Cardiac effects of amodiaquine and sulfadoxine-pyrimethamine in malaria-infected African patients.

0 BEJAMAIN NGOUESSE, LEONARDO K. BASCO, PASCAL RINGWALD, ANNICK KEUNDJIAN The cardiac effect of amodiaquine and sulfadoxine-pyrimethamine was studied in adult Cameroonian patients with acute uncomplicated Plasmodium falciparum malaria by electrocardiographic monitoring over the course of 7 days. Clinical and parasitological responses were monitored until Day 14. Bradycardia was observed in 16 of 20 amodiaquine-treated patients on Day 2, which corresponds to the time when maximal cumulative plasma concentration is reached, and in 12 of 20 patients on Day 7. A bradycardic effect lasting several days was not noted in patients treated with sulfadoxine-pyrimethamine. Significantly prolonged P, PQ, QRS, and QTc intervals were recorded on Day 2 after both 30 and 35 mg of amodiaquine base per kilogram of body weight had been administered, but these intervals were not correlated with the plasma monodesethylamodiaquine (main human active metabolite of amodiaquine) level. Electrocardiographic changes after therapy with sulfadoxine-pyrimethamine were minor and transient. All patients had fever and parasite clearance on or before Day 3 and remained free of fever and parasites until Day 14. None of the patients complained of cardiovascular adverse effects during the follow-up. These results suggest the absence of significant cardiac effects of amodiaquine and sulfadoxine-pyrimethamine at usual therapeutic doses, but they should draw the attention of clinicians treating malaria-infected patients who have taken other antimalarial drugs with cardiovascular side effects or those who are under treatment with cardiovascular drugs. - The spread of chloroquine-resistant Plasmodium falciparum malaria has led to an increasing use of amodiaquine as an alternative first-line drug for uncomplicated infections in Cameroon.1 The World Health Organization (WHO) has adopted contradictory positions on the use of amodiaquine as a result of serious hematologic and hepatic adverse reactions observed in tourists who are taking chemoprophylaxis.2,3 However, several recent clinical studies suggest that adverse reactions are rare when amodiaquine is administered for treatment.46 In addition, these studies have shown that amodiaquine retains a high efficacy against P. falciparum infections in chloroquine-resistant endemic areas in east and central Africa. The clinical efficacy and relative safety of amodiaquine for therapeutic use, even in young children, together with its low cost, explain the continued use of this drug in some African countries. Amodiaquine is a Mannich base derivative and an analog of chloroquine. It has been used since the 1940s. Despite its long use, the pharmacodynamic properties of amodiaquine, including electrocardiographic effects, have not been extensively studied in humans. Other antimalarial drugs containing the quinoline nucleus, including chloroquine, quinine, quinidine, and halofantrine (a phenanthrene amino alcohol derivative), are known to prolong ventricular repolarization, which is evidenced by increased QTc interval in electrocardiogram, at usual therapeutic concentrations.79 Although symptomatic cardiac effects have not been reported after administration of 4-aminoquinolines,9,10 the electrocardiographic changes produced by chloroquine in healthy volunteers and malaria-infected patients are of potential concern in areas where amodiaquine is extensively used because of the similarities in chemical structures and properties of chloroquine and amodiaquine. In this study, we investigated the electrocardiographic effects of amodiaquine in symptomatic, malaria-infected patients and correlated these changes with plasma concentrations of amodiaquine and those of monodesethylamodiaquine, the biologically active metabolite of amodiaquine. We also investigated whether a sulfadoxine-pyrimethamine (SP) combination produces electrocardiographic changes in patients. PATIENTS AND METHODS Symptomatic Cameroonian adult patients who sought treatment at the Nlongkak Catholic missionary dispensary were enrolled in the study if the following criteria were met: monoinfection with P. falciparum, age 15 years, and negative Saker-Solomons urine test.11 Pregnant women and patients with signs and symptoms of severe and complicated malaria were excluded from the study.12 Patients were also excluded if the initial physical examination or if the baseline electrocardiogram revealed abnormal or pathological cardiovascular features. The study was approved by the ethics committee of the Faculty of Medicine, University of Yaounde I, and Cameroonian Ministry of Public Health. After informed consent was obtained, patients were randomly assigned to 1 of 3 regimens. The first regimen (AMQ30) comprised orally administered amodiaquine at a total dose of 30 mg per kilogram of body weight of amodiaquine base, administered in 3 equal doses (10 mg/kg) on Days 0, 1, and 2. The second regimen (AMQ35A) was a total dose of 35 mg/kg, administered in 4 doses as follows: 10 mg/kg at Hour 0 and 5 mg/kg at Hour 6 on Day 0, then 10 mg/kg on Days 1 and 2. The third regimen (AMQ35B) was a total dose of 35 mg/kg, administered in 4 doses as follows: 7.5 mg/kg at Hour 0 and 7.5 mg/kg at Hour 6, and 10 mg/kg on Days 1 and 2. These 3 regimens were evaluated because there is currently no consensus regarding the dosage schedule of amodiaquine. In another nonrandomized study, the fourth group of patients who met the inclusion criteria and who denied history of allergic reactions to sulfonamides was treated with a single orally administered dose of SP. Each dose was administered under supervision, and patients were observed for at least 1 hr after drug intake. The only other drug that the patients received until Day 7 was paracetamol, which was administered for fever or headache. Patients were followed on an outpatient basis on Days 1, 2, 3, 7, and 14. This follow-up schedule was based on the new WHO protocol for monitoring the therapeutic and parasitological response to antimalarial drugs.13 During each visit, a complete physical examination and a thick blood film examination were performed. In addition to these follow-up visits, patients assigned to regimens AMQ35A and AMQ35B received a home visit 6 hr after the first dose for the administration of the second dose under supervision and received an additional examination 10 hr after the first dose. Baseline electrocardiogram (Cardiovit AT-3/1 3-channel electrocardiograph for 12 simultaneous leads; Schiller AG, Baar, Switzerland) was performed before the first dose. In patients assigned to the AMQ30 regimen, serial electrocardiographic monitoring was performed at Day 0/Hour 4, Day 2/Hour 4, Day 3, and Day 7. In patients assigned to either the AMQ35A or AMQ35B groups, electrocardiogram was monitored at Day 0/Hour 10, Day 2/Hour 4, Day 3, and Day 7. For SP-treated patients, an electrocardiogram was per formed 4 hr after the single dose, and subsequent electrocardiograms were r (...truncated)