Indo American Journal of Pharmaceutical Research, 2014

ISSN NO: 2231-6876

PROARRYTHMIC POTENTIAL OF DOFETILIDE AND CHLOROQUINE PHOSPHATE IN

AN IN-VIVO ZEBRAFISH MODEL OF TORSADE DE POINTES
Saravana Kumar Marimuthu1 and Morkonda Rajaram Srinivasan2
1

Animal Health Scienece Department, Natural Remedies, India;

Department of Veterinary Pharmacology and Toxicology, Madras Veterinary College, Chennai.

ARTICLE INFO
Article history
Received 05/12/2014
Available online
22/12/2014

Keywords
Tdp, Zerg,
QT Prolongation,
Antimalarial,
Zebrafish.

ABSTRACT
Zebrafish is an emerging model to predict the drug induced arrhythmias in human beings.
The electrophysiological properties like electrocardiogram (ECG) pattern, ventricular action
potential duration (APD) of zebrafish are similar to humans. In the present study, zebrafish
model is standardized for the recording of ECG and validated using the positive and the
negative control agents such as dofetilide and the chloroquine phosphate respectively. Adult
zebrafish (n=6) were immobilized on a wet sponge with a paralytic dose of Pancuronium
(0.0025 mg/ml) administered by intraperitoneal route (i.p.). HEPES in E-3 solution was
continuously perfused orally for four hours to maintain the fish alive outside the water
environment. 29-gauge needle electrodes were placed on the surface of fish to simulate the
lead II configuration and the stable baseline ECG was recorded for approximately 10 minutes.
Dofetilide (75 M and 50 M for male and female fish) and chloroquine phosphate (5000 M
for both sexes) were orally perfused until various pro-arrhythmic endpoints were observed. A
decrease in heart rate, bradycardia was observed with dofetilide (24%) whereas chloroquine
did not show any effect on heart rate. The QT and the corrected QT intervals prolongation
and Torsades de Pointes were observed after dofetilide administration as predicted. Whereas
no QT prolongation and no incidences of arrhythmia were observed after chloroquine
administration as expected. The results of the drugs used in the current study showed the
effects as observed in mammalian species based on the literature references. Therefore it can
be concluded that the adult zebrafish model is validated for its use to predict the proarrhythmic potential of the new chemical entities or unknown compounds.

Copy right 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical
Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as Saravana Kumar Marimuthu et al. Proarrythmic Potential of Dofetilide and Chloroquine
Phosphate In An In-Vivo Zebrafish Model of Torsade De Pointes. Indo American Journal of Pharm Research.2014:4(12).

5766

Corresponding author
Saravana Kumar Marimuthu
Senior Research Officer
Address: Plot No. 5B, Veerasandra Indl Area,
Hosur Road, Bangalore
saravana_pharmacy@yahoo.co.in
+91-9663101566

Vol 4, Issue 12, 2014.

