phenanthrenes and Long-QT-Syndrome

Most available antimalarial drugs induce cardiac side effects. These side effects include various mild heart rate changes (amodiaquine) to excessive prolongation of the QT interval (halofantrine) which may lead to lethal arrhythmias such as Torsade de Pointes (TdP). The cellular mechanism of such events during antimalarial therapy is principally related to ion channel inhibition (e.g., human ether-a-go-go related gene channel) which may slow the repolarisation process and create a good substrate for arrhythmia (when dispersion of repolarisation is present). However, other antimalarial drugs do not show as potent cardiac side effects, like co-arthemeter and sulfadoxine-pyrimethamine. Considering that TdP are favoured by a complex combination of electrophysiological changes, a predictive cardiosafety strategy for new antimalarial drugs should comprise assays with an increasing level of information from ion channel level, cellular and organ level, to the whole organism. In this review, the actual knowledge on underlying mechanisms of QT prolongation and TdP is described, followed by the cardiac safety profiles of present antimalarial drugs.

Topics: Amodiaquine; Drug Approval; Electrophysiology; Humans; Long QT Syndrome; Malaria; Phenanthrenes; Risk Assessment; Risk Factors; Torsades de Pointes

To evaluate mefloquine versus halofantrine in children suffering from acute uncomplicated falciparum malaria.. Prospective non randomized study in hospitalized children during one year. Acute falciparum malaria was defined by fever and a positive thin and/or thick smear. Malaria was presumed to have been contracted in Comoros archipelago and/or Madagascar 6 months previously. Patients were excluded, when quinine had to be used, according to World Health Organization's severity criteria.. Forty-nine children were included: 29 were treated with halofantrine and 20 with mefloquine. Patients features in the two groups of treatment were identical, with exception for the mean time between first clinical signs and diagnosis (shorter in mefloquine group). Fever's and hospitalization's duration under treatment were similar. An increase in QTc interval was frequently observed in patients treated with halofantrine (56 versus 0%), although patients with mefloquine experienced vomiting (45 versus 0%). Relapses seemed to be more frequent with halofantrine (14 versus 0%).. Halofantrine and mefloquine are efficient for falciparum malaria treatment in our pediatric series, despite a high rate of adverse events. Mefloquine's tolerance may probably be improved with changes in regimen and dose. Relapses are more frequent with a single first treatment of halofantrine, than with mefloquine. Unfortunately, features of a second halofantrine treatment are not defined.

Topics: Adolescent; Antimalarials; Child; Child, Preschool; Female; Humans; Infant; Long QT Syndrome; Malaria, Falciparum; Male; Mefloquine; Phenanthrenes; Treatment Outcome

Co-artemether (Coartem, Riamet) is a tablet containing 20 mg artemether and 120 mg lumefantrine for treatment of falciparum malaria. Lumefantrine has some chemical similarities to halofantrine (Halfan), an antimalarial known for QTc prolongation. Effects on the QTc interval of fed single oral doses of 500 mg halofantrine and 80/480 mg co-artemether were compared in 13 healthy males in a randomized double-blind crossover study. Electrocardiograms (ECGs) were recorded from 48 hours before dosing until 48 hours thereafter. The maximum QTc interval (QTc = QT/square root(RR)) was compared before and after treatment and between treatments, fitting a general linear model. Drug plasma concentrations were determined concomitantly. After halofantrine, all participants showed an increase in the QTc interval; the mean maximum increase was 28 ms. The length of the QTc interval was positively correlated to halofantrine exposure. The QTc interval remained unchanged after co-artemether. The difference between treatments was statistically significant. In conclusion, halofantrine caused a significant, exposure-dependent increase in the QTc interval. No such effect was seen with co-artemether.

