Recrudescence of a high parasitaemia, severe Plasmodium falciparum malaria episode, treated by artesunate monotherapy
Sophie LandréAnne‐Lise BienvenuPatrick MiailhesPaul AbrahamMarie SimonAgathe BeckerAnne ConradGuillaume BonnotYobouet Inès KouakouChristian ChidiacGilles LeboucherThomas RimmeléLaurent ArgaudStéphane Picot
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Abstract:
A patient presenting with severe malaria, with hyperparasitaemia, received 7-day artesunate monotherapy. A severe recrudescence was detected and attributed to hyperparasitaemia, monotherapy and a polyclonal infection without Kelch 13 gene mutation. A second treatment with artesunate, then quinine, followed by artemether-lumefantrine, was successful.Keywords:
Artesunate
Artemether/lumefantrine
Lumefantrine
Severe Malaria
Combination therapy
Artemether
Quinine
Pyronaridine-artesunate is a novel artemisinin-based combination therapy. The efficacy and safety of pyronaridine-artesunate were compared with artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children.This phase III open-label randomized controlled non-inferiority trial was conducted in Western Kenya. Children aged 6 months to ≤ 12 years with a bodyweight > 5 kg and microscopically confirmed P. falciparum malaria were randomly assigned in a 1:1 ratio to orally receive pyronaridine-artesunate or artemether-lumefantrine, dosed according to bodyweight, for 3 days.Of 197 participants, 101 received pyronaridine-artesunate and 96 received artemether-lumefantrine. The day-28 adequate clinical and parasitological response in the per-protocol population, PCR-corrected for reinfections, was 98.9% (93/94, 95% CI 94.2-99.8) for pyronaridine-artesunate and 96.4% (81/84, 95% CI 90.0-98.8) for artemether-lumefantrine. Pyronaridine-artesunate was found to be non-inferior to artemether-lumefantrine: the treatment difference was 2.5% (95% CI - 2.8 to 9.0). Adverse events occurred in 41.6% (42/101) and 34.4% (33/96) of patients in the pyronaridine-artesunate group and the artemether-lumefantrine group, respectively. No participants were found to have alanine or aspartate aminotransferase levels > 3 times the upper limit of normal.Pyronaridine-artesunate was well tolerated, efficacious and non-inferior to artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria in Kenyan children. Results are in line with previous reports and inclusion of pyronaridine-artesunate in paediatric malaria treatment programmes should be considered. This study is registered at clinicaltrials.gov under NCT02411994. Registration date: 8 April 2015. https://clinicaltrials.gov/ct2/show/NCT02411994?term=pyronaridine-artesunate&cond=Malaria&cntry=KE&rank=1.
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Aim In Africa’s malaria-endemic regions, artesunate/amodiaquine (A/A) and artemether/lumefantrine (A/L) are the antimalarial medications that are most frequently prescribed. Antimalarial medications could be overused if they are self-prescribed based on symptoms rather than a parasitological diagnosis. This investigation looked at potential cytotoxic and oxidative stress effects following three dosage treatments spaced 24 h apart. Method Artesunate (50 μM and 100 μM), Amodiaquine (1 μM and 10 μM), Artemether (200 μM and 400 μM), and Lumefantrine (200 μM and 400 μM) were administered to HepG2-derived VL-17A for up to 72 h. Result With a downward trend from 24 h to 48 h to 72 h, the study findings showed that repeated administration of these medications greatly reduced cell viability. Additionally, for artemether 200 μM treatment, the reactive oxygen species (ROS) levels increased after 24 h and 48 h but considerably decreased after 72 h. The ROS levels in artesunate, amodiaquine, artemether 400 μM, and lumefantrine were also noticeably lower after 72 h. Conclusion The results of this experiment show that repeated applications of anti-malaria drugs, A/L and A/A to HepG2 liver cells reduced their viability in a manner that was consistent. These findings have significant implications for those who use antimalarial medications as a preventative measure without a diagnosis of parasite infection.
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To review the pharmacology, pharmacokinetics, safety, and efficacy of artemether-lumefantrine for the treatment of Plasmodium falciparum malaria.English-language articles indexed in PubMed (1947-November 2011) were identified, using the search terms artemether-lumefantrine, artemether-lumefantrine AND malaria, Coartem, and Coartem AND malaria.Available English-language articles were reviewed. In addition, the malaria treatment regimens recommended by region as provided by the World Health Organization and the treatment guidelines from the Centers for Disease Control and Prevention were reviewed.Artemether-lumefantrine is an artemisinin-derived combination antimalarial approved by the Food and Drug Administration in 2009 for the treatment of P. falciparum malaria. The dual mechanisms of action of artemether-lumefantrine provide rapid and sustained parasite clearance. In the reviewed studies, the polymerase chain reaction (PCR)-corrected 28-day cure rates of artemether-lumefantrine were noninferior to the most common comparators, including chloroquine, dapsone, and other artemisinin derivatives (86-100% vs 51-100%, respectively). PCR-corrected day-42 cure rates were 92-99.3% for artemether-lumefantrine versus 62-100% for the comparator groups. The major adverse effects (gastrointestinal and central nervous system) were mild to moderate in severity and did not require a change in therapy. Although adherence to artemether-lumefantrine has been described as a potential problem due to the complicated dosing schedule, studies have described clinical cure rates similar to those of other antimalarials.Artemether-lumefantrine is a safe and effective treatment for children and adults with P. falciparum malaria.
