about 440 ms or about 430 ms for an adult male or above about 450 ms for an adult female. In an embodiment, the QT value or QTc value is measured by the threshold method. In an embodiment, the QT value or QTc value is measured by the tangent method. In an embodiment, lead II is used for the QT measurement using the tangent method or the threshold method. In an embodiment, the QT value or QTc value is measured using the superimposed median beat method.

[0064] In an embodiment, reference herein to a QT interval may also be to a QTc interval. In embodiments, the QTc interval is obtained from an ECG recorder that automatically accounts for heart rate. In other embodiments, the QTc interval is obtain by mathematical correction of a QT measurement using Bazett’s formula. In other embodiments, the QTc interval is obtain by mathematical correction of a QT measurement using Fridericia’s formula. In other embodiments, the QTc interval is obtain by mathematical correction of a QT measurement using a formula selected from Framingham, Hodges, and Rautaharju formulas.

[0065] In an embodiment, the therapeutic agent that induces a long QT interval is an antibiotic. In an embodiment, the antibiotic is a macrolide antibiotic, such as erythromycin, clarithromycin, azithromycin, fidaxomicin and telithromycin. In anembodiment, the antibiotic is a quinolone antibiotic, such as a fluoroquicolone, such as ciprofloxacin, ofloxacin, gemifloxacin, levofloxacin, moxifloxacin and delafloxacin. In an embodiment, the antibiotic is administered for treating a bacterial infection or a suspected bacterial infection in a subject, such as a gram negative or a gram positive bacterial infection. Examples are ear infections, pneumonia, sinusitis, pharyngitis, and tonsillitis.

[0066] In an embodiment, the therapeutic agent that induces a long QT interval is an antipsychotic. In an embodiment, the antipsychotic is not an iboga alkaloid, such as ibogaine. The antipsychotic can be, for example, chlorpromazine, clozapine, haloperidol, quetiapine, risperidone, thioridazine, or ziprasidone.

[0067] In an embodiment, the therapeutic agent that induces a long QT interval is an antidepressant. Examples include amitriptyline, citalopram, desipramine, doxepin, fluoxetine, imipramine, nortriptyline, paroxetine, sertraline, and venlafaxine.

[0068] In an embodiment, the therapeutic agent that induces a long QT interval is an antiarrhythmic. In an embodiment, the antiarrhythmic is not amiodarone. In embodiments, the antiarrhythmic is disopyramide, difetilide, ibutilide, procainamide, quinidine, or sotalol.

[0069] In an embodiment, the therapeutic agent that induces a long QT interval is the synthetic opiate methadone.

[0070] In an embodiment, the therapeutic agent that induces a long QT interval is an antiemetic. Antiemetics that induce a prolonged QT interval include ondansetron and prochlorperazine.

[0071] In embodiments, the therapeutic agent described as one that induces a long QT interval is one that causes (or induces), is known to cause (or induce), is likely to cause (or induce) and / or is at risk of causing (or inducing) a long QT interval.

[0072] The compositions are not limited to any particular chemical form of the therapeutic agent that induces a long QT interval and the compound may be present in the composition as a free base or as a pharmaceutically acceptable salt.

[0073] The dose of the therapeutic agent that induces a long QT interval is readily determined by a person of skill in the medical arts by consulting, for example, the package insert for the therapeutic agent.

[0074] The compositions, devices and kits include a cardioprotective agent. The cardioprotective agent is, in an embodiment, a compound with activity7to reduce risk of a drug-induced long QT syndrome and / or with activity to mitigate risk associated with drug- induced long QT syndrome. In other embodiments, the cardioprotective agent is acompound with activity to reduce long QT syndrome or QT prolongation in a subject. In other embodiments, the cardioprotective agent has a stabilization effect on cardiac membrane that is independent of QT changes.

