Doses Of Artemether Research Articles

Pharmacokinetic properties of the antimalarial combination therapy artemether–lumefantrine in normal-weight, overweight and obese healthy male adults

The component drugs in the widely used antimalarial artemisinin combination therapy artemether–lumefantrine are lipophilic, with the possibility that recommended fixed doses in adults may lead to subtherapeutic concentrations and consequent treatment failure in overweight/obese individuals with malaria. The aim of this study was to investigate the pharmacokinetic properties of artemether, lumefantrine and their active metabolites dihydroartemisinin and desbutyl-lumefantrine in 16 normal-weight, overweight and obese healthy male volunteers [body mass index (BMI) categories ≤25 kg/m², >25–≤30 kg/m² and >30 kg/m², respectively; absolute range 19.3–37.2 kg/m²]. Participants received the conventional six doses of artemether–lumefantrine over 3 days, each dose comprising 80 mg artemether plus 480 mg lumefantrine administered with 6.7 g fat, and blood samples were collected at pre-specified time-points over 14 days. Plasma drug/metabolite concentrations were measured using liquid chromatography-mass spectrometry and included in multi-compartmental population pharmacokinetic models. There was a non-significant trend to a lower area under the plasma concentration–time curve with a higher body weight or BMI for dihydroartemisinin and especially artemether which was attenuated when normalized for mg/kg dose, but this relationship was not evident in the case of the more lipophilic lumefantrine and its metabolite desbutyl-lumefantrine. Simulated Day 7 plasma lumefantrine concentrations were >200 µg/L (the threshold at which Plasmodium falciparum recrudescences are minimized) in all participants. These results indicate that there is no need for artemether–lumefantrine dose modification in overweight and obese patients with malaria.

The pharmacokinetic properties of artemether and lumefantrine in Malaysian patients with Plasmodium knowlesi malaria.

The aim of this study was to assess the pharmacokinetic properties of artemether, lumefantrine and their active metabolites in Plasmodium knowlesi malaria. Malaysian adults presenting with uncomplicated P. knowlesi infections received six doses of artemether (1.7mg/kg) plus lumefantrine (10mg/kg) over 3days. Venous blood and dried blood spot (DBS) samples were taken at predetermined time-points over 28 days. Plasma and DBS artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine were measured using liquid chromatography-mass spectrometry. Multi-compartmental population pharmacokinetic models were developed using plasma with or without DBS drug concentrations. Forty-one participants (mean age 45 years, 66% males) were recruited. Artemether-lumefantrine treatment was well tolerated and parasite clearance was prompt. Plasma and DBS lumefantrine concentrations were in close agreement and were used together in pharmacokinetic modelling, but only plasma concentrations of the other analytes were used because of poor correlation with DBS levels. The areas under the concentration-time curve (AUC0-∞ ) for artemether, dihydroartemisinin and lumefantrine (medians 1626, 1881 and 625 098 μg.h/L, respectively) were similar to those reported in previous pharmacokinetic studies in adults and children. There was evidence of auto-induction of artemether metabolism (mean increase in clearance relative to bioavailability 25.2% for each subsequent dose). The lumefantrine terminal elimination half-life (median 9.5days) was longer than reported in healthy volunteers and adults with falciparum malaria. The disposition of artemether, dihydroartemisinin and lumefantrine in knowlesi malaria largely parallels that in other human malarias. DBS lumefantrine concentrations can be used in pharmacokinetic studies but DBS technology is currently unreliable for the other analytes.

