Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Artemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical stabilities were also evaluated. Furthermore, the in vivo antimalarial activities of the lipid emulsions developed were tested in Plasmodium berghei-infected mice. Artemether, lumefantrine, or artemether in combination with lumefantrine was encapsulated in an oil phase, and the in vivo performance was assessed by comparison with artesunate for injection. It was found that the lumefantrine lipid emulsion (LUM-LE) and artemether-lumefantrine lipid emulsion (ARM-LUM-LE-3) (1:6) began to decrease the parasitemia levels after only 3 days, and the parasitemia inhibition was 90% at doses of 0.32 and 0.27 mg/kg, respectively, with immediate antimalarial effects greater than those of the positive-control group and constant antimalarial effects over 30 days. LUM-LE and ARM-LUM-LE-3 demonstrated the best performance in terms of chemical and physical stabilities and antiplasmodial efficacy, with a mean particle size of 150 nm, and they have many favorable properties for parenteral administration, such as biocompatibility, physical stability, and ease of preparation.     

Update on the in vivo tolerance and in vitro reduced susceptibility to the antimalarial lumefantrine

Coartem(?), the combination of artemether (an artemisinin derivative) and lumefantrine, has been adopted as the first-line treatment for uncomplicated malaria in many countries. The emergence of resistance to artemisinin derivatives has now been proven in South-East Asia, and there is concern that this may spread to other endemic areas. Strategies to contain and control the spread of artemisinin resistance have been proposed. On the other hand, not much attention has been given to lumefantrine. Indeed, for more than 7 years, reports have been emerging that the use of Coartem(?) is associated with rapid selection of lumefantrine-tolerant parasites. These parasites can survive in the presence of sub-therapeutic lumefantrine concentrations, and, interestingly, this in vivo phenotype is translated in vitro into reduced susceptibility to lumefantrine. As a result, such parasites could form the setting in which lumefantrine resistance would emerge. Thus, identifying genetic markers that reflect this phenotype (both in vitro and in vivo) could yield information on the mechanisms of lumefantrine resistance. More interestingly, lumefantrine tolerance is associated with an increase in chloroquine susceptibility, raising the possibility of re-introducing chloroquine. In this work, we have reviewed the current knowledge, and we present existing challenges and gaps with regard to the mechanisms of in vivo tolerance and in vitro reduced susceptibility to lumefantrine. The re-introduction of chloroquine in areas of high lumefantrine resistance is also discussed.     

Population pharmacokinetics of artemether, lumefantrine, and their respective metabolites in Papua New Guinean children with uncomplicated malaria

There are sparse published data relating to the pharmacokinetic properties of artemether, lumefantrine, and their active metabolites in children, especially desbutyl-lumefantrine. We studied 13 Papua New Guinean children aged 5 to 10 years with uncomplicated malaria who received the six recommended doses of artemether (1.7 mg/kg of body weight) plus lumefantrine (10 mg/kg), given with fat over 3 days. Intensive blood sampling was carried out over 42 days. Plasma artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine were assayed using liquid chromatography-mass spectrometry or high-performance liquid chromatography. Multicompartmental pharmacokinetic models for a drug plus its metabolite were developed using a population approach that included plasma artemether and dihydroartemisinin concentrations below the limit of quantitation. Although artemether bioavailability was variable and its clearance increased by 67.8% with each dose, the median areas under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)s) for artemether and dihydroartemisinin (3,063 and 2,839 μg · h/liter, respectively) were similar to those reported previously in adults with malaria. For lumefantrine, the median AUC(0-∞) (459,980 μg · h/liter) was also similar to that in adults with malaria. These data support the higher dose recommended for children weighing 15 to 35 kg (35% higher than that for a 50-kg adult) but question the recommendation for a lower dose in children weighing 12.5 to 15 kg. The median desbutyl-lumefantrine/lumefantrine ratio in the children in our study was 1.13%, within the range reported for adults and higher at later time points because of the longer desbutyl-lumefantrine terminal elimination half-life. A combined desbutyl-lumefantrine and lumefantrine AUC(0-∞) weighted on in vitro antimalarial activity was inversely associated with recurrent parasitemia, suggesting that both the parent drug and the metabolite contribute to the treatment outcome of artemether-lumefantrine.     