[0075] In embodiments, the cardioprotective agent is a mineral, a sodium channel blocker (a class IB antiarrhythmic), a potassium channel blocker, an hERG (human ether-a-go-go- related gene) channel agonist, and / or a beta adrenoceptor agonist. Exemplary sodium channel blockers are mexiletine, tocainide, lidocaine, flecainide, and R-56865 (2- benzothiazolamine, N-(l-(4-(4-fluorophenoxy)butyl)-4-piperidinyl)-N-methyl).Exemplar}' potassium channel blockers are amiodarone and ranolazine. Exemplary minerals are magnesium, calcium and / or potassium. Exemplary hERG channel agonists include RPR260243 ([(37?,47?)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-l-[3-(2,3,5 trifluorophenyl)-prop-2-ynyl]-piperidine-3 -carboxylic acid]), PD-118057 ([2-(4-[2-(3.4- dichloro-phenyl)-ethyl]-phenylamino)-benzoic acid]), and NS 1643 (N,N'-bis[2-hydroxy-5- (trifluoromethyl)phenyl]-urea). An exemplary beta adrenoceptor agonist is isoproterenol. The cardioprotective agent can be in salt, base or elemental form.

[0076] In an embodiment, the cardioprotective agent is not a CYP2D6 inhibitor, a CYP2D6 inhibitor administered at a dose ineffective to inhibit CYP2D6, and / or amiodarone.

[0077] In an embodiment, the cardioprotective agent is a mineral, and in an embodiment, the mineral is present in the composition in the form a salt. In an embodiment, the mineral salt is an electrolyte. In an embodiment, the electrolyte is calcium, sodium, potassium, phosphate, magnesium and / or chloride. Exemplary salts of magnesium include magnesium aspartate, magnesium aspartate hydrochloride, magnesium bisglycenate, magnesium carbonate, magnesium chloride, magnesium citrate, magnesium gluconate, magnesium glycinate, magnesium hydroxide, magnesium lactate, magnesium malate, magnesium oxide, magnesium sulfate, and magnesium taurate. Exemplary salts of potassium and calcium include potassium chloride, potassium citrate, potassium bicarbonate, calcium gluconate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium carbonate, and calcium acetate.

[0078] In an embodiment, the salt form of the mineral or electrolyte is not a fatty acid salt form of the mineral or electrolyte. In an embodiment, a fatty acid refers to a carboxylic acid with a saturated or unsaturated, branched or linear, aliphatic chain. In an embodiment, the aliphatic chain has about four or more, five or more, six or more carbon atoms. For example, the aliphatic chain may have between about 4-26, 5-26, 6-26, 7-26 or 8-26 carbonatoms. In an embodiment, the cardioprotective agent is not a magnesium salt of a fatty acid. In an embodiment, the cardioprotective agent is not magnesium stearate.

[0079] In an embodiment, the cardioprotective agent is a magnesium salt that ionizes in an aqueous medium to a magnesium cation and an anion or anion pair, the anion or the anion pair having a molecular mass of less than about 200 g / mol, 225 g / mol, 250 g / mol, 275 g / mol or 280 g / mol. In an embodiment, the cardioprotective agent is a magnesium salt that is essentially completely soluble in water at 25 °C. In an embodiment, the cardioprotective agent is a magnesium salt that has a water solubility at 25 °C of greater than about 5 g / L, 10 g / L, 25 g / L or 50 g / L.

[0080] Accordingly, in an embodiment, a composition comprising therapeutic agent or salt thereof that induces a long QT interval and a cardioprotective agent are provided.

[0081] In embodiments, the cardioprotective agent is in the composition in an amount effective to achieve a physiologic effect to reduce risk of a drug-induced long QT syndrome. For example, in embodiments where the cardioprotective agent is magnesium, potassium or calcium, the composition can include a salt of magnesium, potassium and / or calcium, where the salt form is present in the composition in an amount effective to achieve a physiologic effect on the QT interval. In embodiments, the cardioprotective agent is administered in an amount effective to shorten the QT interval and / or to reduce risk of developing drug-induced QT prolongation. In an embodiment, the effective amount is an amount to reduce risk associated with a drug-induced long QT syndrome. In an embodiment, the effective amount is an amount to stabilize a cardiac membrane independent of QT change.