Topics: Administration, Oral; Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Cross-Over Studies; Double-Blind Method; Drug Combinations; Electrocardiography; Ethanolamines; Fluorenes; Heart; Heart Rate; Humans; Long QT Syndrome; Male; Phenanthrenes; Sesquiterpenes

1) To characterize the variability of multiple-dose halofantrine pharmacokinetics over time in healthy adults, 2) to correlate the pharmacodynamic measure electrocardiographic (ECG) QT interval with (+)- and (-)-halofantrine plasma concentration and 3) to evaluate the safety and tolerance of halofantrine hydrochloride given over time to healthy adults.. Twenty-one healthy subjects were enrolled and 13 completed the study (180 days). Subjects received either 500 mg of racemic halofantrine once daily in the fasted state for 42 days, or placebo, and then halofantrine washout was documented for the following 138 days. Pharmacokinetic and pharmacodynamic (ECG QTc) measurements were obtained.. Mean accumulation half-times (days) for halofantrine were: 7.0 +/- 4.8 [(+)-halofantrine] and 7.3 +/- 4.8 [(-)-halofantrine]. Mean steady-state concentrations were: 97.6 +/- 52.0 ng ml(-1) [(+)-halofantrine] and 48.5 +/- 20.8 [(-)-halofantrine]. Steady-state oral clearance was: 139 +/- 73 l h(-1) [(+)-halofantrine] and 265 +/- 135 l h(-1) [(-)-halofantrine]. Peak plasma concentrations of both (+)- and (-)-halofantrine were attained at 6 h and maximal ECG QTc prolongation was at 4-8 h following drug administration. Fourteen of 16 subjects who received active drug had ECG QTc prolongation that was positively correlated with both (+)- and (-)-halofantrine concentration. The five subjects who received placebo had no demonstrable change in ECG QTc throughout the study. Conclusions Halofantrine accumulates extensively and shows high intersubject pharmacokinetic variability, is associated with concentration-related ECG QTc prolongation in healthy subjects, and is clinically well tolerated in this subject group.

Topics: Adult; Antimalarials; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Long QT Syndrome; Male; Metabolic Clearance Rate; Molecular Conformation; Phenanthrenes

Topics: Adolescent; Adult; Antimalarials; Drug Monitoring; Electrocardiography; Humans; Long QT Syndrome; Malaria; Male; Phenanthrenes; Prospective Studies

In order to assess cardiac tolerance of halofantrine in children, we studied, retrospectively, 15 non complicated falciparum malaria cases treated with halofantrine, and focused on the effect on ventricular repolarisation. Our data showed that halofantrine can produce a moderate QTc prolongation without any life-threatening arrhythmia. As long as contraindications of the drug are respected, this treatment should be considered as a therapeutical option in young children presenting with non complicated falciparum malaria.

Topics: Adolescent; Antimalarials; Cardiac Electrophysiology; Child; Child, Preschool; Electrophysiological Phenomena; Female; Humans; Infant; Long QT Syndrome; Malaria, Falciparum; Male; Phenanthrenes

Halofantrine can cause a prolongation of the cardiac QT interval, leading to serious ventricular arrhythmias. Hyperlipidaemia elevates plasma concentration of halofantrine and may influence its tissue uptake. The present study examined the effect of experimental hyperlipidaemia on QT interval prolongation induced by halofantrine in rats.. Normolipidaemic and hyperlipidaemic rats (induced with poloxamer 407) were given 4 doses of halofantrine (i.v., 4-40 mg·kg(-1)·d(-1)) or vehicle every 12 h. Under brief anaesthesia, ECGs were recorded before administration of the vehicle or drug and 12 h after the first and last doses. Blood samples were taken at the same time after the first and last dose of halofantrine. Hearts were also collected 12 h after the last dose. Plasma and heart samples were assayed for drug and desbutylhalofantrine using a stereospecific method.. In the vehicle group, hyperlipidaemia by itself did not affect the ECG. Compared to baseline, QT intervals were significantly higher in both normolipidaemic and hyperlipidaemic rats after halofantrine. In hyperlipidaemic rats, plasma but not heart concentrations of the halofantrine enantiomers were significantly higher compared to those in normolipidaemic rats. Despite the lack of difference in the concentrations of halofantrine in heart, QT intervals were significantly higher in hyperlipidaemic compared to those in normolipidaemic rats.. The unbound fraction of halofantrine appeared to be the controlling factor for drug uptake by the heart. Our data suggested a greater vulnerability to halofantrine-induced QT interval prolongation in the hyperlipidaemic state.