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ISSN NO: 2231-6876

INTRODUCTION
In recent years, many drugs were recalled from the market due to life threatening arrhythmias called Torsade de Pointes
(TdP) [1]. TdP is a form of polymorphic ventricular tachycardia (VT) that displays a characteristic twisting of QRS complexes around
the isoelectric axis. The drugs that block human ether-a-go-go related gene (hERG) channel results in delayed cardiac repolarization
and prolonged the QT interval which may result in arrhythmia and fatal TdP [2]. Though there are many pro-arrhythmic models such
as rabbit, guinea pig and dog models are available to screen the pro-arrhythmic potential of any new drug, a quick, cheap, sensitive
and reliable in vivo model which utilizes a very less compound will help in selecting the safe compounds much early in the discovery
stage of the new chemical entities (NCEs). One of such models is the zebrafish model, because over last decade Zebrafish (Danio
rerio, a tropical Cypriniform) is emerging as a popular model system due to the conservation of various genes between zebrafish and
the higher mammals. The hERG homologue in Zebrafish is the Zebrafish ether-a-go-go related gene (zERG) [3] in the heart has
similar function as that of the hERG channel, i.e., responsible for the repolarisation current in the heart of the higher mammals and
humans. The electrophysiological properties like ECG pattern, ventricular APD and heart rate of zebrafish are also similar to humans
[4, 5]. The drugs that showed repolarization abnormalities in humans also reported to show bradycardia and AV block in Zebrafish
model [6, 7]. Rima et al (2007) recorded the Zebrafish ECG with a slight modification from Milan et al (2006) protocol, by using
Pancuronium as a paralytic agent to eliminate motion artifacts. Hence the objectives of the present study are to standardize the
recording of ECG in the adult Zebrafish with slight modification of Milans (2006) protocol and to validate the model to study the proarrhythmic potential of any new drugs, by using chloroquine phosphate (in vitro hERG IC50 of 2.5 M) as a negative control agent
and dofetilide a well-known pro-arrhythmic agent with in vitro hERG IC50 of 39 nM as a positive control agent.
MATERIALS AND METHODS
Zebrafish Husbandry and Management
The present study was performed at the Safety Pharmacology laboratory, Department of Drug Safety Evaluation, Ranbaxy
Research Laboratories, Gurgaon, Haryana, India. Wild type Zebrafish procured from local vendor were maintained in transparent
glass aquarium at the density of 100 fish per 50 liters of reverse osmosis filtered water with aerated oxygen at 60 ml/liter, temperature
between 25 to 28C and pH of 6-7.5. Light cycle of 14 hours light and 10 hours darkness was maintained and fish were fed with Tetra
Bits Discuss Food (Tetra GmbH, Germany). The standardization experiment and the main study were performed on male and female
zebrafish weighing approximately 500 mg and measuring 3-4 cm in length.
Chemicals / Drugs
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES, Sigma Catalog H4034) and pancuronium were procured from
Sigma Aldrich, India. Sodium Chloride (NaCl), calcium chloride (CaCl2), potassium chloride (KCl) and magnesium sulphate
(MgSO4) were procured from authorized vendors of Ranbaxy Research Laboratories. Standard drug dofetilide was procured from
Jinan Phoesher Chemicals Company Limited, China and chloroquine phosphate was kindly provided by Ranbaxy Research
Laboratories, Gurgaon, India.
Preparation and Administration of Chemicals / Drugs
E-3 was prepared by mixing 5mM NaCl (0.2925g), 0.17mM KCl (0.0127g), 0.33mM CaCl2 (0.0367g) and 0.33mM MgSO4
(0.0812g) in 1 liter of Milli-Q (Deionized) water. After preparation of E-3, HEPES (2.385g) was weighed and dissolved in 1 liter of E3 solution. The E-3 solution was administered by oral perfusion system at the rate of 8 ml/min. Pancuronium was prepared in the
concentration of 0.0025 mg/ml in Milli-Q water and administered to each fish intra-peritoneally approximately 0.02 ml. The stock
solution (1000 M/liter) of dofetilide was prepared using dimethylsulphoxide (DMSO) as a vehicle; 1M Hydrochloric acid (HCl) was
used to avoid precipitation and 1M sodium hydroxide (NaOH) was used for adjustment of pH 6.0-6.5. Chloroquine at the
concentration of 5mM/liter in E-3 solution was administered to both male and female fish.

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Preparation of Zebrafish and Acquisition of ECG

Zebrafish ECG was recorded based on Milan et al (2006) protocol using pancuronium as a paralytic agent. Each zebrafish
was kept in damp sponge to restrict movement. Fish was then paralyzed by intra-peritoneal injection of pancuronium (0.02ml) at the
concentration of 0.0025 mg/ml followed by oral perfusion of HEPES in E-3 solution continuously to keep the fish alive for up to 4
hours. The positive needle electrode (BIOPAC System Inc., CA, USA) was placed just beneath the heart in the ventral midline. The
negative electrode was placed just above the pectoral fins in the ventral midline and ground electrode was placed towards the tail of
the fish (Fig.1). Subsequently the electrocardiogram (ECG) was recorded using BIOPAC MP 100 System (BIOPAC System Inc., CA,
USA) and digitalized using AcqKnowledge Software. Once the stable ECG was obtained, a baseline ECG was recorded for about 10
minutes. Thereafter, the drugs (dofetilide for method control group and chloroquine phosphate for test group) were orally perfused for
30 minutes or until the endpoint was observed.

