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Cardiac effect of halofantrine
Cardiac effect of halofantrine SiR-To overcome falciparum malaria resistance in Thailand,1-3 the suggestion is to increase the dose of halofantrine to 3000 mg as two courses of 1500 mg 7 days apart. But halofantrine can prolong the QT interva1.4-6 We report electrocardiographic (ECG) changes after the standard dose of
halofantrine.
patients with acute uncomplifalciparum malaria (asexual parasitaemia < 5% of red cells), aged 15-60 years and weight 45-60 kg with no history of liver or kidney diseases, were studied. Written consent was obtained. The healthy subjects were admitted for at least the first 2 days and returned daily for a week and then once weekly until day 28 for ECG monitoring and for assay of plasma halofantrine and metabolite. The patients were admitted for 28 days. Halofantrine 500 mg was given every 6 h for three doses to all participants. ECG was recorded before and after treatment for 7 days and reviewed by a cardiologist. Bradycardia was diagnosed when heart rate was under 60 min. Halofantrine concentration was measured in 5 patients with prolongation of QTc interval of more than 25 % of their baseline, in 5 with prolongation of QTc under 25%, and in 1 with no change. The concentration of halofantrine was also measured in all healthy 6 healthy Thai males and 29
prolongation of greater than 25% of baseline. Patients and healthy subjects with higher halofantrine concentrations showed more prolonged QTc intervals. In all cases, the maximum change in QTc was noted between 16 and 24 h after the first dose, which coincided with the peak concentration. 1 patient with no change in QTc had the lowest plasma halofantrine (figure). Prolongation of QTc was associated with halofantrine concentration, not with the metabolite (desbutylhalofantrine) : changes in QTc were decreased despite
cated
increased metabolite concentrations. The cardiac effects of halofantrine are similar to those of quinine.7 Thus halofantrine should be used with caution in patients previously treated with quinine (or vice versa). One should keep in mind a potentially toxic interaction of these two drugs, because quinine is widely used in many countries as self-medication. In areas with halofantrine-resistant strains of falciparum malaria, a higher dose of halofantrine may be required.8 The use of two courses of halofantrine 1500 mg a week apart should not put patients at higher risk than a single course, based on ECG findings. However, if the regimen is designed as the continuation of two courses (ie, 3000 mg as 500 mg 6 hourly for six doses), the risk of cardiotoxicity may be higher because change in QTc is concentration-dependent.
volunteers. The ECG abnormalities in patients and healthy volunteers were sinus bradycardia (31 vs 17%), sinus arrhythmia (24 vs
J Karbwang, K Na
17%), tall-peak
T-wave
(17 vs 0%), ectopic beat (3
vs
Bangchang,
D
Bunnag,
T Harinasuta
Clinical Pharmacology Unit, Department of Clinical Tropical Medicine; and Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
0%),
ventricular ectopic beat (0 vs 17%), and first-degree atrioventricular block (3 vs 0%). The occurrence of bradycardia and sinus arrhythmia were not significantly different between the patients and healthy subjects. There were no significant
P Laothavorn
changes in PR or QRS in patients or healthy subjects. Halofantrine prolonged QTc in patients and healthy volunteers. Halofantrine prolonged QTc in 27 patients, and 8 had
1
Cardiovascular Division, Department of Medicine, Medical College, Bangkok
ter
Kuile FO, Dolan G, Nostern F,
et
Pramangkutkloa Hospital and
al. Halofantrine
versus
mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet 1993; 341: 1044-49. 2
Ketrangsee S, Vijaykadga S, Yamokgul P, et al. Comparative trial on the response of Plasmodium falciparum to halofantrine and mefloquine in Trad Province, Eastern Thailand. Southeast Asian J Trop Public Health 1992; 23: 55-58.
Bunnag D, Veeravan C, Karbwang J, et al. Clinical trials with halofantrine in acute uncomplicated falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health (in press). 4 Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet 1993; 341: 1054-56. 5 Castot A, Rapoport P, Le Coz P. Prolonged QT interval with halofantrine. Lancet 1993; 341: 1541. 6 Monlon E, Pillet O, Cochard JF, Favarel Garrigues JCL, Le Bras M. Prolonged QT interval with halofantrine. Lancet 1993; 341: 1541. 7 Karbwang J, Davis TME, Looareesuwan S, Molunto P, Bunnag D, White NJ. A comparison of the pharmacokinetic and pharmacodynamic properties of quinine and quinidine in healthy Thai males. Br J Clin Pharmacol 1993; 35: 265-71. 8 Karbwang J, Milton KA, Na Bangchang K, et al. Pharmacokinetics of halofantrine in Thai patients with acute uncomplicated falciparum malaria. Br J Clin Pharmacol 1991; 31: 484-87. 3
QT prolongation, hypothermia, and alcohol liver disease
Figure: Concentration of halofantrine (Hf) and desbutylhalofantrine (Hfm) and changes in QTc 1-1= Hf, 0-0 A——A
=
Hfm. A: 0-0 QTc increase < 25%, Hf in 1 patient with no change in QTc. B: W——W QTc
increase >25%.