[0082] In embodiments where the cardioprotective agent is magnesium, potassium or calcium, the composition can include a salt of magnesium, potassium and / or calcium in an amount that provides a dose of the mineral (z.e., an elemental dose or amount) effective to achieve a physiologic effect on the QT interval, to shorten the QT interval, to reduce risk of developing a prolonged QT interval, to stabilize a cardiac membrane, and / or to reduce risks of a long QT interval. In an embodiment, the effective amount is an elemental amount to reduce risk of a drug-induced long QT syndrome.

[0083] In studies performed herein, and discussed below with reference to Example 1, the cardioprotective agent magnesium was administered to the subjects. The amount (weight) of magnesium salt in the composition will vary according to its salt form, as can be appreciated. In an embodiment, the composition comprises magnesium salt in an amount between about 50-8000 mg. 250-8000 mg, 500-8000 mg, 1000-8000 mg, 50-6000 mg,250-6000 mg, 500-6000 mg, 1000-6000 mg, 1500-6000 mg, 50-5000 mg, 250-5000 mg, 500-5000 mg, 2000-5000 mg, 50-4000 mg, 250-4000 mg, or 500-4000 mg.

[0084] In other embodiments, the composition comprises an amount of a mineral salt, such as a potassium, a chloride, or a magnesium salt, that provides a dose of elemental mineral of between about 0.01-500 moles, 0.01-300 moles, 0.01-250 moles, 0.01-200 moles, 0.01- 150 moles, 0.01-100 moles, 0.01-50 moles, 0.5-500 moles, 0.5-300 moles, 0.5-250 moles, 0.5-200 moles, 0.5-150 moles, 0.5-100 moles, 0.5-50 moles, 1-500 moles, 1-300 moles, 1- 250 moles, 1-200 moles, 1-150 moles, 1-100 moles, 2-500 moles, 2-300 moles, 2-250 moles. 2-200 moles. 2-150 moles. 2-100 moles, 5-500 moles, 5-300 moles, 5-250 moles, 5- 200 moles, 5-150 moles, 5-100 moles, 10-500 moles, 10-300 moles, 10-250 moles, 10-200 moles, 10-150 moles, or 10-100 moles. In other embodiments, the dose of elemental mineral provides between about 1-500 mEq, 1-300 mEq, 1-250 mEq, 1-200 mEq, 2-500 mEq, 2-300 mEq, 2-250 mEq, 2-200 mEq, 5-500 mEq. 5-300 mEq, 5-250 mEq. 5-200 mEq, or 5-150 mEq.

[0085] In an embodiment, the cardioprotective agent is magnesium administered in the form of a salt, such as magnesium sulfate or magnesium oxide.

[0086] The cardioprotective agent can be administered prior to, concurrently with, and / or subsequent to administration of the therapeutic agent that induces a long QT interval. The cardioprotective agent can be administered via any route of administration.

[0087] The composition comprising the therapeutic agent that induces a long QT interval and cardioprotective agent can be of any form. In embodiments, and as can be appreciated, the form of the composition may depend on the intended route of administration. In embodiments, the therapeutic agent that induces a long QT interval and cardioprotective agent are formulated together in a single dosage form. In embodiments, the therapeutic agent that induces a long QT interval and cardioprotective agent are formulated each in a single dosage form for administration sequentially or concurrently.

[0088] The composition can be a solid dosage form. In an embodiment, the solid dosage form in intended for oral ingestion. Examples of orally ingestible dosage forms include a powder, a capsule, a pill, or a tablet. In other embodiments, the solid dosage form is for sublingual, buccal, rectal or topical administration. The dosage form can be formulated to provide immediate release of one or both of the therapeutic agent that induces a long QT interval and the cardioprotective agent upon oral administration. For example, a dosage form that releases the therapeutic agent that induces a long QT interval or salt thereof atleast about 0.25 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours after release of the cardioprotective agent is contemplated.

