lumefantrine and artenimol

In vivo Therapeutic Efficacy Studies (TES) have been routinely conducted in the Greater Mekong Subregion (GMS) for decades. Results from the last 10 years have contributed to update national antimalarial drug policies, to identify hotspots of multi-drug resistance and from 2008 onwards, to stimulate ambitious multi-country programs and innovative research projects to contain and eliminate artemisinin resistant Plasmodium falciparum strains in the subregion. This paper describes the results of TES of first-line antimalarials in six countries of the GMS from 2008-2010 using the WHO in vivo standard protocol. A total of 91 studies were conducted at 32 sentinel sites testing dihydroartemisinin-piperaquine (DHA-PIP), artesunate+mefloquine (A+M), and artemether-lumefantrine (AL) against P. falciparum malaria, as well as chloroquine and DHA-PIP against P vivax. Overall, artemisinin-based combination therapies (ACTs) remained efficacious against falciparum malaria with some exceptions. The 42-day adequate clinical and parasitological response (ACPR) for DHA-PIP dropped significantly to 73% (95% CI 53-87) in 2010 in the same hotspot area of western Cambodia known to harbor artemisinin resistant P. falciparum strains. Because P falciparum sensitivity to artemisinin is a major concern, especially on the Cambodia-Thailand border, attempts were also made to strengthen the monitoring of parasite clearance time elsewhere in the region and globally. The proportion of patients still blood-smear positive on Day 3 above 10% is considered a proxy indicator to strongly suspect the appearance of falciparum resistance to artesunate. This has led to substantial extra measures to confirm the suspicion and eventually set up interventions to eliminate artemisinin resistant parasites. Notably, increasing proportions (>10%) of Day 3 positives among falciparum malaria patients treated with DHA-PIP have been observed in western Cambodia, Myanmar, Viet Nam and China from 2008. Percent Day 3 parasitemia associated with A+M has increased along the Thailand-Myanmar border to surpass 10% at several sites, adding to the known pool of sites with 'suspected' artemisinin resistance in the GMS. Chloroquine remains highly effective against P. vivax except for northeastern and north-central Cambodia. TES results from this subregional-wide monitoring of antimalarial efficacy have influenced the changes of 1st line drugs against both P. falciparum and P. vivax in Cambodia, against P. falciparum in s

Topics: Antimalarials; Artemether; Artemisinins; Artesunate; Asia, Southeastern; Chloroquine; Directly Observed Therapy; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Malaria, Vivax; Mefloquine; Parasitemia; Quinolines

The World Health Organization recommends uncomplicated P. falciparum malaria is treated using Artemisinin-based Combination Therapy (ACT). This review aims to assist the decision making of malaria control programmes by providing an overview of the relative benefits and harms of the available options.. To compare the effects of ACTs with other available ACT and non-ACT combinations for treating uncomplicated P. falciparum malaria.. We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) to March 2009.. Randomized head to head trials of ACTs in uncomplicated P. falciparum malaria.This review is limited to: dihydroartemisinin-piperaquine; artesunate plus mefloquine; artemether-lumefantrine (six doses); artesunate plus amodiaquine; artesunate plus sulfadoxine-pyrimethamine and amodiaquine plus sulfadoxine-pyrimethamine.. Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on P. vivax, gametocytes, haemoglobin, and adverse events.. Fifty studies met the inclusion criteria. All five ACTs achieved PCR adjusted failure rates of < 10%, in line with WHO recommendations, at most study sites.Dihydroartemisinin-piperaquine performed well compared to the ACTs in current use (PCR adjusted treatment failure versus artesunate plus mefloquine in Asia; RR 0.39, 95% CI 0.19 to 0.79; three trials, 1062 participants; versus artemether-lumefantrine in Africa; RR 0.39, 95% CI 0.24 to 0.64; three trials, 1136 participants).ACTs were superior to amodiaquine plus sulfadoxine-pyrimethamine in East Africa (PCR adjusted treatment failure versus artemether-lumefantrine; RR 0.12, 95% CI 0.06 to 0.24; two trials, 618 participants; versus AS+AQ; RR 0.44, 95% CI 0.22 to 0.89; three trials, 1515 participants).Dihydroartemisinin-piperaquine (RR 0.32, 95% CI 0.24 to 0.43; four trials, 1442 participants) and artesunate plus mefloquine (RR 0.30, 95% CI 0.21 to 0.41; four trials, 1003 participants) were more effective than artemether-lumefantrine at reducing the incidence of P.vivax over 42 days follow up.. Dihydroartemisinin-piperaquine is another effective first-line treatment for P. falciparum malaria.The performance of the non-ACT (amodiaquine plus sulfadoxine-pyrimethamine) falls below WHO recommendations for first-line therapy in parts of Africa.In areas where primaquine is not being used for radical cure of P. vivax, ACTs with long half-lives may provide some benefit.

Topics: Antimalarials; Artemisinins; Artesunate; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Malaria, Vivax; Mefloquine; Parasitemia; Pyrimethamine; Quinolines; Randomized Controlled Trials as Topic; Sulfadoxine

Dihydroartemisinin-piperaquine (DP) has demonstrated excellent efficacy for the treatment and prevention of malaria in Uganda. However, resistance to both components of this regimen has emerged in Southeast Asia. The efficacy of artemether-lumefantrine, the first-line regimen to treat malaria in Uganda, has also been excellent, but continued pressure may select for parasites with decreased sensitivity to lumefantrine. To gain insight into current drug sensitivity patterns,

Topics: Adolescent; Amodiaquine; Antimalarials; Artemisinins; Aspartic Acid Endopeptidases; Child; Child, Preschool; Chloroquine; Drug Resistance; Ethanolamines; Female; Fluorenes; Gene Expression; Humans; Infant; Inhibitory Concentration 50; Lumefantrine; Malaria, Falciparum; Male; Mefloquine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Mutation; Parasitic Sensitivity Tests; Plasmodium falciparum; Protozoan Proteins; Quinolines; Uganda; Young Adult

To investigate the effectiveness of seasonal malaria chemoprevention (SMC) and community case management with long-acting artemisinin-based combination therapies (ACTs) for the control of malaria in areas of extended seasonal malaria transmission.. Individually randomised, placebo-controlled trial in the Ashanti Region of Ghana. A total of 2400 children aged 3-59 months received either: (i) a short-acting ACT for case management of malaria (artemether-lumefantrine, AL) plus placebo SMC, or (ii) a long-acting ACT (dihydroartemisinin-piperaquine, DP) for case management plus placebo SMC or (iii) AL for case management plus active SMC with sulphadoxine-pyrimethamine and amodiaquine. SMC or placebo was delivered on five occasions during the rainy season. Malaria cases were managed by community health workers, who used rapid diagnostic tests to confirm infection prior to treatment.. The incidence of malaria was lower in children given SMC during the rainy season. Compared to those given placebo SMC and AL for case management, the adjusted hazard ratio (aHR) was 0.62 (95% CI: 0.41, 0.93), P = 0.020 by intention to treat and 0.53 (95% CI: 0.29, 0.95), P = 0.033 among children given five SMC courses. There were no major differences between groups given different ACTs for case management (aHR DP vs. AL 1.18 (95% CI 0.83, 1.67), P = 0.356).. SMC may have an important public health impact in areas with a longer transmission season, but further optimisation of SMC schedules is needed to maximise its impact in such settings.

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Chemoprevention; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Ghana; Humans; Infant; Infant, Newborn; Lumefantrine; Malaria; Male; Pyrimethamine; Quinolines; Rain; Seasons; Sulfadoxine

Artemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir-based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions.. An adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine.. We enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336 ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445 μg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8 μg/mL; p < 0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p = 0.004 and p = 0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21 days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p = 0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax.. Despite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group.. Clinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009.

