WO2015119938A1 - Pharmaceutical compositions for terminating acute episodes of cardiac arrhythmia, restoring sinus rhythm, preventing recurrence of cardiac arrhythmia, and/or maintaining normal sinus rhythm in mammals - Google Patents

Abstract

A pharmaceutical composition comprising for preventing or treating acute and/or chronic cardiac arrhythmias in an animal comprising an effective amount of 1-[2-[(4-fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylprypyl)piperazine.

Description

Pharmaceutical Compositions for Terminating Acute Episodes of Cardiac Arrhythmia, Restoring Sinus Rhythm, Preventing Recurrence of Cardiac Arrhythmia, and/or

Maintaining Normal Sinus Rhythm in Mammals

FIELD OF THE INVENTION

[0001] The present disclosure relates to pharmaceutical compositions for terminating acute episodes of cardiac arrhythmia, such as atrial fibrillation or ventricular fibrillation, in a mammal, such as a human, particularly pharmaceutical compositions containing .l -[2-[(4- fliiorophenyl)(phenyl)methoxy]ethyl]"4~(3--phenyipiOpyl)piperazine and a pharmaceutically acceptable carrier, The present disclosure also relates to pharmaceutical compositions for maintaining sinus rhythm in a mammal, such as a human, and so preventing a recurrence of an episode of cardiac arrhythmia in that mammal, particularly pharmaceutical compositions containing l-[2-[(4-fluorophenyl)^henyl)methoxyjethy[]-4-(3-phe^ylpxOpyi)piperazme and a pharmaceutically acceptable carrier.

Background of the Related Art

[0002] Atrial flutter and/or atria! fibrillation (AF) are the most commonly sustained cardiac arrhythmias in clinical practice, and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States, While AF^' is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class Ϊ and Class 10 anti- arrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects, including ventricular proarrhythraia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.

[0003] Ventricular fibrillation ( VFj is the most common cause associated with acute myocardial infarction, ischemic coronary artery disease and congestive heart failure. As with AF, current therapy is inadequate and there is a need to develop new therapeutic approaches.

[0004] in view of the problems associated with current anti -arrhythmic agents, there remains a need for an effective treatment of cardiac arrhythmias in mammals, including terminating acute episodes of cardiac arrhythmia, restoring normal sinus rhythm, preventing recurrence of cardiac arrhythmia and/or maintaining normal sinus rhythm.

[0005] Atrial flutter and/or atrial fibrillation (AF) are the most commonly sustained cardiac arrhythmias in clinical practice, and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III anti-arrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects, including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.

[0006] Ventricular fibrillation (VF) is the most common cause associated with acute myocardial infarction, ischemic coronary artery disease and congestive heart failure. As with AF, current therapy is inadequate and there is a need to develop new therapeutic approaches.

[0007] Although various anti-arrhythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained. For example, anti- arrhythmic agents of Class I, according to the classification scheme of Vaughan- Williams ("Classification of antiarrhythmic drugs," Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted- Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp. 449-472 (1981)), which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (V_max) are inadequate for preventing ventricular fibrillation because they shorten the wave length of the cardiac action potential, thereby favoring re-entry. In addition, they have problems regarding safety, i.e. they cause a depression of myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. The CAST (coronary artery suppression trial) study was terminated while in progress because the Class I antagonists had a higher mortality than placebo controls, β-adrenergenic receptor blockers and calcium channel (I_Ca) antagonists, which belong to Class II and Class IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the anti- arrhythmic agents of Class I.

[0008] Anti-arrhythmic agents of Class III are drugs that cause a selective prolongation of the action potential duration (APD) without a significant depression of the maximum upstroke velocity (V_max). They therefore lengthen the save length of the cardiac action potential increasing refractories, thereby antagonizing re-entry. Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh B. N., Vaughan Williams E. M., "A third class of anti- arrhythmic action: effects on atrial and ventricular intracellular potentials and other pharmacological actions on cardiac muscle of MJ 1999 and AH 3747," Br. J. Pharmacol 39:675-689 (1970), and Singh B. N., Vaughan Williams E. M., "The effect of amiodarone, a new anti-anginal drug, on cardiac muscle," Br. J. Pharmacol 39:657-667 (1970)), but these are not selective Class III agents.

[0009] Sotalol also possesses Class II (β-adrenergic blocking) effects which may cause cardiac depression and is contraindicated in certain susceptible patients.

[0010] Amiodarone also is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects.

(Nademanee, K., "The Amiodarone Odyssey," J. Am. Coll. Cardiol. 20: 1063-1065 (1992)) Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I antiarrhythmic agents.

[0011] Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration (APD). Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na+ or Ca + currents; hereinafter I_NA and I_CA, respectively) or by reducing outward repolarizing potassium K+ currents. The delayed rectifier (I_K) + current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (I_TO) and inward rectifier (I_Ki) K+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively.

[0012] Cellular electrophysiologic studies have demonstrated that I_K consists of two pharmacologically and kinetically distinct K+ current subtypes, Ι_& (rapidly activating and deactivating) and I_Ks (slowly activating and deactivating). (Sanguinetti and Jurkiewicz, "Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by Class III anti-arrhythmic agents," / Gen Physiol 96: 195-215 (1990)). iKr is also the product of the human ether-a-go-go gene (hERG). Expression of hERG cDNA in cell lines leads to production of the hERG current which is almost identical to I_& (Curran et al., "A molecular basis for cardiac arrhythmia: hERG mutations cause long QT syndrome," Cell 80(5):795-803 (1995)).

[0013] Class III anti-arrhythmic agents currently in development, including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide--N--[l'-6- cyano-l,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-l-benzopyran-2, 4'- piperidin]-6yl], (+)-, monochloride (MK-499) predominantly, if not exclusively, block Ικ_τ·

Although, amiodarone is a blocker of I_Ks (Balser J. R. Bennett, P. B., Hondeghem, L. M. and Roden, D. M. "Suppression of time-dependent outward current in guinea pig ventricular myocytes: Actions of quinidine and amiodarone," Circ. Res. 69:519-529 (1991)), it also blocks i a and lea, effects thyroid function, is as a nonspecific adrenergic blocker, acts as an inhibitor of the enzyme phospholipase, and causes pulmonary fibrosis (Nademanee, K. "The Amiodarone Odessey". J. Am. Coll. Cardiol. 20: 1063-1065 (1992)).