Effect of fresh pomegranate juice on the pharmacokinetic profile of artemether: An open-label, randomized, 2- period crossover study in healthy human volunteers

This study was designed to evaluate the effect of fresh pomegranate (Punica granatum L.) juice on the pharmacokinetic profile of artemether in healthy volunteers. A randomized, open-label, crossover study was conducted on healthy subjects (n = 26). Each volunteer received 250 mL of fresh pomegranate juice twice daily for 2 weeks. On day 14, they were administered a single oral dose of artemether (80 mg) with either water or 250 mL of pomegranate juice. Thirteen blood samples were collected up to 12 h and 6 electrocardiograms were recorded. Plasma concentrations of artemether and its metabolite dihydroartemisinin were analyzed by a noncompartmental method using LC–MS/MS. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) for artemether were estimated as 0.3 and 0.8 ng/mL, respectively, while for dihydroartemisinin it was 0.2 and 0.6 ng/mL, respectively. The pharmacokinetic parameters of artemether and dihydroartemisinin were not significantly altered when co-administered with the fresh pomegranate juice. AUC (0-∞) was slightly increased from 742 to 859 ng/mL for artemether [geometric mean ratio: 1.14 (95 % CI, 1.08,1.18); P = 0.45] and from 699 to 818 ng/mL for dihydroartemisinin [geometric mean ratio: 1.15 (95 % CI, 1.09, 1.15); P = 0.4]. Difference in Cmax for artemether was also statistically non-significant [173 vs 195 ng/mL; geometric mean ratio: 1.09 (95 % CI, 0.91, 1.15); P = 0.61]. Likewise, elimination half-life (t1/2) for both artemether and dihydroartemisinin remained unchanged (P = 0.43 and 0.31, respectively). In addition, there was no significant difference in tmax for artemether (P = 0.66) and its metabolite (P = 0.65). In conclusion, findings of the present study demonstrated that the administration of pomegranate juice had no significant effect on the pharmacokinetic profile of artemether.

Effect of CYP3A5*3 genotypes on lumefantrine plasma concentrations among malaria-HIV-infected women.

Aim: We aimed to assess the effect of a functional polymorphism of CYP3A5 on lumefantrine pharmacokinetics. Patients & methods: Sixty-nine women diagnosed with malaria received standard doses of artemether-lumefantrine. Concentration-time data for lumefantrine and genotyping data were obtained for each participant. Pharmacokinetic-genotype associative relationships were assessed using linear regressions, Mann-Whitney U-test or Kruskal-Wallis statistics. Results: Average age and weight (standard deviation) of the patients were 33(6.8) years and 59.5(11.6) kg, respectively. CYP3A5*3genotypeassociated with the log-transformed maximum concentration with the median (interquartile range) values of 8279 (6516-13,420) and 6331 (4093-8631) ng/ml (p = 0.032) among the carriers and noncarriers of CYP3A5*3, respectively. Besides, the NR1I3 c.152-1089T>C genotypes had an associative trend with the lumefantrine area under the curve (AUC0-96h) and clearance. Conclusion:CYP3A5*3 genetic variant is associated with a high maximum plasma concentration of lumefantrine. This warrants further investigations on the association between CYP3A5*3 gene variants, lumefantrine pharmacokinetics and electrophysiological effect.

Deployment and use of mobile phone technology for real-time reporting of fever cases and malaria treatment failure in areas of declining malaria transmission in Muheza district north-eastern Tanzania

BackgroundEarly detection of febrile illnesses at community level is essential for improved malaria case management and control. Currently, mobile phone-based technology has been commonly used to collect and transfer health information and services in different settings. This study assessed the applicability of mobile phone-based technology in real-time reporting of fever cases and management of malaria by village health workers (VHWs) in north-eastern Tanzania.MethodsThe community mobile phone-based disease surveillance and treatment for malaria (ComDSTM) platform, combined with mobile phones and web applications, was developed and implemented in three villages and one dispensary in Muheza district from November 2013 to October 2014. A baseline census was conducted in May 2013. The data were uploaded on a web-based database and updated during follow-up home visits by VHWs. Active and passive case detection (ACD, PCD) of febrile cases were done by VHWs and cases found positive by malaria rapid diagnostic test (RDT) were given the first dose of artemether–lumefantrine (AL) at the dispensary. Each patient was visited at home by VHWs daily for the first 3 days to supervise intake of anti-malarial and on day 7 to monitor the recovery process. The data were captured and transmitted to the database using mobile phones.ResultsThe baseline population in the three villages was 2934 in 678 households. A total of 1907 febrile cases were recorded by VHWs and 1828 (95.9%) were captured using mobile phones. At the dispensary, 1778 (93.2%) febrile cases were registered and of these, 84.2% were captured through PCD. Positivity rates were 48.2 and 45.8% by RDT and microscopy, respectively. Nine cases had treatment failure reported on day 7 post-treatment and adherence to treatment was 98%. One patient with severe febrile illness was referred to Muheza district hospital.ConclusionThe study showed that mobile phone-based technology can be successfully used by VHWs in surveillance and timely reporting of fever episodes and monitoring of treatment failure in remote areas. Further optimization and scaling-up will be required to utilize the tools for improved malaria case management and drug resistance surveillance.