Topics: Adult; Anti-HIV Agents; Artemether; Artemisinins; Drug Interactions; Ethanolamines; Female; Fluorenes; HIV Infections; HIV-1; Humans; Lopinavir; Lumefantrine; Male; Ritonavir

Artemether-lumefantrine (AL) was introduced for treatment of uncomplicated malaria in Guinea-Bissau in 2008. Malaria then resurged and recurrent malaria after treatment with AL and stock-outs of AL were common. This study therefore aimed to assess the efficacy of AL and identify an alternative second line antimalarial. Dihydroartemisinin-piperaquine (DP) was chosen as it has been shown to be safe and efficacious and to reduce the incidence of recurrent malaria.. In a multicentre randomised open-label non-inferiority clinical trial, AL or DP were given over 3 days to children aged 6 months-15 years with uncomplicated P. falciparum mono-infection. Intake was observed and AL was given with milk. Children were seen on days 0, 1, 2 and 3 and then weekly days 7-42. Recurring P. falciparum were classified as recrudescence or new infections by genotyping. Between November 2012 and July 2015, 312 children were randomised to AL (n = 155) or DP (n = 157). The day 42 PCR adjusted per protocol adequate clinical and parasitological responses were 95% and 100% in the AL and DP groups respectively, Mantel-Haenszel weighted odds ratio (OR) 0.22 (95% CI 0-0.68), p = 0.022. In a modified intention to treat analysis in which treatment failures day 0 and reinfections were also considered as treatment failures adequate clinical and parasitological responses were 94% and 97% (OR 0.42 [95% CI, 0.13-1.38], p = 0.15). Parasite clearance and symptom resolution were similar with both treatments.. Both treatments achieved the WHO recommended efficacy for antimalarials about to be adopted as policy. DP was not inferior to AL for treatment of uncomplicated P. falciparum malaria in Guinea-Bissau.. ClinicalTrials.gov NTC01704508.

Topics: Antimalarials; Artemether; Artemisinins; Child; Ethanolamines; Fluorenes; Guinea-Bissau; Humans; Lumefantrine; Malaria, Falciparum; Quinolines; Treatment Outcome

Tafenoquine is in development as a single-dose treatment for relapse prevention in individuals with Plasmodium vivax malaria. Tafenoquine must be coadministered with a blood schizonticide, either chloroquine or artemisinin-based combination therapy (ACT). This open-label, randomized, parallel-group study evaluated potential drug interactions between tafenoquine and two ACTs: dihydroartemisinin-piperaquine and artemether-lumefantrine. Healthy volunteers of either sex aged 18 to 65 years without glucose-6-phosphate dehydrogenase deficiency were randomized into five cohorts (n = 24 per cohort) to receive tafenoquine on day 1 (300 mg) plus once-daily dihydroartemisinin-piperaquine on days 1, 2, and 3 (120 mg/960 mg for 36 to <75 kg of body weight and 160 mg/1,280 mg for ≥75 to 100 kg of body weight), or plus artemether-lumefantrine (80 mg/480 mg) in two doses 8 h apart on day 1 and then twice daily on days 2 and 3, or each drug alone. The pharmacokinetic parameters of tafenoquine, piperaquine, lumefantrine, artemether, and dihydroartemisinin were determined by using noncompartmental methods. Point estimates and 90% confidence intervals were calculated for area under the concentration-time curve (AUC) and maximum observed plasma concentration (C

Topics: Adolescent; Adult; Aged; Aminoquinolines; Antimalarials; Artemisinins; Drug Interactions; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Half-Life; Healthy Volunteers; Humans; Lumefantrine; Malaria, Vivax; Male; Middle Aged; Plasmodium vivax; Quinolines; Young Adult

Artemether-lumefantrine is a first-line regimen for the treatment of uncomplicated malaria during the second and third trimesters of pregnancy. Previous studies have reported changes in the pharmacokinetics and clinical outcomes following treatment with artemether-lumefantrine in pregnant women compared to nonpregnant adults; however, the results are inconclusive. We conducted a study in rural Uganda to compare the pharmacokinetics of artemether-lumefantrine and the treatment responses between 30 pregnant women and 30 nonpregnant adults with uncomplicated Plasmodium falciparum malaria. All participants were uninfected with HIV, treated with a six-dose regimen of artemether-lumefantrine, and monitored clinically for 42 days. The pharmacokinetics of artemether, its metabolite dihydroartemisinin, and lumefantrine were evaluated for 21 days following treatment. We found no significant differences in the overall pharmacokinetics of artemether, dihydroartemisinin, or lumefantrine in a direct comparison of pregnant women to nonpregnant adults, except for a statistically significant but small difference in the terminal elimination half-lives of both dihydroartemisinin and lumefantrine. There were seven PCR-confirmed reinfections (5 pregnant and 2 nonpregnant participants). The observation of a shorter terminal half-life for lumefantrine may have contributed to a higher frequency of reinfection or a shorter posttreatment prophylactic period in pregnant women than in nonpregnant adults. While the comparable overall pharmacokinetic exposure is reassuring, studies are needed to further optimize antimalarial efficacy in pregnant women, particularly in high-transmission settings and because of emerging drug resistance. (This study is registered at ClinicalTrials.gov under registration no. NCT01717885.).

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Cohort Studies; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Middle Aged; Pregnancy; Pregnancy Complications, Parasitic; Prospective Studies; Treatment Outcome; Uganda; Young Adult

The treatment of falciparum malaria poses unique challenges in settings where malaria transmission intensity is high because recurrent infections are common. These could be new infections, recrudescences, or a combination of the two. Though several African countries continue to use quinine as the second line treatment for patients with recurrent infections, there is little information on its efficacy when used for rescue therapy. Moreover, such practice goes against the World Health Organisation (WHO) recommendation to use combination therapy for uncomplicated malaria.. We conducted a nested, randomized, open label, three-arm clinical trial of rescue therapy in children 6-59 months old with recurrent malaria infection during 28 days post treatment with artemisinin combination treatment (ACT). Patients were randomly assigned to receive either quinine, artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHAPQ), and actively followed up for 28 days.. Among 220 patients enrolled, 217 (98·6%) were assigned an efficacy outcome and 218 (99·1%) were assessed for safety. The risk of recurrent infection was significantly higher in patients treated with quinine (70%, 74/110, HR = 3·9; 95% CI: 2·4-6·7, p<0·0001) and AL (60%, 21/35, HR = 3·3; 95% CI: 1·8-6·3, p<0·0002), compared to DHAPQ (25%, 18/72). Recrudescence tended to be lower in the DHAPQ (1%, 1/72) than in the quinine (7%, 8/110) or AL (6%, 2/35) group, though it was not statistically significant. No serious adverse events were reported.. Recurrent infections observed after the administration of an ACT can be successfully treated with an alternative ACT rather than with quinine.. Current Controlled Trials ISRCTN99046537.

Topics: Antimalarials; Artemether; Artemisinins; Child, Preschool; Ethanolamines; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Quinine; Quinolines; Safety; Treatment Outcome; Uganda

The ACT recommended by WHO is very effective and well-tolerated. However, these combinations need to be administered for three days, which may limit adherence to treatment.The combination of dihydroartemisinin-piperaquine phosphate-trimethoprim (Artecom®, Odypharm Ltd), which involves treatment over two days, appears to be a good alternative, particularly in malaria-endemic areas. This study intends to compare the efficacy and tolerability of the combination dihydroartemisinin-piperaquine phosphate-trimethoprim (DPT) versus artemether-lumefantrine (AL) in the treatment of uncomplicated Plasmodium falciparum malaria in Cameroon, Ivory Coast and Senegal.. This was a randomized, controlled, open-label clinical trial with a 28-day follow-up period comparing DPT to AL as the reference drug. The study involved patients of at least two years of age, suffering from acute, uncomplicated Plasmodium falciparum malaria with fever. The WHO 2003 protocol was used.. A total of 418 patients were included in the study and divided into two treatment groups: 212 in the DPT group and 206 in the AL group. The data analysis involved the 403 subjects who correctly followed the protocol (per protocol analysis), i.e. 206 (51.1%) in the DPT group and 197 (48.9%) in the AL group. The recovery rate at D14 was 100% in both treatment groups. The recovery rate at D28 was 99% in the DPT and AL groups before and after PCR results with one-sided 97.5% Confidence Interval of the rates difference > -1.90%. More than 96% of patients who received DPT were apyrexial 48 hours after treatment compared to 83.5% in the AL group (p < 0.001). More than 95% of the people in the DPT group had a parasite clearance time of 48 hours or less compared to approximately 90% in the AL group (p = 0.023). Both drugs were well tolerated. No serious adverse events were reported during the follow-up period. All of the adverse events observed were minor and did not result in the treatment being stopped in either treatment group. The main minor adverse events reported were vomiting, abdominal pain and pruritus.. The overall efficacy and tolerability of DPT are similar to those of AL. The ease of taking DPT and its short treatment course (two days) may help to improve adherence to treatment. Taken together, these findings make this medicinal product a treatment of choice for the effective management of malaria in Africa.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemether; Artemisinins; Cameroon; Child; Child, Preschool; Cote d'Ivoire; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Quinolines; Senegal; Treatment Outcome; Trimethoprim; Young Adult

