(Circulation. 1995;92:2944-2950.)
© 1995 American Heart Association, Inc.
Articles |
Antiarrhythmic Activity of Quinine in Humans
From the Cardiovascular Research Group, University of Calgary, Calgary, Alberta, Canada.
Correspondence to Dr Robert Sheldon, Division of Cardiology, Calgary General Hospital, 841 Centre Avenue East, Calgary, Alberta, Canada T2E 0A1.
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Abstract |
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Background Quinine is the diastereomer of quinidine. In dogs, it has similar effects on conduction time but does not prolong epicardial repolarization time or ventricular refractoriness. It has antiarrhythmic effects in both cats and dogs. We assessed the antiarrhythmic potential of quinine in suppressing ventricular arrhythmias in humans.
Methods and Results Patients underwent open-label, dose-ranging trials of quinine with daily doses of 600, 1200, and 1800 mg in a twice-daily dosing regimen. In 17 patients with frequent spontaneous ventricular ectopy, oral quinine suppressed arrhythmia in 11 of 12 patients who finished the study and was not tolerated by 4 patients, and 1 patient withdrew from the study. The mean effective daily dosage was 927 mg, the mean effect trough serum level was 11 µmol/L (range, 4 to 17 µmol/L), and the half-life was 20±7 hours. In a second open-label, dose-ranging trial in 10 patients with inducible ventricular tachycardia and reduced left ventricular systolic function (left ventricular ejection fraction, 35±16%), quinine suppressed inducibility of ventricular tachycardia in 3 of 10 patients. At a basic pacing cycle length of 500 milliseconds, ventricular effective refractory period was prolonged (279±21 versus 247±10 milliseconds, quinine versus drug free, P=.003). In the remaining patients, ventricular tachycardia cycle length was prolonged (373±48 versus 253±30 milliseconds, quinine versus drug free, P<.001). The corrected QT interval was not prolonged.
Conclusions Quinine is an effective and convenient antiarrhythmic drug for the suppression of ventricular arrhythmias in humans.
Key Words:
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Quinine is the diastereomer of quinidine. Both stereoisomers block the cardiac sodium channel, but only quinidine prolongs action potential duration in vitro and repolarization time in vivo in dogs.1 2 3 4 These results suggested that quinine might be an effective antiarrhythmic drug without the potential for excessive prolongation of repolarization, resulting in torsades de pointes.5
Several studies have addressed the antiarrhythmic potential of quinine in animal models. Klevans et al6 showed that both quinidine and quinine raised ventricular fibrillation thresholds in cats and decreased ouabain-induced premature ventricular complexes in dogs. Jurkiewicz et al2 reported that both isomers were equally effective in preventing ventricular tachycardia and ventricular fibrillation in a canine model of acute ischemia. We used a canine model of inducible ventricular tachycardia late after occlusion-reperfusion injury in dogs7 to compare the electrophysiological and antiarrhythmic properties of quinine and quinidine.8 Both drugs prolonged conduction times to a similar extent, but quinidine prolonged local epicardial repolarization time8 and refractoriness significantly more than did quinine. Limited antiarrhythmic efficacy was seen only with quinidine, and only quinidine prolonged ventricular tachycardia cycle length. Therefore, the data about the antiarrhythmic effects of quinine in animals were inconclusive.
The purpose of the present study was to evaluate the antiarrhythmic potential of quinine in suppressing spontaneous and inducible ventricular arrhythmias in humans. Our primary goal was to determine the ability of oral quinine in open-label, dose-ranging protocols to suppress spontaneous and inducible ventricular arrhythmias. Also, we wanted to determine its ECG and electrophysiological characteristics. In addition, we wanted to establish dose-concentration, dose-response, and concentration-response relations.