[0014] Reentrant excitation (reentry) has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man. Reentrant excitation requires a critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF. Increasing myocardial refractoriness by prolonging APD prevents and/or terminates reentrant arrhythmias. Most selective, Class III antiarrhythmic agents currently in development, such as d- sotalol and dofetilide predominantly, if not exclusively, block Ικ_τ, the rapidly activating component of I_K found both in atrium and ventricle in man.

[0015] Since these Ικ_τ blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias like AF and VF. These agents have a liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsade de pointes, a specific type of polymorphic ventricular tachycardia which is commonly associated with excessive prolongation of the electrocardiographic QT interval, hence termed "acquired long QT syndrome," has been observed when these compounds are utilized (Roden, D. M. "Current Status of Class III Antiarrhythmic Drug Therapy," Am J. Cardiol, 72:44B-49B (1993)). The exaggerated effect at slow heart rates has been termed "reverse frequency-dependence" and is in contrast to frequency-independent or frequency-dependent actions. (Hondeghem, L. M., "Development of Class III Antiarrhythmic Agents," J. Cardiovasc. Cardiol. 20 (Suppl. 2):S 17- S22). The pro-arrhythmic tendency led to suspension of the SWORD trial when d-sotalol had a higher mortality than placebo controls.

[0016] The slowly activating component of the delayed rectifier (I_KS) potentially overcomes some of the limitations of I& blockers associated with ventricular arrhythmias.

Because of its slow activation kinetics, however, the role of IK_s in atrial repolarization may be limited due to the relatively short APD of the atrium. Consequently, although I_KS blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect supraventricular tachyarrhythmias (SVT) is considered to be minimal.

[0017] Another major defect or limitation of most currently available Class III antiarrhythmic agents is that their effect increases or becomes more manifest at or during

bradycardia or slow heart rates, and this contributes to their potential for proarrhythmia. On the other hand, during tachycardia or the conditions for which these agents or drugs are intended and most needed, they lose most of their effect. This loss or diminishment of effect at fast heart rates has been termed "reverse use-dependence" (Hondeghem and Snyders, "Class III antiarrhythmic agents have a lot of potential but a long way to go: Reduced effectiveness and dangers of reverse use dependence," Circulation, 81 :686-690 (1990); Sadanaga et al. , "Clinical evaluation of the use-dependent QRS prolongation and the reverse use-dependent QT prolongation of class III anti-arrhythmic agents and their value in predicting efficacy," Amer. Heart Journal 126: 114- 121 (1993)), or "reverse rate-dependence" (Bretano, "Rate dependence of class III actions in the heart," Fundam. Clin. Pharmacol. 7:51-59 (1993); Jurkiewicz and Sanguinetti, "Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III anti- arrhythmic agent: Specific block of rapidly activating delayed rectifier K+current by dofetilide," Circ. Res. 72:75-83 (1993)). Thus, an agent that has a use-dependent or rate-dependent profile, opposite that possessed by most current class III anti- arrhythmic agents, should provide not only improved safety but also enhanced efficacy. [0018] Vanoxerine ( 1 -[2- [bis(4-fluorophenyl)methoxy] ethyl] -4-(3- phenylpropyl)piperazine), its manufacture and/or certain pharmaceutical uses thereof are described in U.S. Patent No. 4,202,896, U.S. Patent No. 4,476,129, U.S. Patent No. 4,874,765, U.S. Patent No. 6,743,797 and U.S. Patent No. 7,700,600, as well as European Patent EP 243,903 and PCT International Application WO 91/01732.

[0019] Vanoxerine has been used for treating cocaine addiction, acute effects of cocaine, and cocaine cravings in mammals, as well as dopamine agonists for the treatment of

Parkinsonism, acromegaly, hyperprolactinemia and diseases arising from a hypofunction of the dopaminergic system. (See U.S. Patent No. 4,202,896 and WO 91/01732.) Vanoxerine has also been used for treating and preventing cardiac arrhythmia in mammals. (See U.S. Patent No. 6,743,797 and U.S. Patent No. 7,700,600.).

[0020] Studies have looked at the safety profile of vanoxerine and stated that no side- effects should be expected with a daily repetitive dose of 50 mg of vanoxerine. U. Sogaard, et al., International Clinical Psychopharmacology, "A Tolerance Study of Single and Multiple Dosing of the Selective Dopamine Uptake Inhibitor GBR 12909 in Healthy Subjects," 5:237-251 (1990). However, Sogaard, et al. also found that upon administration of higher doses, some effects were seen with regard to concentration difficulties, increase systolic blood pressure, asthenia, and a feeling of drug influence, among other effects. Sogaard, et al. also recognized that there were unexpected fluctuations in serum concentrations with regard to these healthy patients. While they did not determine the reasoning, control of such fluctuations may be important to treatment of patients.

[0021] Prior studies have been performed using single dose administration of flecainide or propafenone in terminating atrial fibrillation. Particular studies investigated the ability to provide patients with a known dose of one of the two drugs so as to self-medicate should cardiac arrhythmia occur. P. Alboni, et al. "Outpatient Treatment of Recent-Onset Atrial Fibrillation with the 'Pill-in-the-Pocket' Approach," NEJM 351; 23 (2004); L. Zhou, et al. "Ά Pill in the Pocket' Approach for Recent Onset Atrial Fibrillation in a Selected Patient Group," Proceedings of UCLA Healthcare 15 (2011). However, the use of flecainide and propafenone have been criticized as including candidates having structural heart disease and thus providing patients likely to have risk factors for stroke and should have received antithrombotic therapy, instead of the flecainide or propafenone. NEJM 352: 11 (Letters to the Editor) (March 17, 2005).

[0022] Further studies have looked at the ability of food to lower the first-pass metabolism of lipophilic basic drugs, such as vanoxerine. S.H. Ingwersen, et al. "Food intake increases the relative oral bioavailability of vanoxerine" Br. J. Clin. Pharmac; 35:308-130 (1993). However, no methods have been utilized or identified for treatment of cardiac arrhythmias in conjunction with the modulating effects of food intake.

[0023] Further, studies have questioned the safety of treatment of propafenone with concurrent use of warfarin, a drug frequently administered as an anti-coagulant, to patients with risk for blood clots, among other disease. These same patients also have some risk for experiencing cardiac arrhythmias.