Teratogenicity of Artemether-Clindamycin Nanostructured Lipid Carriers in Rats.

Currently, artemisinin-based combination therapy is considered the best option in the treatment of malaria. However, toxicity of artemisinins limits their use in pregnancy. In the absence of sufficient toxicity data, the World Health Organization recommends that artemisinins are not to be used in the first trimester of pregnancy and can be used only in second and third trimesters, when other treatments are not available. We have recently observed that drugs loaded in nanolipid carriers are selectively taken up in Plasmodium-infected erythrocytes with a concomitant reduction in the dose required to cure animals. Thus, 20% of the therapeutic dose of artemether-clindamycin (ARM-CP) loaded in nanostructured lipid carriers (NLCs; mean particle size 55 ± 10 nm) resulted in complete parasite clearance and 100% survival of infected mice. Here, we investigate the teratogenicity of this formulation in rodents (dosing on alternate days from 6th day to 18th day of gestation; 12-15 animals/group). The teratogenicity of drug-free NLCs and artesunate-clindamycin (ARS-CP) solution was also evaluated. We found that the therapeutic dose of ARS-CP caused fetal resorptions (87.5% resorptions in 8 litters), suggesting its unsuitability for use in pregnancy. Artesunate-clindamycin NLCs at therapeutic doses also resulted in ∼90% fetal resorptions in 10 litters examined. However, postimplantation losses or fetal malformations were not observed at the dose of ARM-CP NLCs that was required for complete parasite clearance in preclinical trials (ie, 20% of the therapeutic dose). Our data suggest that the NLCs loaded with 20% of the therapeutic dose of ARM-CP may have potential in treating malaria during pregnancy.

Pharmacokinetics of a novel sublingual spray formulation of the antimalarial drug artemether in healthy adults.

The pharmacokinetics of sublingual artemether (ArTiMist) was investigated in two open-label studies. In study 1, 16 healthy males were randomized to each of four single-dose treatments administered in random order: (i) 15.0 mg of sublingual artemether (5 × 3.0 actuations), (ii) 30.0 mg of sublingual artemether (10 × 3.0 mg), (iii) 30.0 mg of sublingual artemether (5 × 6.0 mg), and (iv) 30.0 mg of artemether in tablet form. In study 2, 16 healthy males were randomized to eight 30.0-mg doses of sublingual artemether given over 5 days as either 10 3.0-mg or 5 6.0-mg actuations. Frequent blood samples were drawn postdose. Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (≥1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (≥1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing.

The effect of dose on the antimalarial efficacy of artemether–lumefantrine: a systematic review and pooled analysis of individual patient data

Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. We included 61 studies done between January, 1998, and December, 2012, and included 14,327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. Bill & Melinda Gates Foundation.

Effect of artemether on cytokine profile and egg induced pathology in murine schistosomiasis mansoni

Artemether (ART), the methylated derivative of artemisinin, is an efficacious antimalarial drug that also displays antischistosomal properties. This study was designed to evaluate the immunomodulatory action of a single intramuscular dose (50mg/kg body weight) of ART in comparison with PZQ treatment (42days PI). ART administration was 7, 14, 21 and 45days PI. ART effect was studied parasitologically, histopathologically and immunologically. It was found that maximum effect was reached when ART treatment interfered with 14 or 21days old schistosomula. ART treatment 14 or 21days PI was associated with shift from Th2 to Th1 predominancy (decrease in IL-4 and upgrading of serum IFN-γ levels). In conclusion, ART is a promising drug in control of schistosomiasis mansoni due to its reductive effect on worm burden and its role in improvement of hepatic granulomatous lesions.