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Methods |
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Study Designs
There were two studies. Study 1 was an open-label, dose-ranging protocol, with each step lasting 3 to 5 days. This interval was selected based on two pharmacokinetic studies in malarial patients9 and patients with quinine overdoses10 that estimated quinine mean half-lives of 11 to 27 hours. Patients initially received 600 mg quinine daily in a twice-daily dosing regimen. Efficacy by ambulatory ECG and side effects were assessed after 3 to 5 days, and individuals with neither efficacy nor side affects then received 1200 mg quinine daily in a second step. If necessary, patients also received quinine 1800 mg daily in a third step. The doses of quinine were selected based on earlier animal data suggesting that serum levels of 10 to 30 µmol/L might be necessary to demonstrate efficacy.8 The oral doses necessary to establish these levels were estimated from a compilation of dose-response data of quinine in malaria.9 11 12 13 The maximum dose was selected to keep quinine levels at <30 µmol/L to avoid ocular and aural toxicity.9 10 13
Patients were allowed to withdraw at any time, and all patients who entered the study are reported. Study 1 was conceived and completed before publication of the results of the Cardiac Arrhythmia Suppression Trial.14 15
Study 2 was similar in
design to study 1, but patients received the
maximum tolerated dose of quinine before undergoing evaluation of drug
effectiveness by programmed electrical stimulation. Assessments of drug
efficacy using either ECG, ambulatory ECG, or programmed electrical
stimulation were performed after a minimum period of 72 hours on the
relevant quinine dose. This interval was selected based on an estimated
mean half-life of 19 hours9 10 and was intended to
correspond to 
4 half-lives. At this interval, the serum
concentration should be within 6% of a theoretical steady state level.
The ambulatory ECG studies spanned two drug doses, and the invasive
studies were performed 3 to 9 hours after a quinine dose.
All patients who entered the protocol are reported. All patients gave informed consent, and both studies were approved by the University of Calgary Conjoint Medical Ethics Committee.
Patient Selection
In study 1, adult patients were eligible
for inclusion if they
had 30 or more premature ventricular complexes per hour
during 24-hour ambulatory ECG. In study 2, adult patients were eligible
for inclusion if they had reproducibly inducible sustained monomorphic
ventricular tachycardia in the setting of
structural heart disease and had either not tolerated or failed to
respond to at least one other antiarrhythmic drug during programmed
electrical stimulation. Sustained ventricular
tachycardia was defined as consecutive
ventricular depolarizations 
120 beats per minute lasting
>30 seconds or requiring cardioversion because of
hemodynamic deterioration. Patients were excluded from
both studies if they had developed side effects from quinidine, might
become pregnant, had New York Heart Association Class III or IV
congestive heart failure, had received amiodarone, or were
receiving other antiarrhythmic drugs that could not be
discontinued.
12-Lead ECG
Recordings were made at a speed of 25 mm/s.
Rate-corrected repolarization times (QTc) were
calculated using Bazett's formula (QTc=QT/
RR).
Rate-corrected JT intervals (JTc) were calculated using
the formula JTc=(QT—QRS)/RR. ECGs with
bundle-branch block or ventricular pacing were excluded
from QTc and JTc measurements.
Ambulatory ECG
Two-channel ambulatory ECG recordings were
analyzed with computer assistance using the Marquette 8000
Scanner with version 5.7 of the Marquette Arrhythmia
Analysis program to identify and label each QRS. Tapes
unsuitable for automated analysis were fully disclosed, and
arrhythmias were counted manually. Records with less than
18 hours of analyzable ECG tracings were excluded.
Electrophysiological Studies
A conventional protocol was
used.16 Single, double,
and triple extrastimuli were introduced during diastole
after eight-beat trains of ventricular pacing cycle
lengths of 600, 500, and 400 milliseconds (ms) at the right
ventricular apex, followed if necessary by alternating
trains of 4 and 15 beats in duration of rapid ventricular
pacing at cycle lengths of 300 to 240 ms in 10-ms decrements. The
minimum extrastimulus coupling interval was 180 ms. If
ventricular tachycardia was not reproducibly
induced, the stimulation protocol was repeated from the right
ventricular outflow tract and, if necessary, during an
infusion of isoproterenol. At baseline, the end point was considered to
be completion of the protocol or reproducible induction of sustained
ventricular tachycardia lasting >30 seconds or
requiring early termination because of hemodynamic
deterioration.
