301

Vanoxerine: Cellular Mechanism of a New Antiarrhythmic

ANTONIO E. LACERDA, Ph.D.,∗ YURI A. KURYSHEV, Ph.D.,∗ GAN-XIN YAN, M.D., Ph.D.,†
ALBERT L. WALDO, M.D.,‡ and ARTHUR M. BROWN, M.D., Ph.D.∗
From the ∗ ChanTest Corporation, Cleveland, Ohio, USA; †Main Line Health Heart Center and Lankenau Institute for Medical Research,
Wynnewood, Pennsylvania, USA and The First Hospital of Xi’an Jiaotong University, Xi’an, China; and ‡Department of Medicine,
Division of Cardiology, School of Medicine, Case Western Reserve University, University Hospitals Case Medical Center,
Cleveland, Ohio, USA

Cellular Electrophysiology of Vanoxerine. Introduction: There remains an unmet need for safe and
effective antiarrhythmic drugs, especially for the treatment of atrial fibrillation. Vanoxerine is a drug that
is free of adverse cardiac events in normal volunteers, yet is a potent blocker of the hERG (hK v 11.1) cardiac
potassium channel. Consequently ,we hypothesized that vanoxerine might also be a potent blocker of cardiac
calcium (Ca) and sodium (Na) currents, and would not affect transmural dispersion of repolarization.
Methods: The whole cell patch clamp technique was used to measure currents from cloned ion chan-
nels overexpressed in stable cell lines and single ventricular myocytes. We measured intracellular action
potentials from canine ventricular wedges and Purkinje fibers using sharp microelectrode technique.
Results: We found that vanoxerine was a potent hK v 11.1 blocker, and at submicromolar concentrations,
it blocked Ca and Na currents in a strongly frequency-dependent manner. In the canine ventricular wedge
preparation vanoxerine did not significantly affect transmural action potential waveforms, QT interval or
transmural dispersion of repolarization.
Conclusions: Vanoxerine (1) is a potent blocker of cardiac hERG, Na and Ca channels; (2) block is strongly
frequency-dependent especially for Na and Ca channels; and (3) transmural dispersion of ventricular
repolarization is unaffected. The multichannel block and repolarization uniformity resemble the effects
of amiodarone, the exemplar atrial fibrillation drug. Vanoxerine is a completely different chemical and
has none of amiodarone’s toxic effects. Vanoxerine has characteristics of a potentially effective and safe
antiarrhythmic. (J Cardiovasc Electrophysiol, Vol. 21, pp. 301-310, March 2010)

antiarrhythmic drug, patch clamp, vanoxerine, GBR-12909, cardiac electrophysiology, ventricular wedge, Pur-
kinje fiber action potential

Introduction primarily a single class of channels because it is nonselective

and blocks I K , I Na , and I Ca .3,4 However, its adverse effect pro-
The need for safer and more effective antiarrhythmic file is long and daunting, ultimately limiting its usefulness.
drugs, especially for the treatment of atrial fibrillation (AF), An alternative to amiodarone that had a similar electrophys-
is well recognized.1 Class IA, IC, and III antiarrhythmic iologic profile, was clinically as or more effective, and had
drugs are widely used but have only about 50% efficacy, and fewer serious, if any, potential adverse effects would be quite
have potentially lethal adverse effects.1 Amiodarone2 is the desirable.
most efficacious and widely used drug for treatment of AF.2 Vanoxerine (Vx) {1-[2-[bis(4-fluorophenyl)methoxy]
Amiodarone is unlike Class I or Class III drugs that target ethyl]-4-[3-phenylpropyl] piperazine dihydrochloride} (syn-
onym GBR-12909) is a dopamine transporter (DAT1) antag-
onist.5 It was developed for treatment of Parkinson’s disease
The research described in this report was supported in part by NIH grant and depression,6 but lacked efficacy. During a preclinical
R44 HL067503 and ChanTest Corporation. safety screen for another potential clinical indication, we ob-
served that Vx was a potent blocker of the hK v 11.17 channel
Antonio E. Lacerda and Yuri A. Kuryshev are employed at ChanTest Cor- at concentrations known to be safe in man.6 Despite potent
poration, which holds a use patent on vanoxerine. Dr. Brown is coinventor hK v 11.1 block, Vx did not produce adverse cardiac events
listed on the patent and majority owner of ChanTest. Dr. Waldo reports
participation in research grants supported by CV Therapeutics and Sequel
in normal healthy volunteers,8-10 leading to our hypothesis
Pharmaceuticals; compensation for participation in a speaker’s bureau rel- that Vx also blocked cardiac Na and Ca currents.11,12 In this
evant to this topic from GlaxoSmithKline; honoraria from Sanofi-Aventis article, we demonstrated that Vx was a potent blocker of car-
and participation on the advisory board for dronedarone. diac Na and Ca currents in addition to hK v 11.1, and did not
prolong action potential duration (APD). Block was strongly
Address for correspondence: Antonio E. Lacerda, Ph.D., ChanTest Cor- frequency-dependent, and was unaccompanied by a change
poration, 14656 Neo Parkway, Cleveland, OH 44128. Fax: 216-332-1706;
in transmural dispersion of repolarization. Poly-ionic block
E-mail: alacerda@chantest.com
effects also occurred with amiodarone and our results lead
Manuscript received 15 April 2009; Revised manuscript received 4 August us to propose that vanoxerine might be antiarrhythmic. We
2009; Accepted for publication 11 August 2009. subsequently tested and proved this hypothesis in a sterile
pericarditis animal model of atrial fibrillation.13 A part of
doi: 10.1111/j.1540-8167.2009.01623.x this work has appeared in abstract form.14
302 Journal of Cardiovascular Electrophysiology Vol. 21, No. 3, March 2010