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Figure 1: Zebrafish placed on a damp sponge with oral perfusion tube and needle
electrodes.
Experiment Protocol
Dofetilide was used as a method control to validate the model. A total of six male and six female fishes were used with three
of each sex for dofetilide and chloroquine phosphate respectively. Baseline ECG was recorded for 10 minutes before drug
administration. Based on the dose range finding study at different concentrations of 10 to 5000 M/liter, the concentration which
showed changes in ECG morphology was selected for dofetilide i.e., 75 M/liter for male fish and 50 M/liter for female fish. Based
on above observation, the doses for the main study selected were 75 M/liter for male fish and 50 M/liter for female fish.
Chloroquine did not show any arrhythmic changes till the highest concentration, i.e., 5000 M/liter; hence the same concentration was
selected for the main study.
Statistical Analysis
All data (PR, RR and QT intervals of ECG and heart rate) were expressed as the mean standard deviation. Corrected QT
interval (QTc) was calculated manually as follows, Bazetts method (QTcB = QT / (RR)-1/2) and Fridericias method (QTcF = QT /
(RR)-1/3) for the correction of QT interval with respect to heart rate were used. Data were analyzed for different arrhythmia score,
QT, PR & RR intervals and heart rate. ECG intervals were measured taking the mean of five ECG complexes at each time point.
RESULTS
Dofetilide, a well-known proarrhythmic drug, was used for the validation of zebrafish ECG model and chloroquine
phosphate, an antimalarial drug was used as negative control agent in zebrafish model. Zebrafish ECG was allowed to stabilize in the
above set-up and after 10 minutes of baseline recording and no abnormalities in the ECG waveforms were observed during the
baseline recording. This indicates that the zebrafish ECG could be recorded outside the water Dofetilide (75 M for males and 50 M
for females) and Chloroquine Phosphate (5000M) were infused up to 30 minutes. Effects of dofetilide and Chloroquine Phosphate on
heart rate (HR), RR interval and QT interval were observed and calculated. As the heart rate influences the QT interval, it was
corrected to heart rate in order to study the actual effect of drugs on QT interval. The QT interval was corrected (as QTc) by using
formulae suggested by Bazett (1920) i.e. QTcB and Fredreicia (1920) i.e. QTcF. The ECG morphology was distorted at 15 min
onwards in males and at 10 minutes onwards in females after dofetilide administration. Therefore, the ECG parameters viz. RR and
QT intervals were analyzed only up to 15 min for males and 10 min for females. Treatment of Chloroquine Phosphate did not show
any change in ECG morphology up to 30 min after drug administration.

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ECG Intervals
A time dependent decrease in mean heart rate and increase in mean RR, QT and corrected QT (QTcB and QTcF) intervals
were observed with dofetilide group in both the sexes (Table 1). Chloroquine phosphate at 5000 M/liter did not show any change in
ECG morphology with no incidences of arrhythmia up to 30 min of drug administration in both the sexes (Table 2).

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Table 1: Effects of Dofetilide on (a) Heart Rate, (b) RR, (c) QT, (d) QTcB, (e) QTcF.
Time points
(a) Heart rate (BPM)
Mean SD

Base line
0 min
Male (n-3)
138 8
134 9
Female (n-3) 109 3
104 8
Male (n-3)
0.436 0.023 0.447 0.036
(b) RR (sec) Mean SD
Female (n-3) 0.545 0.016 0.571 0.051
Male (n-3) 0.257 0.019 0.252 0.012
(c) QT (sec) Mean SD
Female (n-3) 0.358 0.049 0.338 0.013
Male (n-3)
0.390 0.030 0.378 0.029
(d) QTcB (sec) Mean SD
Female (n-3) 0.484 0.060 0.449 0.037
Male (n-3)
0.339 0.026 0.330 0.022
(e) QTcF (sec) Mean SD
Female (n-3) 0.437 0.056 0.408 0.028
ND No data due to the arrhythmia observed at 15 minutes of observation.