[0089] An exemplary dosage form is an orally ingestible powder, capsule, pill, or tablet comprising an amount of a therapeutic agent that induces a long QT interval and an amount of a cardioprotective agent. In an embodiment, the cardioprotective agent is an electrolyte, such as magnesium or any of the other minerals mentioned herein. The dosage form comprises an amount of the therapeutic agent that induces a long QT interval suitable for the subject, and an amount of cardioprotective agent in any of the amounts mentioned herein.

[0090] In embodiments, the composition can be suitable for a variety of delivery modes including, without limitation, oral, sublingual, buccal, intrapulmonary, or intranasal delivery. Compositions suitable for internal, rectal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal and subcutaneous routes may also be used. Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A Oslo editor, Easton Pa. 1980).

[0091] In one embodiment, the therapeutic agent that induces a long QT interval or pharmaceutically acceptable salt or solvate thereof is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. Solutions can be prepared using water or physiologically compatible organic solvents such as fatty alcohols, triglycerides, glycerine and the like. Parenteral compositions containing the therapeutic agent that induces a long QT interval or pharmaceutically acceptable salt or solvate thereof may be prepared using conventional techniques that may include sterile isotonic saline, water, Ringer's solution, etc. Compositions for sublingual administration, for example as sublingual tablets may be designed to dissolve rapidly and can contain in addition to the therapeutic agent that induces a long QT interval and / or the cardioprotective agent, excipients such as lactose, sucrose, dextrose or mannitol.

[0092] In other embodiments, a kit comprising a device comprising a plurality of unit doses of a cardioprotective agent and a unit dose or a plurality of unit doses of a therapeutic agent that induces a long QT interval or salt thereof and instructions for use is provided. In one embodiment, the plurality7of unit doses of cardioprotective agent comprises a plurality7of unit doses for oral administration of the cardioprotective agent.For example, each unit dose of cardioprotective agent in the kit can be a solid dosage form, such as a pill, capsule, tablet, caplet, or a powder. Each unit dose of cardioprotective agent, in other embodiments, can be a liquid dosage form, such as a solution, suspension, elixir, or syrup. In other embodiments, the plurality of unit doses of cardioprotective agent comprise a first set that is a solid dosage form and a second set that is a liquid dosage form; that is, the unit doses in the plurality are a mixture of solid dosage forms and liquid dosage forms. In embodiments, one or more of the unit doses is a solid, such as a powder, that is mixed with a liquid, such as water or juice, for ingestion by the patient. In other embodiments, one or more of the unit doses of cardioprotective agent is a liquid suitable for nasal administration or parenteral administration.

[0093] In embodiments, the kit or device of the kit comprises a unit dose or a plurality of unit doses of the therapeutic agent that induces a long QT interval or salt thereof in the form of a solid or a liquid. The solid unit dose can be, for example, a pill, capsule, tablet, caplet, or a powder. The liquid unit dose can be, for example, an elixir, a syrup, a suspension or a solution. In other embodiments, the unit dose of the therapeutic agent that induces a long QT interval or salt thereof is a liquid suitable for nasal administration or parenteral administration.

[0094] In an embodiment, the device comprising one or more unit doses of the therapeutic agent that induces a long QT interval or salt thereof and / or the plurality of unit doses of cardioprotective agent is a blister pack. In other embodiments, the kit comprises a device comprising one or more unit doses of the therapeutic agent that induces a long QT interval and a container or collection of packets with a plurality of doses of the cardioprotective agent. In other embodiments, the kit comprises a blister pack with at least one unit dose of the therapeutic agent that induces a long QT interval or salt thereof and at least one unit dose of a cardioprotective agent. In other embodiments, the kit comprises a blister pack with a plurality of unit doses of the therapeutic agent that induces a long QT interval or salt thereof and two or more unit dose of a cardioprotective agent. In embodiments, each unit dose in the blister pack is in a separate blister of the blister pack. By way of example, a kit comprising a plurality of doses of a magnesium salt, calcium salt or potassium salt (or combination of mineral salts) is provided, where in embodiments the plurality of doses are in a blister pack of individual unit doses, in a collection of containers each with a unit dose, or in a single container comprising the plurality7of doses. The kit further comprises at least one dose of, and preferably a plurality of unit doses of, therapeutic agent that induces a long QT interval.