[0024] Accordingly, in view of the known issues with Vanoxerine, it is necessary to identify new and novel approaches to treating cardiac arrhythmias and to identify compounds and compositions suitable for inhibiting hERG current in mammalian cells.

BRIEF DESCRIPTION OF THE FIGURE

[0025] FIG. 1 depicts a concentration-response relationship of MFV (CV-8282) on hERG current.

SUMMARY OF THE INVENTION

[0026] it is therefore an object of the present disclosure to provide pharmaceutical compositions for and methods of preventing or treating acute and/or chronic cardiac arrhythmias in a mammal, including terminating acute episodes of cardiac arrhythmia, restoring normal sinus rhythm, preventing recurrence of cardiac arrhythmia and/or maintaining normal sinus rhythm. Other objects, features and advantages of the invention will be set forth in the detailed description of preferred embodiments that follows, and in part will be apparent from the description or may be learned by practice of the invention. These objects and advantages of the invention will be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof. [0027] in accordance with these and other objects, the present disclosure provides a pharmaceutical composition which contains l.-[2-[(4-fluorophenyl)(phenyl).methoxy]ethyl3-4-(3- phenylpropyl)piperazine, and/or pharmaceutically acceptable salts and/or solvates thereof. In addition, the pharmaceutical composition optionally further contains vanoxerine and/or pharmaceutically acceptable salts and/or solvates thereof.

[0028] in another embodiment of the present disclosure, a method is provided for treating acute and/or chronic cardiac arrhythmias in a mammal which comprises administering an effective amount of l.-[2-iX4-fluox phenyi)(pheny])methoxy]ethyl3-4-(3-phenylpropyl)piperaziiie and/or pharmaceutically acceptable salts and/or solvates thereof.

[0029] In yet another embodiment of the present disclosure, a method is provided for terminating acute episodes of cardiac arrhythmia in a mammal which comprises administering an effective amount of l--[2-[(4-fluorophenyl)(phenyl)methoxy]ethy!]-4--(3- phenylpropyl)piperazine and/or pharmaceutically acceptable salts and/or solvates thereof.

[0030] In yet another embodiment of the present disclosure, a method is provided for restoring normal sinus rhythm in a mammal which comprises administering an effective amount of l-[2-[(4-fluorophenyl)(phenyl)meu¾oxy]eu¾yl]-4-(3-phenylpropyl)piperazine and/or pharmaceutically acceptable salts and/or solvates thereof.

[0031] In yet another embodiment of the present disclosure, a method is provided for preventing recurrence of cardiac arrhythmia in a mammal which comprises administering an effective amount of l-[2-[(4-fluorophenyl)(phen)d)methoxy]ethyl]- -(3- phenylpropyijpiperazine and/or pharmaceutically acceptable salts and/or solvates thereof.

[0032] In yet another embodiment of the present disclosure, a method is provided for maintaining normal sinus rhythm in a mammal that has previously experience at least one episode of cardiac arrhythmia which comprises administering an effective amount of .l -[2-i(4- fluorophenyl)(phenyl)methoxy]etiiyl]-4"(3-phenylpropyl)piperazine and/or pharmaceutically acceptable salts and/or solvates thereof,

[0033] In yet another embodiment of the present disclosure includes pharmaceutical compositions which contain about 99.0% to about 99.9% of I- [2- [(4- fluoropheny!)(phenyl)raethoxy]etiiyl]-4"(3-phenylpropyl)piperazine, and/or pharmaceutically acceptable salts and/or solvates thereof, and about 0, 1% to about 1 .0% of G BR] 2909 and/or pharmaceutically acceptable salts and/or solvates thereof.

[0034] In yet another embodiment of the present disclosure includes a method for treating acute and/or chronic cardiac arrhythmias in a mammal which comprises administering an effective amount of a composition comprising about 90.0% to about 99.9%· of i-[2-[(4- fluorophenyl)(phenyi)memoxy3emyl]-4-(3-phenylpropyl)piperazine and about 0.1% to about .10.0% of G BR] 2909, and/or pharmaceutically acceptable salts and/or solvates of one or both thereof.

[0035] In yet another embodiment of the present disclosure includes a method for terminating acute episodes of cardiac arrhythmia in a mammal which comprises administering an effective amount of a composition comprising about 50,1% to about 99.9% of i-[2-[(4- fluorophenyl)(phenyl)memoxy]emyl3-4-(3-phenylpropyl)piperazine and about 0.1% to about 49,9%' of G BR12909, and/or pharmaceutically acceptable salts and/or solvates thereof.

[0036] In yet another embodiment of the present disclosure includes a method for restoring normal sinus rhythm in a mammal which comprises administering an effective amount of a composition comprising about 90,0% to 99.9% of l-[2-[(4- fluorophenyl)(phenyl)methoxy]etliyl]-4"(3-phenylpropyl)piperazine and about 0.1 % to about .10.0% of GBR 12909, and/or pharmaceutically acceptable salts and/or solvates thereof.

[0037] In yet another embodiment of the present disclosure Includes a .method for preventing recurrence of cardiac arrhythmia in a mammal which comprises administering an effective amount of composition comprising about 75.0% to about 99,9% of l-[2-[(4- fluorophenyl){phenyl.)methoxy]e yl]-4-(3-phenylpropyl)piperazine and about 0.1 % to about 25% of GBRI2909, and/or pharmaceutically acceptable salts and/or solvates thereof.

[0038] in yet another embodiment of the present disclosure includes a method for maintaining normal sinus rhythm in a mammal that has previously experience at least one episode of cardiac arrhythmia which comprises administering an effective amount of a composition comprising about 50.0% of l-[2-i(4-fl.uorophenyl)(phenyl)mefhoxy]ethyl]-4-(3- phenylpropy!)piperazine and about 50.0% of GBR12909, and/or pharmaceutically acceptable salts and/or solvates thereof.

[0039] A pharmaceutical composition comprising and effective amount of l-[2-[(4- fliiorophenyl)(phenyl)methoxy]ethyl]--4~(3--phenyipiOpyl)piperazine to initiate between about 48% and about 99% inhibition of hERG current in a mammalian cell.