Artemisinin-based combination therapy, including artemether-lumefantrine (AL), is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. The objectives of the current analysis were to compare the efficacy and safety of AL across different body weight ranges in African children, and to examine the age and body weight relationship in this population.. Efficacy, safety and pharmacokinetic data from a randomized, investigator-blinded, multicentre trial of AL for treatment of acute uncomplicated P. falciparum malaria in infants and children in Africa were analysed according to body weight group.. The trial included 899 patients (intent-to-treat population 886). The modified intent-to-treat (ITT) population (n = 812) comprised 143 children 5 to < 10 kg, 334 children 10 to < 15 kg, 277 children 15 to < 25 kg, and 58 children 25 to < 35 kg. The 28-day PCR cure rate, the primary endpoint, was comparable across all four body weight groups (97.2%, 98.9%, 97.8% and 98.3%, respectively). There were no clinically relevant differences in safety or tolerability between body weight groups. In the three AL body weight dosing groups (5 to < 15 kg, 15 to < 25 kg and 25 to < 35 kg), 80% of patients were aged 10-50 months, 46-100 months and 90-147 months, respectively.. Efficacy of AL in uncomplicated falciparum malaria is similar across body weight dosing groups as currently recommended in the label with no clinically relevant differences in safety or tolerability. AL dosing based on body weight remains advisable.

Topics: Age Factors; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Body Weight; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Plasmodium falciparum; Polymerase Chain Reaction; Time Factors; Treatment Outcome

Artemisinin-based combination therapies (ACT) are now being adopted as first-line treatments against uncomplicated malaria in sub-Saharan Africa. Between December 2009 and February 2010, the efficacies of two ACT - dihydroartemisinin-piperaquine (DHA-P) and artemether-lumefantrine (AL) - in the treatment of uncomplicated Plasmodium falciparum malaria were compared in Sinnar, central Sudan. Overall, 149 patients (75 given DHA-P and 74 given AL) completed the 28 days of follow-up. All the patients were found to be afebrile and aparasitaemic on day 3. By day 28, only one patient, who had been given AL, showed late treatment and parasitological failures, while each of the other 148 patients showed an adequate treatment response. After the results of a PCR-based assay confirmed that the recrudescent parasitaemia was probably the result of treatment failure, the frequencies of cure by day 28 were calculated as 100% for DHA-P and 98.7% for AL (P>0.05). None of the patients was found gametocytaemic during the follow-up, and the adverse effects observed were mild (nausea, vomiting, abdominal pain, dizziness and/or rash), resolved spontaneously and occurred in only five patients in each treatment arm. Thus, both treatments appeared effective and safe for the treatment of uncomplicated P. falciparum malaria in central Sudan, although treatment with DHA-P (which requires a simpler dosing regimen) might be preferred to treatment with AL.

Topics: Antimalarials; Artemisinins; Child; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Plasmodium falciparum; Quinolines; Sudan; Treatment Outcome

The combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model.

Topics: Antimalarials; Artemether; Artemisinins; Body Temperature; Child; Child, Preschool; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Tanzania; Treatment Outcome

Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are highly efficacious antimalarial therapies in Africa. However, there are limited data regarding the tolerability of these drugs in young children. We used data from a randomized control trial in rural Uganda to compare the risk of early vomiting (within one hour of dosing) for children 6-24 months of age randomized to receive DP (n = 240) or AL (n = 228) for treatment of uncomplicated malaria. Overall, DP was associated with a higher risk of early vomiting than AL (15.1% versus 7.1%; P = 0.007). The increased risk of early vomiting with DP was only present among breastfeeding children (relative risk [RR] = 3.35, P = 0.001) compared with children who were not breastfeeding (RR = 1.03, P = 0.94). Age less than 18 months was a risk factor for early vomiting independent of treatment (RR = 3.27, P = 0.02). Our findings indicate that AL may be better tolerated than DP among young breastfeeding children treated for uncomplicated malaria.

Topics: Antimalarials; Artemether; Artemisinins; Child, Preschool; Ethanolamines; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Quinolines; Risk; Uganda; Vomiting

Artemisinin combination therapies (ACTs) are currently the preferred option for treating uncomplicated malaria. Dihydroartemisinin-piperaquine (DHA-PQP) is a promising fixed-dose ACT with limited information on its safety and efficacy in African children.. The non-inferiority of DHA-PQP versus artemether-lumefantrine (AL) in children 6-59 months old with uncomplicated P. falciparum malaria was tested in five African countries (Burkina Faso, Kenya, Mozambique, Uganda and Zambia). Patients were randomised (2:1) to receive either DHA-PQP or AL. Non-inferiority was assessed using a margin of -5% for the lower limit of the one-sided 97.5% confidence interval on the treatment difference (DHA-PQP vs. AL) of the day 28 polymerase chain reaction (PCR) corrected cure rate. Efficacy analysis was performed in several populations, and two of them are presented here: intention-to-treat (ITT) and enlarged per-protocol (ePP). 1553 children were randomised, 1039 receiving DHA-PQP and 514 AL. The PCR-corrected day 28 cure rate was 90.4% (ITT) and 94.7% (ePP) in the DHA-PQP group, and 90.0% (ITT) and 95.3% (ePP) in the AL group. The lower limits of the one-sided 97.5% CI of the difference between the two treatments were -2.80% and -2.96%, in the ITT and ePP populations, respectively. In the ITT population, the Kaplan-Meier estimate of the proportion of new infections up to Day 42 was 13.55% (95% CI: 11.35%-15.76%) for DHA-PQP vs 24.00% (95% CI: 20.11%-27.88%) for AL (p<0.0001).. DHA-PQP is as efficacious as AL in treating uncomplicated malaria in African children from different endemicity settings, and shows a comparable safety profile. The occurrence of new infections within the 42-day follow up was significantly lower in the DHA-PQP group, indicating a longer post-treatment prophylactic effect.. Controlled-trials.com ISRCTN16263443.

Topics: Africa; Antiparasitic Agents; Artemether; Artemisinins; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Malaria, Falciparum; Plasmodium falciparum; Polymerase Chain Reaction; Quinolines; Time Factors

Uganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission.. Patients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0-28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI -0.2-7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated.. DP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda.. Controlled-Trials.com ISRCTN75606663.

Topics: Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Fluorenes; Health Policy; Humans; Infant; Lumefantrine; Malaria, Falciparum; Quinolines; Uganda

To assess the therapeutic efficacy of the combinations dihydroartemisinin-piperaquine and artemether-lumefantrine in treating uncomplicated falciparum malaria cases in an area with high level resistance of Plasmodium falciparum to chloroquine in Hainan Province.. Patients aged 1 to 60 with uncomplicated P. falciparum infection and parasite density 1,000 to 200,000 parasites/microl were enrolled following an informed consent. Eligible patients were randomly assigned to 2 groups for receiving either a 3-day course of dihydroartemisinin-piperaquine (40/320 mg, DP, group A) or 6-dose course of artemether/lumefantrine (20/120 mg tablets, AL, group B) over three days. They were followed up with clinical and laboratory examinations until day 28 using standard WHO in vivo antimalarial drug test protocol.. Altogether 107 eligible patients were enrolled but 106 completed the study. Adequate clinical and parasitological response (ACPR) was observed in 51 (100%) and 55 (100%) cases in groups A and B respectively. The mean time of fever clearance and mean time of asexual parasite clearance were (20.99 +/- 11.38) h and (36.45 +/- 12.60) h in AL and (22.35 +/- 13.26)h and (34.99 +/- 12.28) h in DP, respectively. There was no statistical difference on the mean time of fever clearance and asexual parasite clearance between AL and DP (P > 0.05). None of the participants showed recrudescence and serious adverse effect.. Both combinations artemether-lumefantrine and dihydroartemisinin-piperaquine show a high cure rate and proper tolerability among the patients with uncomplicated falciparum malaria in Hainan.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; China; Dose-Response Relationship, Drug; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Quinolines; Treatment Outcome; Young Adult