Quinine Levels
Serum from study 1 patients was obtained for
quinine levels
either 30 minutes preceding a dose to determine trough levels or
periodically after discontinuation of quinine to determine the
pharmacokinetic half-life. Quinine levels were assayed using
high-pressure liquid
chromatography.8
Radionuclide Ventriculography
Left ventricular ejection
fraction was determined by
quantitative radionuclide ventriculography using the multiple-gated
blood pool equilibrium method.17 Ejection fractions were
measured in study 2 patients in the absence of antiarrhythmic agents
and negative inotropic agents and subsequently while receiving
quinine.
Criteria for Drug Efficacy
In study 1, a drug dose was deemed
to be effective if it
suppressed at least 80% of single premature ventricular
complexes, 90% of couplets, and 100% of runs of
ventricular tachycardia (three or more
consecutive premature ventricular complexes at a rate 120
min-1).16 In study 2, a drug dose was deemed
to be effective if fewer than 16 beats of ventricular
tachycardia could be induced despite the application of up
to three extrastimuli at basic pacing cycle lengths of 600, 500, and
400 ms and burst pacing at the same pacing site at which
ventricular tachycardia was originally
induced.16
Statistical Analysis
Results are expressed as mean±SD.
One-way ANOVA was used to
compare the differences between multiple groups. The differences
between subgroups were tested with the Newman-Keuls test. Student's
t tests (paired or unpaired) were used to compare
differences between pairs of groups. The correlation of continuous
variables between groups was determined by linear regression
analysis. The null hypothesis was rejected at a level of
P<.05.
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Results |
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Twenty-four subjects participated in these studies. Of these, 17 participated in study 1, 10 participated in study 2, and 3 participated in both studies. Data common to both studies are presented first.
ECG Characteristics
ECG data were obtained from all 24
subjects in studies 1 and 2 who
were in the drug-free state, 23 subjects receiving 600 mg quinine
daily, 15 subjects receiving 1200 mg quinine daily, and 6 subjects
receiving 1800 mg daily. The data in the Table
document
mean resting heart rate, QRS duration, QT interval, and QTc
interval in the total study population (top), study 1 (middle), and
study 2 (bottom). Mean QRS duration was significantly longer in
subjects receiving 1200 mg quinine daily than in drug-free patients
(120±41 versus 91±23 ms, P<.05, Newman-Keuls test).
In
study 1 patients, the QRS durations in drug-free patients and
patients receiving quinine 1200 mg daily were 81±11 and 93±16
ms,
respectively, whereas the QRS durations in comparable study 2 patients
were 106±27 versus 143±37 ms. The small number of patients who
received quinine 1800 mg daily precluded the use of ANOVA in
study 1 and study 2.
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To explore further the effects of quinine on ECG
characteristics, we
analyzed the differences in 15 drug-free patients and the
same patients receiving quinine 1200 mg daily. The use of quinine
increased QTc by 22±59 ms, increased QRS duration by
22±27 ms, and increased JTc by 2±53 ms. Multiple
linear
regression analysis revealed the relation (
QTc),
ms=(2 ms+1.0 ([QRS]), ms+1.0
([JTc]), ms
(r2=.95, P<.001). Although
the effects of quinine on QTc and JTc were
closely correlated (r=.85), the direction of these effects
were variable, as manifest by the change in JTc of
2±53 ms. In contrast, quinine increased QRS duration, and this also
correlated with an increase in QTc interval
(r=.46).
Suppression of Spontaneous Ventricular
Arrhythmias (Study 1)
The mean age of the subjects in study 1 was
61±8 years, and 14 of
17 were men. Fourteen had structurally normal hearts and were either
asymptomatic or had palpitations, whereas 3 had old
myocardial infarctions and presented with sustained
ventricular tachyarrhythmias. The mean
baseline frequency of ventricular arrhythmias in
all 17 enrolled patients was 468±580 premature ventricular
complexes per hour, 14±23 couplets per hour, and 4±8 runs of
nonsustained ventricular tachycardia per
hour.