Use of artemether–lumefantrine to treat malaria during pregnancy: what do we know and need to know?

Artemether–lumefantrine is a fixed-dose combination containing 20 mg artemether/120 mg lumefantrine per tablet, used for treating uncomplicated malaria in patients weighing ≥5 kg. It is the first artemisinin-based combination registered in some European countries and in the USA. It is marketed in Europe as Riamet^® (Novartis, Basel, Switzerland) and in malaria-endemic countries as Coartem^® (Novartis). Safety concerns prevent early pregnancy usage, while limited postmarketing surveillance has delayed safety assessment and policy development. Large clinical studies, postmarketing surveillance and pharmacovigillance ongoing in some countries may soon bridge safety issues. Fatty diet requirements for optimal absorption, pregnancy-induced changes in pharmacokinetics, pregnancy-related anorexia and food taboos, and emerging reduced parasite sensitivity to artemisinin, challenges optimal artemether–lumefantrine dosing and efficacy during pregnancy. This evaluation addresses drug usage, safety concerns following early exposure, implications for changed pharmacokinetics and reduced parasite susceptibility. Clinical-use updates and strategies to address some knowledge gaps including key operational research are discussed.     

Pharmacokinetic Properties of Artemether,Dihydroartemisinin, Lumefantrine,and Quinine in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria in 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.     

In Vitro Activity of Lumefantrine (Benflumetol) against Clinical Isolates of Plasmodium falciparum in Yaoundé, Cameroon