5 min
113 22
99 8
0.534 0.103
0.604 0.051
0.302 0.089
0.377 0.038
0.410 0.081
0.485 0.046
0.370 0.085
0.446 0.042

10 min
104 16
83 13
0.591 0.106
0.733 0.119
0.372 0.089
0.445 0.085
0.481 0.073
0.518 0.057
0.441 0.079
0.492 0.067

15 min
94 7
ND
0.671 0.106
ND ND
0.409 0.032
ND
0.501 0.036
ND
0.468 0.030
ND

Table 2: Effects of Chloroquine phosphate on (a) Heart Rate, (b) RR, (c) QT, (d) QTcB, (e) QTcF.
Time points
A Heart rate
(BPM) Mean SD
B RR (sec)
Mean SD

Male (n-3)
Female (n-3)
Male (n-3)
Female (n-3)
Male (n-3)

C QT (sec)
Mean SD

Female (n-3)

D QTcB (sec)
Mean SD

E QTcF (sec)
Mean SD

Male (n-3)
Female (n-3)
Male (n-3)
Female (n-3)

Base line
134 13
130 12
0.434
0.027
0.458
0.045
0.241
0.027
0.252
0.019
0.365
0.031
0.373
0.026
0.318
0.030
0.328
0.022

0 min
134 12
131 10
0.441
0.032
0.451
0.034
0.251
0.042
0.256
0.018
0.377
0.052
0.381
0.027
0.329
0.049
0.333
0.023

5 min
134 12
133 4
0.435
0.023
0.445
0.016
0.245
0.041
0.253
0.018
0.371
0.055
0.380
0.029
0.323
0.050
0.332
0.025

10 min
131 8
130 7
0.450
0.020
0.453
0.026
0.281
0.009
0.263
0.032
0.419
0.006
0.390
0.037
0.367
0.007
0.342
0.036

15 min
131 9
126 5
0.443
0.036
0.465
0.018
0.259
0.037
0.266
0.033
0.389
0.041
0.390
0.042
0.340
0.040
0.343
0.039

30 in
132 13
124 3
0.446 0.039
0.478 0.012
0.254 0.032
0.267 0.017
0.380 0.032
0.386 0.024
0.332 0.033
0.341 0.021

Arrhythmias
The incidence of various arrhythmic endpoints in individual fish after Dofetilide administration is tabulated below (Table 3
and Fig. 2). The onset time for premature ventricular contraction (PVC) at 6 4 min, Ventricular Tachycardia (VT) at 11 6 min and
Torsades de Pointes (TdP) at 20.5 2.5 min were observed. Chloroquine phosphate at 5000 M/liter did not show any change in ECG
morphology with no incidences of arrhythmia up to 30 min of drug administration in both the sexes.

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Animal
Sex VPC VEC BG AV Block VT TdP
No.
1
M
+
+
+
+
+
2
M
+
+
+
+
+
3
M
+
+
+
+
4
F
+
+
+
+
+
5
F
+
+
+
+
6
F
+
+
+ indicates presence and - indicates absence of particular syndrome; M Male , F Female

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Table 3: Individual data of incidences of arrhythmia after Dofetilide administration.