[0040] A pharmaceutical composition comprising and effective amount of l-[2-[(4- fluox pheny]){pheny].)methoxy]etliyl]-4-(3-phenylpropyl)piperazine to initiate between about 48% and about 64% inhibition of hERG current in a mammalian cell.

[0041] A pharmaceutical composition comprising and effective amount of !--[2--[(4- f1viorophei\yl)(phenyl)methoxy]ethyl -4-(3-phenylpropyl)piperazine to initiate between about 84% and about 93% inhibition of hERG current in a mammalian cell.

[0042] A pharmaceutical composition comprising and effective amount of l-[2--[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenyIpiOpyl)piperazine to initiate more than about 99% inhibition of hERG current in a mammalian cell.

[0043] A method for treatment of acute and/or chronic cardiac arrhythmias, for restoring normal sinus rhythm, for maintaining normal sinus rhythm, or for preventing recurrence of cardiac arrhythmia in a mammal comprising administering to a mammal an effective amount of

!-[2"[(4-fiuorophenyi)(phenyl)methoxy]ethyl]-4--(3--phenylpropyl)piperazine to inhibit hERG current of at least about 99% n a cell of said mammal,

[0044] in yet another embodiment of the present disclosure, an article of manufacture is provided which comprises a package having deposited thereon a label describing the contents of the package and having deposited therein a pharmaceutical composition as described above in a suitable dosage form.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0045] All references cited herein are hereby incorporated by reference in their entirety. [0046] As used herein, the singular forms "a," "an," and "the" include the jural reference unless the context clearly dictates otherwise,

[0047] As used herein, the term "about" is intended to encompass a range of values

+10% of the specified value(s). For example, the phrase "about 20" is intended to encompass +10% of 20, i.e. from 18 to 22, inclusive.

[0048] As used herein, the term "consisting essentially of is intended to mean the specified materials and those that do not materially affect the basic and novel characteristics of the claimed invention.

[0049] As used herein, the terms "vanoxerine" and "GBR 12909" refer to the compound,

1-[2-|¾is(4-:fluorophenyl)me^ and pharmaceutically acceptable salts thereof.

[0050] As used herein, the term "MFV" refers to the compound !--[2--[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenyIpiOpyl)piperazine having the follow structure:

[0051] As used herein, the term "pharmaceutically acceptable" refers to those

compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of and/or for consumption by human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.

[0052] As used herein, the term "subject" refers to a warm blooded animal such as a mammal, preferably a human or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and conditions described herein. [0053] As used herein, "therapeutically effective amount" refers to an amount which is effective in reducing, eliminating, treating, preventing or controlling the symptoms of the herein- described diseases and conditions. The term "controlling" is intended to refer to all processes wherein there may be a slowing, interrupting, arresting, or stopping of the progression of the diseases and conditions described herein, but does not necessarily indicate a total elimination of all disease and condition symptoms, and is intended to include prophylactic treatment.

[0054] As used herein, "unit dose" means a single dose which is capable of being administered to a subject, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either vanoxerine or a pharmaceutically acceptable composition comprising vanoxerine.

[0055] As used herein, "administering" or "administer" refers to the actions of a medical processional or caregiver, or alternatively self-administration by the patient.

[0056] Treatment and control of symptoms of cardiac arrhythmia, including Atrial fibrillation and atrial flutter, among others, has been achieved through the administration of vanoxerine. Control and prevention of events of cardiac arrhythmia are important to these patients to prevent future recurrences and the deleterious effects and morbidity. One issue is that cardiac arrhythmia is a progressive disease and patients who suffer from a first cardiac arrhythmia are pre-disposed to suffering from additional episodes of cardiac arrhythmia. Any cardiac arrhythmia involves risk with regard to mortality and morbidity, and so terminating the cardiac arrhythmia in a timely and safe manner is a critical need for these patients.

[0057] In seeking to control cardiac arrhythmias, some studies have also questioned whether sustained, and/or chronic use of vanoxerine is suitable for mammalian patients.

Preliminary studies have suggested that daily use of a drug over seven, 10, and 14 days leads to increase heart rate and systolic blood pressure when taking concentrations of 75, 100, 125, and 150 mg of vanoxerine a day.

[0058] Applicants have discovered that MFV is a strong-inhibitor of hERG ion-channels and provides a mechanism for treatment of cardiac arrhythmias. Accordingly, pharmaceutical compositions comprising MFV are suitable for use in the treatment of cardiac arrhythmias, and in the prevention of future cardiac arrhythmias and in the maintenance of sinus rhythm in individuals suffering from cardiac arrhythmia or susceptible to cardiac arrhythmia.

[0059] In preparation of suitable pharmaceutical compositions, it is appropriate to generate pharmaceutically acceptable salts and/or solvates MFV and/or GBR 12909 may be utilized in various embodiments described herein. In some embodiments, combination compositions comprising MFV and GBR 12909, the salt of MFV may be different than the salt utilized for GBR12909,

[0060] The pharmaceutically acceptable salts which may be used include, but are not limited to, salts formed from non-toxic inorganic or organic acids. For example,

pharmaceutically acceptable salts include, but are not limited to, the following; salts derived from inorganic acids, such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; salts derived from organic acids, such as acetic, propionic, succinic, glyeolic, stearic, lactic, malic, tartaric, citric, ascorbic, panioie, nialeic, hydroxymaleic, phenylacetic, benzoic, salicylic, sulfanilic, 2-aeetoxy- benzoic, fumaric, toluenesulfonic, methanes ulibnic, ethane disulfonic, oxalic, isethionic, tritluoroacetic and the like; and salts derived from amino acids, such as glutamic acid or asparric acid.

[0061] The pharmaceu tically acceptable sails useful in the compositions and methods of the particular embodiments described herein can be synthesized from the parent compound by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-formins inorganic or organic acid in a suitable solvent or various combinations of sol ents.

[0062] When employed in the present methods, an effective amount M FV or a pharmaceutically acceptable salt and/or solvate thereof, may be administered by any technique capable of introducing pharmaceutically active agent(s) to a. desired site of action, including, but not limited to, buccal, sublingual, nasal, oral, topical, rectal and parenteral administration.