Methods and hK v 7.1/hKCNE1 channels. All pipette solutions were

prepared in batches, aliquoted, and stored frozen at −20◦ C
Animal Use and Care (−80◦ C for solutions containing enzyme), and were freshly
All animal experiments were conducted in accordance thawed each day of use. Measurements were made at room
with the guidelines of the American Heart Association on temperature (20–25◦ C).
Research Animal Use and the Public Health Service Pol-
Voltage clamp protocols
icy on Use of Laboratory Animals. Animals were housed in
AAALAC accredited facilities at Case Western Reserve Uni- Methods for voltage clamp of cells, drug application, data
versity (Cleveland, OH) and Main Line Health Heart Center acquisition, and analysis of were performed essentially as
and Lankenau Institute for Medical Research (Wynnewood, previously described.18 HCa v 3.2 currents were measured
PA). Tissues were isolated following Institutional Animal with a commercial automated patch clamp assay (FAST-
Care and Use Committee approved protocols at each institu- Patch) developed at ChanTest Corporation (Cleveland, OH,
tion. USA) using a PatchXpress 7000A (MDS Analytical Tech-
nologies, Sunnyvale, CA, USA).
Statistical Analysis Cells stably expressing cardiac ion channel cDNAs were
Changes in measured parameters relative to control were held at −80 mV and block was measured using pulse patterns
evaluated using ANOVA and Dunnett’s multiple comparison with fixed amplitudes. The hK v 1.5 current was measured at
test. Data were presented as mean ± standard error of the the end of a 300-ms step to +20 mV repeated at 10 sec-
mean (SEM); (n) indicates number of replicates; a P value onds intervals. hK v 7.1/hKCNE1 peak current at −40 mV
<0.05 was considered statistically significant. was evaluated with pulses (depolarization: +20 mV for 2
seconds; repolarization: −40 mV for 0.5 seconds) repeated
Patch Clamp Concentration—Response Measurements at 15 seconds intervals. The rK v 4.3 currents at peak and af-
ter 70 ms were evaluated during 300-ms pulses to +20 mV
Cell preparation repeated at 15 seconds intervals. hCa v 3.2 peak inward cur-
Human HEK-293 (ATCC, Manassas, VA, USA) cells rent during a 50-ms step to −30 mV was measured after
were stably transfected with hK v 11.1 or hNa v 1.5 cDNA and a hyperpolarizing conditioning step (−100 mV amplitude,
mouse L cells were stably transfected with hK v 1.5 or rK v 4.3 250-ms duration) repeated at 10 seconds intervals. hK v 11.1
cDNA.15 L-type calcium currents were recorded from acutely peak tail current was measured during a 2 seconds step to
isolated, enzymatically dispersed adult guinea pig ventricu- −50 mV following a 2 seconds step to +20 mV repeated
lar myocytes.16 hCa v 3.2 was stably expressed in HEK-293 at 10 seconds intervals. HNa v 1.5 peak inward current was
cells. measured during a 10-ms step to −15 mV following a 20 ms
conditioning voltage step to −120 mV repeated at 10 sec-
Solutions onds intervals. Guinea pig single ventricular myocyte L-type
calcium channel (I Ca,L ) currents were measured by holding
Except for hNa v 1.5 and I Ca,L recordings, extracellular Vx cells at −40 mV to inactivate Na channels and peak inward
concentrations were prepared by diluting aqueous stock so- I Ca,L was measured during a 300-ms step to 0 mV repeated
lutions into a HEPES buffered physiological solution (HB- at 20 seconds intervals.
PS; composition in mM): NaCl, 137; KCl, 4.0; CaCl 2 , 1.8;
MgCl 2 , 1; HEPES, 10; Glucose, 10; pH adjusted to 7.4 with Frequency-dependence of drug block
NaOH. For hNa v 1.5 recordings, extracellular Vx concentra-
tions were prepared by diluting stock solutions into a low-Na The increase in drug block produced by repetitive stimu-
solution (NaCh-PS) with 40 mM NaCl and 97 mM L-aspartic lation (use-dependence) was measured relative to control at
acid substituted for NaCl in HB-PS (pH adjusted with N- selected pulse frequencies (1 and 3 Hz). After holding the cell
methyl-D-glucamine). Guinea pig myocytes were superfused for a period of at least 1 minute at rest, the time course of peak
with a Ca-channel isolating external solution (CaCh-PS) with or isochronal currents during a train of pulses was measured.
5.4 mM CsCl substituted for KCl in HB-PS to record I Ca,L . Measured current magnitudes from each pulse in the train
Intracellular pipette solution for whole cell recordings were normalized to the first pulse magnitude. Vx-induced
(except for hNa v 1.5, I Ca,L and hCa v 3.2) was (composition increases in block were expressed as the ratio of normalized
in mM): K-aspartate, 130; MgCl 2 , 5; EGTA, 5; ATP, 4; steady state current in the presence of Vx to the normalized
HEPES, 10; pH adjusted to 7.2 with KOH. Internal solu- steady state current in the absence of Vx measured at the
tions for hNa v 1.5, I Ca,L , and hCa v 3.2 measurements were de- end of the train.
signed to reduce overlapping currents through other channels.
The intracellular pipette solution for hNa v 1.5 and hCa v 3.2 Purkinje Fiber Action Potential
was (composition in mM): cesium-aspartate, 130; MgCl 2 , 5; Concentration—Response Measurements
EGTA, 5; Na 2 ATP, 4; GTP, 0.1; HEPES, 10; pH adjusted to Purkinje fiber solutions
7.2 with aspartic acid. The internal solution for I Ca,L measure-
ments in adult guinea pig myocytes had the following compo- Standard Purkinje fiber Tyrode’s (PFT) solution was pre-
sition (in mM): Cs-methanesulfonate, 130; tetraethylammo- pared fresh weekly and refrigerated (composition in mM):
nium chloride, 20; MgCl 2 , 1; EGTA, 10; HEPES, 10 adjusted NaCl, 131; KCl, 4.0; CaCl 2 , 2.0; MgCl 2 , 0.5; NaHCO 3 , 18.0;
to pH 7.2 with methanesulfonic acid. Internal solutions were NaH 2 PO 4 , 1.8; Glucose, 5.5. Before and during use, solu-
supplemented with (composition in mM): Mg-ATP, 4; GTP, tions were aerated with a mixture of 95% O 2 and 5% CO 2
0.3; tris-phosphocreatine, 14; and creatine phosphokinase, (pH 7.2 at room temperature) and warmed to 37◦ C by the
50 U/mL to prevent rundown of L-type calcium channels17 superfusion system.
 Lacerda et al. Cellular Electrophysiology of Vanoxerine 303