Malaria control is difficult where there is intense year-round transmission of multiple plasmodium species, such as in Papua New Guinea.. Between April 2005 and July 2007, we conducted an open-label, randomized, parallel-group study of conventional chloroquine-sulfadoxine-pyrimethamine and artesunate-sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, and artemether-lumefantrine in children in Papua New Guinea 0.5 to 5 years of age who had falciparum or vivax malaria. The primary end point was the rate of adequate clinical and parasitologic response at day 42 after the start of treatment with regard to Plasmodium falciparum, after correction for reinfections identified through polymerase-chain-reaction (PCR) genotyping of polymorphic loci in parasite DNA. Secondary end points included the rate of adequate clinical and parasitologic response at day 42 with regard to P. vivax without correction through PCR genotyping.. Of 2802 febrile children screened, 482 with falciparum malaria and 195 with vivax malaria were included. The highest rate of adequate clinical and parasitologic response for P. falciparum was in the artemether-lumefantrine group (95.2%), as compared with 81.5% in the chloroquine-sulfadoxine-pyrimethamine group (P=0.003), 85.4% in the artesunate-sulfadoxine-pyrimethamine group (P=0.02), and 88.0% in the dihydroartemisinin-piperaquine group (P=0.06). The rate of adequate clinical and parasitologic response for P. vivax in the dihydroartemisinin-piperaquine group (69.4%) was more than twice that in each of the other three treatment groups. The in vitro chloroquine and piperaquine levels that inhibited growth of local P. falciparum isolates by 50% correlated significantly (P<0.001). Rash occurred more often with artesunate-sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine than with chloroquine-sulfadoxine-pyrimethamine (P=0.004 for both comparisons).. The most effective regimens were artemether-lumefantrine against P. falciparum and dihydroartemisinin-piperaquine against P. vivax. The relatively high rate of treatment failure with dihydroartemisinin-piperaquine against P. falciparum may reflect cross-resistance between chloroquine and piperaquine. (Australian New Zealand Clinical Trials Registry number, ACTRN12605000550606.)

Topics: Antimalarials; Artemether; Artemisinins; Artesunate; Child, Preschool; Chloroquine; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Kaplan-Meier Estimate; Lumefantrine; Malaria, Falciparum; Malaria, Vivax; Male; Proportional Hazards Models; Pyrimethamine; Quinolines; Recurrence; Sulfadoxine

To determine the pharmacokinetic properties of artemether and lumefantrine (AL) in pregnant women with recrudescent uncomplicated multi-drug resistant falciparum malaria.. Pregnant women who had recurrence of parasitaemia following 7 days supervised quinine treatment were treated with AL. Serial blood samples were taken over a 7-day period, and pharmacokinetic parameters were estimated. For lumefantrine, these data were compared in a population pharmacokinetic model with data from non-pregnant, mainly male adults with acute malaria.. The pregnant women (five in the second trimester and eight in the third trimester) had lower concentrations of artemether, dihydroartemisinin and lumefantrine, and the elimination of lumefantrine in pregnant women was more rapid than reported previously in non-pregnant adults.. Pregnancy is associated with reduced plasma concentrations of both artemether and lumefantrine. This is likely to be of therapeutic significance as plasma concentrations of lumefantrine, after elimination of artemether, are an important determinant of cure. Further studies are needed to determine the optimum dose regimen of artemether-lumefantrine in pregnancy.

Topics: Adolescent; Adult; Antimalarials; Area Under Curve; Artemether; Artemisinins; Drug Administration Schedule; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Half-Life; Humans; Lumefantrine; Malaria, Falciparum; Male; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Recurrence; Remission Induction; Sesquiterpenes; Tablets; Thailand

An open randomized comparison of two-fixed dose artemisinin derivative-containing combination regimens was conducted in adults with acute uncomplicated multidrug resistant falciparum malaria in Thailand. DNP, a combination of dihydroartemisinin with napthoquine and trimethoprim developed recently in China, has been evaluated in China, Vietnam, Cambodia and Thailand. This study was performed to compare the safety, tolerability and efficacy of DNP and artemether-lumefantrine/Coartem. One hundred and thirty eligible uncomplicated falciparum malaria patients were enrolled into the study. Patients were randomly assigned in a 2:1 ratio into group A, which received DNP one tablet twice a day for one day; and group B, which received Coartem/Riamet four tablets twice a day for 3 days. The cure rates at 28-day were 99% and 97% in group A and group B, respectively. No serious adverse events occurred. We concluded that both DNP and Coartem/ Riamet were safe, well tolerated and highly efficacious in the treatment of acute uncomplicated falciparum malaria in Thailand.

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Sesquiterpenes; Thailand; Treatment Outcome; Trimethoprim

Multiple dose pharmacokinetics of artemether and dihydroartemisinin were investigated in chinese patients treated for malaria. They received over 2 days either 4 x 80 mg artemether orally (n = 48) or 4 x 80-480 mg co-artemether (n = 40), a combination of artemether and lumefantrine (benflumetol). Lag time = 0.48 h (mean), Cmax after first dose = 157 ng/ml, t(max) = 1.73 h and elimination half-life = 1.16 h. The lag and absorption times were 0.5 h longer for co-artemether compared with artemether. Dihydroartemisinin paralleled artemether pharmacokinetics. Artemether Cmax after the last dose was one-third of the Cmax after the first dose while, inversely, dihydroartemisinin Cmax increased over time. We suggest that auto-induction of gut mucosa enzymes and/or liver enzymes causes a time-dependent increase in first-pass metabolisation of artemether.

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; China; Double-Blind Method; Drug Evaluation; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Models, Chemical; Sesquiterpenes; Time Factors

Artemisinin-based combination therapy (ACT) is the first-line treatment for uncomplicated malaria in Ghana. Artemisinin (ART) tolerance in Plasmodium falciparum has arisen in Southeast Asia and recently, in parts of East Africa. This is ascribed to the survival of ring-stage parasites post treatment. The present study sought to assess and characterize correlates of potential ART tolerance based on post-treatment parasite clearance, ex vivo and in vitro drug sensitivity, and molecular markers of drug resistance in P. falciparum isolates from children with uncomplicated malaria in Ghana.. The observed low proportion of participants with day-3 post-treatment parasitaemia is consistent with rapid ART clearance. However, the increased rates of survival observed in the ex vivo RSA against DHA, maybe a pointer of an early start of ART tolerance. Furthermore, the role of two novel mutations in PfK13 and Pfcoronin genes, harboured by the two RSA positive isolates that had high ring survival in the present study, remains to be elucidated.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Drug Tolerance; Ghana; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Plasmodium falciparum

Malaria remains a public health concern globally. Resistance to anti-malarial drugs has consistently threatened the gains in controlling the malaria parasites. Currently, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the treatment regimens against Plasmodium falciparum infections in many African countries, including Kenya. Recurrent infections have been reported in patients treated with AL or DP, suggesting the possibility of reinfection or parasite recrudescence associated with the development of resistance against the two therapies. The Plasmodium falciparum cysteine desulfurase IscS (Pfnfs1) K65 selection marker has previously been associated with decreased lumefantrine susceptibility. This study evaluated the frequency of the Pfnfs1 K65 resistance marker and associated K65Q resistant allele in recurrent infections collected from P. falciparum-infected individuals living in Matayos, Busia County, in western Kenya.. Archived dried blood spots (DBS) of patients with recurrent malaria infection on clinical follow-up days after treatment with either AL or DP were used in the study. After extraction of genomic DNA, PCR amplification and sequencing analysis were employed to determine the frequencies of the Pfnfs1 K65 resistance marker and K65Q mutant allele in the recurrent infections. Plasmodium falciparum msp1 and P. falciparum msp2 genetic markers were used to distinguish recrudescent infections from new infections.. The K65 wild-type allele was detected at a frequency of 41% while the K65Q mutant allele was detected at a frequency of 22% in the recurrent samples. 58% of the samples containing the K65 wild-type allele were AL treated samples and while 42% were DP treated samples. 79% of the samples with the K65Q mutation were AL treated samples and 21% were DP treated samples. The K65 wild-type allele was detected in three recrudescent infections (100%) identified from the AL treated samples. The K65 wild-type allele was detected in two recrudescent DP treated samples (67%) while the K65Q mutant allele was identified in one DP treated (33%) recrudescent sample.. The data demonstrate a higher frequency of the K65 resistance marker in patients with recurrent infection during the study period. The study underscores the need for consistent monitoring of molecular markers of resistance in regions of high malaria transmission.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Combinations; Humans; Kenya; Lumefantrine; Malaria; Malaria, Falciparum; Mutation; Plasmodium falciparum; Prevalence; Quinolines; Reinfection