During quinine daily doses of 600, 1200, and 1800 mg in study 1
patients, the quinine trough serum levels were 9.0±3.7,
11.7±3.4, and
19.0±2.7 µmol/L, respectively. Data for the rate of disappearance
of
quinine from serum after drug discontinuation were obtained from 7
subjects. Fig 1 shows that quinine was cleared
monoexponentially with a mean half-life of 20±7
hours (range, 11.2 to 27.5 hours). These data support the
appropriateness of twice-daily dosing and suggest that
dose-ranging steps of 3 to 5 days allow serum levels to approach
steady state.
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Of the 17 patients in study 1, 12 completed the protocol.
Of the 5
patients who withdrew, 2 had gastrointestinal side effects, 1 had
tinnitus, 1 was noncompliant, and 1 had flulike symptoms. An effective
and tolerated dose of quinine was found for 11 of 12 patients (92%),
and 1 patient did not respond to 1800 mg quinine daily. In the 11
responding patients, the mean baseline frequency of
ventricular arrhythmias was 334±335 premature
ventricular complexes per hour, 16±27 couplets per hour,
and 4±8 runs of ventricular tachycardia per
hour. The mean frequency of ventricular arrhythmias
at the well-tolerated and effective quinine dose was 16±27
premature ventricular complexes per hour, 0.25±0.42
couplet per hour, and no ventricular
tachycardia. The individual data for the 11 suppressed
patients and 1 incompletely suppressed patient are shown in Fig
2. No patients had proarrhythmia or new
heart block on quinine.
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The dose-response relation is as follows. Of
the 17 patients who
received quinine 600 mg daily and underwent ambulatory ECG, 6 had
suppression of ventricular arrhythmias. Of the 11
patients who received quinine 1200 mg daily, 5 withdrew and 4 of 6 had
effective suppression of ventricular arrhythmias.
Of the 2 patients who received quinine 1800 mg daily, 1 had suppression
of ventricular arrhythmias. On an
intent-to-treat basis, the three doses of quinine were
cumulatively effective in 35%, 59%, and 65% of 17 patients. On a
therapy-delivered basis, the three doses of quinine cumulatively
were effective in 33%, 83%, and 92% of 12 patients (Fig 3). The
numbers of patients responding to each dose were
6 patients receiving 600 mg daily, 4 receiving 1200 mg daily, and 1
receiving 1800 mg daily. The mean daily effective dose was 927 mg.
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The
relation between quinine trough levels and the probability of
antiarrhythmic response is shown in Fig 4. There is an
apparently linear relation between the cumulative response rate and
serum quinine level. The quinine trough level that was associated with
an antiarrhythmic response in 50% of subjects was 11±5 µmol/L, and
the range of effective concentrations was 4 to 17 µmol/L.
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In summary, oral quinine was well tolerated in 12 of 17 subjects (71%) and effectively suppressed spontaneous ventricular arrhythmias in 11 of 12 completely evaluable subjects (92%). The mean effective daily dose was 927 mg, and the mean effective trough serum level was 11±5 µmol/L.
Suppression of Inducible Ventricular
Tachycardia (Study 2)
The ability of oral quinine to prevent the
induction of sustained
monomorphic ventricular tachycardia was tested
in 10 male subjects with structural heart disease and inducible
ventricular tachycardia. Their mean age was
67±6 years, 9 had had an old myocardial infarction, and 1 had a
dilated cardiomyopathy. The mean left
ventricular ejection fraction was 35±16%. One
presented with a cardiac arrest, 7 with sustained
ventricular tachycardia and syncope or
presyncope, and 2 with sustained ventricular
tachycardia and angina and dyspnea. Each of the 10 subjects
had failed to respond to at least one antiarrhythmic drug (quinidine or
procainamide, 7; mexiletine and either quinidine or
procainamide, 2; propafenone, 2; sotalol, 2).
Six patients had received quinidine before receiving quinine. While on quinidine, 2 had torsades de pointes and a third had a cardiac arrest due to ventricular fibrillation. An additional 2 patients developed markedly long QT intervals without torsades de pointes, and the sixth patient had inducible ventricular tachycardia while taking quinidine. None had evidence of these events while taking quinine.
