METHOD OF TREATING ARRHYTHMIAS
Methods are provided for treating arrhythmias including tachycardias, such as idiopathic ventricular tachycardia, ventricular fibrillation, and Torsade de Pointes (TdP) in a manner that minimizes undesirable side effects.
1 . A method of treating arrhythmias in a mammal comprising administration of a therapeutically effective amount of a compound of Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or an isomer thereof, or a pharmaceutically acceptable salt or ester of a compound of Formula I or its isomer.
2 . The method of claim 1 wherein the compound of formula I is ranolazine, which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, or an isomer thereof or a pharmaceutically acceptable salt of the compound or its isomer.
3 . The method of claim 1 wherein the compound of Formula I is administered at dose levels that inhibit I kr , I ks , and late I Na ion channels but do not inhibit calcium channels.
4 . The method of claim 2 wherein ranolazine is in the form of a pharmaceutically acceptable salt.
5 . The method of claim 4 wherein the pharmaceutically acceptable salt is the dihydrochloride salt.
6 . The method of claim 2 wherein ranolazine is in the form of the free base.
7 . The method of claim 1 wherein the administration comprises a dose level that inhibits late I Na ion channels.
8 . The method of claim 1 wherein the administration comprises a dose level that inhibits I Kr , I Ks , and late I Na ion channels
9 . The method of claim 1 wherein the administration comprises a dose level that inhibits I Kr , I Ks , and late I Na ion channels but does not inhibit calcium channels.
10 . The method of claim 1 wherein a compound of Formula I is administered in a manner that provides plasma level of the compound of Formula I of at least 350±30 ng/mL for at least 12 hours.
11 . A method of treating arrhythmias in a mammal comprising administering a compound of Formula I
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or an isomer thereof, or a pharmaceutically acceptable salt or ester of a compound of Formula I or its isomer,
as a sustained release formulation that maintains plasma concentrations of the compound of Formula I at less than a maximum of 4000 ng/mL, preferably between about 350 to about 4000 ng base/mL, for at least 12 hours.
12 . The method of claim 1 wherein a compound of Formula I is administered in a formulation that contains between about 10 mg and 700 mg of a compound of Formula I.
13 . The method of claim 12 wherein the compound of Formula I is ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer.
14 . The method of claim 1 wherein the compound is administered in a formulation that provides a dose level of about 1 to about 30 micromoles per liter of formulation.
15 . The method of claim 14 wherein the said formulation provides a dose level of about 1 to about 10 micromoles per liter of formulation.
16 . A method of treating or preventing arrhythmias in a mammal comprising administering an effective amount of ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
17 . A method of treating or preventing acquired arrhythmias (arrhythmias caused by sensitivity to prescription medications or other chemicals) comprising administering a therapeutically effective amount of ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
18 . A method of treating or preventing inherited arrhythmias (arrhythmias caused by gene mutations) comprising administering an effective amount of ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
19 . A method of treating or preventing arrhythmias in a mammal with genetically determined congenital LQTS comprising administering an effective amount or ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
20 . A method of preventing Torsade de Pointes comprising administering an effective amount of ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
21 . A method of treating or preventing arrhythmias in mammals afflicted with LQT3 comprising administering an effective amount of ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
22 . A method of treating or preventing arrhythmias in mammals afflicted with LQT1, LQT2, and LQT3 comprising administering an effective amount of ranolazine, or an isomer thereof or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
23 . A method of reducing arrhythmias in mammals afflicted with LQT3 comprising administering an effective amount of ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
24 . A method of reducing arrhythmias in mammals afflicted with LQT1, LQT2, and LQT3 comprising administering an effective amount of ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a mammal in need thereof.
25 . A method of preventing arrhythmias comprising screening the appropriate population for SCN5A genetic mutation and administering an effective amount of ranolazine, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer, to a patient afflicted with this genetic mutation.
26 . A method for treating ventricular tachycardia in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective dose of a compound of Formula I:
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or an isomer thereof, or a pharmaceutically acceptable salt or ester of the compound or an isomer thereof,
that concurrently inhibits I Kr , I Ks and late sodium ion channels.
27 . The method of claim 26 wherein the compound inhibits cardiac I Kr , I Ks and late sodium ion channels at a dose level that does not inhibit cardiac calcium ion channels.
28 . The method of claim 27 wherein the ventricular tachycardia is Torsades de Pointes.
29 . The method of claim 26 wherein the compound is ranolazine which is named N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide, or an isomer thereof, or a pharmaceutically acceptable salt of the compound or its isomer.
30 . The method of claim 27 wherein the dose level required to effectively modulate the cardiac I Kr , I Ks and late sodium ion channels without modulating the cardiac calcium ion channel provides plasma levels of said compound between 1-100 μM.
31 . The method of claim 30 wherein the dose level required to effectively modulate the cardiac I Kr , I Ks and late sodium ion channels without modulating the cardiac calcium ion channel provides plasma levels of said compound between 1-50 μM.
32 . The method of claim 31 wherein the dose level required to effectively modulate the cardiac I Kr , I Ks and late sodium ion channels without modulating the cardiac calcium ion channel provides plasma levels of said compound between 1-20 μM.
33 . The method of claim 32 wherein the dose level required to effectively modulate the cardiac I Kr , I Ks and late sodium ion channels without modulating the cardiac calcium ion channel provides plasma levels of said compound between 1-10 μM.
34 . A method for treating ventricular tachycardia in a cardiac compromised mammal comprising administering to a mammal in need of such treatment a therapeutically effective dose of a compound that modulates the cardiac I Kr , I Ks and late sodium ion channels without modulating the cardiac calcium ion channel.
35 . A method of treating or preventing drug induced ventricular tachycardia in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound that inhibits the cardiac I Kr , I Ks and late sodium ion channels.
36 . A method of treating or preventing inherited ventricular tachycardia in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound that inhibits the cardiac I Kr , I Ks and late sodium ion channels.
37 . The method of claim 1 wherein the compound is administered by bolus or sustained release composition.
38 . The method of claim 1 wherein the compound is administered intravenously.
39 . Use of a compound of formula I
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or an isomer thereof, or a pharmaceutically acceptable salt or ester of the compound or its isomer,
for the treatment of arrhythmias in mammals.
40 . A method for treating ventricular tachycardias arising in myocardial ischemia, such as unstable angina, chronic angina, variant angina, myocardial infarction, acute coronary syndrome, and additionally in heart failure (acute and/or chronic) comprising administration of a therapeutically effective amount of a compound of formula I
wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or N-optionally substituted alkylamido, provided that when R 1 is methyl, R 4 is not methyl;
or R 2 and R 3 together form —OCH 2 O—;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, or di-lower alkyl amino; or
R 6 and R 7 together form —CH═CH—CH═CH—; or
R 7 and R 8 together form —O—CH 2 O—;
R 11 and R 12 are each independently hydrogen or lower alkyl; and
W is oxygen or sulfur;
or an isomer thereof, or a pharmaceutically acceptable salt or ester of the compound or its isomer.