A a

B a
c

Figure 1. Block of hK v 11.1, I Ca,L ,

and hNa v 1.5 current by Vx. The
concentration-response relation for Vx
(GBR-12909) block of hK v 11.1 currents
was fit with an IC 50 value of 0.00084 μM
(panel A:a). Numbers in parenthesis indi-
cate measurements at each concentration.
Sample current records during applica-
tion of control and 0.003 μM Vx solutions
(panel A:b). Time course of peak tail cur- C a
rent values during control, application of
0.003 μM Vx and partial washout (panel
A:c). The concentration-response relation
c
for Vx block of I Ca,L currents was fit with
an IC 50 value of 0.32 μM (panel B:a).
Sample current records during applica-
tion of control, 0.3 and 1 μM Vx solu-
tions (panel B:b). Time course of peak
current values during application of Vx
(panel B:c). The concentration-response b
relation for Vx block of hNa v 1.5 currents
was fit with an IC 50 value of 0.83 μM
(panel C:a). Sample current records dur-
ing application of control and 1 μM GBR-
12909 solutions (panel C:b). Time course
of peak current values during application
of GBR-12909 (panel C:c). A steady state
was maintained for at least 30 seconds be-
fore and after applying Vx. Peak current
was measured until a new steady state was
achieved.
304 Journal of Cardiovascular Electrophysiology Vol. 21, No. 3, March 2010

TABLE 1
Patch Clamp IC 50 Values for Block of Cardiac Ion Channels by Vx∗

Vx Concentration–Response Relationship
Channel Hz Test Pulses/Minute Cell Line IC 50 (μM)

hK v 11.1 (I Kr ) 0.1 6 HEK-293 0.00084 (n = 3–8)

I Ca,L 0.05 3 Ventricular myocyte 0.32 (n = 2–4)
hCa v 3.2 0.1 6 HEK-293 2.0†
hNa v 1.5 (I Na ) 0.1 6 HEK-293 0.83 (n = 2–5)
hK v 1.5 (I Kur ) 0.1 6 HEK-293 1.0 (n = 2–3)
rK v 4.3 (Ito peak) 0.067 4 L 9.8
(Ito 70 ms) 0.067 4 L 2.0 (n = 2–3)
hK v 7.1/hKCNE1 (I Ks ) 0.067 4 CHO 2.9 (n = 3–5)
∗ Data from 2 or more cells were pooled for IC 50 measurements; n indicates the range of replicates from all concentrations used to construct the IC 50 . See
Figure 1 for n at each concentration for hK v 11.1, I Ca,L , and hNa v 1.5.
† Estimated IC from 83% block at 10 μM (n = 2).
50

Electrophysiological recording and buffer compartments was determined by LC-MS/MS