The highest tolerated daily quinine
doses during which patients
underwent electrophysiological studies were
600 mg (n=1), 1200 mg (n=7), and 1800 mg (n=2). The mean
daily dose of
quinine was 1260±340 mg. There were no significant differences in
His-to-ventricle times between patients who were drug free and
those who were receiving quinine (55±18 versus 60±17 ms,
respectively). However, ventricular effective refractory
periods increased significantly during treatment with quinine. At a
basic pacing cycle length of 500 ms, the effective refractory period
increased from 247±10 to 279±21 ms (n=10,
P=.003, paired
t test). The individual data obtained a pacing cycle length
of 500 ms are shown in Fig 5. Similarly, at a pacing
cycle length of 600 ms, the effective refractory period increased from
255±9 to 291±23 ms (n=8, P=.002), and at
a pacing cycle
length of 400 ms, the refractory period increased from 254±10 to
284±21 ms (n=7, P=.012). In 6 patients who
received
quinidine before quinine, the QTc intervals were 513±69
and 434±53 ms for quinidine and quinine, respectively
(P=.013).
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Quinine prevented ventricular tachycardia
induction in 3 of 10 patients. Two of these 3 patients had developed
torsades de pointes while taking quinidine. In the remaining 7 of 10
patients, quinine prolonged ventricular
tachycardia cycle length from 253±30 to 373±48 ms
(P<.001). The change in cycle length did not correlate with
changes in QRS duration or QTc interval. The individual
cycle length data are shown in Fig 6. Quinine also
improved the symptomatic outcome of the
electrophysiological study: in the absence
and presence of quinine, 7 and 1 of 10 patients, respectively, became
syncopal and required cardioversion. No patients had
proarrhythmia or new heart block on quinine.
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The effect of quinine on systolic left ventricular function was assessed by measuring left ventricular ejection fraction in study 2 in drug-free patients and in patients receiving quinine. There was no significant difference between drug-free patients (left ventricular ejection fraction, 35±16%) and patients receiving quinine (left ventricular ejection fraction, 31±13%).
Eight patients left hospital on quinine. None of 3 patients rendered noninducible by quinine have had recurrences after 24, 41, and 49 months. Of 5 patients receiving quinine as a "second-best" treatment, 3 had well-tolerated recurrences after 1 day, 3 months, and 7 months, and 1 developed side effects after 4 months and required readmission for medication change.
In summary, oral quinine suppressed ventricular tachycardia induction in 3 of 10 patients and markedly prolonged ventricular refractoriness and ventricular tachycardia cycle length.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The data in this report demonstrate the antiarrhythmic potential of quinine, the diastereomer of quinidine. Quinine was selected for study because it has similar sodium channel–blocking properties as quinidine, has a known side effect profile, and has a conveniently long half-life in malarial patients. Unlike quinidine, quinine has relatively little effect on epicardial repolarization time in vitro or in vivo or QT interval in vivo and thus offers the potential of antiarrhythmic efficacy without the proarrhythmic potential of causing torsades de pointes.5
Antiarrhythmic Efficacy and Tolerance
On an intent-to-treat
basis, quinine suppressed
spontaneous ventricular arrhythmias using
conventional suppression criteria in 11 of 17 patients (65%). On a
treatment-delivered basis, quinine suppressed spontaneous
ventricular arrhythmias in 11 of 12 patients
(92%). These response rates compare well with those of the Cardiac
Arrhythmia Pilot Study,18 in which 52% to 83% of
patients responded to the class I antiarrhythmic drug to which they
were first randomized. The drugs in this study were encainide,
flecainide, morizicine, and imipramine.
Similarly, quinine suppressed inducible ventricular tachycardia in 3 of 10 patients, each of whom had failed to tolerate or respond to at least one previous antiarrhythmic drug. This antiarrhythmic efficacy is comparable to other antiarrhythmic drugs. Quinine also caused significant prolongation of ventricular tachycardia cycle length in the remaining patients.
Although quinine was generally well tolerated, 4 of 17 subjects (24%) dropped out of study 1 due to intolerance. Quinine had no significant effect on left ventricular ejection fraction in patients with structural heart disease and sustained ventricular tachycardia. None of the 24 subjects developed proarrhythmia or heart block, and neither of the patients who developed torsades de pointes on quinidine had this arrhythmia on quinine. Thus, quinine effectively suppresses both spontaneous and inducible ventricular arrhythmias but has an appreciable side effect profile, even in a healthy, ambulatory population.
