Dataset Information

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015.

ABSTRACT: High treatment failure rates for Plasmodium falciparum malaria have been reported in Colombia for chloroquine, amodiaquine, and sulfadoxine-pyrimethamine. Artemisinin combination therapies were introduced in 2006 in Colombia, where artemether-lumefantrine (AL) is currently used to treat uncomplicated P. falciparum malaria. Artemisinin (ART) resistance was initially observed in Southeast Asia as an increased parasite clearance time, manifesting as a positive thick-blood smear on day 3 after treatment (D3 positivity). Recently, mutations in the propeller domain of the P. falciparumkelch13 gene (K13 propeller) have been associated with ART resistance. In this study, we surveyed AL effectiveness at D3 and molecular markers of drug resistance among 187 uncomplicated P. falciparum cases in 4 regions of Colombia from June 2014 to July 2015. We found that 3.2% (4/125) of patients showed D3 positivity, 100% (163/163) of isolates carried wild-type K13 propeller alleles, 12.9% (23/178) of isolates had multiple copies of the multidrug resistance 1 gene (mdr1), and 75.8% (113/149) of isolates harbored the double mutant NFSDD mdr1 haplotype (the underlining indicates mutant alleles). These data suggest that ART resistance is not currently suspected in Colombia but that monitoring for lumefantrine resistance and AL failures should continue.

SUBMITTER: Montenegro M

PROVIDER: S-EPMC5700320 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015.

Montenegro Madeline M Neal Aaron T AT Posada Maritza M De Las Salas Briegel B Lopera-Mesa Tatiana M TM Fairhurst Rick M RM Tobon-Castaño Alberto A

Antimicrobial agents and chemotherapy 20171122 12

High treatment failure rates for Plasmodium falciparum malaria have been reported in Colombia for chloroquine, amodiaquine, and sulfadoxine-pyrimethamine. Artemisinin combination therapies were introduced in 2006 in Colombia, where artemether-lumefantrine (AL) is currently used to treat uncomplicated P. falciparum malaria. Artemisinin (ART) resistance was initially observed in Southeast Asia as an increased parasite clearance time, manifesting as a positive thick-blood smear on day ...[more]

PMID: 28947476

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Project description:BACKGROUND:Dissolution of artemether (ART) and lumefantrine (LUM) active pharmaceutical ingredients (APIs) in fixed dose combination (FDC) ART/LUM tablets is one of the critical quality attributes. Thus, the verification of the release profile of ART and LUM from FDC ART/LUM tablets using a robust and discriminatory dissolution method is crucial. Therefore, the aim of this study was to develop and validate an appropriate dissolution method for quality control of FDC ART/LUM tablets. METHODS:The dissolution medium was selected based on saturation solubility data and sink conditions. The effect of agitation speed, pH and surfactant concentration on the release of ART and LUM was evaluated by employing a two-level factorial experiment. The resulting final method was validated for linearity, precision, robustness and API stability. In addition, the discriminatory power of the method was evaluated using expired and unexpired FDC ART/LUM products. RESULTS:A suitable dissolution profile of FDC ART/LUM tablets was obtained in 900 ml HCl (0.025 N, pH 1.6) with 1%Myrj 52 using paddle method at 100 rpm and 37 °C. ART and LUM were analysed using a HPLC method with UV detection at wavelengths of 210 and 335 nm, respectively. The results from the stability study showed that ART and LUM were sufficiently stable in HCl (0.025 N, pH 1.6) with 1%Myrj 52 at 37 °C. The method was linear (r2 = 0.999) over the concentration range of 6.25-100 μg/ml. The results for precision were within the acceptance limit (%RSD < 2). The percent relative standard deviation (< 2%) and statistically non-significant (p > 0.05) difference in release of ART and LUM observed between deliberately changed dissolution method settings (pH = 1.6 ± 0.2 or agitation speed = 100 ± 2) and optimized dissolution conditions revealed the robustness of the dissolution method. The method was capable to discriminate among different FDC ART/LUM products with different quality. CONCLUSIONS:The developed dissolution method is robust and discriminatory. It can be used in the quality evaluation of FDC ART/LUM tablets.

Project description:BackgroundLate treatment failures after artemisinin-based combination therapies (ACTs) for falciparum malaria have increased in the Greater Mekong subregion in southeast Asia. Addition of amodiaquine to artemether-lumefantrine could provide an efficacious treatment for multidrug-resistant infections.MethodsWe conducted an open-label, randomised trial at five hospitals or health centres in three locations (western Cambodia, eastern Cambodia, and Vietnam). Eligible participants were male and female patients aged 2-65 years with uncomplicated Plasmodium falciparum malaria. Patients were randomly allocated (1:1 in blocks of eight to 12) to either artemether-lumefantrine alone (dosed according to WHO guidelines) or artemether-lumefantrine plus amodiaquine (10 mg base per kg/day), both given orally as six doses over 3 days. All received a single dose of primaquine (0·25 mg/kg) 24 h after the start of study treatment to limit transmission of the parasite. Parasites were genotyped, identifying artemisinin resistance. The primary outcome was Kaplan-Meier 42-day PCR-corrected efficacy against recrudescence of the original parasite, assessed by intent-to-treat. Safety was a secondary outcome. This completed trial is registered at ClinicalTrials.gov (NCT03355664).FindingsBetween March 18, 2018, and Jan 30, 2020, 310 patients received randomly allocated treatment; 154 received artemether-lumefantrine alone and 156 received artemether-lumefantrine plus amodiaquine. Parasites from 305 of these patients were genotyped. 42-day PCR-corrected treatment efficacy was noted in 151 (97%, 95% CI 92-99) of 156 patients with artemether-lumefantrine plus amodiaquine versus 146 (95%, 89-97) of 154 patients with artemether-lumefantrine alone; hazard ratio (HR) for recrudescence 0·6 (95% CI 0·2-1·9, p=0·38). Of the 13 recrudescences, 12 were in 174 (57%) of 305 infections with pfkelch13 mutations indicating artemisinin resistance, for which 42-day efficacy was noted in 89 (96%) of 93 infections with artemether-lumefantrine plus amodiaquine versus 73 (90%) of 81 infections with artemether-lumefantrine alone; HR for recrudescence 0·44 (95% CI 0·14-1·40, p=0·17). Artemether-lumefantrine plus amodiaquine was generally well tolerated, but the number of mild (grade 1-2) adverse events, mainly gastrointestinal, was greater in this group compared with artemether-lumefantrine alone (vomiting, 12 [8%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·03; and nausea, 11 [7%] with artemether-lumefantrine plus amodiaquine vs three [2%] with artemether-lumefantrine alone, p=0·05). Early vomiting within 1 h of treatment, requiring retreatment, occurred in no patients of 154 with artemether-lumefantrine alone versus five (3%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·06. Bradycardia (≤54 beats/min) of any grade was noted in 59 (38%) of 154 patients with artemether-lumefantrine alone and 95 (61%) of 156 with artemether-lumefantrine plus amodiaquine, p=0·0001.InterpretationArtemether-lumefantrine plus amodiaquine provides an alternative to artemether-lumefantrine alone as first-line treatment for multidrug-resistant P falciparum malaria in the Greater Mekong subregion, and could prolong the therapeutic lifetime of artemether-lumefantrine in malaria-endemic populations.FundingBill & Melinda Gates Foundation, Wellcome Trust.

Dataset Information

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015.

Publications

<i>K13</i> Propeller Alleles, <i>mdr1</i> Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015.

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