Delivery of the compound may also be through the use of controlled release formulations in subcutaneous implants or transdermal patches. [0063] When employed in the present methods, an effective amount of a combination of

MFV and GBR 12909, or a phamiaceuticaliv acceptable salt and/or solvate of one or both thereof, may be administered by any technique capable of introducing pharmaceutically active agent(s) to a desired site of action, including, but not limited to, buccal, sublingual, nasal, oral, topical, rectal and parenteral admi istration. Delivery of the compound may also be through the use of controlled release formulations in subcutaneous implants or transdermal patches.

[0064] Suitable doses of MFV and GBR12909, or a pharmaceutically acceptable salt and/or solvate of one or both thereof, may be determined empirically by one skilled in the art depending upon such factors as the particular cardiac arrhythmias being treated (e.g. chronic or acute, atrial fibrillation or ventricular fibrillation, etc.), the species of mammal being treated (e.g. human), the physical characteristics of the mammal being treated (e.g. sex, weight, age, other physiological conditions, etc) and the particular mode of administration being employed (e.g. oral, parenteral, etc.). In certain preferred embodiments, suitable amounts of the active pharmaceutical ingredient or ingredients are about 1 to 1000 mg in a given dose. Other preferred embodiments are about 25 to 800 mg, 50 to 500 mg, 50 to 400 mg, 50 to 300 mg, and 100 to 200 mg.

[0065] it is also suitable to determine the amount of either MFV or a combination product comprising MFV and GBR 12909 wherein the dose of the active pharmaceutical ingredient or ingredients is determined based on about 1 to about 10 mg/kg of the subject for administration of the pharmace tical composition. It is also suitable for administration of about 1 to about 5 mg/kg or about 2 to about 5 mg/kg.

[0066] According to certain preferred embodiments, pharmaceutical compositions contain a combination, exclusive of any excipients or carriers or other active agents, of from 0.01% to 1 % of GBR 12909 and from 99% to 99.99% of MFV^".

[0067] More preferably, pharmaceutical compositions of preferred embodiments contain a combination composition containing from 0.05% to 1.0% of GBR 12909 and even more preferably from 0.1 % to 1.0% of GBR 12909 and contain about 99,95% to 99.0% of MFV, or about 99.0% to about 99.9% MFV. [0068] In certain preferred embodiments, a pharmaceutical composition is consisting essentially of MFV, GBR12909 and a diluent, a binder, a disintegrant, a flowing agent, and a lubricant.

[0069] In other preferred embodiments, a pharmaceutical composition suitable for administration to a human for treatment of cardiac arrhythmias or for maintenance or restoration of normal sinus rhythm consists of about 90.0% to 99.9% of MFV and about 0.1% to about 10.0% of GBR12909.

[0070] In other preferred embodiments, a pharmaceutical composition suitable for administration to a human for treatment of cardiac arrhythmias or for maintenance or restoration of normal sinus rhythm consists of about 75.0% to 90.0% of MFV and about 10.0% to about 25.0% of GBR12909.

[0071] In other preferred embodiments, a pharmaceutical composition suitable for administration to a human for treatment of cardiac arrhythmias or for maintenance or restoration of normal sinus rhythm consists of about 50.1% to 75.0% of MFV and about 25.0% to about 49.9% of GBR12909.

[0072] hi preferred embodiments, a combination containing MFV and GBR.12909 generally comprises from about 20-50% by weight of the pharmaceutical composition, more preferably from about 25-40% and most preferably from about 30-35%,

[0073] In manufacturing a pharmaceutical composition comprising MFV or a

combination of MFV and GBR12909, the active ingredients may be optionally combined with one or more excipients, such as those pharmaceutically acceptable diluents, disintegrants, binders and lubricants known and available to those skilled in the art. Preferably, the excipients meet the standards of the National Formulary ("NF") and/or United States Pharmacopoeia ("USP"). In a particular preferred embodiment, there is provided a pharmaceutical composition comprising vanoxerine with one or more diluents, disintegrants, binders and/or lubricants.

[0074] The excipients are selected to ensure the delivery of a consistent amount of vanoxerine and to maintain plasma levels of the vanoxerine, in a convenient unit dosage form and to optimize the cost, ease and reliability of the manufacturing process. All excipients must be inert, organoleptically acceptable, and compatible with vanoxerine. The excipients used in a solid oral formulation commonly include fillers or diluents, binders, disintegrants, lubricants, antiadherents, glidants, wetting and surface active agents, colors and pigments, flavoring agents, sweeteners, adsorbents, and taste-maskers.

[0075] Preferably, the inventive compositions also comprise; a diluent, such as lactose monohydrate; a binder, such as macrocrystalline cellulose; a disintegrant, such as cross-linked sodium carboxymethyl cellulose; a flowing agent, such as colloidal silicon dioxide; and a lubricant, such as magnesium stearate. Suitable amounts of each excipient may be determined empirically by one skilled in the art considering such factors as the particular mode of administration (e.g. oral, sublingual, buccal, etc.), amount of active ingredient {e.g. 50 mg, 60 mg, 80 mg, 100 mg, 150 mg, etc.), particular patient (e.g. adult human, human child, etc.) and dosing regimen (e.g. once a day, twice a day, etc.).

[0076] In yet another embodiment of the present disclosure, an article of manufacture is provided which comprises a package having deposited thereon a label describing the contents of the package and having deposited therein one or more unit doses of a pharmaceutical composition as described above in a suitable form.

[0077] For oral administration, a suitable pharmaceutical composition may be prepared in the form of tablets, dragees, capsules, syrups and aqueous or oil suspensions. The inert ingredients used in the preparation of these compositions are known in the art. For example, tablets may be prepared by mixing the active compound with an inert diluent, such as lactose or calcium phosphate, in the presence of a disintegrating agent, such as potato starch or

microcrystailine cel lulose, and a lubricating agent, such as magnesium stearate or talc, and then tableting the mixture by known methods.

[0078] For the preparation of capsules or caplets, a mixture of MFV or MFV and

GBR 12909 and the desired additives may be filled into a capsule, such as a hard or soft gelatin capsule. The contents of a capsule and/or caplet may also be formulated using known methods to give sustained release of the active compound. [0079] Liquid oral dosage forms may be an elixir, suspension and/or syrup, where the compound is mixed with a non-toxic suspending agent. Liquid oral dosage forms may also comprise one or more sweetening agent, flavoring agent, preservative and/or mixture thereof.