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The choice of appropriate artemisin-based combination therapy depends on several factors (cost, efficacy, safety, reinfection rate, and simplicity of administration). In this study, we tested the hypothesis that artesunate-mefloquine (Artequin™) is as efficacious as artemether-lumefantrine (Coartem®) in treatment of uncomplicated Plasmodium falciparum malaria. The study was carried out from August 2004 through February 2005 in Kambila, Mali. Subjects with weights ≥ 10 kg and uncomplicated malaria were enrolled. Artesunate-mefloquine was given once a day for three days and artemether/lumefantrine twice a day for three days. A total of 470 (235 in each arm) patients were enrolled. The unadjusted 28-day cure rate was higher in artesunate-mefloquine arm than in the artemether-lumefantrine arm (79.7% versus 67.8%; P < 0.004). After correction for reinfection, the 28-day cure rates were similar in the two groups (96.04% versus 96.93%). Artesunate-mefloquine is well-tolerated and is as effective as artemether-lumefantrine for the treatment of P. falciparum malaria. Artesunate-mefloquine also prevented more new infections.
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This chapter provides the basic characteristics, side effects/toxicity, drug interactions, and dosing of the coartem (artemether/lumefantrine). Artemether is metabolized into dihydroartemisinin (DHA). Lumefantrine inhibits the formation of β-hematin by forming a complex with hemin. Both artemether and lumefantrine inhibit nucleic acid and protein synthesis. Artemether/lumefantrine tablets should be taken with food. When artemether/lumefantrine is coadministered with an inhibitor of CYP3A4, including grapefruit juice, it may result in increased concentrations of artemether and/or lumefantrine and potentiate QT prolongation. When artemether/lumefantrine is coadministered with inducers of CYP3A4 it may result in decreased concentrations of artemether and/or lumefantrine and loss of antimalarial efficacy. Coartem tablets contain 20 mg of artemether and 120 mg of lumefantrine. Artemether/lumefantrine is not approved for patients with severe or complicated Plasmodium falciparum malaria. It is not approved for the prevention of malaria. Coartem tablets may be crushed and mixed with a small amount of water.
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ABSTRACT Chemotherapy remains an important approach in the fight against malaria. Artemether–lumefantrine combination is widely in use due to its effectiveness against Plasmodium falciparum . Misuse in the form of multiple repeated doses of this anti‐malaria drug is rampant in Nigeria. This study was designed to assess the hepatotoxic and clastogenic potential of extreme misuse of artemether–lumefantrine in rats. Graded doses of artemether–lumefantrine (1–5 mg/kg body weight) were administered by oral gavage for 6 weeks, twice daily, for 3 consecutive days per week. Artemether–lumefantrine, at all doses, did not have significant effects on the body and relative liver weight of treated group compared to the negative control group. The mean γ‐glutamyltransferase, alanine, and aspartate aminotransaminase activity in groups of artemether–lumefantrine treated rats were significantly higher ( p < 0.05) than that of the negative control group indicating that repeated administration of artemether–lumefantrine may be hepatotoxic. Findings from histological analyses of liver cross‐section support the enzyme pattern of hepatoxicity. In addition, the drug, at all experimental doses, significantly induced ( p < 0.05) formation of micronucleated polychromatic erythrocytes in the bone marrow cells of the treated rats compared with the negative control indicating clastogenic potential of the drug when misused. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 301–307, 2015.
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In an efficacy trial of artemisinin-based combination treatments (ACT) in central Sudan, cases of uncomplicated, Plasmodium falciparum malaria were given artesunate–sulfadoxine–pyrimethamine (ASP) or artemether–lumefantrine (AL) as first-line treatment. On enrolment, the 71 patients given ASP were similar to the 72 given AL, apart from having generally lower parasitaemias (geometric mean counts of 4893 ν. 10,215 asexual parasites/μl) and having a lower mean age (15 ν. 23 years). Each patient was treated on days 0, 1 and 2, and all 137 who completed follow-up without further, unscheduled treatment were found aparasitaemic and afebrile from day 2 until the last follow-up, on day 28. No moderate or severe adverse side-effects, clinical failures or parasitological failures were observed among these 137 patients. ACT therefore appear both efficacious and safe for the treatment of uncomplicated malaria in central Sudan.
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Background World Health Organization (WHO) has recommendedthat countries with drug resistant malaria problem usecombination therapies, especially artemisinin-based combinationtherapy (ACT). However, there is limited information on theefficacy of ACT in North Sulawesi.Objective To compare the efficacy of artemether-lumefanttine andartesunate plus sulfadoxine-pyrimethamine (SP).Methods This was a randomized experimental study, conducted inProf. Dr. R. D. Kandou General Hospital, Manado from Januaryuntil July 2009. There were 42 patients aged less than 13 yearstreated with artemether-lumefanttine and artesunate plus SP. Bodytemperature, parasite and gametocyte count were recorded everyday until day 7 and follow-up reviews were done on day 14 and28.Results Fever clearance time showed a significant differencebetween artemether-lumefanttine group (median 27 hours) andartesunate plus SP group (median 18 hours), P<0.05). There wasno significant difference in parasite clearance time (P>0.05) andgame tocyte clearance time (P > 0. 05) . The 28 day cure rate were100% in the two groups. No side effect was found.Conclusion Both artemether-lumefanttine and artesunate plus SPcombination are effective and safe for the treatment of falciparummalaria in children.
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Artemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg.This multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up).A total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg.A three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown.Clinicaltrials.gov NCT01619878.
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