[0095] In an embodiment, the device further comprises a second unit dose or a second plurality of unit doses of the therapeutic agent that induces a long QT interval or salt thereof. In an embodiment, the second unit dose or plurality of unit doses of the therapeutic agent that induces a long QT interval agent or salt thereof is at a dose different than the first unit doses or at the same dose as the first unit doses. In an embodiment, the second unit dose of the therapeutic agent that induces a long QT interval or salt thereof is at a dose less than the dose of the therapeutic agent that induces a long QT interval or salt thereof in the first unit dose. In an embodiment, the plurality of unit doses of cardioprotective agent comprise a plurality of unit doses at different doses and / or of unit doses formulated for different routes of administration.III. Methods of Treatment

[0096] In an aspect, a method for reducing risk of drug-induced long QT syndrome is provided. In another aspect, a method for administering a drug that induces long QT syndrome is provided. The methods comprise administering, or instructing to administer, to a subject in need a cardioprotective agent in an amount effective to achieve a physiologic effect to reduce risk of long QT syndrome: and administering, or instructing to administer, a therapeutic agent or salt thereof that causes a prolonged QT interval.

[0097] In an embodiment, administering or instructing to administer the cardioprotective agent occurs before, simultaneous with, or after the administering, or instructing to administer, the therapeutic agent or salt thereof that causes a prolonged QT interval.

[0098] In another aspect, a method for administenng a drug that induces long QT syndrome is provided. The method comprises providing a device comprised of a plurality7of unit doses of a cardioprotective agent and a plurality of unit doses of a therapeutic agent or salt thereof that causes a prolonged QT interval or salt thereof and instructing a subject to self-administer one or more unit doses from the plurality of unit doses of the cardioprotective agent, the unit dose of the cardioprotective agent effective to achieve a physiologic effect to reduce risk of long QT syndrome. The subject is also instructed to self-administer a unit dose from the plurality of unit doses of a therapeutic agent or salt thereof that causes a prolonged QT interval to the subject.

[0099] In embodiments, the methods are for use in treating subjects with a condition or disorder for which the therapeutic agent or salt thereof that causes a prolonged QT interval is prescribed. For example, in embodiments the therapeutic agent or salt thereof that causes a prolonged QT interval is an antibiotic and the subject has a bacterial infection. Inembodiments, the subject has a drug addiction and the therapeutic agent or salt thereof that causes a prolonged QT interval is methadone. In embodiments, the subject is at risk of or is experiencing nausea and / or vomiting, and the therapeutic agent or salt thereof that causes a prolonged QT interval is an anti emetic. In embodiments, the subject has a cardiac disorder and the therapeutic agent or salt thereof that causes a prolonged QT interval is an antiarrhythmic. In embodiments, the subject has a psychotic disorder and the therapeutic agent or salt thereof that causes a prolonged QT interval is an antipsychotic. In embodiments, the psychotic disorder is schizophrenia. In embodiments, the subject has psychotic symptoms in connection with depression or bipolar disorder. In embodiments, the subject has a mood disorder and the therapeutic agent or salt thereof that causes a prolonged QT interval is an antipsychotic. In embodiments, the subject has depression and the therapeutic agent or salt thereof that causes a prolonged QT interval is an antidepressant.IV. Examples

[0100] The following examples are illustrative in nature and are in no way intended to be limiting.EXAMPLE 1METHOD OF REDUCING RISK OF DRUG-INDUCED LONG QT SYNDROME

[0101] A 42-year-old woman with a history of psychiatric disease is taking amitriptyline and haloperidol. She is transferred to a hospital for respiratory distress. An initial ECG shows a QRS duration of 118 msec and a QTCinterval of 610 msec. The subject is given an oral dose of magnesium sulfate and instructed to take magnesium sulfate concurrent with haloperidol. A week after the combination therapy her ECG shows a shorter QTCinterval of 420 msec. The ECGs are illustrated in FIGS. 1A-1B.EXAMPLE 2METHOD OF REDUCING RISK OF DRUG-INDUCED LONG QT SYNDROME

