Methods for preventing or treating cardiac arrhythmia
Disclosed are methods of preventing or treating cardiac arrhythmia comprising administering to a mammal in need thereof, such as a human, an effective amount of vanoxerine (GBR 12909) or a pharmaceutically acceptable salt, derivative or metabolite thereof.
1 . A method for preventing or treating cardiac arrhythmia comprising administering to a mammal in need thereof an effective amount of vanoxerine or a pharmaceutically acceptable salt, derivative or metabolite thereof.
2 . The method of claim 1 , wherein a pharmaceutically acceptable salt of vanoxerine is administered.
3 . The method of claim 2 , wherein said pharmaceutically acceptable salt is selected from the group consisting of salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, glutamic acid and aspartic acid.
4 . The method of claim 1 , wherein a pharmaceutically acceptable derivative of vanoxerine is administered.
5 . The method of claim 4 , wherein said pharmaceutically acceptable derivative of vanoxerine is a compound of the formula:
wherein X is a hydroxy, C 1-4 alkoxy, phenylcarbamoyloxy or C 1-4 alkylcarbamoyloxy group, and Y is a hydrogen atom or a C 1-3 alkyl group, or X and Y together with the carbon atom to which they are linked form a carbonyl group, or a pharmaceutically acceptable salt thereof.
6 . The method of claim 4 , wherein said pharmaceutically acceptable derivative of vanoxerine is a phenolic derivative of vanoxerine or a methoxy congener thereof, or a pharmaceutically acceptable salt thereof.
7 . The method of claim 4 , wherein said pharmaceutically acceptable derivative of vanoxerine is GBR 13069 or GBR 12783, or a pharmaceutically acceptable salt thereof.
8 . The method of claim 1 , wherein the mammal is a human.
9 . The method of claim 1 , wherein said vanoxerine is administered in combination with a pharmaceutically acceptable carrier or vehicle.
10 . A method of modulating the activity of an ion channel of mammalian cell, comprising contacting a mammalian cell with an effective amount of vanoxerine, or pharmaceutically acceptable salt, derivative or metabolite thereof.
11 . The method of claim 10 , wherein said ion channel is a cardiac potassium ion channel, a cardiac calcium ion channel and a cardiac sodium ion channel.
12 . The method of claim 11 , wherein said cardiac potassium ion channel produces I Kr , said calcium ion channel produces I Ca and said sodium ion channel produces I Na .
13 . The method of claim 10 , wherein said mammalian cell is a human cardiac muscle cell.
14 . A method of screening for compounds that bind to I Kr or hERG comprising: (i) contacting a mammalian cell that stably expresses I Kr or hERG with labeled vanoxerine, or a pharmaceutically acceptable salt, derivative or metabolite thereof, to form a labeled binding pair, (ii) contacting said labeled binding pair with a compound of interest; and (iii) determining whether said compound of interest displaces said labeled vanoxerine, or said pharmaceutically acceptable salt, derivative or metabolite thereof.