The in vitro antimalarial activity of the new Chinese synthetic drug, lumefantrine, also known as benflumetol (a fluorene derivative belonging to the aminoalcohol class), was determined by an isotopic microtest against 61 fresh clinical isolates of Plasmodium falciparum and compared with that of other established antimalarial agents. The geometric mean 50% inhibitory concentration of lumefantrine was 11.9 nmol/liter (95% confidence intervals, 10.4 to 13.6 nmol/liter; range, 3.3 to 25.6 nmol/liter). The in vitro activities of lumefantrine against the chloroquine-sensitive and the chloroquine-resistant isolates did not differ (P > 0.05). There was a significant positive correlation of responses between lumefantrine and two other aminoalcohols studied, mefloquine (r = 0.688) and halofantrine (r = 0.677), and between lumefantrine and artesunate (r = 0.420), suggesting a potential for in vitro cross-resistance. Our data suggest high in vitro activity of lumefantrine, comparable to that of mefloquine, and are in agreement with the promising results of preliminary clinical trials.The spread of resistance to chloroquine and sulfadoxine-pyrimethamine in many regions where malaria is endemic, as well as diminished sensitivity to quinine and mefloquine in some restricted areas, calls for a continuous search for new antimalarial drugs that are effective against drug-resistant Plasmodium falciparum (31). New antimalarial drugs that possess high in vitro activity and show high clinical efficacy for the treatment of multidrug-resistant falciparum malaria include halofantrine, atovaquone, artemisinin derivatives (artesunate, artemether, and arteether), and pyronaridine (23). Halofantrine, a 9-phenanthrenemethanol (aminoalcohol), has several disadvantages, such as rare occurrences of cardiotoxicity and poor absorption (8, 22). Atovaquone, a hydroxynaphthoquinone derivative, is a ubiquinone analog that has a wide antiprotozoal spectrum of activity (17). Despite its high in vivo efficacy, preliminary clinical trials have revealed a few cases of recrudescence, leading to the use of a synergistic combination, atovaquone-proguanil (11, 25). Artemisinin derivatives are sesquiterpene lactones that are useful for both oral treatment of uncomplicated malaria due to multidrug-resistant P. falciparum and emergency treatment of severe and complicated malaria (16). Despite their proven clinical efficacy, there are concerns regarding their potential neurotoxicity (9, 24). Pyronaridine, a benzonnaphthyridine (aminoacridine) derivative, has been used in China for over 2 decades and has been confirmed to be effective, safe, and well tolerated in Thailand and Cameroon (12, 15, 19, 26).Of these four latest kinds of antimalarial drugs, two of them, artemisinin derivatives and pyronaridine, were drawn from the Chinese pharmacopoeia. A third Chinese type of drug, lumefantrine, has recently been identified as a promising candidate for use in therapy (Fig. ​(Fig.1).1). Lumefantrine (also called benflumetol, code no. CGP 56695; 1:1 racemate of the dextrogyre and levogyre enantiomers) is a fluorene derivative (2,3-benzindene) that belongs to the aminoalcohol class (32). The compound was synthesized at the Academy of Military Medical Sciences, Beijing, China, and has undergone preliminary clinical studies in China. Lumefantrine, in combination with artemether (called coartemether), was registered for the oral treatment of malaria in China in 1987. In early clinical studies conducted in China, cure rates of 96% (n = 314 patients) and 92.5% (n = 40 patients) were reported with oral lumefantrine alone (a total dose of 2,000 mg in divided doses over 4 days) and lumefantrine-artemether oral combination (1,920 mg of lumefantrine–320 mg of artemether in divided doses over 3 days), respectively (32). The clinical efficacy of the lumefantrine-artemether combination has been confirmed recently in China, Thailand, and The Gambia (28–30, 33). Open in a separate windowFIG. 1Chemical structures of chloroquine, mefloquine, and lumefantrine.In view of the highly promising preliminary in vivo data, we have (i) assessed the in vitro activity of lumefantrine against clinical isolates of P. falciparum obtained from symptomatic Cameroonian patients in Yaoundé, Cameroon; (ii) compared its activity with those of chloroquine, monodesethylamodiaquine (a biologically active metabolite of amodiaquine), quinine, mefloquine, halofantrine, artesunate, and pyrimethamine; and (iii) evaluated the potential for in vitro cross-resistance between lumefantrine and other antimalarial compounds.     

Plasmodium falciparum-based bioassay for measurement of artemisinin derivatives in plasma or serum

Artemisinin and its derivatives, artesunate and artemether, are rapidly acting antimalarials that are used for the treatment of severe and uncomplicated multidrug-resistant falciparum malaria. To optimize treatment regimens that use this new class of antimalarials, there is a need for readily available and reproducible assays to monitor drug levels closely in patients. A sensitive and reproducible bioassay for the measurement of the concentrations of artemisinin derivatives in plasma and serum is described. By modifying the in vitro drug susceptibility test, it was found that antimalarial activity in plasma or serum containing an unknown concentration of drug could be equated to the known concentrations of dihydroartemisinin (DHA) required to inhibit parasite growth. Dose-response curves for a Plasmodium falciparum clone (clone W2) and DHA were used as a standard for each assay. Assays with plasma or serum spiked with DHA proved to be reproducible (coefficient of variation, 相似文献   

An electrodeposited molecularly imprinted quartz crystal microbalance sensor sensitized with AuNPs and rGO material for highly selective and sensitive detection of amantadine