[0102] A 64-year-old male presents with a 2-week history of nausea and poor appetite. The subject currently takes quinidine 200 mg four times daily. An ECG is obtained and shows a baseline QTc interval of 550 msec. The subject is given an oral dose of magnesium sulfate and instructed to take magnesium sulfate concurrent with quinidine. A week after the combination therapy an ECG is obtained and shows a shorter QTCinterval of 310 msec. The ECGs are illustrated in FIGS. 2A-2B.EXAMPLE 3METHOD OF PREVENTING DRUG-INDUCED LONG QT SYNDROME

[0103] A 38-year-old male with depression is prescribed paroxetine and instructed to take it twice daily in combination with 300 mg calcium citrate. One month after taking the combination, an ECG is obtained, and the subject has a QT interval of 368 ms.EXAMPLE 4METHOD OF PREVENTING DRUG-INDUCED LONG QT SYNDROME

[0104] A 43-year-old male with psychosis is prescribed olanzapine and instructed to take 15 mg PO once daily. The patient is instructed to also take orally magnesium sulfate (1030 mg) before or after the olanzapine. One month after taking the combination, an ECG is obtained, and the subject has a QT interval of 350 ms.EXAMPLE 5METHOD OF PREVENTING DRUG-INDUCED LONG QT SYNDROME

[0105] A 48-year-old woman with a history of psychiatric disease is instructed to take amitriptyline, haloperidol and magnesium sulfate. At a first follow-up visit 30 days later, an ECG is obtained and the QTc interval is normal. At another follow-up visit 90 days later, the patient informs her psychiatrist that she ran out of her magnesium prescription two weeks ago. The psychiatrist obtains an ECG and finds that the QTc is prolonged.EXAMPLE 6METHOD OF PREVENTING DRUG-INDUCED LONG QT SYNDROME

[0106] A 56-year-old male with a pre-existing cardiac condition and presenting with schizophrenia is prescribed risperidone. An ECG is obtained for baseline purposes. He is instructed to take 3 mg once per day and prior to or concurrent with the oral risperidone to ingest 1200 mg magnesium sulfate. At a first follow-up visit 30 days later, an ECG is obtained and the QTc interval is normal and essentially unchanged from the baseline ECG.

[0107] While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, permutations, additions and sub-combinations as are within their true spirit and scope.

Claims

IT IS CLAIMED:

1. A method for reducing risk of drug-induced long QT syndrome, comprising: administering, or instructing to administer, to a subject in need a cardioprotective agent in an amount effective to achieve a physiologic effect to reduce risk of long QT syndrome; administering, or instructing to administer, a therapeutic agent or salt thereof that causes a prolonged QT interval.

2. A method for administering a drug that induces long QT syndrome, comprising: administering, or instructing to administer, to a subject in need a cardioprotective agent in an amount effective to achieve a physiologic effect to reduce risk of long QT syndrome; administering, or instructing to administer, a therapeutic agent or salt thereof that causes a prolonged QT interval.

3. The method of claim 1 or claim 2, where administering or instructing to administer the cardioprotective agent is before, simultaneous with, or after the administering, or instructing to administer, the therapeutic agent or salt thereof that causes a prolonged QT interval.

4. A method for administering a drug that induces long QT syndrome, comprising: providing a device comprising a plurality of unit doses of a cardioprotective agent and a plurality of unit doses of a therapeutic agent or salt thereof that causes a prolonged QT interval or salt thereof; instructing a subject to self-administer one or more unit doses from the plurality of unit doses of the cardioprotective agent, the unit dose of the cardioprotective agent effective to achieve a physiologic effect to reduce risk of long QT syndrome; and instructing a subject to self-administer a unit dose from the plurality of unit doses of a therapeutic agent or salt thereof that causes a prolonged QT interval to the subject.