analysis and the % binding reported.
Purkinje fibers were excised from adult canine ventricles
by standard methods.17 Purkinje fibers were mounted in a
glass-bottomed Plexiglas chamber (approximate volume, 1 Results
mL) affixed to a heated platform, and superfused with PFT Block of Cardiac Ion Channels
solutions warmed to 37 ± 1◦ C at approximately 4 mL/minute.
Intracellular membrane potentials were recorded using con- Vx is a potent blocker of hK v 11.1 current with an IC 50
ventional intracellular microelectrodes filled with 3 M KCl of 0.00084 μM (Fig. 1 Panel A:abc), and of I Ca,L (Fig. 1,
solution and connected to an intracellular electrometer am- Panel B:abc) and hNa v 1.5 (Fig. 1, Panel C:abc) channel
plifier (Warner Instruments IE 210; Hamden, CT, USA). currents as well. The rank order of potency was hK v 11.1
Action potentials (APs) were evoked by a commercial > I Ca,L > hNa v 1.5 with IC 50 values of 0.84, 320, and 830
electronic stimulator. Analog signals were low-pass filtered nM, respectively (Table 1). The IC 50 values for Vx block of
at 20 kHz before digitization with a Notocord-Hem 3.5 sys- hK v 7.1/hKCNE1, rK v 4.3, and hK v 1.5, the channels thought
tem (Notocord Systems SA, Croissy sur Seine, France). Ac- to underlie the cardiac currents I Ks , I to , and I Kur , respectively,
ceptable fibers were stimulated continuously at a basic cycle fell in the range of 1–10 μM with a rank order of potency of
length (BCL) of 2 seconds for 20 minutes to establish a con- hK v 1.5 > delayed rK v 4.3 > hK v 7.1/hKCNE1 >peak rK v 4.3
trol response following a stabilization period of at least 25 (Table 1). The low-voltage-activated or T-type Ca channel
minutes. At the end of the control period, baseline AP rate- was blocked 83% by 10 μM Vx (Table 1) when evaluated
dependence was measured at 2, 1, and 0.5 second BCLs. in a commercial automated patch clamp assay, similar to
Responses were measured from means of the last 5 recorded amiodarone.20
APs at each BCL. Use- or frequency-dependent block is a desirable property
for an antiarrhythmic drug and we evaluated Vx for this
characteristic. Block of hK v 11.1, I Ca,L , and hNa v 1.5 channels
Arterially Perfused Canine Ventricular Wedge Preparation at frequencies from 0.3 to 3 Hz showed that Vx’s potency
Details of the methods used have been published previ- increased with rate, especially for Na and Ca channels, so
ously.19 Transmembrane action potentials in wedge prepa- that block values converge at higher frequencies (Fig. 2 and
rations were recorded simultaneously from epicardial (Epi), Table 2). Block of hK v 11.1 at 10 nM and 3 Hz was increased
subepicardial (M cells), and endocardial (Endo) sites in ca- 30% (Fig. 2A), Ca-channel block at 300 nM and 1 Hz was
nine left ventricular wedge preparations by use of 3 separate increased by 83% (Fig. 2B) and Na-channel block at 300 nM
intracellular floating microelectrodes. A transmural ECG was and 3 Hz was increased by 66% (Fig. 2C), relative to control.
recorded concurrently in all experiments. Transmural disper- Data from a compound without frequency-dependent block
sion of repolarization (TDR) was defined as the difference would superimpose the control time course data.
between the longest and shortest repolarization times across
Purkinje Fiber Action Potential Concentration—Response
the left ventricular wall.
Intracellular recordings from canine Purkinje fibers were
Plasma Protein Binding of Vx in Dogs and Humans used to evaluate proarrhythmia arising from the complex ion
channel effects of Vx. Action potentials were recorded from
Binding to dog and human plasma proteins of Vx was canine Purkinje fibers at BCL’s of 2, 1, and 0.5 seconds.
measured in a commercial assay by equilibrium dialysis at Measurements from 3 fibers of action potential duration at
concentrations of 0.1, 0.4, and 1 μM at Ricerca Biosciences, 60% (APD 60 ) and 90% (APD 90 ) repolarization, the action
LLC (Concord, OH, USA). Pooled human plasma, prepared potential amplitude (APA), and the resting membrane poten-
by blood collection from healthy paid donors into sodium tial at each cycle length in vehicle and 0.01, 0.1, and 1 μM Vx
EDTA in FDA licensed and inspected donor blood centers, were analyzed. No statistically significant differences were
was purchased by Ricerca Biosciences from Bioreclamation, observed between control and all Vx concentrations tested
Hicksville, NY. The concentration of test article in the plasma (Fig. 3 and Table 3).
 Lacerda et al. Cellular Electrophysiology of Vanoxerine 305

Figure 2. Use-dependent block of

hK v 11.1, I Ca,L and hNa v 1.5 currents.
Use-dependent block was measured
relative to control. Steady state block
of Vx measured at 0.1 to 0.05 Hz was
established before measurement of Vx’s
rate-dependence at higher frequencies.
Data in the presence and absence of
Vx at the indicated concentrations were
normalized to the first pulse amplitude
after a rest at the holding potential
of at least 1-minute duration. Rapid
stimulation alone can cause a decline
of current over time in the absence of
drug, especially for Ca2+ channels. In
all cases Vx enhanced the rate and extent
of current decay relative to control. If
rate did not enhance block, the control
and drug time courses would overlay
in this analysis. Upper panel A shows
use-dependent block of hK v 11.1 at 3 Hz
before and after equilibration of the cell
with Vx at 10 nM (30% increase, n = 3).
Panel B shows use-dependent block of
I Ca,L at 1 Hz and 300 nM concentration
(83% increase, n = 2) and Panel C shows
the same for Vx block of hNa v 1.5 at 3 Hz
and 300 nM Vx (66% increase, n = 2).

Ventricular Wedge Recordings of Action Potentials, nine ventricular wedge preparation were compared to those
Transmural ECG, and Transmural Dispersion of dofetilide and amiodarone. Figure 4 and Tables 4 and 5
of Repolarization show that Vx acts similarly to amiodarone and is distinctly
different from dofetilide in this assay. Dofetilide significantly
We used intracellular recordings from canine ventricu- increased the APD 90 and QT of all ventricular cardiomy-
lar wedge preparations to search for any proarrhythmic sig- ocytes. Vx rarely prolonged APD 90 significantly and pro-
nals in the transmural ECG and action potentials measured duced no significant changes in QT or TDR. Amiodarone
simultaneously from myocytes in the epicardium, midmy- significantly decreased APD 90 only at the highest concen-
ocardium, and endocardium. Vx’s effects on the perfused ca- tration tested in all ventricular myocytes and decreased QT
306 Journal of Cardiovascular Electrophysiology Vol. 21, No. 3, March 2010

TABLE 2 TABLE 3
Vx Ion Channel Block Use-Dependence Vx Modulation of Canine Purkinje Fiber AP Parametersa,∗