[0080] For rectal administration, a suitable composition may be prepared in the form of a suppository, In addition to the active ingredient, the suppository may contain a suppository mass commonly used in pharmaceutical practice, such as Tbeobroma oil, glyeermated gelatin or a high molecular weight polyethylene glycol,

[0081] For parenteral administration, a suitable composition may be prepared in the form of an injectable solution or suspension. For the preparation of injectable solutions or suspensions, the active ingredients can be dissolved in aqueous or non-aqueous isotonic sterile injection solutions or suspensions, such as glycol ethers, or optionally in the presence of solubilizing agents such as polyoxyethylene sorbitan monola rate, raonooleate or monostearate. These solutions or suspension may be prepared from sterile powders or granules having one or more carriers or diluents mentioned for use in the formulations for oral administration. Parenteral administration may be through intravenous, intradermal, intramuscular or subcutaneous injections,

[0082] A composition comprising MFV or MFV and GBR 12909 may also be

administered nasally, for example by sprays, aerosols, nebulised solutions and/or powders.

Metered dose systems known to those in the art may also be used.

[0083] Pharmaceutical compositions may be administered to the buccal cavity (for example, sublingual].}') in known pharmaceutical forms for such administration, such as slo dissolving tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/or powders,

[0084] MFV or a combination of MFV and GBR.1.2909 may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a. source of the compound placed within the body. Internal sources include implanted reservoirs which continuously release active(s) by osmosis and implants which may be (a) liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound(s) to be infused for example in the form of a very sparingly water -soluble derivative such as a dodecanoate salt or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused. The support may be a single body containing all the compound or a series of several bodies each containing part of the compounds to be delivered. The amount of active should be such that a therapeutically effective amount is delivered over a long period of time.

[0085] In addition, an injectable solution of MFV or combinations of MFV and

GBRI2909 can contain various additives such as preservatives, such as benzyl alcohol, methyl or propyl 4-· hydroxybenzoate, benzalkonium chloride, phenylmercury borate and the like; as well as antioxidants, such as ascorbic acid, tocopherol, sodium pyrosulfate and optionally complex forming agents, such as an ethylenedi amine tetraacetate salt for binding the metal traces, as well as buffers for adjusting the pH value and optionally a local anaesthetizing agent, e.g. iidocaine. The injectable solution is filtered before fil ling into the ampule and sterilized after filling,

[0086] Tablets may also be formulated in a manner known in the art so as to give a sustained release of MFV and GBR 12909. Such tablets may, if desired, he provided with enteric coatings by known method, for example by the use of cellulose acetate phthaiate. Suitable binding or granulating agents are e.g. gelatine, sodium carboxymethylceUulose, methylcellulose, polyvinylpyrrolidone or starch gum. Talc, colloidal silicic acid, stearin as well as calcium and magnesium stearate or the like can he used as anti-adhesive and gliding agents,

[0087] Tablets may also be prepared by wet granulation and subsequent compression, A mixture containing MFV and GBR12909 and, at least one diluent, and optionally a part of the disintegrating agent, is granulated together with an aqueous, ethanolic or aqueous-ethanolic solution of the binding agents in an appropriate equipment, then the granulate is dried.

Thereafter, other preservative, surface acting, dispersing, disintegrating, gliding and anti- adhesive additives can be mixed to the dried granulate and the mixture can be compressed to tablets or capsules,

[0088] The tablets may also be prepared by the direct compression of the mixture containing the active ingredients together with the needed additives, If desired, the tablets may be transformed to dragees by using protective, flavoring and dyeing agents such as sugar, cellulose derivatives (methyl- or ethylcellulose or sodium carboxymethylcellulose),

polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, aromatizing agents, iron oxide pigments and the like which are commonly used in the phannaceutical industry.

[0089] Diluents are typically added to a small amount of the active drug to increase the size of the tablet. A suitable diluent for use in the inventive compositions is lactose, which exists in two isomeric forms, alpha-lactose or beta-lactose, and can be either crystalline or amorphous. Various types of lactose include spray dried lactose monohydrate (such as Super-Tab™), alpha- lactose monohydrate (such as Fast Flo®), anhydrous alpha-lactose, anhydrous beta-lactose, and agglomerated lactose. Other diluents include sugars, such as compressible sugar NF, dextrose excipient NF, and dextrates NF. A preferred diluent is lactose monohydrate (such as Fast Flo®). Other preferred diluents include microcrystalline cellulose (such as Avicel® PH, and Ceolus™), and microfine cellulose (such as Elcema®).

[0090] Suitable diluents also include starch and starch derivatives. Starches include native starches obtained from wheat, corn, rice and potatoes. Other starches include

pregelatinized starch NF, and sodium starch glycolate NF. Starches and starch derivatives can also function as disintegrants. Other diluents include inorganic salts, including, but not limited to, dibasic calcium phosphate USP (such as Di-Tab® and Emcompress®), tribasic calcium phosphate NF (such as Tri-Tab® and Tri-Cafos®), and calcium sulfate NF (such as

Compactrol®). Polyols such as mannitol, sorbitol, and xylitol may also serve as diluents. Many diluents can also function both as disintegrants and as binders, and these additional properties should be taken into account when developing particular formulations.

[0091] Disintegrants may be included to break larger particles, such as tablets, granules, beads, nonpareils and/or dragees, into smaller particles comprising the active pharmaceutical ingredient and, optionally, other excipients which may facilitate dissolution of the active ingredient and/or enhance bioavailability of the active ingredient. Starch and starch derivatives, including cross-linked sodium salt of a carboxymethyl ether of starch (such as sodium starch glycolate NF, Explotab®, and Primogel®) are useful disintegrants. A preferred disintegrant is cross-linked sodium carboxymethyl cellulose (such as Croscarmellose Sodium NF, Ac-Di- Sol®). Other suitable disintegrants include, but are not limited to, cross-linked

polyvinylpyrrolidone (such as Crospovidone NF) and microcrystalline cellulose (such as Avicel® PH).