5. A composition, comprising: a dosage form comprising a therapeutic agent or salt thereof that causes a prolonged QT interval and a salt of magnesium, potassium and / or calcium, the saltof magnesium, potassium and / or calcium present in the dosage form in an amount effective to achieve a physiologic effect to reduce risk of a drug-induced long QT syndrome.

6. The composition of claim 5, wherein the dosage form is orally administrable.

7. The method of any one of claims 1-4 or the composition of claim 5 or claim 6. wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is an antibiotic.

8. The method or composition of claim 7, wherein the antibiotic is a fluoroquinolone or a macrolide9. The method of any one of claims 1-4 or the composition of claim 5 or claim 6, wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is methadone.

10. The method of any one of claims 1-4 or the composition of claim 5 or claim 6, wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is an antiarrhythmic.

11. The method of any one of claims 1-4 or the composition of claim 5 or claim 6, wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is an antipsychotic.

12. The method of any one of claims 1-4 or the composition of claim 5 or claim 6, wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is an antiemetic.

13. The method of any one of claims 1-4 or the composition of claim 5 or claim 6, wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is an antidepressant.

14. The method or composition of any preceding claim, wherein the physiologic effect is achieved when the cardioprotective agent is at a threshold concentration in the blood for a period of time, and the therapeutic agent or salt thereof that causes a prolonged QT interval is administered during the period of time.

15. The method or composition of any preceding claim, wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is at a therapeutic concentration in the blood for a treatment period, and the method further comprises administering to the subject a further amount of the cardioprotective agent to achieve a physiologic effect to reduce risk of a long QT syndrome.

16. The method or composition of any preceding claim, wherein the further amount of the cardioprotective agent is administered parenterally or orally.

17. The method or composition of any preceding claim, wherein the method further comprises assessing a baseline QT interval, or receiving information on a baseline QT interval, of the subject prior to administering the cardioprotective agent, after administering the cardioprotective agent, and / or after administering the antipsychotic therapeutic agent or salt thereof.

18. The method or composition of any preceding claim, wherein the cardioprotective agent is administered in an amount effective to achieve a physiologic effect to reduce risk of a drug-induced or acquired long QT syndrome.

19. The method or composition of any preceding claim, wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is not an iboga alkaloid.

20. The method or composition of claim 19, wherein the iboga alkaloid is ibogaine.

21. The method or composition of any preceding claim, wherein the therapeutic agent or salt thereof that causes a prolonged QT interval is administered orally, parenterally or intrathecally.

22. The method of any one of claims 1-4 and claims 7-21, wherein administering, or instructing to administer, the cardioprotective agent comprises orally administering or instructing to orally administer.

23. The method or composition of any preceding claim, wherein the cardioprotective agent is selected from the group consisting of a mineral, a sodium channel blocker (a class IB antiarrhythmic), a potassium channel blocker, an hERG (human ether-a- go-go-related gene) channel agonist, and beta adrenoceptor agonists.

24. The method of claim 23, wherein the sodium channel blocker is selected from the group consisting of mexiletine, tocainide, lidocaine, flecainide, and R-56865 (2- benzothiazolamine, N-(l-(4-(4-fluorophenoxy)butyl)-4-piperidinyl)-N-methyl).

25. The method of claim 23, wherein the potassium channel blocker is not amiodarone.

26. The method of claim 23, wherein the mineral is selected from the group consisting of magnesium, calcium and potassium.

27. The method of claim 26, wherein the mineral is in the form a salt, and wherein said administering or instructing to administer the cardioprotective agent comprises administering or instructing to administer prior to said administering the antipsychotic therapeutic agent or salt thereof.

28. The method of claim 26, wherein the mineral is in the form a salt, and wherein said administering or instructing to administer the cardioprotective agent comprises administering or instructing to administer concurrent with and / or subsequent to said administering the therapeutic agent or salt thereof that induces a long QT interval.

29. The method of claim 23, wherein the hERG channel agonist is selected from the group consisting of RPR260243 ([(3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo- propyl]-l-[3-(2,3,5 trifluorophenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid]), PD-118057 ([2-(4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino)-benzoic acid]), and NS 1643 (N,N'-bis[ 2-hydroxy-5-( trifluoromelhyl) phenyl ]-urea).