BCL Vx Increase Vx BCL APD 60 APD 90 RMP APA

Channel (s) (nM) (%) (μM) (s) (%) (%) (mV) (mV)

I Ca,L 1 30 11 ± 1 (3) 0.01 0.5 2.7 ± 1.6 1.8 ± 1.9 0.1 ± 3.7 5.9 ± 6.2
1 100 23 ± 19 (2) 1 4.3 ± 0.8 3.6 ± 1.6 0.6 ± 3.9 6.3 ± 6.5
1 300 83 ± 10 (2)∗ 2 7.5 ± 1.9 7.0 ± 2.7 0.4 ± 3.8 6.7 ± 6.5
0.3 30 10 ± 7 (2) 0.1 0.5 1.8 ± 3.3 4.9 ± 1.8 2.0 ± 5.0 −3.1 ± 14.6
0.3 100 60 ± 13 (2)∗ 1 2.7 ± 2.9 10.1 ± 2.5 2.5 ± 5.9 −2.7 ± 15.0
hNa v 1.5 3 300 5 ± 5 (2) 2 2.7 ± 3.9 0.1 ± 6.1 3.9 ± 6.4 −1.0 ± 13.4
0.3 300 70 ± 11 (2)∗ 1 0.5 −5.3 ± 5.8 2.1 ± 3.2 −0.4 ± 2.7 4.3 ± 8.5
hK v 11.1 3 10 3 ± 3 (3) 1 −5.0 ± 7.0 2.6 ± 4.5 −0.1 ± 3.2 5.5 ± 8.3
0.3 10 30 ± 8 (3)∗ 2 −4.6 ± 8.1 2.7 ± 5.5 0.7 ± 3.3 3.8 ± 7.0
∗ Statistically significant change from control (P < 0.05) using ANOVA and a Data were obtained from 3 canine Purkinje fibers. BCL = basic cycle
Dunnett’s multiple comparison test. length; APD 60 = action potential duration at 60% repolarization; and
APD 90 = at 90% repolarization; RMP = resting membrane potential;
APA = action potential amplitude.
∗
No statistically significant changes from control (P < 0.05) were observed
at 2 and 1 second BCL. Vx did not produce any phase 2 using ANOVA and Dunnett’s multiple comparison test.
early after depolarizations, R-on-T extrasystoles or torsades
de pointes arrhythmias over the concentration range tested
(0.01–3.0 μM).
fiber APD 60 and APD 90 . Vx had no significant effect on QT
Plasma Protein Binding of Vx or TDR. Block of hNa v 1.5 and I Ca,L was strongly frequency-
dependent. Vx appears to have similar effects to amiodarone.
Protein binding for Vx was greater than 99% for both dog
Based on Vx’s use in previous clinical trials to treat Parkin-
and human plasma at all 3 concentrations tested: 0.1, 0.4, and
son’s disease and depression, its adverse effect profile is
1 μM. The results demonstrated a high propensity for Vx to
much less than amiodarone’s. The available clinical trial
bind plasma proteins. Cytochrome P450 enzymes generate
data suggests that concentrations of Vx that are effective
a single Vx metabolite in vitro, primarily due to CYP3A4
in nonclinical data are well tolerated and safe in man as
isoform activity, with lesser contributions by the CYP2C8
opposed to amiodarone’s toxic effects on pulmonary and
and CYP2E1 isoforms.21 The Vx metabolite has not been
corneal function. Vx terminated AF in a preclinical in vivo
characterized chemically or pharmacologically.
animal model.13 An ongoing clinical trial to assess oral Vx’s
efficacy as an antiarrhythmic for treatment of AF showed
Discussion promising efficacy for acute termination of AF without proar-
Using in vitro techniques we initially demonstrated that, rhythmia and significant adverse effects (unpublished obser-
unexpectedly, Vx was a potent hK v 11.1 channel blocker. vations from ChanTest Corporation).
Since previous studies in man and mammals indicated no Vernakalant is a promising antiarrhythmic for treatment
cardiovascular risk for Vx,6 we evaluated Vx’s interactions of recent-onset AF,22 but fails to terminate atrial flutter.23 Vx
with other cardiac ion channels for offsetting effects. Subse- terminated both AF and atrial flutter in the canine sterile peri-
quently, we demonstrated that Vx was also a potent blocker carditis model.13 Dronedarone (derived from amiodarone) is
of cardiac Na and Ca currents, activities that can offset another recent antiarrhythmic targeting multiple ion chan-
hK v 11.1 block, and did not significantly prolong Purkinje nels with efficacy similar to amiodarone but with reduced
toxicity,24 like Vx. However, intravenous Vx is effective at
terminating recent-onset AF in minutes,13 while dronedarone
is likely to share the delayed onset of cardioversion seen with
amiodarone.25
Relationship between Pharmacokinetics of Vx in Man
and AF/AFL Termination
Phase I clinical trials of Vx indicated no significant effects
on ECG, heart rate, or blood pressure.6 In a dose-escalation
phase I study of Vx, 4 healthy males aged 20–45 years re-
ceived 100, 200, and 300 mg oral doses of Vx.8 At the 300-mg
dose, the peak plasma concentration (C max ) of Vx ranged up
to 831 nM (mean C max was 533 ± 109 nM). This mean value
is greater than the mean plasma concentration measured at
termination of sustained AF/AFL in the canine sterile peri-
Figure 3. Effect of Vx on Purkinje fiber action potential waveforms. Super- carditis model (399 ± 69 nM, n = 19).13 No adverse cardiac
imposed records before (control) and after sequential 20 minute equilibra- events (AEs) were reported for any of the doses. No sig-
tion periods with Vx at the indicated concentrations (0.01, 0.1, and 1 μM). nificant effects on heart rate (HR) or blood pressure (BP)
Temperature = 37 ± 1◦ C, BCL = 2 seconds. Vx did not cause significant occurred. At the 100 and 200 mg doses there was one oc-
changes in any of the measured action potential parameters (n = 3). currence of a slight reduction in the T-wave of the ECG.
 Lacerda et al. Cellular Electrophysiology of Vanoxerine 307