Drug Levels
The desirable characteristics of a clinically
useful drug include
not only a reasonable benefit/toxicity profile but also a convenient
dosing interval and predictable dose-response and
concentration-response relations. Two previous pharmacokinetic
studies of quinine have been reported. White et al9 showed
that the mean half-life of quinine in malarial patients was 17
hours and that this dropped to 11 hours when patients were studied
after recovery. Bateman et al10 reported the mean
half-life of quinine in patients with clinical toxicity due to
quinine overdosage to be 26 hours. Given this range of estimates, we
believed that it was warranted to determine the elimination
half-life of quinine in aging patients with ventricular
arrhythmias. We report that quinine is cleared
monoexponentially with a half-life of 20±7 hours,
which is consistent with the previous findings. Most patients
who responded to quinine did so at doses of 600 to 1200 mg daily with
an effective mean daily dose of quinine for suppressing spontaneous
ventricular ectopy of 927 mg. These doses are below typical
antimalarial daily doses of 30 mg/kg, or 2.1 g/day for a 70-kg
person,9 and produced a mean effective trough serum
concentration of 11 µmol/L. The antiarrhythmic response to quinine
was linearly related to serum quinine levels. Thus, the therapeutic
response to quinine has predictable dose-response and
concentration-response relations and demonstrated no
proarrhythmia or heart block, and the serum half-life
is sufficiently long that once- or twice-daily drug administration
is feasible.
Electrophysiological Effects of
Quinine
This is the first report to document the
electrophysiological effects of quinine in
humans. Like quinidine, quinine is a sodium channel–blocking
agent. It binds to the class I antiarrhythmic drug receptor on freshly
isolated cardiac myocytes3 and prolongs conduction time in
dogs,1 2 8 both in vitro and in vivo.
Consistent
with this, we have shown that it prolongs surface QRS duration
(P<.05) in patients receiving 1200 mg of quinine daily. In
contrast to quinidine, quinine has very little effect on QT intervals,
even in patients with inducible ventricular
tachycardia. The increase in QTc in patients
who received quinine 1200 mg daily was 22±59 ms, but of this
relatively little (2±53 ms) was due to an increase in JTc.
QTc was also significantly shorter in patients receiving
quinine than in the same patients who received quinidine. These data
are consistent with the negligible effects of quinine in dogs
on action potential duration in vitro1 2 and
epicardial
repolarization time in vivo8 and suggest that quinine may
have at most a minor effect on the potassium currents blocked by
quinidine.
In light of this, the marked prolongation of refractoriness by quinine is a striking finding. This may be due to an interaction of quinine with the sodium channel, given the correlation between the prolongation of QRS duration and repolarization time. Quinine is known to bind to the class I drug receptor associated with the cardiac sodium channel3 and decreases the maximum velocity of the upstroke of the action potential in canine Purkinje fibers.4 Quinine appears to differ from propafenone,17 18 which prolongs conduction time, prevents induction of ventricular tachycardia, prolongs ventricular tachycardia cycle length, but does not prolong refractoriness.
Potential Study Limitations
Quinine is a sodium
channel–blocking drug, and the routine
use of these drugs for the suppression of asymptomatic
ventricular arrhythmias using spontaneous
suppression is no longer advocated.14 15 Also, the
usefulness of the selection of effective class I drugs with programmed
electrical stimulation has been called into question by the results of
the ESVEM study,21 although debate continues regarding the
structure and implications of this study (16). Two potential
limitations arise due to the patient population and the mode of testing
of drug efficacy. Only 3 of 17 study 1 patients had coronary
artery disease, and therefore the study 1 population might be expected
to be more responsive to antiarrhythmic therapy and less prone to
proarrhythmic effects. Thus, the study might overestimate the response
to quinine of patients with structural heart disease. Second, quinine
was judged to be effective if no more than 16 beats of
ventricular tachycardia could be induced
throughout a complete study and at the same site at which it was
originally induced. Possibly more stringent criteria, such as
suppressing inducibility to no more than four beats or performing a
complete drug study at two sites, might have resulted in a lower
estimate of the efficacy of quinine. However, optimal protocol and
criteria have not been defined or adopted universally, and our criteria
are broadly representative of other
centers.16 Finally, changing criteria would not have
altered the other electrophysiological
effects reported here or changed the noted effect on
ventricular tachycardia cycle length.
