Quinine and Quinidine

White, Nicholas J.; Looareesuwan, Sornchai; Warrell, David A.

doi:10.1097/00005344-198303000-00001

Cited by 84 publications

(8 citation statements)

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“…This therefore does not add to concerns raised by a recent large multicentric clinical trial about the possibility of increased incidence of this event after a repeated dose (7). Our results support previous findings that QT/QTc prolongation following DHA-PQP administration is consistently lower than that caused by other commonly used antimalarial drugs, such as quinine (12,13) or chloroquine (14). Previous studies assessing the cardiotoxicity of DHA-PQP have shown minimal QTc prolongation following a single 3-day course.…”

Section: Discussionsupporting

confidence: 90%

Electrocardiographic Safety of Repeated Monthly Dihydroartemisinin-Piperaquine as a Candidate for Mass Drug Administration

Millat-Martínez¹,

Ila²,

Laman³

et al. 2018

Antimicrob Agents Chemother

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Mass drug administration (MDA) of sequential rounds of antimalarial drugs is being considered for use as a tool for malaria elimination. As an effective and long-acting antimalarial, dihydroartemisinin-piperaquine (DHA-PQP) appears to be suitable as a candidate for MDA. However, the absence of cardiac safety data following repeated administration hinders its use in the extended schedules proposed for MDA. We conducted an interventional study in Lihir Island, Papua New Guinea, using healthy individuals age 3 to 60 years who received a standard 3-day course of DHA-PQP on 3 consecutive months. Twelve-lead electrocardiography (ECG) readings were conducted predose and 4 h after the final dose of each month. The primary safety endpoint was QT interval correction (QTc using Fridericia’s correction [QTcF]) prolongation from baseline to 4 h postdosing. We compared the difference in prolongations between the third course postdose and the first course postdose. Of 84 enrolled participants, 69 (82%) participants completed all treatment courses and ECG measurements. The average increase in QTcF was 19.6 ms (standard deviation [SD], 17.8 ms) and 17.1 ms (SD, 17.1 ms) for the first-course and third-course postdosing ECGs risk difference, −2.4 (95% confidence interval [95% CI], −6.9 to 2.1; P = 0.285), respectively. We recorded a QTcF prolongation of >60 ms from baseline in 3 (4.3%) and 2 (2.9%) participants after the first course and third course (P = 1.00), respectively. No participants had QTcF intervals of >500 ms at any time point. Three consecutive monthly courses of DHA-PQP were as safe as a single course. The absence of cumulative cardiotoxicity with repeated dosing supports the use of monthly DHA-PQP as part of malaria elimination strategies.

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Section: Discussionsupporting

confidence: 90%

Electrocardiographic Safety of Repeated Monthly Dihydroartemisinin-Piperaquine as a Candidate for Mass Drug Administration

Millat-Martínez¹,

Ila²,

Laman³

et al. 2018

Antimicrob Agents Chemother

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“…This suggests that the quinine concentrations used in this experimental model may prove clinically relevant. The observed higher QT prolongation effect of quinidine (EC 50 = 0.49 ± 0.61 μM) over quinine (1.68 ± 0.43 μM) is consistent with the findings in humans that the former is more cardiotoxic than the latter in terms of developing serious ventricular arrhythmias [2] and prolonging the QT interval [3]. An in vitro study was conducted on the inhibition of potassium channel currents on Xenopus oocytes expressing the human ether-a-go-go -related gene (hERG), which represents an underlying molecular mechanism of QT prolongation [17].…”

Section: Discussionsupporting

confidence: 88%

“…Parenteral forms of artemisinin derivatives are increasingly being used in developing countries and more recently also in industrialized countries. Cardiac toxicity has been a major concern with the use of IV quinine or quinidine, with quinidine considered to be more toxic than quinine [2,3]. The primary mechanism of cardiotoxicity caused by quinine or quinidine is the prolongation of the electrocardiographic (ECG) QT interval which can cause potentially fatal ventricular arrhythmias, including torsades de pointes, and even sudden death.…”

Section: Introductionmentioning

confidence: 99%

Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system

Kinoshita

Yamada

Kotaki

et al. 2010

Malar J

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BackgroundConcern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart.MethodsThe guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects.ResultsQuinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine.ConclusionsIn this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity.

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“…The cardiotoxicity of these drugs mainly focuses on delayed ventricular repolarization which increases the risk of LQTS and TdP. In addition, QT prolongation with quinine is about four times less than with quinidine [25]. Drug-induced LQTS is often associated with the inhibition of the hERG potassium channel [10].…”

Section: Discussionmentioning

confidence: 99%

Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

Meng

Fan

Shi

et al. 2016

IJMS

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Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics. The results imply their stereospecific block effect on the hERG channel. However, F656C-hERG reversed this stereoselectivity. The mutation decreases affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. These data suggest that F656 residue contributes to the stereoselective pocket for quinidine and quinine. Further study demonstrates that both drugs do not change hERG protein levels. In rescue experiments, we found that they exert no reverse effect on pentamidine- or desipramine-induced hERG trafficking defect, although quinidine has been reported to rescue trafficking-deficient pore mutation hERG G601S based on the interaction with F656. Our research demonstrated stereoselective effects of quinidine and quinine on the hERG channel, and this is the first study to explore their reversal potency on drug-induced hERG deficiency.

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Quinine and Quinidine

Cited by 84 publications

References 0 publications

Electrocardiographic Safety of Repeated Monthly Dihydroartemisinin-Piperaquine as a Candidate for Mass Drug Administration

Electrocardiographic Safety of Repeated Monthly Dihydroartemisinin-Piperaquine as a Candidate for Mass Drug Administration

Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system

Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

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