Figure 4. Effect of Vx on ventricular wedge action potential waveforms and transmural ECG. Transmural dispersion of repolarization was measured in the
canine ventricular wedge preparation (n = 8). Recordings from endocardial, midmyocardial and epicardial layers of the ventricular wall and the transmural
ECG are shown. The effects of Vx are similar to amiodarone and distinct from those of dofetilide, which has a proarrhythmic risk.

At the 300-mg dose all subjects had a reduction in T-wave rate, especially for Na and Ca channels, and the IC 50 values
amplitude; however, none were flat or negative. The Bazett’s for all 3 target channels became closer at fast physiological
corrected QT, QTc(B), was within the normal range (<0.47 frequencies. We believe Vx will demonstrate antiarrhythmic
seconds). efficacy because of its (1) potent block of hK v 11.1 com-
In a phase I study on relative oral bioavailability in 12 bined with strongly frequency-dependent block of cardiac
healthy men aged 22–34 years, a 100-mg single oral dose calcium and sodium currents; and (2) maintenance of TDR.
was well tolerated.10 In a 14-day repeat oral dosing phase Confirmation of Vx antiarrhythmic activity in the canine ster-
I study in 14 healthy men aged 19–33 years administered ile pericarditis model is presented in detail in a companion
doses up to 125 mg of Vx, noncardiac adverse events were paper.13
mild and generally of short duration.9 In these Phase I trials,
C max values exceeded the minimum plasma concentrations Limitations
measured at termination of AF/AFL in the canine sterile
pericarditis model. We showed that Vx was safe and effective for acute phar-
macological cardioversion of AF/AFL in an animal model,13
Preclinical Studies and initial clinical trial data show that Vx is safe for this in-
dication in man (ChanTest Corporation, unpublished data).
Vx was compared to dofetilide and amiodarone in the arte- Although the longest repeat dosing period used in Vx clin-
rially perfused canine ventricular wedge preparation. Vx was ical trials is 14 days and amiodarone pulmonary toxicity
similar to amiodarone in its small effects on action potentials typically develops over a longer period, amiodarone pul-
from the endocardial, midmyocardial, and epicardial ventric- monary toxicity can appear in a few days and in a third of
ular myocytes, transmural ECG, and TDR, and distinct from cases in weeks.28 Corneal microdeposits appear in weeks
the large changes associated with dofetilide. Increased TDR and occur in 76–100% of patients.29 We have not evaluated
is associated with proarrhythmia,19 and Vx’s lack of effect Vx’s potential to prevent AF/AFL experimentally, although
on TDR, similar to amiodarone, suggests that Vx is also not our initial experience with maintained intravenous dosing at
likely to be proarrhythmic. Independent studies with teleme- 1 mg/kg throughout the electrophysiology parameter mea-
tered conscious dogs found no adverse effects of oral Vx at surement period following termination prevented induction
doses up to 30 mg/kg.26 of AF/AFL on the following day. Stopping Vx infusion at
Predominantly, Class III hK v 11.1 blockers like sotalol and termination reduced the total dose of Vx and allowed ini-
dofetilide always carry the concern of proarrhythmia associ- tiation of sustained AF/AFL on the following experimental
ated with QT prolongation and hK v 11.1 block.27 However, days.13 Our oral dosing experiments were consistent with
other potent hK v 11.1 blockers like verapamil do not have the possibility that Vx might provide effective maintenance
a QT prolongation risk due to compensatory block of Ca therapy.30
channels at similar potency. We expected this would explain Vanoxerine is a substrate for CYP3A4, and drug interac-
the lack of QT prolongation risk for Vx, although the po- tions will need to be considered with its use.21 Metabolism
tencies at low frequencies for the Ca and Na compensatory of Vx by human liver microsomes, human hepatocytes,
currents were lower. However, Vx potency increased with and microsomes containing cDNA-expressed human P450
 308

TABLE 4
Vx, Dofetilide, and Amiodarone Modulation of APD 90 in the Canine Left Ventricular Wedgea