Second, the effect of quinine on atrial myocardium and atrioventricular nodal tissue has not been determined.
A third potential limitation is the small size of this study, which prevented meaningful conclusions on the long-term outcome of patients taking quinine. The small size of the study might account for our inability to demonstrate that quinine prolongs the HV interval, as would be expected of a sodium channel–blocking drug. However, the purpose of this study was to determine the antiarrhythmic potential of quinine, and as such was ethically limited to a small number of patients.
Quinine has several interesting features that suggest further investigation and use. It is reasonably well tolerated, has a long half-life that should allow once- or twice-daily use, does not significantly depress left ventricular ejection fraction, and should not cause torsades de pointes. In patients with sustained ventricular tachycardia, quinine may be useful in slowing ventricular tachycardia, thereby being an effective "second-best" medication.22 The latter effect may be useful in patients receiving frequent shocks from implantable defibrillators for rapid ventricular tachycardia. Quinine may slow ventricular tachycardia to a rate not associated with hemodynamic compromise and therefore more amenable to antitachycardia pacing therapies.23
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Acknowledgments |
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This work was supported by grants from the Medical Research Council of Canada, Ottawa, Ontario (PG11188), and the Calgary General Hospital and Foothills Hospital Research and Development Committees, Calgary, Alberta, Canada. Dr Sheldon was a Scholar of the Heart and Stroke Foundation of Canada, and Dr Duff is a Scientist of the Alberta Heritage Foundation for Medical Research.
Received March 20, 1995; revision received June 12, 1995; accepted June 25, 1995.
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References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
-
Mirro MJ, Watanabe AM, Bailey JC.
Electrophysiologic effects of the optical isomers of
disopyramide and quinidine in the dog: dependence of
stereochemistry. Circ Res. 1981;48:867-874.
[Abstract/Free Full Text]
-
Jurkiewicz MK, Rodzinski JA, Colatsky TA.
Antiarrhythmic action of quinidine: relative importance of QT
prolongation versus use dependence.
Circulation. 1985;71(suppl II):II-225. Abstract.
-
Hill RJ, Duff HJ, Sheldon RS. Determinants of
stereospecific binding of type I antiarrhythmic drugs to cardiac sodium
channels. Mol Pharmacol. 1988;34:659-663. [Abstract]
-
Bird LB, Colatsky TJ. Use-dependent block
of Vmax by quinidine in dog Purkinje fibres is not
stereospecific. Circulation. 1985;72(suppl
III):III-38.
-
Sasyniuk BI, Valois M, Toy W. Recent advances
in understanding the mechanisms of drug-induced torsades de pointes
arrhythmias. Am J Cardiol. 1989;64:29J-32J. [Medline]
[Order article via Infotrieve]
-
Klevans LR, Kelly RJ, Kovaco JL. Comparison of
the antiarrhythmic activity of quinidine and quinine.
Arch Int Pharmacodyn. 1978;227:57-68.
-
Duff HJ, Martin JME, Rahmberg M.
Time-dependent change in electrophysiologic milieu following
myocardial infarction in conscious dogs.
Circulation. 1988;70:209-220.
[Abstract/Free Full Text]
-
Sheldon RS, Rahmberg M, Duff HJ.
Quinidine/quinine: stereospecific electrophysiologic and
antiarrhythmic effects in a canine model of ventricular
tachycardia. J Cardiovasc
Pharmacol. 1990;16:818-823. [Medline]
[Order article via Infotrieve]
-
White NJ, Looareesuwan S, Warrell DA, Warrell MJ,
Dunnog D, Harinasuta T. Quinine pharmacokinetics and toxicity in
cerebral and uncomplicated falciparum malaria. Am J
Med. 1982;73:564-572. [Medline]
[Order article via Infotrieve]
-
Bateman DN, Blain PG, Woodhouse KW, Rawling MD,
Duyson H, Heyworth R, Prescott LF, Proudfoot AT.