Topics: Animals; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Hyperlipidemias; Long QT Syndrome; Male; Phenanthrenes; Rats; Rats, Sprague-Dawley

The main objective of the present study was to evaluate the reduction in halofantrine (Hf) toxicity, an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram, by its entrapment in poly-epsilon-caprolactone nanocapsules (NC). The acute lethal dose (LD(100)) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD(50) was 154 mg/kg. In contrast, the LD(100) for Hf-NC was 300 mg/kg with a longer mean time to death than Hf.HCl. The calculated LD(50) was 249 mg/kg for Hf-NC. The Hf entrapped in PCL NC presented a greater efficacy than PLA-PEG NC and than Hf solution in P. berghei-infected mice at 1 mg/kg. The cardiovascular parameters, ECG and arterial blood pressure, were evaluated in anaesthetized Wistar rats after the IV administration of a single, especially high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. It was observed that Hf solution caused prolongation of the QT and PR intervals of the ECG; however, this effect was significantly (P<0.001) reduced when Hf was administered entrapped in nanocapsules. The treatment with Hf.HCl induced a pronounced bradycardia and severe hypotension leading to death. The effect of Hf-NC upon heart rate was reduced from 58 to 75% for 100 and 150 mg/kg, respectively, when compared with Hf.HCl solution. These findings show that the encapsulation of halofantrine reduces the QT interval prolongation of ECG in rats and suggest that a modification of drug distribution was possible by using nanocapsules. Hf encapsulation was the main factor responsible for the significant reduction in cardiac toxicity observed.

Topics: Animals; Antimalarials; Bradycardia; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart; Hypotension; Lethal Dose 50; Long QT Syndrome; Malaria; Male; Mice; Nanocapsules; Phenanthrenes; Plasmodium berghei; Rats; Rats, Wistar

Halofantrine has been observed to cause QT interval prolongation in susceptible patients and the effect has most commonly been observed after post-prandial administration. Halofantrine-induced QT prolongation occurs in conjunction with a significant increase in plasma halofantrine concentrations and an increase in halofantrine association with post-prandial plasma lipoproteins. The increased association of halofantrine with post-prandial lipoproteins is accompanied by a marked change in drug distribution between the different plasma lipoprotein fractions. This study was designed to evaluate the putative role of myocardium-based lipoprotein receptor-mediated uptake of lipoproteins as a possible contributing factor to the observed effect of halofantrine on QT intervals. The extent of QT interval prolongation following intravenous halofantrine administration (10 mg kg(-1)) to normolipidaemic (fasted) or hyperlipidaemic (induced with Intralipid infusion) anaesthetized New Zealand White rabbits (n = 6) was determined, as was the distribution of halofantrine between the plasma lipoprotein classes. The results, however, were in contrast to the suggested hypothesis since the QT interval was reduced (and not increased) after halofantrine administration to hyperlipidaemic rabbits relative to fasted rabbits. Therefore, it is unlikely that lipoprotein-based uptake of halofantrine into the myocardium is a major contributor to the previously observed increase in QT prolongation after post-prandial administration of halofantrine.

Topics: Animals; Antimalarials; Blood Proteins; Electrocardiography; Fasting; Food-Drug Interactions; Lipoproteins; Long QT Syndrome; Phenanthrenes; Postprandial Period; Protein Binding; Rabbits

Desbutylhalofantrine (Hfm) is an active and equipotent metabolite of halofantrine (Hf). Both compounds are effective in the treatment of sensitive and multidrug-resistant and In vitro data and interpretation of some clinical studies of Hf have suggested that, unlike Hf, Hfm may be devoid of adverse cardiac effects. The aim of these investigations was to provide the first in vivo examination of the intrinsic capacity of Hfm to affect repolarization in the heart, using an anesthetized rabbit model. Using a dose-rising regimen, Hfm was administered IV at doses of 1, 1, 2, 4, and 8 mg/kg and the baseline rate-corrected QT interval (QTc) value of 377 +/- 13 ms rose to 394 +/- 16, 396 +/- 12, 429 +/- 18, 433 +/- 16, and 489 +/- 15 ms, respectively. There were no significant changes in blood pressure, heart rate, or PR or QRS intervals. The Hfm plasma concentrations were quantitated after high-performance liquid chromatographic analysis, the results indicating a significant correlation between Hfm plasma concentration and QT(c) prolongation. The study also identified a concentration-dependent hemolysis of erythrocytes after administration of Hfm. The conclusions from this study are that IV administration of Hfm does cause a significant prolongation of the QT(c) interval in a rabbit model.

