The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria

Ambler, Michael; Dubowitz, Lilly; Arunjerdja, Ratree; Hla, Eh Paw; Thwai, Kyaw L.; Viladpai-nguen, Jacher; Singhasivanon, Pratap; Luxemburger, Christine; Nosten, François; McGready, Rose

doi:10.1186/1475-2875-8-207

Cited by 9 publications

(12 citation statements)

References 36 publications

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“… 37 In a recent study, neither artesunate nor mefloquine resulted in significant impairment of behavior or motor function in Karen children, aged between 3 months and 5 years, when compared with non-febrile controls. 38 Our study in young African children confirmed these findings. We observed a low incidence of neuropsychiatric AEs; none represented a safety concern.…”

Section: Discussionsupporting

confidence: 85%

“…One study performed in Southeast Asia found no evidence for such effects in children less than 5 years of age (weighing > 5 kg), when mefloquine, either alone or combined with an artemisinin derivative, was administered to treat falciparum or vivax malaria 37. In a recent study, neither artesunate nor mefloquine resulted in significant impairment of behavior or motor function in Karen children, aged between 3 months and 5 years, when compared with non-febrile controls 38. Our study in young African children confirmed these findings.…”

Section: Discussionmentioning

confidence: 99%

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Tolerability and Efficacy of a Pediatric Granule Formulation of Artesunate-Mefloquine in Young Children from Cameroon with Uncomplicated Falciparum Malaria

Tietche¹,

Chelo²,

Ntoto³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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A fixed-dose pediatric formulation of artesunate and mefloquine (Artequin Pediatric) has been developed. In this open, non-comparative study in Cameroonian children with uncomplicated falciparum malaria, the safety and efficacy of this formulation was tested, with a particular emphasis on the risk of neuropsychiatric adverse events (AEs). In total, 220 subjects, weighing between 10 and 20 kg, were enrolled; 213 qualified for analysis. Artesunate-mefloquine was given once daily for 3 days. Overall, 13.1% of patients reported mild to moderate neuropsychiatric AEs (elicited through a structured questionnaire or reported spontaneously) out of which 3.8% (mainly insomnia) were considered drug-related. Other drug-related AEs were infrequent (< 3%). Polymerase chain reaction-corrected cure rate (adequate clinical and parasitological response) determined by survival analysis at 28 and 63 days was 96.6%. New infections were observed in 11.2% of evaluable patients at 63 days. The new formulation was well tolerated and efficacious in the population investigated.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Tolerability and Efficacy of a Pediatric Granule Formulation of Artesunate-Mefloquine in Young Children from Cameroon with Uncomplicated Falciparum Malaria

Tietche¹,

Chelo²,

Ntoto³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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“…Thus, late onset neurological and neuropsychiatric adverse events were recorded in contrast to the study by Ambler et al [2]. Hyperactivity, as the only neuropsychiatric adverse event (0.5%), was detected after day 28.…”

Section: Discussionmentioning

confidence: 58%

Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety

Frey

Chelo

Kinkela

et al. 2010

Malar J

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BackgroundMefloquine-artesunate combination therapy for uncomplicated falciparum malaria is one of the treatments used in African children. Data concerning neurological safety in adults and children treated with mefloquine and artesunate combination therapy is well documented in Asia. Safety data for neurological and neuropsychiatric side effects of mefloquine and artesunate combination therapy in African children are scarce, although WHO recommends this therapy in Africa.MethodsA phase IV, open label, single arm study was conducted among African children between 10 and 20 kg with acute uncomplicated falciparum malaria. They were treated over three consecutive days with a paediatric fixed-dose combination of artesunate (50 mg/d) and mefloquine (125 mg/d). Parasitological, clinical and neurological examinations and standardized questions about neuropsychiatric symptoms were carried out on days 0, 4, 7, 28 and 63. The primary objective was to assess the neurological and neuropsychiatric safety of artesunate-mefloquine combination therapy in young children.ResultsFrom December 2007 to March 2009, 220 children with uncomplicated Plasmodium falciparum malaria were treated with artesunate and mefloquine. 213 children were analysed according to study protocol. 50 neurological and neuropsychiatric adverse events occurred in 28 patients. Eleven drug-related neurological and neuropsychiatric adverse events occurred in eight patients. Sleeping disorders were present in 2.3%, neurological disorders in 1.4%, neuropsychiatric disorders in 1% and eating disorders in 0.5% of the patients. Adverse events were of mild to moderate intensity and resolved spontaneously.ConclusionAfrican children showed a low percentage of self-limited neurological and neuropsychiatric adverse events, confirming studies on neurological safety in Asian children treated with artesunate and mefloquine. Sleeping disorders were most frequently observed.