In the present work, a new amantadine (AM) imprinted quartz crystal microbalance (QCM) sensor sensitized by Au nanoparticles (AuNPs) and reduced graphene oxide (rGO) material was fabricated by electrodeposition in the presence of o-aminothiophenol (o-AT) by cyclic voltammetry scanning. AuNPs and graphene, with the advantages of great chemical stability, electrical conductivity, and large surface area, show exceptionally high sensitivity. The results of different modifications of the QCM sensor fabrication process were characterized using transmission electron microscopy (TEM), scanning electron microscopy (SEM), atomic force microscopy (AFM) and Raman spectroscopy. Under the optimal experimental conditions, the frequency shift of the MIP-QCM sensor showed a linear relationship with the concentration of the AM template in the range of 1.0 × 10⁻⁵ to 1.0 × 10⁻³ mmol L⁻¹ with a limit of detection (LOD) of 5.40 × 10⁻⁶ mmol L⁻¹. The imprinting factor for AM reached 7.1, the selectivity coefficient for the analogues rimantadine (RT), adamantine (AMT) and 1-chloroadamantane (CMT) were 7.3, 5.6, and 6.1, respectively. Here, a highly sensitive, selective and stable QCM sensor prepared via the imprinting approach is reported for the first time for detection of AM from animal-derived food samples.

In the present work, a new amantadine imprinted quartz crystal microbalance sensor sensitized by Au nanoparticles and reduced graphene oxide material was fabricated by electrodeposition of o-aminothiophenol by cyclic voltammetry scanning.     

Standby emergency treatment of malaria in travelers: experience to date and new developments

The concept of 'standby emergency treatment' (SBET) describes the strategy where travelers carry an emergency malaria treatment for self-administration when no medical attention is available or for use under medical supervision after a confirmed malaria diagnosis, and raises many issues for discussion. International guidelines vary on the topic, and there is controversy regarding the appropriate niche for this imperfect strategy. There are situations when SBET can supplement chemoprophylaxis with mosquito bite prevention and for some travelers, particularly those visiting minimal malaria risk areas, carriage of SBET and concomitant anti-mosquito bite measures can constitute the main antimalaria strategy. A strong argument in support of equipping travelers with a quality effective antimalarial treatment as part of their travel medical kit is the global proliferation of counterfeit antimalarials, a situation that is increasing in Africa but is especially prevalent in Asia where more than 50% of artemisinin products are fake. New developments such as improved rapid malaria tests and their wider distribution together with the availability of effective, well-tolerated malaria treatments, such as atovaquone/proguanil, artemether/lumefantrine and a new artemisinin combination dihydroartemisin/piperaquine, which is licensed in Europe for uncomplicated malaria, suggest that it is time to revisit and re-evaluate this strategy for travelers.     

Au@bovine serum albumin nanoparticle-based acid-resistant nanozyme quartz crystal microbalance sensing of urine glucose

A robust, efficient and sensitive quartz crystal microbalance (QCM) for glucose detection has been constructed using Au@bovine serum albumin (Au@BSA) nanoparticles as an active layer. The nanoparticles serve as tandem nanozymes and their stability over natural enzymes enable the sensor to show a wider linear dynamic range between 0.05 and 15 mM, a higher acid-resistance (pH 2.0–8.0) and heat-resistance (35–60 °C) than conventional glucose oxidase (GOx)-based sensors. The sensor has been further applied to measure glucose content in artificial urine directly without dilution, where the recovery of 99.6–105.2% and the relative standard deviations (RSDs) below 0.88% confirm a good reproducibility for the measurement results. In addition, the developed Au@BSA QCM sensor can retain 95% of its initial activity after 40 days of storage. Overall, the Au@BSA sensor shows better comprehensive performance than the commercial sensor strips for urine glucose analysis and provides a promising approach in a more precise and robust manner.

Tandem nanozyme (Au@BSA NPs) QCM sensor fabricated by one-step deposition method can be used to detect non-enzymatic urine glucose based on precipitation-amplified signal.     

Artemether-Lumefantrine Pharmacokinetics and Clinical Response Are Minimally Altered in Pregnant Ugandan Women Treated for Uncomplicated Falciparum Malaria

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. {"type":"clinical-trial","attrs":{"text":"NCT01717885","term_id":"NCT01717885"}}NCT01717885.)     

Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.Pregnancy has considerable effects on the pharmacokinetic properties of many of the drugs used to treat uncomplicated Plasmodium falciparum malaria. Whereas blood chloroquine and quinine concentrations are relatively unaffected (1, 25), artesunate, artemether, dihydroartemisinin, sulfadoxine, atovaquone, proguanil, and cycloguanil concentrations are all reduced in later pregnancy (14, 30-33). The reductions are often substantial, and as a result, antimalarial cure rates in pregnancy for any given antimalarial drug tend to be lower (24, 34). Unfortunately, pregnant women are especially vulnerable to malaria and the fetus is adversely affected.The fixed combination of artemether and lumefantrine is the result of research undertaken by Chinese scientists and has become the most widely used coformulated artemisinin-based combination therapy (ACT). Artemether-lumefantrine has proved effective (cure rates, >97%) and safe in adults and children in trials conducted throughout the areas of the world affected by malaria (2, 13, 15, 20, 23, 35, 43, 44, 59). There is a reluctance to prescribe new drugs to pregnant women, and there have been concerns over the safety of artemisinin derivatives in early pregnancy. The current assessment of the benefits compared with the potential risks suggests that the artemisinin derivatives should be used to treat uncomplicated P. falciparum malaria in the second and third trimesters, as a result of documented experience with the treatment of more than 1,500 pregnant women (9, 40, 56). Evaluation of the new fixed ACTs is lagging behind these recommendations (53).A recent preliminary study with 13 pregnant women with frequent venous plasma sampling for pharmacokinetic analysis showed that the levels of artemether, dihydroartemisinin, and lumefantrine exposure were lower in this group than in nonpregnant adult patients in the same area (32). The maximum concentration (C_max) of dihydroartemisinin (the principal metabolite of artemether) and total drug exposure (the area under the concentration-time curve from time zero to 8 h [AUC_0-8]) were 20% and 40% lower, respectively, in pregnant patients than in nonpregnant patients. The level of exposure to lumefantrine after the last dose (the AUC from 60 h to infinity [AUC_60-∞]) was 6% (90% confidence interval [CI], 5 to 12%) lower in pregnant patients than in nonpregnant patients, but because elimination was more rapid, later exposure (AUC from 120 h to infinity [AUC_120-∞]) was 49% (95% CI, 28 to 91%) lower in pregnant patients than in nonpregnant patients (32). The total exposure to lumefantrine has previously been shown to be a good predictor of outcome in the same population (55), although it is believed that the later concentrations in the third and subsequent parasite life cycles (>4 days) may be the main determinant (52). The day 7 concentrations of lumefantrine correlate well with total drug AUCs, and this measurement has therefore been used as a measure of drug exposure in clinical studies of artemether-lumefantrine (55). Indeed, there are reasons to believe that this may be a better determinant of the therapeutic response than the total AUC for many antimalarial drugs used today (54). Venous plasma lumefantrine concentrations of 175 ng/ml (42) and 280 ng/ml (11, 12) at day 7 have been suggested to be cutoffs below which there is a 25% and a 50% risk of therapeutic failure, respectively, in this area. A plasma lumefantrine concentration of >500 ng/ml on day 7 is associated with a treatment success rate of >90% (11, 55). A high proportion (38%) of the pregnant patients in the preliminary pharmacokinetic study described previously had day 7 lumefantrine concentrations below 280 ng/ml, suggesting that lower concentrations on day 7 may result in lower cure rates in this vulnerable group (32).The main objective of the study described here was to investigate the pharmacokinetic properties of lumefantrine by use of a population-based modeling approach in pregnant women treated with the standard dose of artemether-lumefantrine.     