The choice of malaria treatment for HIV-infected pregnant women receiving efavirenz-based antiretroviral therapy must consider the potential impact of drug interactions on antimalarial exposure and clinical response. The aim of this study was to investigate the effects of efavirenz on artemether-lumefantrine (AL) because no studies have isolated the impact of efavirenz for HIV-infected pregnant women.. A prospective clinical pharmacokinetic (PK) study compared HIV-infected, efavirenz-treated pregnant women with HIV-uninfected pregnant women in Tororo, Uganda. All women received the standard 6-dose AL treatment regimen for Plasmodium falciparum malaria with intensive PK samples collected over 21 days and 42-days of clinical follow-up. PK exposure parameters were calculated for artemether, its active metabolite dihydroartemisinin (DHA), and lumefantrine to determine the impact of efavirenz.. Nine HIV-infected and 30 HIV-uninfected pregnant women completed intensive PK evaluations. Relative to controls, concomitant efavirenz therapy lowered the 8-hour artemether concentration by 76% (P = 0.013), DHA peak concentration by 46% (P = 0.033), and day 7 and 14 lumefantrine concentration by 61% and 81% (P = 0.046 and 0.023), respectively. In addition, there were nonsignificant reductions in DHA area under the concentration-time curve0-8hr (35%, P = 0.057) and lumefantrine area under the concentration-time curve0-∞ (34%, P = 0.063) with efavirenz therapy.. Pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy during malaria treatment with AL showed reduced exposure to both the artemisinin and lumefantrine. These data suggest that malaria and HIV coinfected pregnant women may require adjustments in AL dosage or treatment duration to achieve exposure comparable with HIV-uninfected pregnant women.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Anti-Retroviral Agents; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Benzoxazines; Cyclopropanes; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Pregnancy; Prospective Studies; Uganda; Young Adult

In 2006, the National Malaria Control Program in Mali recommended artemisinin-based combination therapy as the first-line treatment for uncomplicated malaria. Since the introduction of artemisinin-based combination therapy, few reports are available on the level of resistance of Plasmodium falciparum to the most common anti-malarial drugs in Mali.. From 2016 to 2017, we assessed the ex-vivo drug sensitivity of P. falciparum isolates in Kéniéroba, a village located in a rural area of southern Mali. We collected P. falciparum isolates from malaria-infected children living in Kéniéroba. The isolates were tested for ex-vivo sensitivity to commonly used anti-malarial drugs, namely chloroquine, quinine, amodiaquine, mefloquine, lumefantrine, dihydroartermisinin, and piperaquine. We used the 50% inhibitory concentration determination method, which is based on the incorporation of SYBR. Plasmodium falciparum isolates were found to have a reduced ex-vivo sensitivity to quinine (25.7%), chloroquine (12.2%), amodiaquine (2.7%), and mefloquine (1.3%). In contrast, the isolates were 100% sensitive to lumefantrine, dihydroartermisinin, and piperaquine. A statistically significant correlation was found between 50% inhibitory concentration values of quinine and amodiaquine (r = 0.80; p < 0.0001).. Plasmodium falciparum isolates were highly sensitive to dihydroartermisinin, lumefantrine, and piperaquine and less sensitive to amodiaquine (n = 2), mefloquine (n = 1), and quinine (n = 19). Therefore, our data support the previously reported increasing trend in chloroquine sensitivity in Mali.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemisinins; Child; Child, Preschool; Chloroquine; Drug Resistance; Endemic Diseases; Humans; Infant; Inhibitory Concentration 50; Lumefantrine; Malaria, Falciparum; Mali; Mefloquine; Plasmodium falciparum; Quinine; Quinolines

Topics: Animals; Artemether; Artemisinins; Chromatography, Supercritical Fluid; Ethanolamines; Fluorenes; Lumefantrine; Male; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Tandem Mass Spectrometry

Multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion of Southeast Asia is a major threat to malaria elimination and requires close surveillance. In this study, we collected 107 longitudinal clinical samples of P. falciparum in 2007-2012 from the malaria hypoendemic region of the China-Myanmar border and measured their in vitro susceptibilities to 10 antimalarial drugs. Overall, parasites had significantly different IC

Topics: Antimalarials; Artemisinins; China; Chloroquine; Drug Resistance, Multiple; Epidemiological Monitoring; Genotype; Humans; In Vitro Techniques; Inhibitory Concentration 50; Lumefantrine; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Mutation; Myanmar; Plasmodium falciparum; Protozoan Proteins

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Female; Humans; Lumefantrine; Malaria, Falciparum; Pregnancy; Tandem Mass Spectrometry; Young Adult

Antimalarial interventions have yielded a significant decline in malaria prevalence in The Gambia, where artemether-lumefantrine (AL) has been used as a first-line antimalarial for a decade. Clinical

Topics: Amodiaquine; Antimalarials; Artemisinins; Chloroquine; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Fluorenes; Gambia; Humans; Lumefantrine; Malaria, Falciparum; Membrane Transport Proteins; Microsatellite Repeats; Multidrug Resistance-Associated Proteins; Parasitic Sensitivity Tests; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Quinolines

Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children.. Malarious <5 year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6 weeks. Anaemia was defined as haematocrit <30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28-42 days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28-42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit <30% occurring within 1 week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH >4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively.. Pre-treatment, 355 of 959 children were anaemic. Duration of illness >2 days and parasitaemia ≤10,000 μL. After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH >4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children.. Pan African Clinical Trial Registry (PACTR) [ PACTR201709002064150, 1 March 2017 ].

Topics: Amodiaquine; Anemia; Antimalarials; Area Under Curve; Artemisinins; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Hematocrit; Humans; Infant; Kaplan-Meier Estimate; Logistic Models; Lumefantrine; Malaria, Falciparum; Male; Nigeria; Odds Ratio; Quinolines; ROC Curve; Treatment Outcome

Polymorphisms and the overexpression of transporter genes, especially of the ATP-binding cassette superfamily, have been involved in antimalarial drug resistance. The objective of this study was to use 77 Senegalese

Topics: Amodiaquine; Antimalarials; Artemisinins; Artesunate; Asparagine; ATP-Binding Cassette Transporters; Chloroquine; Doxycycline; Drug Resistance; Ethanolamines; Fluorenes; Gene Expression; Humans; Inhibitory Concentration 50; Lumefantrine; Malaria, Falciparum; Mefloquine; Naphthyridines; Plasmodium falciparum; Polymorphism, Genetic; Protein Isoforms; Protozoan Proteins; Quinine; Quinolines; Repetitive Sequences, Amino Acid; Senegal

The RING E3 ubiquitin protein ligase is crucial for facilitating the transfer of ubiquitin. The only polymorphism identified in the E3 ubiquitin protein ligase gene was the D113N mutation (62.5%) but was not significantly associated with the 50% inhibitory concentration (IC50) of conventional antimalarial drugs. However, some mutated isolates (D113N) present a trend of reduced susceptibility to piperaquine (P = 0.0938). To evaluate the association of D113N polymorphism with susceptibility to antimalarials, more isolates are necessary.

Topics: Antimalarials; Artemisinins; Artesunate; Chloroquine; Doxycycline; Ethanolamines; Fluorenes; Lumefantrine; Mefloquine; Naphthyridines; Plasmodium falciparum; Polymorphism, Genetic; Quinine; Quinolines; Senegal; Ubiquitin-Protein Ligases

In vitro drug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage in Plasmodium falciparum This response has been proposed to play a role in the recrudescence of P. falciparum infections following monotherapy with artesunate and may contribute to the development of artemisinin resistance in P. falciparum malaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest of P. falciparum parasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage of P. falciparum and prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistant P. falciparum malaria.

Topics: Antimalarials; Artemether; Artemisinins; Drug Resistance; Erythrocytes; Ethanolamines; Fluorenes; Humans; Indoles; Inhibitory Concentration 50; Life Cycle Stages; Lumefantrine; Plasmodium falciparum; Rhodamine 123; Spiro Compounds

Episodes of delayed hemolysis 2-6 weeks after treatment of severe malaria with intravenous artesunate have been described. We performed a prospective observational study of patients with uncomplicated malaria to investigate whether posttreatment hemolysis also occurs after oral artemisinin-based combination therapy. Eight of 20 patients with uncomplicated malaria who were given oral artemisinin-based combination therapy met the definition of posttreatment hemolysis (low haptoglobin level and increased lactate dehydrogenase level on day 14). Five patients had hemolysis persisting for 1 month. Patients with posttreatment hemolysis had a median decrease in hemoglobin level of 1.3 g/dL (interquartile range 0.3-2.0 g/dL) in the posttreatment period, and patients without posttreatment hemolysis had a median increase of 0.3 g/dL (IQR -0.1 to 0.7 g/dL; p = 0.002). These findings indicate a need for increased vigilance for hemolytic events in malaria patients, particularly those with predisposing factors for anemia.

