High efficacy of two artemisinin‐based combinations (artemether–lumefantrine and artesunate plus amodiaquine) for acute uncomplicated malaria in Ibadan, Nigeria

Falade, CO; Ogundele, A. O.; Yusuf, Bidemi; Ademowo, Olusegun G.; Ladipo, S. M.

doi:10.1111/j.1365-3156.2008.02043.x

Cited by 46 publications

(33 citation statements)

References 17 publications

(22 reference statements)

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“…However, it should be borne in mind that Coartem is effective at treating malaria, with high success rates (Ͼ90 to 95%), in many areas where malaria is endemic, including Kenya (11,12,18,42). Thus, the mechanisms of Coartem resistance in vivo will likely involve other genes.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Mwai

Kiara

Abdi

et al. 2009

Antimicrob Agents Chemother

150

156

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We have analyzed the in vitro chemosensitivity profiles of 115 Kenyan isolates for chloroquine (CQ), piperaquine, lumefantrine (LM), and dihydroartemisinin in association with polymorphisms in pfcrt at codon 76 and pfmdr1 at codon 86, as well as with variations of the copy number of pfmdr1. The median drug concentrations that inhibit 50% of parasite growth (IC 50 s) were 41 nM (interquartile range [IQR], 18 to 73 nM), 50 nM (IQR, 29 to 96 nM), 32 nM (IQR, 17 to 46 nM), and 2 nM (IQR, 1 to 3 nM) for CQ, LM, piperaquine, and dihydroartemisinin, respectively. The activity of CQ correlated inversely with that of LM (r 2 ‫؍‬ ؊0.26; P ‫؍‬ 0.02). Interestingly, parasites for which LM IC 50 s were higher were wild type for pfcrt-76 and pfmdr1-86. All isolates had one pfmdr1 copy. Thus, the decrease in LM activity is associated with the selection of wild-type pfcrt-76 and pfmdr1-86 parasites, a feature that accounts for the inverse relationship between CQ and LM. Therefore, the use of LM-artemether is likely to lead to the selection of more CQ-susceptible parasites.Chemotherapy is still the main approach for the control of malaria, and current strategies for malaria treatment rely on the use of combinations of drugs that include artemisinin compounds. Although this strategy is designed to reduce the chance of resistance emerging, there is considerable concern that this will inevitably occur.For instance, the combination of lumefantrine (LM) and artemether (ATM), known as Coartem, has become the firstline treatment for malaria in many African countries, including Kenya (19). ATM is converted in vivo to dihydroartemisinin (DHA). Emerging reports indicate that the use of LM (in Coartem) selects for parasites that show increased tolerance to Coartem, and these parasites select for a wild-type pfmdr1 genotype or show increased copy numbers of pfmdr1, a gene associated with chloroquine (CQ) and mefloquine (MFQ) resistance (7,13,15,20,36,38). Thus, there is concern that resistance to LM could emerge rapidly. On the other hand, recent reports from Southeast Asia indicate that resistance to artemisinin derivatives is increasing, threatening the concept of artemisinin-based combinations (8).Another combination, piperaquine (PQ) and DHA, known as Artekin, is undergoing clinical evaluation (17,39,42). This drug is efficacious, safe, and affordable and thus is likely to become an alternative to Coartem. PQ is a bisquinoline derivative consisting of two linked CQ molecules. Although reports indicate that PQ retains potency against CQ-resistant parasites (3), there is concern that PQ could become less susceptible against a backdrop of high CQ resistance (17,22).In this paper, we sought to analyze the in vitro activities of the antimalarials LM, DHA, and PQ in relation to polymorphisms in pfcrt at codon 76 (pfcrt-76) and in pfmdr1 at codon 86 (pfmdr1-86) and in relation to pfmdr1 copy number variations in Kenyan isolates. We used CQ as a reference drug. MATERIALS AND METHODSCQ was purchased from Sigma Chemical Co. (Poole, Dorset, United...

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Section: Discussionmentioning

confidence: 99%

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Mwai

Kiara

Abdi

et al. 2009

Antimicrob Agents Chemother

150

156

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“…27,28 With the adoption of these ACTs, small-scale studies have been frequent in the country, 29,30 but evaluation of relatively large numbers of children over a relatively long period is an exception. The present study attempted to rectify this deficiency.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacies of Artemisinin-Based Combination Therapies in Nigerian Children with Uncomplicated Falciparum Malaria during Five Years of Adoption as First-Line Treatments

Gbotosho

Sowunmi²,

Happi³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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Abstract. The therapeutic efficacies of 3-day regimens of artesunate-amodiaquine and artemether-lumefantrine during 5 years of adoption as first-line treatments were evaluated in 811 ≤ 12-year-old malarious children. Compared with artemether-lumefantrine, amodiaquine-artesunate significantly reduced the proportion of children with fever and parasitemia 1 day after treatment (day 1; P < 0.008 for both). The proportion of parasitemic children on day 2 and gametocytemia on presentation and carriage reduced significantly over the years ( P < 0.000001 and P < 0.03, respectively; test for trend). Overall efficacy was 96.5% (95% confidence interval [CI] = 94.5-98.6) and remained unchanged over the years ( P = 0.87; test for trend). Kinetics of parasitemias after treatments were estimated by a non-compartmental model. Declines of parasitemias were monoexponential, with a mean elimination half-life of 1.09 hours (95% CI = 1.0-1.16). Parasitemia half-lives and efficacy were similar for both regimens and in all ages. Artesunate-amodiaquine and artemether-lumefantrine remain efficacious treatments of uncomplicated falciparum malaria in Nigerian children 5 years after adoption.

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“…The polymerase chain reaction (PCR) corrected day 28 cure rates per protocol of the two patient populations were 98.4% for AS-AQ and 100% for AL. Both drug combinations were well tolerated, the efficacy comparison demonstrated that AS-AQ was as effective as AL, and both combinations were shown to be both efficacious and safe [14].…”

Section: The Six-dose Regimen Of Al Is Similar To the Efficacy Achievmentioning

confidence: 94%

The Impact of Pharmacokinetic Mismatched Antimalarial Drug Combinations on the Emergence and Spread of Drug Resistant Parasites

Li¹,

Hickman²

2015

Basic Pharmacokinetic Concepts and Some Clinical Applications

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High efficacy of two artemisinin‐based combinations (artemether–lumefantrine and artesunate plus amodiaquine) for acute uncomplicated malaria in Ibadan, Nigeria

Cited by 46 publications

References 17 publications

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

In Vitro Activities of Piperaquine, Lumefantrine, and Dihydroartemisinin in Kenyan Plasmodium falciparum Isolates and Polymorphisms in p fcrt and p fmdr1

Therapeutic Efficacies of Artemisinin-Based Combination Therapies in Nigerian Children with Uncomplicated Falciparum Malaria during Five Years of Adoption as First-Line Treatments

The Impact of Pharmacokinetic Mismatched Antimalarial Drug Combinations on the Emergence and Spread of Drug Resistant Parasites

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