Efficacy of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Malaria in Children in Zaire and Uíge Provinces,Angola

The development of resistance to antimalarials is a major challenge for global malaria control. Artemisinin-based combination therapies, the newest class of antimalarials, are used worldwide but there have been reports of artemisinin resistance in Southeast Asia. In February through May 2013, we conducted open-label, nonrandomized therapeutic efficacy studies of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in Zaire and Uíge Provinces in northern Angola. The parasitological and clinical responses to treatment in children with uncomplicated Plasmodium falciparum monoinfection were measured over 28 days, and the main outcome was a PCR-corrected adequate clinical and parasitological response (ACPR) proportion on day 28. Parasites from treatment failures were analyzed for the presence of putative molecular markers of resistance to lumefantrine and artemisinins, including the recently identified mutations in the K13 propeller gene. In the 320 children finishing the study, 25 treatment failures were observed: 24 in the AL arms and 1 in the DP arm. The PCR-corrected ACPR proportions on day 28 for AL were 88% (95% confidence interval [CI], 78 to 95%) in Zaire and 97% (91 to 100%) in Uíge. For DP, the proportions were 100% (95 to 100%) in Zaire, and 100% (96 to 100%) in Uíge. None of the treatment failures had molecular evidence of artemisinin resistance. In contrast, 91% of AL late-treatment failures had markers associated with lumefantrine resistance on the day of failure. The absence of molecular markers for artemisinin resistance and the observed efficacies of both drug combinations suggest no evidence of artemisinin resistance in northern Angola. There is evidence of increased lumefantrine resistance in Zaire, which should continue to be monitored.     

Preparation of a quartz microbalance sensor based on molecularly imprinted polymers and its application in formaldehyde detection

Quartz crystal microbalances (QCMs) have been widely used in the food industry, environmental monitoring, and biomedicine. Here, a molecularly imprinted QCM sensor was prepared and used for formaldehyde detection. Using polyvinyl chloride as the embedding material and tetrahydrofuran as the solvent, a QCM electrode was modified with HCHO molecularly imprinted polymers (HCHO-MIPs). The detection conditions of the sensor were optimized, and its selectivity was investigated. The theoretical calculation results revealed that the acrylamide and pentaerythritol triacrylate were potential candidate functional monomer and cross-linking agent, respectively, in the preparation of HCHO-MIPs with high adsorbability, superselectivity, and stability. According to the calculated results, a sensor had been prepared. When the pH was 7, the added mass of the HCHO-MIPs (or NIPs) was 20 mg, and the amount of PVC coating was 20 μL, the sensor exhibited good adsorption, selectivity, repeatability, high sensitivity, high accuracy, and a short response time. The lowest detection limit was 10.72 ng mL⁻¹. The sensor exhibited higher selectivity for HCHO than for propionaldehyde and benzaldehyde. The HCHO contents in fresh shrimp samples were detected using the sensor for four cycles, and the detection rates were in the range of 97.56–98.60%. This study provided a theoretical and experimental basis for the rapid detection of HCHO.

A QCM electrode was modified with HCHO-MIPs. The detection conditions of sensor were optimized, and its selectivity was discussed. It was applied to detect the HCHO content in fresh shrimp samples.     

Interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1-infected patients

Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naïve patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naïve groups, respectively (P = 0.0002). The median artemether area under the plasma concentration-time curve from 0 to 8 h [AUC_{(0-8 h)}] (P < 0.0001) and dihydroartemisinin AUC_{(60-68 h)} (P = 0.01) were lower in the nevirapine group. Combined artemether and dihydroartemisinin exposure decreased over time only in the nevirapine group (geometric mean ratio [GMR], 0.76 [95% confidence interval {CI}, 0.65 to 0.90]; P < 0.0001) and increased with the weight-adjusted artemether dose (GMR, 2.12 [95% CI, 1.31 to 3.45]; P = 0.002). Adverse events were similar between groups, with no difference in electrocardiographic Fridericia corrected QT and P-R intervals at the expected time of maximum lumefantrine concentration (T_max). Nevirapine-based ART decreased artemether and dihydroartemisinin AUCs but unexpectedly increased lumefantrine exposure. The mechanism of the lumefantrine interaction remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.     