Topics: Administration, Oral; Adolescent; Adult; Anemia; Antimalarials; Artemether; Artemisinins; Child; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Hemolysis; Humans; Lumefantrine; Malaria, Falciparum; Male; Prospective Studies; Quinolines

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. Over time, ex vivo sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of pfcrt K76 and pfmdr1 N86 and D1246 increased, and the prevalences of pfdhfr and pfdhps polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased ex vivo lumefantrine sensitivity and increased prevalence of pfcrt K76 and pfmdr1 N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of pfmdr1 86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.

Topics: Amodiaquine; Antimalarials; Artemisinins; Child, Preschool; Chloroquine; Clinical Trials as Topic; Ethanolamines; Fluorenes; Humans; Infant; Lumefantrine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Parasitic Sensitivity Tests; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Quinine; Quinolines; Uganda

Coadministration of nevirapine-based antiretroviral therapy (ART) and artemether-lumefantrine is reported to result in variable changes in lumefantrine exposure. We conducted an intensive pharmacokinetic study with 11 HIV-infected adults who were receiving artemether-lumefantrine plus nevirapine-based ART, and we compared the results with those for 16 HIV-negative adult historical controls. Exposure to artemether and lumefantrine was significantly lower and dihydroartemisinin exposure was unchanged in subjects receiving nevirapine-based ART, compared with controls. Nevirapine exposure was unchanged before and after artemether-lumefantrine administration.

Topics: Adult; Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; Case-Control Studies; Coinfection; Drug Combinations; Drug Interactions; Ethanolamines; Female; Fluorenes; HIV Infections; HIV-1; Humans; Lumefantrine; Malaria, Falciparum; Male; Nevirapine; Nigeria; Plasmodium falciparum

Artemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association of Plasmodium falciparum polymorphisms and ex vivo drug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n = 96), fixed-dose artesunate-amodiaquine (n = 96), and sulfadoxine-pyrimethamine (n = 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed. pfcrt, pfmdr1, pfmrp1, pfdhfr, and pfdhps polymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates by Plasmodium lactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for the pfmdr1 N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance of pfmdr1 N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection of pfmdr1 loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical, ex vivo, molecular, and pharmacological data is warranted.

Topics: Amodiaquine; Antimalarials; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Inhibitory Concentration 50; Lumefantrine; Male; Mefloquine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Pyrimethamine; Quinine; Sulfadoxine

The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D, and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. The Pfmdr1 86Y mutation was significantly associated with increased susceptibility to MDAQ (P = 0.0023), LMF (P = 0.0001), DHA (P = 0.0387), and MQ (P = 0.00002). The N86Y mutation was not associated with CQ (P = 0.214) or QN (P = 0.287) responses. The Pfmdr1 184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P = 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). The Pfmdr1 86Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P = 0.0136), LMF (P = 0.0019), and MQ (P = 0.0001). The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to MDAQ (P < 0.0001), LMF (P < 0.0001), MQ (P < 0.0001), and QN (P = 0.0026) in wild-type Pfcrt K76 parasites. The additional Pfmdr1 86Y mutation significantly increased the in vitro susceptibility to CQ (P = 0.0179) in Pfcrt 76T CQ-resistant parasites.

Topics: Adult; Amodiaquine; Antimalarials; Artemisinins; Biological Transport; Child; Chloroquine; Drug Resistance; Erythrocytes; Ethanolamines; Female; Fluorenes; Gene Expression; Haplotypes; Humans; Inhibitory Concentration 50; Lumefantrine; Malaria, Falciparum; Male; Mefloquine; Multidrug Resistance-Associated Proteins; Parasitic Sensitivity Tests; Plasmodium falciparum; Polymorphism, Single Nucleotide; Quinine; Senegal

There are currently several recommended drug regimens for uncomplicated falciparum malaria in Africa. Each has different properties that determine its impact on disease burden. Two major antimalarial policy options are artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQP). Clinical trial data show that DHA-PQP provides longer protection against reinfection, while AL is better at reducing patient infectiousness. Here we incorporate pharmacokinetic-pharmacodynamic factors, transmission-reducing effects and cost into a mathematical model and simulate malaria transmission and treatment in Africa, using geographically explicit data on transmission intensity and seasonality, population density, treatment access and outpatient costs. DHA-PQP has a modestly higher estimated impact than AL in 64% of the population at risk. Given current higher cost estimates for DHA-PQP, there is a slightly greater cost per case averted, except in areas with high, seasonally varying transmission where the impact is particularly large. We find that a locally optimized treatment policy can be highly cost effective for reducing clinical malaria burden.

Topics: Africa; Antimalarials; Artemisinins; Cost-Benefit Analysis; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Models, Theoretical; Quinolines; Seasons

Little is known about resistance of Plasmodium falciparum to antimalarials in Sahelian countries. Here we investigated the drug susceptibilities of fresh isolates collected in Niger post-deployment of artemisinin-based combination therapies (ACTs). We found that the parasites remained highly susceptible to new (dihydroartemisinin, lumefantrine, pyronaridine, and piperaquine) and conventional (amodiaquine and chloroquine) antimalarial drugs. The introduction of ACTs in 2005 and their further deployment nationwide have therefore not resulted in a decrease in P. falciparum susceptibilities to these antimalarials.

Topics: Amodiaquine; Antimalarials; Artemisinins; Chloroquine; Drug Resistance; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Naphthyridines; Niger; Parasitic Sensitivity Tests; Plasmodium falciparum; Quinolines

To investigate the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine during rifampicin intake and after stopping rifampicin.. An open-label, two-phase, longitudinal drug interaction study with patients serving as their own controls.. We recruited HIV-1-seropositive Ugandan adults who were receiving rifampicin-based tuberculosis treatment and who did not have malaria. Pharmacokinetic sampling after six doses of artemether-lumefantrine was performed during rifampicin-based tuberculosis treatment (phase 1) and repeated at least 3 weeks after stopping rifampicin-based tuberculosis treatment (phase 2).. Six and five patients completed phases 1 and 2, respectively. Median age and weight were 30 years and 64 kg. Artemether and dihydroartemisinin area under the concentration-time curve (AUC(0-12h)) were significantly lower by 89% [geometric mean ratio (GMR) 90% confidence interval (CI) 0.11, 0.05-0.26] and 85% (0.15, 0.10-0.23), respectively, during rifampicin-based treatment when compared to AUC(0-12h) after stopping rifampicin intake. Similarly, artemether and dihydroartemisinin C(max) were 83% (0.17, 0.08-0.39) and 78% (0.22, 0.15-0.33) lower, respectively, during rifampicin treatment. For artemether, mean (±SD) C(12) was 0.5(±1.0) and 5.9(±2.5) ng/ml in phases 1 and 2, respectively. Corresponding values for dihydroartemisinin (DHA) were 0.3(±0.4) and 4.7(±2.0) ng/ml, respectively. Day 8 lumefantrine concentration was significantly lower by 84% (GMR 90% CI 0.16, 0.09-0.27), and AUC(Day3-Day25) was significantly lower by 68% (GMR 90% CI 0.32, 0.21-0.49) during rifampicin-based treatment when compared to exposure values after stopping rifampicin.. Pharmacokinetic parameters for artemether-lumefantrine were markedly lower during rifampicin-based tuberculosis treatment. Artemether-lumefantrine should not be co-administered with rifampicin.

Topics: Adult; Antimalarials; Antitubercular Agents; Artemether; Artemisinins; Drug Antagonism; Ethanolamines; Female; Fluorenes; HIV Infections; Humans; Longitudinal Studies; Lumefantrine; Male; Rifampin; Tuberculosis; Uganda

Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.

