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Ion channel modulating activity II

a technology of ion channel and activity, applied in the field of ion channel modulating compounds, can solve the problems of sudden death and complex treatment of arrhythmias, and achieve the effects of prolonging qt interval, prolonging qt interval, and reducing/or eliminating the prolongation of qt interval

Inactive Publication Date: 2006-09-07
CORREVIO INT SARL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The patent describes a method for treating arrhythmias, particularly those caused by drugs that prolong the QT interval, using an ion channel modulating compound. The compound can block the early component of a cardiac sodium channel current, reducing the risk of arrhythmias. The patent also describes various formulations and dosing regimes for the compound, including intravenous and oral formulations, as well as continuous and repeat dosing. The compound can be used in combination with other drugs to treat arrhythmias. Overall, the patent provides a way to reduce the risk of arrhythmias and treat them effectively."

Problems solved by technology

In serious cases, arrhythmias can cause sudden death.
Treatment of arrhythmias is complex and aspects of care, especially the decision to control the ventricular rate vs. convert the arrhythmia, remain controversial.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

An Example of a Compound Showing a Rate-Dependent Inhibition of INA

[0542]FIG. 1 shows a rate- and concentration-dependent inhibition of sodium current (INa) in human atrial myocytes by COMPOUND B. Human myocytes were obtained from specimens of human right atrial appendage obtained during surgery from hearts of patients undergoing cardiopulmonary bypass. Cells were isolated and whole-cell voltage-clamped. Experiments were performed at 22±1° C. INa was elicited by a pulse to −20 mV from a holding potential of −70 mV (pulse duration was 40 ms. Peak inward current was measured in control and in the presence of 0.1, 1, 10, and 100 μM COMPOUND B. Symbols are mean±SE (n=4) and data was fit with a Hill equation.

[0543] A second example used HEK293 cells stably expressing human heart (hH1) sodium channels that were whole-cell patch clamped to measure currents. Concentration and rate-dependent inhibition of hH1 channels by COMPOUND A was tested by applying depolarizing pulses at 0.25, 1, 10,...

example 2

An Example Showing a Minimal Effect on Cardiac QRS Duration in Human Volunteers is shown by the table below:

[0546]

EFFECT OF COMPOUND A ON QRS DURATION IN HUMAN VOLUNTEERS(10 MIN AFTER INFUSION)SummaryMeasurementStatistic0.1 mg / kg0.25 mg / kg0.5 mg / kg1.0 mg / kg2.0 mg / kg4.0 mg / kg5.0 mg / kgPlaceboQRS (ms)Mean89.089.085.389.893.897.594.391.0S.D...4.25.29.81.76.35.1

example 3

An Example Showing a Voltage-Dependent Inhibition of Sodium Channels

[0547]FIG. 3 shows a voltage-dependent block of hH1 by COMPOUND A. Panel A shows a single experiment for which hH1 current amplitude is plotted for each recorded trace in response to escalating concentrations of Compound A when pulsed from a holding potential of −100 mV. Dose-response curves (FIG. 3, panel B) show that at holding potentials of −60 mV, −80 mV, −100 mV, and −120 mV the IC50 values were 31±1 μM (Hill coefficient=0.92±0.06; n=5), 43±8 μM (Hill coefficient=0.98±0.03; n=5), 60±4 μM (Hill coefficient=0.85±0.06; n=3) and 107±11 μM (Hill coefficient=0.89±0.03; n=3). Cells were held at either −120 mV, −100 mV, −80 mV, and −60 mV and stepped to −30 mV for 6 ms (1 Hz). Cells held at −60, −80 and −100 mV received a 2 ms pulse to −120 mV to relieve channel inactivation prior to the −30 mV step.

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Abstract

Methods, compositions, dosing regimes, and routes of administration for the treatment or prevention of arrhythmias. In these methods, arrythmias (e.g. atrial fibrillation, atrial flutter, early afterdepolarizations and prolongation of QT interval) may be reduced or eliminated by administering ion channel modulating compounds to a subject in need thereof. The ion channel modulating compounds may be cycloalkylamine ether compounds, particularly cyclohexylamine ether compounds. Also described are compositions of ion channel modulating compounds and drugs which induce early afterdepolarizations, prolongation of QT interval and / or Torsades de Pointes.

Description

RELATED PATENTS AND PATENT APPLICATIONS [0001] This patent application is a continuation-in-part of U.S. patent application Ser. No. 10 / 674,684 filed Sep. 29, 2003, which is a continuation of U.S. patent application Ser. No. 09 / 680,988 filed Oct. 6, 2000 (now abandoned), which is a continuation-in-part of U.S. patent application Ser. No. 09 / 283,873 filed Mar. 31, 1999 which claims priority to U.S. Provisional Patent Application 60 / 118,954 filed Feb. 5, 1999 and 60 / 080,347 filed Apr. 1, 1998, which are herein incorporated by reference in their entirety. [0002] This patent application claims the priority benefit of U.S. provisional patent application 60 / 493,392 (filed Aug. 7, 2003), 60 / 544,941 (filed Feb. 13, 2004), 60 / 516,486 (filed Oct. 31, 2003), and 60 / 516,248 (filed Oct. 31, 2003), which are hereby incorporated by reference in their entirety. [0003] U.S. Provisional application 60 / 467,159 (filed May 2, 2003) is incorporated by reference in its entirety.TECHNICAL FIELD [0004] The ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D211/82A61K31/455A61K31/40A61K31/4965A61K31/519C07C217/52C07D207/12C07D207/26C07D207/27C07D277/04C07D295/096C07D295/15C07D295/185C07D333/54C07D333/56C07D491/10
CPCA61K31/00A61K31/40A61K31/455A61K31/4965A61K31/519C07C217/52C07C2101/14C07D207/12C07D207/24C07D207/27C07D277/04C07D295/096C07D295/15C07D295/185C07D333/54C07D333/56C07D491/10A61P25/00C07C2601/14
Inventor FEDIDA, DAVIDBEATCH, GREGORY N.EZRIN, ALAN M.ORTH, PETER M. R.
Owner CORREVIO INT SARL
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