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DISCUSSION
This study was designed to standardize and validate the adult Zebrafish model to predict arrhythmia with QT prolonging
drugs. Dofetilide is a class III antiarrhythmic agent marketed by Pfizer under the trade name Tikosyn for the treatment of
supraventricular tachyarrhythmias. Snyders and Chaudhary (1996) reported that open IKr channel was selectively blocked by dofetilide
at nanomolar concentrations (39 nM) in hERG channel assay. Demolis et al (1996) reported that dofetilide prolonged only the QT
interval duration without augmenting QT interval dispersion in the healthy subjects. In the clinical studies, 1-2 % of patients treated
with dofetilide showed TdP [11, 12, 13, 14] Van der Linde et al (2005) reported that dofetilide administration to anesthetized dogs
delayed ventricular repolarization. Similarly bradycardia and QT corrected (QTc) prolongation were observed in guinea pig after the
treatment of dofetilide [16]. In ex-vivo method (Langendorff-perfused hearts) dofetilide prolonged action potential duration; induced
triangulation, reverse use-dependence, instability and TdP [17]. Kijtawornrat et al (2006) reported that dofetilide induced TdP in rabbit
both in normal heart and in failing heart [19, 20]. Dofetilide frequently evoked ventricular premature beats (VPC), bigeminies,
conduction blocks, non-torsades de pointes ventricular tachycardias and torsade de pointes in anaesthetized rabbits [19].
In the present study, dofetilide induced ventricular premature complex, bigeminy, ventricular ectopic complex, ventricular
tachycardia and Torsade de Pointes in adult zebrafish at 75M in male and at 50M in female fish. It is proposed that these
arrhythmic effects of dofetilide in Zebrafish could be due to the selective IKr blocking effect followed by prolongation of action
potential duration as observed in other species. Therefore in vivo zebrafish model could be considered as a potential model to predict
drug induced cardiac arrhythmias as suggested by Milan et al (2006).
In current experiment chloroquine phosphate was used as a negative control drug. It is a unique antimalarial drug used by
oral or intramuscular route in malarial patients. Chloroquine phosphate is also used as an anti-inflammatory agent in rheumatoid
arthritis and in lupus erythematosus [21]. Rodriguez-Menchaca et al (2008) reported that chloroquine phosphate blocks the inward
rectifier K(+) (IK1) cardiac current and can induce lethal ventricular arrhythmias in in-vitro studies. Sanchez-chapula et al (2001)
observed that the chloroquine phosphate diminished maximum diastolic potential, delayed APD and augmented firing frequency of
spontaneous activity (automaticity) in cat purkinje fibers and chloroquine phosphate inhibited in the order of IK1 > IKr > INa > ICa
currents in the voltage-clamp experiments. In anaesthetized guinea pig chloroquine phosphate prolonged the action potential duration

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Figure 2 : (a) Premature Ventricular Contraction (PVC) (b) Bigeminy (c) Ventricular tachycardia (VT) (d) Torsade de
Pointes.

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but with only minimal effects on alternans (~10 ms) [24]. Similarly chloroquine phosphate showed QT prolongation with mild TdP
risk scores in Rabbit ventricular wedge preparations [25]. But the hERG IC50 of chloroquine phosphate is 2.5 M which is 64 times
higher than the hERG IC50 of Dofetilide.
On the other hand Wozniacka et al (2006) reported that there was no episode of arrhythmias or conduction disturbances in 28
patients after the administration of chloroquine phosphate. Edwards et al (1987) reported that the chloroquine phosphate by
intravenous infusion did not show severe cardiovascular toxicity in patients with falciparum malaria. Bustos et al (1994) reported that
chloroquine phosphate after 3 days of curative dose prolonged QTc interval along with T wave diminution, but they found that the
electrocardiographic parameters were stabilized after the treatment period as drug concentrations reduced gradually. In the present
study, as expected, chloroquine phosphate did not show any arrhythmic changes as compared to the dofetilide group. The results of
the present study in the Zebrafish model are consistent with those observed with human and animal studies that the chloroquine
phosphate perfused at a concentration up to 5000M/L did not induce any pro-arrhythmic episodes. The results of both dofetilide and
chloroquine phosphate validated the adult zebrafish as a model for screening the pro-arrhythmic potential of the new chemical entities.
The limitation of the current study is the compounds which lack the aqueous solubility cannot be used in this model. Only
two compounds are used in the current study does not make this a robust model, however, using more number of positive and negative
control substances screened in this model will make this model more reliable, cheap and robust model for the screening of proarrhythmic potential of NCEs.
CONCLUSIONS
Standardization of the recording of ECG on the adult zebrafish outside the water environment was accomplished using slight
modification of Milans (2006) protocol. Chloroquine phosphate when tested in Zebrfish ECG model did not produce any incidence of
arrhythmia after single dose perfusion as expected which is consistent with the findings of various human trials. Dofetilide, a wellknown pro-arrhythmic drug used as positive control showed a drug related progressive difference in the QT interval and leading to the
expression of various arrhythmic end points such as PVC, VT and Torsade de Pointes (TdP).Hence the results of the chloroquine
phosphate and dofetilide validated the use of adult zebrafish as a model to screen the pro-arrhythmic potential of new chemical entities
well early in the drug discovery stages.