Topics: Adolescent; Adult; Artemether; Artemisinins; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Pregnancy; Quinine; Young Adult

The Plasmodium falciparum genome is rich in regions of low amino acid complexity which evolve with few constraints on size. To explore the extent of diversity in these loci, we sequenced repeat regions in pfmdr1, pfmdr5, pfmdr6, pfmrp2, and the antigenic locus pfmsp8 in laboratory and cultured-adapted clinical isolates. We further assessed associations between the repeats and parasite in vitro responses to 7 antimalarials to determine possible adaptive roles of these repeats in drug tolerance. Our results show extensive repeat variations in the reference and clinical isolates in all loci. We also observed a modest increase in dihydroartemisinin activity in parasites harboring the pfmdr1 sequence profile 7-2-10 (reflecting the number of asparagine repeats, number of aspartate repeats, and number of asparagine repeats in the final series of the gene product) (P = 0.0321) and reduced sensitivity to chloroquine, mefloquine, quinine, and dihydroartemisinin in those with the 7-2-11 profile (P = 0.0051, 0.0068, 0.0011, and 0.0052, respectively). Interestingly, we noted an inverse association between two drugs whereby isolates with 6 asparagine repeats encoded by pfmdr6 were significantly more susceptible to piperaquine than those with 8 (P = 0.0057). Against lumefantrine, those with 8 repeats were, however, more sensitive (P = 0.0144). In pfmrp2, the 7-DNNNTS/NNNNTS (number of DNNNTS or NNNNTS motifs; underlining indicates dimorphism) repeat group was significantly associated with a higher lumefantrine 50% inhibitory concentration (IC50) (P = 0.008) than in those without. No associations were observed with pfmsp8. These results hint at the probable utility of some repeat conformations as markers of in vitro antimalarial response; hence, biochemical functional studies to ascertain their role in P. falciparum are required.

Topics: Amino Acid Motifs; Antimalarials; Artemisinins; Asparagine; Aspartic Acid; Chloroquine; Drug Resistance; Ethanolamines; Fluorenes; Gene Expression; Genome, Protozoan; Lumefantrine; Mefloquine; Molecular Sequence Data; Multidrug Resistance-Associated Proteins; Parasitic Sensitivity Tests; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Quinine

Drug resistance has always been one of the most important impediments to global malaria control. Artemisinin resistance has recently been confirmed in the Greater Mekong Subregion (GMS) and efforts for surveillance and containment are intensified. To determine potential mechanisms of artemisinin resistance and monitor the emergence and spread of resistance in other regions of the GMS, we investigated the in vitro sensitivity of 51 culture-adapted parasite isolates from the China-Myanmar border area to four drugs. The 50% inhibitory concentrations (IC₅₀s) of dihydroartemisinin, mefloquine and lumefantrine were clustered in a relatively narrow, 3- to 6-fold range, whereas the IC₅₀ range of artesunate was 12-fold. We assessed the polymorphisms of candidate resistance genes pfcrt, pfmdr1, pfATP6, pfmdr6 and pfMT (a putative metabolite/drug transporter). The K76T mutation in pfcrt reached fixation in the study parasite population, whereas point mutations in pfmdr1 and pfATP6 had low levels of prevalence. In addition, pfmdr1 gene amplification was not detected. None of the mutations in pfmdr1 and pfATP6 was associated significantly with in vitro sensitivity to artemisinin derivatives. The ABC transporter gene pfmdr6 harbored two point mutations, two indels, and number variations in three simple repeats. Only the length variation in a microsatellite repeat appeared associated with altered sensitivity to dihydroartemisinin. The PfMT gene had two point mutations and one codon deletion; the I30N and N496- both reached high levels of prevalence. However, none of the SNPs or haplotypes in PfMT were correlated significantly with resistance to the four tested drugs. Compared with other parasite populations from the GMS, our studies revealed drastically different genotype and drug sensitivity profiles in parasites from the China-Myanmar border area, where artemisinins have been deployed extensively for over 30 years.

Topics: Antimalarials; Artemisinins; Artesunate; Calcium-Transporting ATPases; China; Drug Resistance; Ethanolamines; Fluorenes; Lumefantrine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Myanmar; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins

Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda.. Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies.. The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches.. The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.

Topics: Administration, Oral; Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Chromatography; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Mass Spectrometry; Models, Statistical; Plasma; Pregnancy; Pregnancy Complications, Infectious; Uganda; Young Adult

Chemotherapy is a critical component of malaria control. However, the most deadly malaria pathogen, Plasmodium falciparum, has repeatedly mounted resistance against a series of antimalarial drugs used in the last decades. Southeast Asia is an epicenter of emerging antimalarial drug resistance, including recent resistance to the artemisinins, the core component of all recommended antimalarial combination therapies. Alterations in the parasitic membrane proteins Pgh-1, PfCRT and PfMRP1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation. The pfcrt, pfmdr1 and pfmrp1 genes were sequenced from a set of P.falciparum field isolates from the Thai-Myanmar border. In vitro drug susceptibility to artemisinin, dihydroartemisinin, mefloquine and lumefantrine were assessed. Positive correlations were seen between the in vitro susceptibility responses to artemisinin and dihydroartemisinin and the responses to the arylamino-alcohol quinolines lumefantrine and mefloquine. The previously unstudied pfmdr1 F1226Y and pfmrp1 F1390I SNPs were associated significantly with artemisinin, mefloquine and lumefantrine in vitro susceptibility. A variation in pfmdr1 gene copy number was also associated with parasite drug susceptibility of artemisinin, mefloquine and lumefantrine. Our work unveils new candidate markers of P. falciparum multidrug resistance in vitro, while contributing to the understanding of subjacent genetic complexity, essential for future evidence-based drug policy decisions.

Topics: Animals; Antimalarials; Artemisinins; ATP-Binding Cassette Transporters; Base Sequence; Drug Resistance; Ethanolamines; Fluorenes; Gene Frequency; Genotype; Haplotypes; Humans; Inhibitory Concentration 50; Lumefantrine; Malaria, Falciparum; Mefloquine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins

Clinical studies and mathematical models predict that, to achieve malaria elimination, combination therapies will need to incorporate drugs that block the transmission of Plasmodium falciparum sexual stage parasites to mosquito vectors. Efforts to measure the activity of existing antimalarials on intraerythrocytic sexual stage gametocytes and identify transmission-blocking agents have, until now, been hindered by a lack of quantitative assays. Here, we report an experimental system using P. falciparum lines that stably express gametocyte-specific GFP-luciferase reporters, which enable the assessment of dose- and time-dependent drug action on gametocyte maturation and transmission. These studies reveal activity of the first-line antimalarial dihydroartemisinin and the partner drugs lumefantrine and pyronaridine against early gametocyte stages, along with moderate inhibition of mature gametocyte transmission to Anopheles mosquitoes. The other partner agents monodesethyl-amodiaquine and piperaquine showed activity only against immature gametocytes. Our data also identify methylene blue as a potent inhibitor of gametocyte development across all stages. This thiazine dye almost fully abolishes P. falciparum transmission to mosquitoes at concentrations readily achievable in humans, highlighting the potential of this chemical class to reduce the spread of malaria.

Topics: Amodiaquine; Animals; Anopheles; Antimalarials; Artemisinins; Blotting, Southern; Dose-Response Relationship, Drug; Ethanolamines; Fluorenes; Genetic Vectors; Germ Cells, Plant; Green Fluorescent Proteins; Luciferases; Lumefantrine; Malaria; Methylene Blue; Naphthyridines; Plasmodium falciparum; Quinolines; Sexual Development

Artemether-lumefantrine (AL), dihydroartemisinin-piperaquine (DP), and amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) offer excellent antimalarial efficacy but may select for parasite polymorphisms that decrease drug sensitivity. We evaluated the selection of known polymorphisms in genes encoding putative transporters (pfcrt and pfmdr1) and SP targets (pfdhfr and pfdhps) in parasites that caused new infections within 42 days of therapy for uncomplicated falciparum malaria in Burkina Faso. In 559 children in 2006, 42-day genotype-uncorrected failures were seen in 31.2% with AL, 11.8% with AQ-SP, and 7.6% with DP. After prior AL therapy, selection of wild-type sequences was seen for K76T in pfcrt (72.7% mixed or mutant results pretreatment versus 52.1% in new infections; P = 0.008) and N86Y (36.0% versus 18.7%; P = 0.025) and Y184F (66.7% versus 45.8%; P = 0.009) in pfmdr1. After prior AQ-SP therapy, selection of mutant sequences was seen for N51I (30.8% versus 61.5%; P = 0.05), C59R (28.2% versus 76.9%; P = 0.002), and S108N (30.8% versus 76.9%; P = 0.005) in pfdhfr. After prior DP therapy, selection was not seen for K76T (72.7% versus 77.8%; P = 0.96) in pfcrt or N86Y (36.0% versus 33.3%; P = 0.84), Y184F (66.7% versus 77.8%; P = 0.39), or D1246Y (9.3% versus 0%; P = 0.42) in pfmdr1. In 378 additional treatments with DP in 2007, 42-day uncorrected failure was seen in 10.9%. After prior DP, selection was again not seen for K76T (66.7% mixed or mutant results versus 59.5%; P = 0.43) in pfcrt or N86Y (38.7% versus 40.5%; P = 0.85), Y184F (67.6% versus 73.0%; P = 0.54), or D1246Y (3.6% versus 8.1%; P = 0.50) in pfmdr1. Despite its chemical similarity, piperaquine did not select for the same polymorphisms as chloroquine or AQ, suggesting different mechanisms of resistance.