Epicardial Midmyocardial Endocardial

APD 90
BCL(s) 0.5 1 2 0.5 1 2 0.5 1 2

Vx (μM) % % % % % % % % %
0.01 −0.1 ± 0.7 (7) 1.1 ± 0.7 (7) 1.4 ± 0.6 (7) 1.2 ± 1.0 (7) 1.6 ± 0.4 (7) 0.6 ± 0.8 (7) 0.7 ± 0.5 (7) 2.6 ± 0.9 (7) 2.0 ± 1.5 (7)
0.03 0.0 ± 0.8 (8) 1.1 ± 0.8 (8) 2.8 ± 0.8 (8) 1.3 ± 0.7 (8) 2.2 ± 0.5 (8) 1.5 ± 0.8 (8) 0.9 ± 0.8 (8) 3.3 ± 0.8 (8) 2.8 ± 1.2 (8)
0.1 0.5 ± 1.1 (8) 2.0 ± 1.3 (8) 3.5 ± 0.5 (8) 2.3 ± 1.2 (8) 3.5 ± 0.5 (8) 2.8 ± 1.3 (8) −0.7 ± 1.4 (8) 4.2 ± 0.6 (8) 4.5 ± 1.9 (8)
0.3 2.1 ± 0.9 (8) 3.4 ± 1.2 (8) 4.2 ± 0.8 (8) 4.0 ± 0.7 (8) 5.5 ± 1.0 (8) 5.6 ± 1.2 (8) 0.4 ± 2.0 (8) 5.2 ± 0.9 (8) 6.9 ± 1.4 (8)
1 4.2 ± 1.2 (8) 4.8 ± 1.0 (8) 5.6 ± 0.8 (8) 4.4 ± 0.7 (8) 7.0 ± 0.9 (8)∗ 7.4 ± 1.1 (8) 3.4 ± 0.6 (8) 6.4 ± 0.7 (8) 8.7 ± 1.0 (8)
3 6.1 ± 1.8 (5)∗ 6.0 ± 1.2 (5) 5.1 ± 0.7 (5) 6.0 ± 0.9 (5) 6.9 ± 1.0 (5) 7.8 ± 1.3 (5) 4.8 ± 0.6 (5) 6.8 ± 0.7 (5) 9.8 ± 1.2 (5)
Dof (μM) % % % % % % % % %
0.01 11.7 ± 2.1 (6)∗ 8.9 ± 1.3 (6)∗ 7.4 ± 0.9 (6) 10.9 ± 1.9 (6)∗ 10.5 ± 1.8 (6)∗ 8.8 ± 1.3 (6) 11.9 ± 1.5 (6) 10.5 ± 2.0 (6) 10.7 ± 2.3 (6)
0.03 14.7 ± 1.4 (6)∗ 13.5 ± 1.8 (6)∗ 15.4 ± 1.3 (6)∗ 13.4 ± 2.0 (6)∗ 15.0 ± 1.3 (6)∗ 17.3 ± 1.4 (6)∗ 13.3 ± 2.9 (6)∗ 16.1 ± 3.7 (6) 18.3 ± 1.4 (6)∗
0.1 17.8 ± 2.0 (6)∗ 17.8 ± 1.7 (6)∗ 18.3 ± 1.6 (6)∗ 17.6 ± 2.6 (6)∗ 20.7 ± 1.8 (6)∗ 22.5 ± 1.8 (6)∗ 15.3 ± 2.4 (6)∗ 20.6 ± 3.5 (6)∗ 23.4 ± 1.6 (6)∗
0.3 19.0 ± 2.0 (6)∗ 20.2 ± 2.0 (6)∗ 20.7 ± 1.8 (6)∗ 21.5 ± 2.6 (6)∗ 22.3 ± 1.8 (6)∗ 24.7 ± 1.3 (6)∗ 18.1 ± 3.0 (6)∗ 23.2 ± 2.9 (6)∗ 26.2 ± 2.4 (6)∗
1 19.9 ± 1.9 (6)∗ 23.3 ± 1.9 (6)∗ 23.4 ± 1.5 (6)∗ 21.6 ± 2.8 (6)∗ 25.1 ± 2.1 (6)∗ 29.5 ± 1.9 (6)∗ 19.8 ± 1.6 (6)∗ 24.9 ± 3.2 (6)∗ 27.0 ± 2.7 (6)∗
Amio (μM) % % % % % % % % %
Journal of Cardiovascular Electrophysiology Vol. 21, No. 3, March 2010

0.01 1.2 ± 0.5 (4) 2.0 ± 0.8 (4) 1.8 ± 0.5 (4) 0.7 ± 0.3 (4) 0.8 ± 0.3 (4) 1.0 ± 0.9 (4) 0.0 ± 1.0 (4) 1.7 ± 0.8 (4) 0.7 ± 0.8 (4)
0.03 3.1 ± 0.7 (4) 3.1 ± 1.4 (4) 2.0 ± 0.4 (4) 0.1 ± 0.8 (4) 2.1 ± 0.5 (4) 1.9 ± 0.5 (4) −0.2 ± 0.8 (4) 2.4 ± 1.2 (4) 2.6 ± 1.0 (4)
0.1 1.2 ± 0.5 (4) 1.4 ± 0.6 (4) 2.7 ± 1.3 (4) 0.9 ± 1.0 (4) 1.9 ± 0.3 (4) 1.8 ± 0.7 (4) −1.3 ± 1.5 (4) 1.1 ± 1.0 (4) 2.2 ± 0.6 (4)
0.3 −2.1 ± 1.3 (4) −0.7 ± 1.4 (4) 0.7 ± 1.4 (4) −2.8 ± 2.3 (4) −2.6 ± 1.1 (4) −2.1 ± 1.2 (4) −4.7 ± 2.6 (4) −3.1 ± 3.7 (4) −0.9 ± 1.3 (4)
1 −2.3 ± 2.3 (4) −3.2 ± 2.7 (4) −2.8 ± 1.9 (4) −7.1 ± 4.1 (4) −5.5 ± 2.3 (4) −3.1 ± 1.6 (4) −5.8 ± 3.5 (4) −4.6 ± 4.1 (4) −2.8 ± 1.2 (4)
3 −3.9 ± 2.6 (4) −5.3 ± 3.8 (4) −4.2 ± 3.1 (4) −4.6 ± 3.7 (4) −4.9 ± 1.8 (4) −4.2 ± 2.1 (4) −9.1 ± 4.8 (4) −9.4 ± 5.4 (4) −4.3 ± 1.2 (4)
10 −6.4 ± 2.0 (4)∗ −8.9 ± 2.5 (4)∗ −10.8 ± 5.2 (4)∗ −36.0 ± 21.4 (4)∗ −13.1 ± 4.3 (4)∗ −12.0 ± 4.9 (4)∗ −9.7 ± 4.4 (4) −14.2 ± 3.9 (4) −10.6 ± 4.0 (4)∗
∗ Statistically significant change from control (P < 0.05) using ANOVA and Dunnett’s multiple comparison test.
a Data are shown as mean ± SEM (n). Vx = vanoxerine; Dof = dofetilide; Amio = amiodarone.
 Lacerda et al. Cellular Electrophysiology of Vanoxerine 309