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REFERENCES
1. Haverkamp W, Breithardt G, Camm AJ, Janse MJ, Rosen MR, Antzelevitch C et al. The potential for QT prolongation and
proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Cardiovasc Res. 2000, 47, 219-33.
2. Viskin S. Long QT syndromes and torsade de pointes. Lancet, 1999, 354, 1625-33.
3. Langheinrich U, Vacun G, Wagner T. Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QTprolonging drugs inducing severe arrhythmia. Toxicol Appl Pharmacol. 2003, 193, 370-82.
4. Sedmera D, Reckova M, deAlmeida A, Sedmerova M, Biermann M, Volejnik J et al. Functional and morphological evidence for
a ventricular conduction system in zebrafish and Xenopus hearts. Am J Physiol Heart Circ Physiol. 2003, 284, 1152-60.
5. Kopp R, Schwerte T, Pelster B. Cardiac performance in the zebrafish breakdance mutant. J Exp Biol. 2005, 208, 2123-34.
6. Milan DJ, Peterson TA, Ruskin JN, Peterson RT, MacRae CA. Drugs that induce repolarization abnormalities cause bradycardia
in zebrafish. Circulation. 2003, 107, 1355-358.
7. Rima A, Tania F, Jan H, Kenneth S, Didier YRS, Martin T et al. Zebrafish model for human long QT syndrome. Proc Natl Acad
Sci U S A. 2007, 104, 11316-21.
8. Milan DJ, Jones IL, Ellinor PT, MacRae CA. In vivo recording of adult zebrafish electrocardiogram and assessment of druginduced QT prolongation. Am J Physiol Heart Circ Physiol. 2006, 291, 269-73.
9. Snyders DJ, Chaudhary A. High affinity open channel block by dofetilide of HERG expressed in a human cell line. Mol
Pharmacol. 1996, 49, 949-55.
10. Dmolis JL, Funck-Brentano C, Ropers J, Ghadanfar M, Nichols DJ, Jaillon P. Influence of Dofetilide on QT-Interval Duration
and Dispersion at Various Heart Rates During Exercise in Humans. Circulation. 1996, 94, 1592-99.
11. Prystowsky EN, Freeland S, Branyas NA, Rardon DP, Fogel RI, Padanilam BJ et al. Clinical Experience with Dofetilide in the
Treatment of Patients with Atrial Fibrillation. J Cardiovasc Electrophysiol. 2003, 14, 287-90.
12. Boriani G, Lubinski A, Capucci A, Niederle P, Kornacewicz-Jack Z, Wnuk-Wojnar AM et al. A multicentre, double-blind
randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained
ventricular tachycardia and ischaemic heart disease. Eur Heart J. 2001, 22, 2180-91.
13. Kber L, Bloch Thomsen PE, Mller M, Torp-Pedersen C, Carlsen J, Sande E, Egstrup K, Agner E et al. Effect of dofetilide in
patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet. 2000, 356, 2052-58.
14. Mller M, Torp-Pedersen CT, Kber L. Dofetilide in patients with congestive heart failure and left ventricular dysfunction: safety
aspects and effect on atrial fibrillation. The Danish Investigators of Arrhythmia and Mortality on Dofetilide (DIAMOND) Study
Group. Congest Heart Fail. 2001, 7, 146-50.
15. Van der Linde H, Van de Water A, Loots W, Van Deuren B, Lu HR, Van Ammel K et al. A new method to calculate the beat-tobeat instability of QT duration in drug-induced long QT in anesthetized dogs. J Pharmacol Toxicol Methods. 2005, 52, 168-77.