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“…Relevant neuropsychiatric adverse events are difficult to identify in young children and are consequently under-reported. Another study of artesunate–mefloquine (fixed dose of 50 mg artesunate and 125 mg mefloquine per day for 3 days) in 213 young children in Africa, 28 with a 63-day follow-up, actively tested for neuropsychiatric effects (using standard infant neurological tests) and reported mild-to-moderate, spontaneously resolving neuropsychiatric adverse events, with sleeping disorders being the most common (2·3% of patients). Notably, because of the risk of serious psychiatric side-effects, the latest WHO antimalarial treatment guideline 3 recommends an interval of 60 days between consecutive periods of mefloquine treatment.…”

Section: Discussionmentioning

confidence: 99%

Comparison of artesunate–mefloquine and artemether–lumefantrine fixed-dose combinations for treatment of uncomplicated Plasmodium falciparum malaria in children younger than 5 years in sub-Saharan Africa: a randomised, multicentre, phase 4 trial

Sirima

Ogutu

Lusingu

et al. 2016

The Lancet Infectious Diseases

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SummaryBackgroundWHO recommends combinations of an artemisinin derivative plus an antimalarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infection. In Africa, artemether–lumefantrine is the most widely used artemisinin-based combination therapy, whereas artesunate–mefloquine is used infrequently because of a perceived poor tolerance to mefloquine. WHO recommends reconsideration of the use of artesunate–mefloquine in Africa. We compared the efficacy and safety of fixed-dose artesunate–mefloquine with that of artemether–lumefantrine for treatment of children younger than 5 years with uncomplicated P falciparum malaria.MethodsWe did this multicentre, phase 4, open-label, non-inferiority trial in Burkina Faso, Kenya, and Tanzania. Children aged 6–59 months with uncomplicated malaria were randomly assigned (1:1), via a computer-generated randomisation list, to receive 3 days' treatment with either one or two artesunate–mefloquine tablets (25 mg artesunate and 55 mg mefloquine) once a day or one or two artemether–lumefantrine tablets (20 mg artemether and 120 mg lumefantrine) twice a day. Parasitological assessments were done independently by two microscopists who were blinded to treatment allocation. The primary outcome was the PCR-corrected rate of adequate clinical and parasitological response (ACPR) at day 63 in the per-protocol population. Non-inferiority was shown if the lower limit of the 95% CI for the difference between groups was greater than −5%. Early vomiting was monitored and neuropsychiatric status assessed regularly during follow-up. This study is registered with ISRCTN, number ISRCTN17472707, and the Pan African Clinical Trials Registry, number PACTR201202000278282.Findings945 children were enrolled and randomised, 473 to artesunate–mefloquine and 472 to artemether–lumefantrine. The per-protocol population consisted of 407 children in each group. The PCR-corrected ACPR rate at day 63 was 90·9% (370 patients) in the artesunate–mefloquine group and 89·7% (365 patients) in the artemether–lumefantrine group (treatment difference 1·23%, 95% CI −2·84% to 5·29%). At 72 h after the start of treatment, no child had detectable parasitaemia and less than 6% had fever, with a similar number in each group (21 in the artesunate–mefloquine group vs 24 in the artemether–lumefantrine group). The safety profiles of artesunate–mefloquine and artemether–lumefantrine were similar, with low rates of early vomiting (71 [15·3%] of 463 patients in the artesunate–mefloquine group vs 79 [16·8%] of 471 patients in the artemether–lumefantrine group in any of the three dosing days), few neurological adverse events (ten [2·1%] of 468 vs five [1·1%] of 465), and no detectable psychiatric adverse events.InterpretationArtesunate–mefloquine is effective and safe, and an important treatment option, for children younger than 5 years with uncomplicated P falciparum malaria in Africa.FundingAgence Française de Développement, France; Department for International Development, UK; Dutch Ministry of F...

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The neurological assessment in young children treated with artesunate monotherapy or artesunate-mefloquine combination therapy for uncomplicated Plasmodium falciparum malaria

Cited by 9 publications

References 36 publications

Tolerability and Efficacy of a Pediatric Granule Formulation of Artesunate-Mefloquine in Young Children from Cameroon with Uncomplicated Falciparum Malaria

Tolerability and Efficacy of a Pediatric Granule Formulation of Artesunate-Mefloquine in Young Children from Cameroon with Uncomplicated Falciparum Malaria

Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety

Comparison of artesunate–mefloquine and artemether–lumefantrine fixed-dose combinations for treatment of uncomplicated Plasmodium falciparum malaria in children younger than 5 years in sub-Saharan Africa: a randomised, multicentre, phase 4 trial

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