=
=
=
SIR—Day and colleagues (June 5, p 1423) report that QT interval prolongation in patients with alcoholic liver disease is associated with adverse prognosis. The mechanisms of arrhythmogenesis, by which both chronic alcoholism and QT prolongation predispose to ventricular tachycardias and sudden death, remain uncertain. Hendrickse (July 3, p 61) emphasise the part played by autonomic neuropathy. Another risk factor to consider is hypothermia. Alcohol-induced hypothermia is mediated by impaired behavioural thermoregulation, inadequate autonomic reactivity, and hypoglycaemia.1 A prolonged QTc interval is the most characteristic electrocardiographic (ECG) indicator of altered myocardial 501
halofantrine.
patients with acute uncomplifalciparum malaria (asexual parasitaemia < 5% of red cells), aged 15-60 years and weight 45-60 kg with no history of liver or kidney diseases, were studied. Written consent was obtained. The healthy subjects were admitted for at least the first 2 days and returned daily for a week and then once weekly until day 28 for ECG monitoring and for assay of plasma halofantrine and metabolite. The patients were admitted for 28 days. Halofantrine 500 mg was given every 6 h for three doses to all participants. ECG was recorded before and after treatment for 7 days and reviewed by a cardiologist. Bradycardia was diagnosed when heart rate was under 60 min. Halofantrine concentration was measured in 5 patients with prolongation of QTc interval of more than 25 % of their baseline, in 5 with prolongation of QTc under 25%, and in 1 with no change. The concentration of halofantrine was also measured in all healthy 6 healthy Thai males and 29
prolongation of greater than 25% of baseline. Patients and healthy subjects with higher halofantrine concentrations showed more prolonged QTc intervals. In all cases, the maximum change in QTc was noted between 16 and 24 h after the first dose, which coincided with the peak concentration. 1 patient with no change in QTc had the lowest plasma halofantrine (figure). Prolongation of QTc was associated with halofantrine concentration, not with the metabolite (desbutylhalofantrine) : changes in QTc were decreased despite
cated
increased metabolite concentrations. The cardiac effects of halofantrine are similar to those of quinine.7 Thus halofantrine should be used with caution in patients previously treated with quinine (or vice versa). One should keep in mind a potentially toxic interaction of these two drugs, because quinine is widely used in many countries as self-medication. In areas with halofantrine-resistant strains of falciparum malaria, a higher dose of halofantrine may be required.8 The use of two courses of halofantrine 1500 mg a week apart should not put patients at higher risk than a single course, based on ECG findings. However, if the regimen is designed as the continuation of two courses (ie, 3000 mg as 500 mg 6 hourly for six doses), the risk of cardiotoxicity may be higher because change in QTc is concentration-dependent.
volunteers. The ECG abnormalities in patients and healthy volunteers were sinus bradycardia (31 vs 17%), sinus arrhythmia (24 vs
J Karbwang, K Na
17%), tall-peak
T-wave
(17 vs 0%), ectopic beat (3
vs
Bangchang,
D
Bunnag,
T Harinasuta
Clinical Pharmacology Unit, Department of Clinical Tropical Medicine; and Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
0%),
ventricular ectopic beat (0 vs 17%), and first-degree atrioventricular block (3 vs 0%). The occurrence of bradycardia and sinus arrhythmia were not significantly different between the patients and healthy subjects. There were no significant
P Laothavorn
changes in PR or QRS in patients or healthy subjects. Halofantrine prolonged QTc in patients and healthy volunteers. Halofantrine prolonged QTc in 27 patients, and 8 had
1
Cardiovascular Division, Department of Medicine, Medical College, Bangkok
ter
Kuile FO, Dolan G, Nostern F,
et
Pramangkutkloa Hospital and
al. Halofantrine
versus
mefloquine in treatment of multidrug-resistant falciparum malaria. Lancet 1993; 341: 1044-49. 2
Ketrangsee S, Vijaykadga S, Yamokgul P, et al. Comparative trial on the response of Plasmodium falciparum to halofantrine and mefloquine in Trad Province, Eastern Thailand. Southeast Asian J Trop Public Health 1992; 23: 55-58.
Bunnag D, Veeravan C, Karbwang J, et al. Clinical trials with halofantrine in acute uncomplicated falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health (in press). 4 Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of antimalarial treatment with halofantrine. Lancet 1993; 341: 1054-56. 5 Castot A, Rapoport P, Le Coz P. Prolonged QT interval with halofantrine. Lancet 1993; 341: 1541. 6 Monlon E, Pillet O, Cochard JF, Favarel Garrigues JCL, Le Bras M. Prolonged QT interval with halofantrine. Lancet 1993; 341: 1541. 7 Karbwang J, Davis TME, Looareesuwan S, Molunto P, Bunnag D, White NJ. A comparison of the pharmacokinetic and pharmacodynamic properties of quinine and quinidine in healthy Thai males. Br J Clin Pharmacol 1993; 35: 265-71. 8 Karbwang J, Milton KA, Na Bangchang K, et al. Pharmacokinetics of halofantrine in Thai patients with acute uncomplicated falciparum malaria. Br J Clin Pharmacol 1991; 31: 484-87. 3
QT prolongation, hypothermia, and alcohol liver disease
Figure: Concentration of halofantrine (Hf) and desbutylhalofantrine (Hfm) and changes in QTc 1-1= Hf, 0-0 A——A
=
Hfm. A: 0-0 QTc increase < 25%, Hf in 1 patient with no change in QTc. B: W——W QTc
increase >25%.
=
=
=
SIR—Day and colleagues (June 5, p 1423) report that QT interval prolongation in patients with alcoholic liver disease is associated with adverse prognosis. The mechanisms of arrhythmogenesis, by which both chronic alcoholism and QT prolongation predispose to ventricular tachycardias and sudden death, remain uncertain. Hendrickse (July 3, p 61) emphasise the part played by autonomic neuropathy. Another risk factor to consider is hypothermia. Alcohol-induced hypothermia is mediated by impaired behavioural thermoregulation, inadequate autonomic reactivity, and hypoglycaemia.1 A prolonged QTc interval is the most characteristic electrocardiographic (ECG) indicator of altered myocardial 501