[0092] Binders may also be used as an excipient, particularly during wet granulation processes, to agglomerate the active pharmaceutical ingredient and the other excipients. In all formulation, whether prepared by wet or dry granulation, a particular binder is generally selected to improve powder flow and/or to improve compactibility. Suitable binders include, but are not limited to, cellulose derivatives, such as microcrystalline cellulose NF, methylcellulose USP, carboxymethycellulose sodium USP, hydroxypropyl methylcellulose USP, hydroxyethyl cellulose NF, and hydroxypropyl cellulose NF. Other suitable binders include polyvidone, polyvinyl pyrrolidone, gelatin NF, natural gums (such as acacia, tragacanth, guar, and pectin), starch paste, pregelatinized starch NF, sucrose NF, corn syrup, polyethylene glycols, sodium alginate, ammonium calcium alginate, magnesium aluminum silicate and polyethylene glycols.

[0093] Lubricants may be used, particularly in tablet formulations, to prevent sticking of the ingredients and/or dosage form to the punch faces and to reduce friction during the compression stages. Suitable lubricants include, but are not limited to, vegetable oils (such as corn oil), mineral oils, polyethylene glycols (such as PEG-4000 and PEG-6000), salts of stearic acid (such as calcium stearate and sodium stearyl fumarate), mineral salts (such as talc), inorganic salts (such as sodium chloride), organic salts (such as sodium benzoate, sodium acetate, and sodium oleate) and polyvinyl alcohols. A preferred lubricant is magnesium stearate.

EXAMPLES

[0094] The materials, methods, and examples presented herein are intended to be illustrative, and not to be construed as limiting the scope or content of the invention. Unless otherwise defined, all technical and scientific terms are intended to have their art-recognized meanings.

[0095] The objective of this study was to examine the in vitro effects of MFV (CV-8282) on the hERG (human ether-a-go-go-related gene) ion channel expressed in mammalian cells. The objective of this study was to examine the in vitro effects of a metabolite of vanoxerine, MFV (CV-8282), on the hERG (human ether-a-go-go related gene) channel, a surrogate for IKr, the rapidly activating, delayed rectifier cardiac potassium current in human heart, expressed in human embryonic kidney (HEK293) cells.

[0096] Test Article

• Test Article ID: MFV, fumaric acid salt

• Product Number: CV-8282

• Lot / Reference Number: 220RM 153

• Molecular Weight: 548.0 g/mol

• Purity: 97.9%

• Storage Conditions (bulk): Room Temperature

• Carrier: Sterile Water for Injection, USP

[0097] Initial testing was performed at 1 μΜ. Based on the results of initial testing, additional testing was conducted at 0.01, 0.03 and 0.1 μΜ.

[0098] Formulations: Chemicals used in solution preparation were of ACS reagent grade purity or higher. Stock solutions of the test article were prepared in sterile water and stored frozen. Test article concentrations were prepared fresh daily into appropriate vehicle control solutions.

[0099] Vehicle Control: Test article concentrations were prepared fresh daily by diluting stock solutions into HEPES -buffered physiological saline (HB-PS) solution (composition in mM): NaCl, 137; KCl, 4.0; CaC12, 1.8; MgC12, 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with NaOH (stored refrigerated).

[00100] HEK/hERG:

• Organism: Homo sapiens

• Designation: 293

• Tissue: Kidney; Transformed with adenovirus 5 DNA;

• Transfected with human-ether-a-go-go cDNA

• Morphology: Epithelial

• Age Stage: Embryo

• Source Strain: ATCC, Manassas, VA [00101] HEK293 Culture Procedures: HEK293 cells were stably transfected with the appropriate ion channel cDNA encoding the pore-forming channel subunit. Stable transfectants were selected using the G418-resistance gene incorporated into the expression plasmid. Selection pressure was maintained with G418 in the culture medium. Cells were cultured in Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 (D-MEM/F-12) supplemented with 10% fetal bovine serum, 100 U/mL penicillin G sodium, 100μg/mL streptomycin sulfate and 500 μg/mL G418.

[00102] Treatment Groups: All experiments were performed at room temperature. Each cell acted as its own control. Four concentrations were selected to evaluate the concentration- response relationship. Each concentration as tested in at least three cells (n > 3).

[00103] Electrophysiology: Cells were transferred to the recording chamber and superfused with vehicle control solution. Pipette solution for whole cell patch clamp recordings was composed of (mM): potassium aspartate, 130; MgC12, 5; EGTA, 5; ATP, 4; HEPES, 10; pH adjusted to 7.2 with KOH. Pipette solution was prepared in batches, aliquoted, stored frozen and a fresh aliquot was thawed each day. Patch pipettes were made from glass capillary tubing using a P-97 micropipette puller (Sutter Instruments, Novato, CA). A commercial patch clamp amplifier was used for whole cell recordings. Before digitization, current records were low-pass filtered at one-fifth of the sampling frequency.

[00104] Experimental Procedures: MFV (CV-8282) at 1 μΜ was applied to three cells (n

= 3) in each channel. Based on the results of initial testing, three additional nominal

concentrations were selected to evaluate the concentration-response relationship (0.01, 0.03 and 0.1 μΜ).

[00105] One or more test article concentrations were applied sequentially (without washout between test substance concentrations) in ascending order, to each cell (n > 3). Peak current was measured during the test ramp. A steady state was maintained for at least 30 s before applying test article. Peak current was measured until a new steady state was achieved.

[00106] Test Procedures: Onset and steady state inhibition of hERG current was measured using a pulse pattern with fixed amplitudes (conditioning prepulse: +20 mV for 2 s; test pulse: -50 mV for 2 s) repeated at 10 s intervals, from a holding potential of -80 mV. Peak tail current was measured during the 2 s step to -50 mV.

[00107] Data Analysis: Data were stored on the ChanTest computer network for off-line analysis. Data acquisition and analyses were performed using the suite of pCLAMP (version 8.2) programs (MDS-AT, Sunnyvale, CA) and were reviewed by the Study Director. Steady state was defined by the limiting constant rate of change with time (linear time dependence). The steady state before and after test article application was used to calculate the percentage of current inhibited at each concentration. Concentration response data of each channel were fit to an equation of the form: % Inhibition = { l-l/[l+([Test]/IC50) N] }*100

[00108] Where [Test] was the test article concentration, IC50 was the test article concentration at half-maximal inhibition, N was the Hill coefficient and % Inhibition was the percentage of current inhibited at each test article concentration. Nonlinear least squares fits were solved with the Solver add- in for Excel 2003 and the IC₅₀ was calculated.

[00109] Results: the effect of MFV (CV-8282) on hERG current. Figure 1 summarizes the hERG concentration-response relationship. The IC50 for the inhibitory effect of mono- fluoro-vanoxerine (CV-8282) on hERG current was 0.02 μΜ (Hill coefficient =1.3).