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ACKNOWLEDGEMENT
The author would like to thank Pushkar, Milind, Vyas and Ranbaxy Laboratories Limited for providing necessary facilities to
conduct the experiment as a part of master thesis.

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16. Fossa AA, Wisialowski T, Duncan JN, Deng S, Dunne M. Azithromycin/Chloroquine Combination Does Not Increase Cardiac
Instability despite an Increase in Monophasic Action Potential Duration in the Anesthetized Guinea Pig. Am J Trop Med Hyg.
2007, 77, 929-38.
17. Dujardin KS, Dumotier B, David M, Guizy M, Valenzuela C, Hondeghem LM. Ultra-Fast Sodium Channel Block by Dietary Fish
Oil Prevents Dofetilide-Induced Ventricular Arrhythmias in Rabbit Hearts. Am J Physiol Heart Circ Physiol. 2008, 295, 1414-21.
18. Kijtawornrat A, Nishijima Y, Roche BM, Keene BW, Hamlin RL. Use of a Failing Rabbit Heart as a Model to Predict
Torsadogenicity. Toxicol Sci. 2006, 93, 205-12.
19. Vincze D, Farkas AS, Rudas L, Makra P, Csk N, Lepran I et al. Relevance of anaesthesia for dofetilide-induced torsades de
pointes in 1-adrenoceptor-stimulated rabbits. Br J Pharmacol. 2008, 153, 75-89.
20. Diness TG, Yeh YH, Chartier D, Tsuji Y, Hansen RS, Olesen SP et al. Antiarrhythmic properties of a rapid delayed-rectifier
current activator in rabbit models of acquired long QT syndrome. Cardiovasc Res. 2008, 79, 61-69.
21. Webster LT. Drugs used in the chemotherapy of Malaria. In: Goodman LS, Gilman AG, editor. Goodman and Gilmans The
pharmacological basis of therapeutics, 7th ed. New York:Collier Macmillan: 1985. p. 978-98.
22. Rodriguez-Menchaca AA, Navarro-Polanco RA, Ferrer-Villada T, Rupp J, Sachse FB, Tristani-Firouzi M et al. The molecular
basis of chloroquine block of the inward rectifier Kir2.1 channel. Proc Natl Acad Sci U S A. 2008, 105, 1364-68.
23. Sanchez-Chapula JA, Salinas-Stefanon E, Torres-Jacome J, Benavides-Haro DE, Navarro-Polanco RA. Blockade of Currents by
the Antimalarial Drug Chloroquine in Feline Ventricular Myocytes. J Pharmacol Exp Ther. 2001, 297, 437-45.
24. Hess P, Rey M, Wanner D, Steiner B, Clozel M. Measurements of blood pressure and electrocardiogram in conscious freely
moving guineapigs: a model for screening QT interval prolongation effects. Laboratory Animals Ltd. Lab Anim. 2007, 41, 47080.
25. Borsini F, Crumb W, Pace S, Ubben D, Wible B, Yan GX et al. In Vitro Cardiovascular Effects Of Dihydroartemisin-Piperaquine
Combination: Comparison With Other Antmalarials. Antimicrob Agents Chemother. 2012, 56, 3261-70.
26. Wozniacka A, Cygankiewicz I, Chudzik M, Sysa-Jedrzejowska A, Wranicz JK. The cardiac safety of chloroquine phosphate
treatment in patients with systemic lupus erythematosus: the influence on arrhythmia, heart rate variability and repolarization
parameters. Lupus. 2006, 15, 521-25.
27. Edwards G, Davies AJ, Phillips RE, Looareesuwan S, Karbwang J, White NJ et al. Plasma concentrations and toxicity of
chloroquine after slow intravenous infusion in patients with falciparum malaria. Ann Trop Med Parasitol. 1987, 81, 79-84.
28. Bustos MD, Gay F, Diquet B, Thomare P, Warot D. The pharmacokinetics and electrocardiographic effects of chloroquine in
healthy subjects. Trop Med Parasitol. 1994, 45, 83-86.

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