Pharmacokinetics and clinical toxicity of quinine overdosage:
lack of efficacy of techniques intended to enhance elimination.
Q J Med New Ser. 1985;54:125-131.
-
Shannon JA, Earle DP, Berliner RW, Taggart JV.
Studies on the chemotherapy of the human malarias, I: method of
the quantiative assay of suppressive antimalarial action in vivax
malaria. J Clin Invest. 1948;27:66-74.
-
Earle DP, Berliner RW, Taggart JV, Welch WJ, Zubrod CG,
Wise NG, Chalmers TC, Greif RL, Shannon JA. Studies on the
chemotherapy of the human malarias, II: method of the quantitative
assay of suppressive antimalarial action in falciparum malaria.
J Clin Invest. 1948;27:75-79.
-
Taggart JV, Earle DP, Berliner RW, Aubrod CG, Welch WJ,
Wise NB, Schroeder EF, London IM, Shannon JA. Studies on the
chemotherapy of the human malarias, III: the
physiological disposition and antimalarial activty
of the cinchona alkaloids. J Clin Invest. 1947;27:80-86.
-
Cardiac Arrhythmia Suppression Trial (CAST)
Investigators. Effect of encainide and flecainide on mortality
in a randomized trial of arrhythmia suppression after
myocardial infarction. N Engl J Med. 1992;321:406-412. [Abstract]
-
Cardiac Arrhythmia Suppression Trial (CAST)
Investigators. Effect of the antiarrhythmic agent moricizine on
survival after myocardial infarction. N Engl J
Med. 1992;327:227-233. [Abstract]
-
Mitchell LB, Duff HJ, Manyari DE, Wyse DG. A
randomized clinical trial of the noninvasive and invasive approaches to
drug therapy of ventricular
tachycardia. N Engl J Med. 1987;317:1681-1687. [Abstract]
-
Sheldon RS, Mitchell LB, Duff HJ, Wyse DG, Manyari DE,
Reynolds K. Right and left ventricular function
during chronic amiodarone therapy. Am J
Cardiol. 1988;62:736-740. [Medline]
[Order article via Infotrieve]
-
Cardiac Arrhythmia Pilot Study (CAPS)
Investigators. Effects of encainide, flecainide, imipramine and
moricizine on ventricular arrhythmias during the
year after acute myocardial infarction: the CAPS. Am J
Cardiol. 1988;61:501-509. [Medline]
[Order article via Infotrieve]
-
Breithard G, Borggrefe M, Wiebringhaus E, Seipel L.
Effect of propafenone in the Wolff-Parkinson-White syndrome:
electrophysiologic findings and long-term follow-up.
Am J Cardiol. 1984;54:29D-39D. [Medline]
[Order article via Infotrieve]
-
Prystowsky EN, Heger JJ, Chilson DA, Miles WM, Hubbard
J, Zipes DP. Antiarrhythmic and electrophysiologic effect of
oral propafenone. Am J Cardiol. 1984;54:26D-28D. [Medline]
[Order article via Infotrieve]
-
Mason JW, for the ESVEM Investigators. A
comparison of electrophysiologic testing with Holter monitoring to
predict antiarrhythmic-drug efficacy for ventricular
tachyarrhythmias. N Engl J
Med. 1993;329:445-451.
[Abstract/Free Full Text]
-
Waller TJ, Kay HR, Spielman SR, Kutalek SP, Greenspan
AM, Horowitz LN. Reduction in sudden death and total mortality
by antiarrhythmic therapy evaluated by electrophysiologic drug testing:
criteria of efficacy in patients with sustained ventricular
tachycardia. J Am Coll
Cardiol. 1987;10:83-89. [Abstract]
-
Leitch JW, Gillis AM, Wyse DG, Yee R, Klein GJ,
Guiraudon G, Sheldon RS, Duff HJ, Keiser TM, Mitchell LB.
Reduction in defibrillator shocks with an implantable device
combining antitachycardia pacing and shock therapy.
J Am Coll Cardiol. 1991;18:145-151.[Abstract]
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