Table 1: Percentage of hERG current inhibited at each concentration of

131110_0000.abf

C OO MT 35.2% 55.1%

131110_0000.abf

F 00 MT 23.3% 49.6%

131110_0000.abf

G OO MT 23.3% 56.8%

131110_0000.abf

[00111] Table 2: Summary Statistics for mono-fluoro-vanoxerine (CV-8282) inhibition of hERG current.

[00112] Mean percentage of current inhibited at each MFV (CV-8282) concentration

(Mean), standard deviation (SD), standard error of the mean (SEM), and number of cells (N).

[00113] As depicted in FIG 1: Concentration-response relationship of MFV (CV-8282) on hERG current. Percent inhibition of hERG current due to mono-fluoro-vanoxerine (CV- 8282) (Mean +SEM) is illustrated. The IC50 for hERG was determined to be 0.02 μΜ with a Hill coefficient of 1.3.

[00114] Summary: MFV (CV-8282) inhibited hERG current (Mean + SEM) by 27.8 +

2.8% at 0.01 μΜ (n = 4), 56.3 + 2.9% at 0.03 μΜ (n = 4), 89.1 + 2.6% at 0.1 μΜ (n = 3) and 103.1 + 0.7% at 1 μΜ (n = 3). The IC50 for the inhibitory effect of MFV CV-8282) on hERG current was 0.02 μΜ (Hill coefficient = 1.3).

[00115] Accordingly, as MFV is a potent inhibitor of hERG, as used as a model for prediction of IKr, the rapidly activating, delayed rectifier cardiac potassium current in human heart, MFV possesses ability inhibit IKr and have effect on cardiac arrhythmias in the heart. Indeed, MFV is therefore suitable for treatment of acute and/or chronic cardiac arrhythmias, for restoring normal sinus rhythm, for maintaining normal sinus rhythm, or for preventing recurrence of cardiac arrhythmia in a mammal comprising administering to a mammal an effective amount of H2 i4~fluorophe.ny1)( he¾

to inhibit hi i. C i current of at least about 99% in a cell of said mammal,

[00116] Although embodiments of the invention have been described in considerable detail, those skilled in the art will appreciate that numerous changes and modifications may be made to the embodiments and preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all equivalent variations as fall within the scope of the invention.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition for preventing or treating acute and/or chronic cardiac arrhythmias in an animal comprising an effective amount of l-[2-[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.

2. The pharmaceutical composition of claim 1 consisting essentially of an effective amount of l-[2-[(4-fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.

3. The pharmaceutical composition of claim 1 consisting of an effective amount of l-[2-[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, a diluent, a binder, a disintegrant, a flowing agent, and a lubricant.

4. The pharmaceutical composition of claim 1 further comprising an effective amount GBR12909.

5. The pharmaceutical composition of claim 4 wherein said l-[2-[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine comprises from about 99% to about 99.9% of said composition and wherein said GBR12909 comprises about .01% to about 1.0% of said composition.

6. The pharmaceutical composition of claim 4 wherein said l-[2-[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine comprises from about 90% to about 99.0% of said composition and wherein said GBR12909 comprises about 1.0% to about 10.0% of said composition.

7. The pharmaceutical composition of claim 4 wherein said l-[2-[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine comprises from about 50% to about 90.0% of said composition and wherein said GBR12909 comprises about 10.0% to about 50.0% of said composition.

8. The pharmaceutical composition of claim 4 wherein said l-[2-[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine comprises from about 75% to about 99.9% of said composition and wherein said GBR12909 comprises about .01% to about 25.0% of said composition.

9. A method of restoring normal sinus rhythm to a mammal having previously suffered from an episode of cardiac arrhythmia comprising administering to said mammal an effective amount of a pharmaceutical composition comprising l-[2-[(4- fluorophenyl)(phenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.

10. The method of claim 9, wherein the effective amount of said pharmaceutical composition is effective in inhibiting hERG current by between about 48% and about 99% in a mammalian cell.

11. The method of claim 10, wherein the effective amount of said pharmaceutical

composition is effective in inhibiting hERG current by between about 48% and 64% in a mammalian cell.

12. The method of claim 10, wherein the effective amount of said pharmaceutical

composition is effective in inhibiting hERG current by between about 84% and about 93% in a mammalian cell.

13. The method of claim 9, wherein the effective amount of said pharmaceutical composition is effective in inhibiting hERG current by more than 99% inhibition of hERG current in a mammalian cell.

14. The method of claim 9 wherein said l-[2-[(4-fluorophenyl)(phenyl)methoxy]etfiyl]-4-(3- phenylpropyl)piperazine is administered in an effective amount to inhibit IKr cardiac potassium current in the human heart.

15. The method of claim 14, wherein the effective amount of said pharmaceutical

composition is effective at inhibiting IKr cardiac potassium current in the human heart by more than 50%,

16. The method of claim 14, wherein the effective amount of said pharmaceutical

composition is effective at inhibiting IKr cardiac potassium current in the human heart by more than 99%.

17. A method for treatment of acute and/or chronic cardiac arrhythmias, for restoring normal sinus rhythm, for maintaining normal sinus rhythm, or for preventing recurrence of cardiac arrhythmia in a mammal comprising administering to a mammal an effective amount of !--[2--[(4- fluoropheny])(phenyl)rnethoxy]ethyl]-4-(3-phenylpropyl)p.iperazine to inhibit hERG current of at least about 99% in a cell of said mammal.

18. The method of claim 17 wherein said effective amount of l-[2-[(4- fluoropheiiyl)(p enyl)methoxy]e hy]J-4-(3-pheny[propyl)piperazine also inhibits IKr cardiac potassium current in the human heart.

19. The roeihod of claim 18 wherein said effective amount of i--[2-[(4- f1viorophei\yl)(phenyl)methoxy]ethyl -4-(3-phenylpropyl)piperazine also inhibits IKr cardiac potassium current in the human heart by more than 50%.

20. The method of claim 18 wherein said effective amount of l-[2-[(4- fluox pheny]){pheny].)methoxyjetliyl]-4-(3-phenylpropyl)piperazine also inhibits IKr cardiac potassium current in the human heart by more than 99%.