30. The method of claim 23, wherein the beta adrenoceptor agonist is isoproterenol.

31. The method or composition of any preceding claim, wherein the cardioprotective agent is (i) not a CYP2D6 inhibitor or (ii) a CYP2D6 inhibitor administered at a dose ineffective to inhibit CYP2D6 or (iii) not amiodarone.

32. The method of or composition of any preceding claim, wherein the cardioprotective agent is a magnesium salt, and wherein said magnesium salt is administered in an amount of between about 50-8000 mg per day.

33. The composition of any one of claims 5-6 and 14-23, wherein the dosage form is a solid.

34. The composition of claim 33, wherein the solid dosage form is for oral ingestion.

35. The composition of any one of claims 33-34, wherein the solid dosage form is selected from the group consisting of a sublingual composition, a buccal composition, a powder, a capsule, a pill, and a tablet.

36. The composition of any one of claims 33Error! Reference source not found.-35, wherein the salt of magnesium, potassium and / or calcium is formulated for immediate release upon oral administration of the dosage form.

37. The composition of any one of claims 33-36, wherein the therapeutic agent or salt thereof that induces a long QT interval is formulated for delayed release after oral administration of the dosage form.

38. The composition of claim 37, wherein a therapeutic agent or salt thereof that induces a long QT interval is formulated for release at least 2 hours after the salt of magnesium, potassium and / or calcium is released from the dosage form.

39. A kit, comprising: a device comprising a plurality’ of unit doses of a cardioprotective agent and a plurality of unit doses of a therapeutic agent or salt thereof that causes a prolonged QT interval; and instructions for use.

40. The kit of claim 39. wherein one or more of the unit doses of cardioprotective agent in the plurality comprise an oral dosage form.

41. The kit of claim 40, wherein the oral dosage form is a solid or a liquid.

42. The kit of claim 41, wherein the solid is selected from the group consisting of a capsule, a pill, a powder and a tablet.

43. The kit according to any one of claims 40-42, wherein the oral dosage form is a powder, and the instructions for use instruct to prepare a solution for ingestion.

44. The kit of claim 41, wherein the unit dose of cardioprotective agent is a liquid selected from the group consisting of an elixir, a syrup, a suspension and a solution.

45. The kit of claim 44, wherein the liquid is formulated for parenteral administration or for nasal administration.

46. The kit of any one of claims 39-45, wherein the unit dose of the therapeutic agent or salt thereof that causes a prolonged QT interval is a solid or a liquid.

47. The kit of claim 46, wherein the unit dose is a solid selected from the group consisting of a capsule, a pill, a powder and a tablet.

48. The kit of claim 46, wherein the unit dose is a liquid selected from the group consisting of an elixir, a syrup, a suspension and a solution.

49. The kit of claim 48, wherein the unit dose is a liquid.

50. The kit of claim 49, wherein the liquid is formulated for parenteral administration or for nasal administration.

51. The kit of claim 50, wherein the unit dose is formulated for oral administration as a liquid selected from the group consisting of an elixir, a syrup, a suspension and a solution.

52. The kit of any one of claims 39-51, wherein the device is a blister pack comprising each unit dose in a separate blister of the blister pack.

53. The kit of any one of claims 39-52, wherein the cardioprotective agent is an electrolyte.

54. The kit of claim 53, wherein the electrolyte is magnesium, potassium or calcium.

55. The kit of any one of claims 39 54, wherein the electrolyte is a salt form of the electrolyte.

56. The kit of claim 55, wherein the electrolyte is a salt form of magnesium selected from the group consisting of magnesium aspartate, magnesium bisglycenate, magnesium carbonate, magnesium chloride, magnesium citrate, magnesium gluconate, magnesium glycinate, magnesium hydroxide, magnesium malate, magnesium oxide, magnesium sulfate, and magnesium taurate.

7. The method, composition or kit of any preceding claim, wherein the cardioprotective agent is a magnesium salt for administration to the subject of at a dose of between about 50-8000 mg.

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