Topics: Animals; Blood Pressure; Cardiovascular System; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Heart Rate; Infusions, Intravenous; Long QT Syndrome; Male; Phenanthrenes; Rabbits

1. The antimalarial drug halofantrine can prolong the QT interval and this may be enhanced by prior use of mefloquine. This possible interaction has been investigated by examining the effects of halofantrine and mefloquine alone and in combination. 2. In anaesthetized rabbits (n=6 per group), halofantrine given as bolus doses of 1, 3, 10, and 30 mg kg(-1) at 25 min intervals dose-dependently prolonged the rate-corrected QT (QTc) interval from 313+/-12 ms pre-drug to 410+/-18 ms after the highest dose. Similar doses of mefloquine did not alter QTc intervals significantly. The highest dose of mefloquine (30 mg kg(-1)) caused cardiac contractile failure. 3. Pretreatment with 3 mg kg(-1) mefloquine 25 min before the first dose of halofantrine potentiated the effects of all doses of halofantrine on QTc intervals. 4. The blood concentrations of halofantrine were two to six times higher in the group pretreated with mefloquine compared to the halofantrine alone group; e.g. 1.03+/-0.17 and 0.16+/-0.02 microM respectively after 1 mg kg(-1) halofantrine. There was a significant correlation between blood halofantrine concentrations and QTc intervals (r=0.673). Even after making allowance for overestimation of the potency of halofantrine that may result from the hypokalaemia that is prevalent in anaesthetized rabbits, these effects occurred with concentrations of halofantrine that are found in clinical use. 5. These data indicate clearly that while mefloquine does not alter QTc intervals itself, it does enhance the effects of halofantrine by increasing the circulating concentration of halofantrine.

Topics: Action Potentials; Animals; Antimalarials; Blood Gas Analysis; Drug Synergism; Electrocardiography; Female; Hemodynamics; Hydrogen-Ion Concentration; Long QT Syndrome; Mefloquine; Phenanthrenes; Potassium; Rabbits

Topics: Adolescent; Adult; Amino Acid Sequence; Antimalarials; Electrocardiography; Female; Humans; Long QT Syndrome; Male; Molecular Sequence Data; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Pedigree; Phenanthrenes; Sodium Channels; Tachycardia, Ventricular

Topics: Adult; Antimalarials; Cardiomyopathy, Hypertrophic; Contraindications; Death, Sudden, Cardiac; Humans; Long QT Syndrome; Malaria; Male; Mefloquine; Phenanthrenes; Togo; Travel

To determine the importance of prolonged QT interval and electrocardiographic changes in children treated with halofantrin for an acute malaria attack.. Out of 25 children treated with halofantrin, nine had an increase of QTc interval < 440 ms and ten a QTc > 440 ms on control 24 h after the first dose. A 9-year-old girl, treated with halofantrin, had bradycardia and increase of QTc interval for six days, with a normal halofantrin blood level.. These data show that cardiac monitoring during halofantrin treatment is mandatory in children as in adults. Contraindications of halofantrin treatment must be respected, particularly a long congenital QT interval.

Topics: Adolescent; Antimalarials; Bradycardia; Child; Child, Preschool; Electrocardiography; Female; Humans; Infant; Long QT Syndrome; Malaria; Male; Phenanthrenes

Halofantrine has been shown to be very effective against multiple drug resistant falciparum malaria. It is usually administered in children at 24 mg/kg at six-hour intervals for three doses, and a second therapeutic course one week following the initial treatment is recommended. It is usually well tolerated. However, prolongation of the QT interval has been reported in adults receiving this drug for malaria.. Two children experienced a prolongation of the QTc interval while receiving halofantrine. The first child, aged two years, had a prolonged QTc interval (490 ms) six hours after the third administration, at the usual therapeutic dose. The second child, aged six years, had a normal QT interval (360 ms) after the first 24 mg/kg dose and had a prolonged QTc (450 ms) during the second course seven days later, 15 h after the last dose. In both cases, the QTc interval returned to normal values (below 440 ms) rapidly after the end of treatment.. Cardiotoxic effects are felt to be dose-dependant and young children may be particularly at risk due to pharmacological and cardiac immaturity. Therefore, guidelines for drug administration should be followed (administration in a child with an empty stomach, drug not recommended in combination with drugs known to prolong the QTc interval) and monitoring ECG in pediatric patients may be justified. The modalities of the second course in children, which is recommended by the manufacturer to travellers from non-endemic areas, should also be discussed.