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Burkina Faso; Drug Combinations; Drug Resistance, Bacterial; Ethanolamines; Fluorenes; Genotype; Humans; Infant; Lumefantrine; Malaria, Falciparum; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins; Pyrimethamine; Quinolines; Randomized Controlled Trials as Topic; Recurrence; Sulfadoxine

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.

Topics: Animals; Antimalarials; Artemisinins; Ethanolamines; Fluorenes; Genotype; Humans; Lumefantrine; Malaria, Falciparum; Membrane Transport Proteins; Microbial Sensitivity Tests; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Quinolines

Topics: Antimalarials; Artemether; Artemisinins; Biological Availability; Drug Therapy, Combination; Ethanolamines; Fats; Fluorenes; Humans; Lumefantrine; Malaria; Quinolines; Treatment Failure

We have selected piperaquine (PQ) and lumefantrine (LM) resistant Plasmodium berghei ANKA parasite lines in mice by drug pressure. Effective doses that reduce parasitaemia by 90% (ED(90)) of PQ and LM against the parent line were 3.52 and 3.93 mg/kg, respectively. After drug pressure (more than 27 passages), the selected parasite lines had PQ and LM resistance indexes (I(90)) [ED(90) of resistant line/ED(90) of parent line] of 68.86 and 63.55, respectively. After growing them in the absence of drug for 10 passages and cryo-preserving them at -80 degrees C for at least 2 months, the resistance phenotypes remained stable. Cross-resistance studies showed that the PQ-resistant line was highly resistant to LM, while the LM-resistant line remained sensitive to PQ. Thus, if the mechanism of resistance is similar in P. berghei and Plasmodium falciparum, the use of LM (as part of Coartem) should not select for PQ resistance.

Topics: Amodiaquine; Animals; Antimalarials; Artemisinins; Chloroquine; Disease Models, Animal; Drug Resistance; Ethanolamines; Female; Fluorenes; Lumefantrine; Malaria; Male; Mice; Parasitemia; Plasmodium berghei; Quinolines; Serial Passage

Artemether-lumefantrine is the most widely recommended artemisinin-based combination treatment for falciparum malaria. Quantification of artemether and its metabolite dihydroartemisinin in biological matrices has traditionally been difficult, with sensitivity being an issue.. A high-throughput bioanalytical method for the analysis of artemether and its metabolite dihydroartemisinin in human plasma using solid-phase extraction in the 96-well plate format and liquid chromatography coupled to positive ion mode tandem mass spectroscopy has been developed and validated according to US FDA guidelines. The method uses 50 µl plasma and covers the calibration range 1.43-500 ng/ml with a limit of detection at 0.36 ng/ml.. The developed liquid chromatography-tandem mass spectrometry assay is more sensitive than all previous methods despite using a lower plasma volume (50 µl) and is highly suitable for clinical studies where plasma volumes are limited, such as pediatric trials.

Topics: Antimalarials; Artemether; Artemisinins; Calibration; Chromatography, Liquid; Drug Therapy, Combination; Ethanolamines; Fluorenes; High-Throughput Screening Assays; Humans; Lumefantrine; Malaria, Falciparum; Reproducibility of Results; Solid Phase Extraction; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

The aim of this study was to assess the ability of currently deployed antimalarials to inhibit mammalian sarcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA). Artemisinins exert their antiplasmodial action by inhibiting parasite PfATP6, a SERCA enzyme, and possess neurotoxic potential; mefloquine is neurotoxic and inhibits mammalian SERCA, an orthologue of PfATP6. SERCA in rabbit muscle was tested in vitro for inhibition by artemisinin and amino alcohol antimalarials. Significant inhibition of mammalian SERCA, as mean difference from uninhibited, control values was seen with both enantiomers of mefloquine: (+)-mefloquine (10 microM: -35.83, 95% CI -59.63 to -12.03; 50 microM: -54.06, 95% CI -77.86 to -30.26); (-)-mefloquine (10 microM: -24.35, 95% CI -41.56 to -7.15; 50 microM: -58.42, 95% CI -75.62 to -41.22); lumefantrine (1 microM: -25.46, 95% CI -45.82 to -5.10; 5 microM -34.83, 95% CI -60.08 to -9.58; 10 microM: -25.80, 95% CI -51.05 to -0.55); desbutyl-lumefantrine (5 microM: -50.16, 95% CI -84.24 to -16.08); dihydroartemisinin (1 microM: -39.25, 95% CI -63.74 to -14.76; 5 microM: -39.30, 95% CI -64.88 to -13.72). Dihydroartemisinin in higher concentrations (10 microM) stimulated SERCA activity: (+40.90, 95% CI 11.37 to 70.44). No statistically significant inhibition was seen with artemether at 1, 5 and 10 microM. Equimolar combinations of artemether and lumefantrine or of dihydroartemisinin and lumefantrine, when studied at concentrations that inhibit SERCA individually, failed to show any inhibition. Dihydroartemisinin, mefloquine, lumefantrine and desbutyl lumefantrine inhibit mammalian SERCA at periphysiological concentrations, although the neurotoxicity of mefloquine is not wholly attributable to this property. Candidate antimalarials should be screened pre-clinically for SERCA inhibition.

Topics: Animals; Antimalarials; Artemisinins; Dose-Response Relationship, Drug; Ethanolamines; Fluorenes; In Vitro Techniques; Isoenzymes; Lumefantrine; Mefloquine; Rabbits; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Stereoisomerism

Recent drug trials in Laos have shown high levels of Plasmodium falciparum resistance to chloroquine, but there are no published data on in vitro antimalarial drug susceptibility. We used the double-site enzyme-linked pLDH immunodetection (DELI) assay to estimate the in vitro antimalarial drug susceptibility of 108 fresh P. falciparum isolates from southern Laos. The geometric mean (95% confidence interval) 50% inhibitory concentration values (nmol/L) were 152.4 (123.8-187.6) for chloroquine, 679.8 (533.8-863.0) for quinine, 45.9 (37.9-55.7) for mefloquine, 5.0 (4.4-6.4) for artesunate, 6.3 (4.5-8.9) for dihydroartemisinin, and 59.1 (46.4-75.3) for lumefantrine. The proportion of isolates defined as resistant were 65%, 40%, and 8% for chloroquine, quinine, and mefloquine, respectively. Of 53 isolates genotyped for the pfcrt T76K chloroquine-resistance mutation, 48 (91%) were mutants. P. falciparum in Laos is multi-drug resistant; antimalarial immunity resulting from the use of ineffective chloroquine before 2005 probably contributes significantly to the therapeutic responses in clinical trials.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemisinins; Artesunate; Child; Child, Preschool; Chloroquine; DNA, Protozoan; Drug Resistance; Ethanolamines; Female; Fluorenes; Humans; Inhibitory Concentration 50; Laos; Lumefantrine; Malaria, Falciparum; Male; Mefloquine; Membrane Transport Proteins; Middle Aged; Plasmodium falciparum; Point Mutation; Polymerase Chain Reaction; Protozoan Proteins; Sesquiterpenes

The combination of artemether and lumefantrine was introduced in 2005 as the official first line therapy for uncomplicated falciparum malaria in Bangladesh. Fresh P. falciparum samples from patients with acute uncomplicated falciparum malaria who presented to the field site at the Bandarban Sadar Hospital in Bangladesh were tested in checkerboard in vitro drug sensitivity assays to assess the interaction between dihydroartemisinin (DHA) and lumefantrine (LUM). Clearly synergistic interactions with an overall mean FIC(50) of 0.52 and individual mean FICs between 0.26 and 0.85 were found. Lowest FICs were 0.41, 0.18, 0.22, 0.15 and 0.11 at different combination ratios. The optimal combination ratio of the drug combination indicated by the lowest mean FIC average was found to be 1:150 DHA:LUM. Although activity correlations between DHA and lumefantrine were significant, indicating possible cross sensitivity patterns, our data confirm that artemether-lumefantrine is a highly synergistic drug combination.

Topics: Animals; Antimalarials; Artemisinins; Bangladesh; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lethal Dose 50; Lumefantrine; Malaria, Falciparum; Plasmodium falciparum; Survival Rate; Treatment Outcome