TABLE 5
Vx, Dofetilide, and Amiodarone Modulation of the QT and TDR Intervals in the Canine Left Ventricular Wedgea

QT TDR
BCL(s) 0.5 1 2 0.5 1 2

Vx (μM) % % % % % %
0.01 0.7 ± 1.0 (6) 1.5 ± 1.4 (8) 0.8 ± 0.7 (8) 3.2 ± 13.2 (6) 1.6 ± 5.9 (7) 1.7 ± 3.2 (8)
0.03 2.4 ± 2.1 (7) 1.9 ± 1.8 (8) 1.3 ± 1.1 (8) −3.3 ± 16.6 (7) 1.6 ± 5.2 (8) 4.5 ± 3.5 (8)
0.1 3.0 ± 0.6 (7) 2.3 ± 1.6 (8) 2.8 ± 1.2 (8) 16.1 ± 16.6 (7) 3.0 ± 5.8 (8) 10.0 ± 4.4 (8)
0.3 4.8 ± 1.1 (8) 4.5 ± 1.5 (8) 5.0 ± 0.8 (8) 9.2 ± 18.2 (8) 4.4 ± 6.4 (8) 12.4 ± 3.3 (8)
1 3.6 ± 1.9 (7) 6.5 ± 0.9 (8) 7.3 ± 0.7 (8) 6.8 ± 18.2 (8) 5.5 ± 6.3 (8) 18.5 ± 3.2 (8)
3 4.1 ± 7.1 (2) 6.8 ± 1.1 (5) 6.7 ± 0.5 (5) 8.7 ± 31.3 (5) 7.0 ± 6.9 (5) 15.8 ± 4.3 (5)
Dof (μM) % % % % % %
0.01 9.2 ± 1.0 (6)∗ 10.5 ± 1.0 (6)∗ 9.2 ± 1.2 (6)∗ 20.4 ± 9.3 (6) 9.9 ± 14.6 (6) 8.8 ± 4.7 (6)
0.03 11.5 ± 0.9 (6)∗ 15.0 ± 1.2 (6)∗ 15.4 ± 1.8 (6)∗ 14.7 ± 11.6 (6) 17.0 ± 17.2 (6) 12.5 ± 4.7 (6)
0.1 16.4 ± 1.2 (6)∗ 20.5 ± 1.4 (6)∗ 20.3 ± 1.8 (6)∗ 32.2 ± 19.2 (6) 27.4 ± 18.9 (6) 23.3 ± 6.4 (6)
0.3 16.8 ± 1.2 (6)∗ 22.4 ± 0.6 (6)∗ 22.9 ± 1.8 (6)∗ 19.8 ± 15.7 (6) 30.7 ± 13.2 (6) 28.1 ± 3.1 (6)
1 18.2 ± 1.9 (6)∗ 24.8 ± 1.1 (6)∗ 28.0 ± 1.8 (6)∗ 19.9 ± 11.7 (6) 41.0 ± 14.1 (6)∗ 44.3 ± 2.6 (6)∗
Amio (μM) % % % % % %
0.01 1.1 ± 0.8 (4) 0.3 ± 0.2 (4) 1.6 ± 0.8 (4) 3.4 ± 2.6 (4) 1.3 ± 1.0 (4) 5.5 ± 2.8 (4)
0.03 1.5 ± 1.1 (4) 1.6 ± 0.5 (4) 2.3 ± 0.8 (4) 4.6 ± 5.6 (4) 5.3 ± 4.5 (4) 10.8 ± 2.2 (4)
0.1 −0.5 ± 1.6 (4) 0.4 ± 0.6 (4) 1.8 ± 1.0 (4) −1.6 ± 8.1 (4) 0.5 ± 6.4 (4) 7.5 ± 1.6 (4)
0.3 −1.1 ± 0.8 (4) −2.6 ± 1.1 (4) −2.2 ± 1.3 (4) −3.1 ± 8.6 (4) −13.3 ± 11.3 (4) 0.3 ± 5.9 (4)
1 −2.7 ± 1.1 (4) −4.5 ± 1.8 (4) −3.9 ± 2.2 (4) −1.0 ± 12.3 (4) −12.9 ± 11.4 (4) −4.1 ± 7.8 (4)
3 −2.3 ± 1.9 (4) −6.9 ± 1.5 (4)∗ −5.6 ± 2.4 (4) 0.7 ± 18.7 (4) −28.7 ± 10.6 (4) −8.4 ± 5.4 (4)
10 −6.8 ± 2.1 (2) −13.5 ± 0.3 (3)∗ −10.3 ± 2.9 (4)∗ −21.3 ± 44.4 (2) −31.2 ± 11.7 (3) −14.0 ± 8.4 (4)
∗ Statistically significant change from control (P < 0.05) using ANOVA and Dunnett’s multiple comparison test.
a Data are shown as mean ± SEM (n).
Vx = Vanoxerine; Dof = dofetilide; Amio = amiodarone.

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