Topics: Adult; Antimalarials; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Humans; Infant; Long QT Syndrome; Malaria, Falciparum; Male; Phenanthrenes

Topics: Adult; Antimalarials; Female; Humans; Long QT Syndrome; Phenanthrenes; Ventricular Fibrillation

1. Several unrelated drugs have pro-arrhythmic activity associated with an ability to prolong the QT interval of the ECG. The aim of this work was to examine the effects of the antimalarial drug halofantrine in vivo and in vitro. 2. In anaesthetized guinea-pigs consecutive bolus doses of halofantrine (0.3, 1, 3, 10 and 30 mg kg(-1), i.v.) at 25 min intervals caused dose-dependent prolongation of the rate corrected QTc interval and bradycardia. The change in heart rate became significant after administration of 10 mg kg(-1) halofantrine (-23+/-9 beats min[-1]) whereas the increase in QTc was significant with only 1 mg kg(-1) halofantrine (22+/-10 ms). It was only with the highest dose of halofantrine that the PR interval was increased (from 52+/-3 to 67+/-4 ms) and second degree atrioventricular (AV) block (type 1 Mobitz) occurred in all animals. No changes were observed in any parameters in a separate group of guinea-pigs which received vehicle (dimethylacetamide 60% propylene glycol 40%) at equivalent time points. 3. The blood concentrations of halofantrine ranged from 0.26+/-0.17 microM after administration of 0.3 mg kg(-1) to 2.79+/-0.87 microM after 30 mg kg(-1), i.v. There was a significant correlation between the blood concentrations of halofantrine and the changes in QTc interval. 4 In guinea-pig left papillary muscles the effective refractory period was increased significantly 60 min after addition of halofantrine; from 161+/-4 to 173+/-6 ms with 10 microM, 156+/-8 to 174+/-6 ms with 30 microM and 165+/-6 to 179+/-5 ms with 100 microM halofantrine. However, the vehicle (0.1% Tween 80 in DMSO; final concentration of vehicle in Krebs, 1%) also increased the effective refractory period from 164+/-5 to 173+/-6 ms. Similar results were obtained in right ventricular strips but left atrial effective refractory periods were not altered by either the vehicle or halofantrine. 5. The results of these experiments suggest that any direct effects that halofantrine may have had on the effective refractory period of cardiac muscle cannot be separated from those of the vehicle. The prolongation of QTc and consistent observation of AV block with halofantrine in anaesthetized guinea-pigs suggest that in vivo models may be more useful for further studies investigating the mechanisms underlying the cardiotoxicity of halofantrine.

Topics: Animals; Antimalarials; Blood Pressure; Electrocardiography; Guinea Pigs; Heart Rate; In Vitro Techniques; Long QT Syndrome; Male; Myocardial Contraction; Papillary Muscles; Phenanthrenes; Refractory Period, Electrophysiological

This report deals with two patients who suffered sustained episodes of torsade de pointes ventricular tachycardia while using the novel antimalarial drug halofantrine. Both patients had congenital long QT syndrome, and their QT interval was further prolonged at the time of the event. This first electrocardiographic documentation of ventricular arrhythmias together with halofantrine's known prolonging effect on the QT interval demonstrates that the drug has the potential to induce life-threatening arrhythmias.

Topics: Adolescent; Adult; Antimalarials; Electrocardiography; Female; Follow-Up Studies; Humans; Long QT Syndrome; Male; Phenanthrenes; Syncope; Tachycardia, Ventricular; Torsades de Pointes

Topics: Adult; Antimalarials; Electrocardiography; Female; Humans; Long QT Syndrome; Phenanthrenes

Topics: Adult; Antimalarials; Female; Humans; Long QT Syndrome; Phenanthrenes; Torsades de Pointes

Topics: Antimalarials; Electrocardiography; Humans; Long QT Syndrome; Malaria, Falciparum; Malaria, Vivax; Phenanthrenes