Lead Clinical and Preclinical Antimalarial Drugs Can Significantly Reduce Sporozoite Transmission to Vertebrate Populations

To achieve malarial elimination, we must employ interventions that reduce the exposure of human populations to infectious mosquitoes. To this end, numerous antimalarial drugs are under assessment in a variety of transmission-blocking assays which fail to measure the single crucial criteria of a successful intervention, namely impact on case incidence within a vertebrate population (reduction in reproductive number/effect size). Consequently, any reduction in new infections due to drug treatment (and how this may be influenced by differing transmission settings) is not currently examined, limiting the translation of any findings. We describe the use of a laboratory population model to assess how individual antimalarial drugs can impact the number of secondary Plasmodium berghei infections over a cycle of transmission. We examine the impact of multiple clinical and preclinical drugs on both insect and vertebrate populations at multiple transmission settings. Both primaquine (>6 mg/kg of body weight) and NITD609 (8.1 mg/kg) have significant impacts across multiple transmission settings, but artemether and lumefantrine (57 and 11.8 mg/kg), OZ439 (6.5 mg/kg), and primaquine (<1.25 mg/kg) demonstrated potent efficacy only at lower-transmission settings. While directly demonstrating the impact of antimalarial drug treatment on vertebrate populations, we additionally calculate effect size for each treatment, allowing for head-to-head comparison of the potential impact of individual drugs within epidemiologically relevant settings, supporting their usage within elimination campaigns.     

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in 91 young African children with severe malaria or who could not tolerate oral antimalarial therapy. Each received 3.0 mg/kg of body weight of artemether at 0, 8, 24, 36, 48, and 60 h or until the initiation of oral treatment. Few blood samples were drawn postdose. Plasma artemether and dihydroartemisinin (DHA) levels were measured using liquid chromatography-mass spectrometry, and the data were analyzed using established population compartmental pharmacokinetic models. Parasite clearance was prompt (median parasite clearance time, 24 h), and there were no serious adverse events. Consistent with studies in healthy adults (S. Salman, D. Bendel, T. C. Lee, D. Templeton, and T. M. E. Davis, Antimicrob Agents Chemother 59:3197–3207, 2015, http://dx.doi.org/10.1128/AAC.05013-14), the absorption of sublingual artemether was biphasic, and multiple dosing was associated with the autoinduction of the metabolism of artemether to DHA (which itself has potent antimalarial activity). In contrast to studies using healthy volunteers, pharmacokinetic modeling indicated that the first absorption phase did not avoid first-pass metabolism, suggesting that the drug is transferred to the upper intestine through postdose fluid/food intake. Simulations using the present data and those from an earlier study in older Melanesian children with uncomplicated malaria treated with artemether-lumefantrine tablets suggested that the bioavailability of sublingual artemether was at least equivalent to that after conventional oral artemether-lumefantrine (median [interquartile range] areas under the concentration-time curve for artemether, 3,403 [2,471 to 4,771] versus 3,063 [2,358 to 4,514] μg · h/liter, respectively; and for DHA, 2,958 [2,146 to 4,278] versus 2,839 [1,812 to 3,488] μg · h/liter, respectively; P ≥ 0.42). These findings suggest that sublingual artemether could be used as prereferral treatment for sick children before transfer for definitive management of severe or moderately severe malaria.     

Desbutyl-lumefantrine is a metabolite of lumefantrine with potent in vitro antimalarial activity that may influence artemether-lumefantrine treatment outcome

Desbutyl-lumefantrine (DBL) is a metabolite of lumefantrine. Preliminary data from Plasmodium falciparum field isolates show greater antimalarial potency than, and synergy with, the parent compound and synergy with artemisinin. In the present study, the in vitro activity and interactions of DBL were assessed from tritium-labeled hypoxanthine uptake in cultures of the laboratory-adapted strains 3D7 (chloroquine sensitive) and W2mef (chloroquine resistant). The geometric mean 50% inhibitory concentrations (IC(50)s) for DBL against 3D7 and W2mef were 9.0 nM (95% confidence interval, 5.7 to 14.4 nM) and 9.5 nM (95% confidence interval, 7.5 to 11.9 nM), respectively, and those for lumefantrine were 65.2 nM (95% confidence interval, 42.3 to 100.8 nM) and 55.5 nM (95% confidence interval, 40.6 to 75.7 nM), respectively. An isobolographic analysis of DBL and lumefantrine combinations showed no interaction in either laboratory-adapted strain but mild synergy between DBL and dihydroartemisinin (sums of the fractional inhibitory concentrations of 0.92 [95% confidence interval, 0.87 to 0.98] and 0.94 [95% confidence interval, 0.90 to 0.99] for 3D7 and W2mef, respectively). Using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay and 94 day 7 samples from a previously reported intervention trial, the mean plasma DBL was 31.9 nM (range, 1.3 to 123.1 nM). Mean plasma DBL concentrations were lower in children who failed artemether-lumefantrine treatment than in those with an adequate clinical and parasitological response (ACPR) (P = 0.053 versus P > 0.22 for plasma lumefantrine and the plasma lumefantrine-to-DBL ratio, respectively). DBL is more potent than the parent compound and mildly synergistic with dihydroartemisinin. These properties and the relationship between day 7 plasma concentrations and the ACPR suggest that it could be a useful alternative to lumefantrine as a part of artemisinin combination therapy.     

Nanoporous MIL-101(Cr) as a sensing layer coated on a quartz crystal microbalance (QCM) nanosensor to detect volatile organic compounds (VOCs)

The application of metal–organic frameworks (MOFs) as a sensing layer has been attracting great interest over the last decade, due to their high porosity and tunability, which provides a large surface area and active sites for trapping or binding target molecules. MIL-101(Cr) is selected as a good candidate from the MOFs family to fabricate a quartz crystal microbalance (QCM) nanosensor for the detection of volatile organic compound (VOC) vapors. The structural and chemical properties of synthesized MIL-101(Cr) are investigated by X-ray diffraction (XRD), Fourier-transfer infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) and so on. A stable and uniform layer of MOF is coated onto the surface of a QCM sensor by the drop casting method. The frequency of the QCM crystal is changed during exposure to different concentrations of target gas molecules. Here, the sensor response to some VOCs with different functional groups and polarities, such as methanol, ethanol, isopropanol, n-hexane, acetone, dichloromethane, chloroform, tetrahydrofuran (THF), and pyridine under N₂ atmosphere at ambient conditions is studied. Sensing properties such as sensitivity, reversibility, stability, response time, recovery time, and limit of detection (LOD) of the sensor are investigated. The best sensor response is observed for pyridine detection with sensitivity of 2.793 Hz ppm⁻¹. The sensor shows short response/recovery time (less than two minutes), complete reversibility and repeatability which are attributed to the physisorption of the gases into the MOF pores and high stability of the device.

Metal–organic frameworks can be used as sensing layer in QCM fabrication because of their huge surface area.     

Coartemether (artemether and lumefantrine): an oral antimalarial drug

Coartemether (Riamet^®, Coartem^®, Novartis), a tablet formulation of artemether and lumefantrine, is a well-tolerated, fast-acting and effective blood schizontocidal drug that serves primarily in the treatment of uncomplicated falciparum malaria that is resistant to other antimalarials. Initial clinical-parasitological response relies mainly on the artemether component, while lumefantrine effects radical cure. The absorption of lumefantrine is poor during the fasting state, the normal condition in acutely ill malaria patients, but with return to normal diet it becomes adequate. This highlights the need for an appropriate adjustment of the dose regimen. In the area where Plasmodium falciparum shows the highest degree of multidrug resistance worldwide, the best results (99% cure) were obtained with a six-dose regimen given over 5 days. Extensive cardiological investigations have demonstrated the high cardiac safety of coartemether.