The effect of lopinavir/ritonavir on the antimalarial activity of artemether or artemether/lumefantrine in a mouse model of Plasmodium berghei

The possibility of drug–drug interactions occurring during the treatment of malaria infection in human immunodeficient virus (HIV) patients receiving antiretroviral drugs is very high and limited data are available. This study reports the effect of lopinavir/ritonavir (LR) an antiretroviral drug on the antimalarial activity of standard dose of artemether/lumefantrine (AL) or artemether (AM) in a mouse model of Plasmodium berghei. The 50% effective dose (ED50) of AM alone (0·80±0·15 and 2·18±0·75 mg/kg) or in combination with LR (0·88±0·40 and 3·53±1·09 mg/kg) on days 4 and 5 post-infection was similar. In addition, treatment with a standard dose of AL alone or in combination with LR resulted in complete suppression of parasite growth. However, co-administration of LR with AL appears to be toxic resulting in lower survival of experimental animals in comparison to those treated with standard dose of AL alone.

In vivo effect of single oral dose of artemether against early juvenile stages of Schistosoma mansoni Egyptian strain

The current treatment and control of schistosomiasis, rely on a single drug, praziquantel, although, it has minor activity against juvenile stages of the parasite. Studies have shown that artemether (ART) exhibits effects against juveniles of Schistosoma mansoni Liberian and Puerto Rican strains, Schistosoma japonicum and Schistosoma haematobium. Aiming to assess the in vivo activity of single oral dose of ART against early juvenile stages of S. mansoni Egyptian strain, this study was established. Mice were treated with ART (400mg/kg) at two time points evenly spaced over the period of larval development (7 and 21days post-infection; pi), and a third treatment point (day 49 pi) was included to elucidate when susceptibility decreases. Administration of ART on day 7 pi reduced the total worm burden by 85.94%. The greatest reductions were seen when treatment was given on day 21 pi, with total and female worm burden reductions of 91.52% and 90.57%, respectively, and cessation of oviposition. Similar dose given on day 49 pi reduced total worm burden by 55.17% and female worm burden by 66.51%. Moreover, it induced significant reduction in the tissue egg load and significant alterations in the oogram pattern with decreased immature eggs and increased dead eggs. Antipathological activities were evident in significant reductions in granulomata count and diameter. In conclusion, ART exhibits major in vivo schistosomicidal effects against the early larval migratory stages of S. mansoni Egyptian strain, mainly the 21-day old schistosomula, hence preventing disease progression and morbidity.

In Vitro and In Vivo Studies of Antileishmanial Effect of Artemether on Leishmania infantum

Background: Visceral leishmaniasis is the most acute form of leishmaniasis. Instead of administering usual drugs with different side effects, applying a herbal drug can put forward a novel horizon in dealing with this parasite. Artemether is one of the derivatives of artemisinin, a new anti-malarial drug, and can be activated by heme to produce free radicals which, in turn, have toxic effect on the parasite. Objectives: In this study we used artemether as a new drug for treatment of visceral leishmaniasis. Materials and Methods: In the present study, BALB/c mice infected with Leishmania infantum (MHOM/TN/80/IPI1) were treated with the most effective dose of artemether assessed with In Vitro assay. Artemether was given in parenteral and oral forms. Parasite burdens in the spleen and liver were determined by homogenizing and counting the parasite rate and were compared with those in the untreated mice. To evaluate the apoptotic properties of artemether by FACS flowcytometry, annexin-V FLUOS staining was performe. Results: IC50 of the drug on Leishmania infantum was determined to be 25 μg/mL after 24 h. In Vivo experiments indicated that oral artemether treatment of mice, during 3 days and every 6 h (0.625 mg/kg) was more significant than parenteral (0.625 mg/kg IP) treatment. Artemether exerts its cytotoxic effect on this parasite via apoptosis-related mechanism. Accordingly, parasite burden in the current study decreased in the liver and spleen of mice by oral treatment. Conclusions: Artemether especially in oral treatment is an effective and simple method and may be used as a new method to treat visceral leishmaniasis.

Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz.

PurposeTo treat malaria, HIV-infected patients normally receive artemether (80 mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and artemether. Artemether dose adjustments were then simulated in order to predict optimal dosing in co-infected patients and inform future interaction study design.MethodsIn vitro data describing the chemical properties, absorption, distribution, metabolism and elimination of efavirenz and artemether were obtained from published literature and included in a physiologically based pharmacokinetic model (PBPK) to predict drug disposition simulating virtual clinical trials. Administration of efavirenz and artemether, alone or in combination, were simulated to mirror previous clinical studies and facilitate validation of the model and realistic interpretation of the simulation. Efavirenz (600 mg once daily) was administered to 50 virtual subjects for 14 days. This was followed by concomitant administration of artemether (80 mg eight hourly) for the first two doses and 80 mg (twice daily) for another two days.ResultsSimulated pharmacokinetics and the drug-drug interaction were in concordance with available clinical data. Efavirenz induced first pass metabolism and hepatic clearance, reducing artemether Cmax by 60% and AUC by 80%. Dose increases of artemether, to correct for the interaction, were simulated and a dose of 240 mg was predicted to be sufficient to overcome the interaction and allow therapeutic plasma concentrations of artemether.ConclusionsThe model presented here provides a rational platform to inform the design for a clinical drug interaction study that may save time and resource while the optimal dose is determined empirically. Wider application of IVIVE could help researchers gain a better understanding of the molecular mechanisms underpinning variability in drug disposition.

Changes in some biochemical parameters of kidney functions of Plasmodium berghei infected rats administered with some doses of artemether

+) and potassium (K + ) of Plasmodium berghei infected rats during a week of intramuscular administration of artemether (12.5 to 50.0 mg/kg/day) and one week thereafter. Their concentrations and that of creatinine and urea in the plasma were also determined at the end of the study. The observed changes were related to the effects of artemether on the kidneys of the rats. The urine levels of the two electrolytes decreased significantly during treatment (P<0.05). One week post-treatment with 12.5 mg/kg of artemether, the urine concentrations of the electrolytes increased to values that were not significantly different from that of day 0. At 25 and 50 mg/kg, their urine concentrations still remained significantly lower than day 0 values (P<0.05). Plasma concentrations of the electrolytes one week post-treatment increased, but they were only significant at 25 mg/kg for K + . A significant increase in the plasma level of creatinine was observed at all the doses of the drug at one week post-treatment. A dose-dependent degeneration of the renal tissue of all the experimental rats was also observed. We concluded that high doses of artemether caused progressive degeneration of the renal tissue of P. berghei infected rats.

Efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis

BackgroundPraziquantel has been used as first-line drug for chemotherapy of schistosomiasis since 1984. Besides praziquantel, artemether and artesunate have also been used for the control of this infectious disease since late 1990s. In this article, we conducted a systematic review and meta-analysis to evaluate the antischistosomal efficacy of different medication strategies including monotherapy or combination therapies of these drugs.ResultsA number of 52 trials from 38 articles published in peer-reviewed journals before July 2011 were selected for analysis after searching the following literature databases: the Cochrane Library, PubMed/Medline, ISI Web of Science, Chinese Biomedicine Literature Database, and China National Knowledge Infrastructure. Our meta-analyses showed that a dosage of 30-60 mg/kg praziquantel compared with placebo produced a protection rate of about 76% (95% CI: 67%-83%) for treating human schistosomiasis, which varied from 70% to 76% with no significant differences among the subspecies S. haematobium, S. japonicum or S. mansoni. Protection rates were higher when praziquantel doses were elevated, as concluded from the nRCTs results: the protection rate of praziquantel at 40 mg/kg was 52% (95% CI: 49%-55%), and it increased to 91% (95% CI: 88%-92%) when the dosages were elevated to 60/80/100 mg/kg divided two or more doses. Multiple doses of artemether or artesunate over 1- or 2-week intervals resulted in protection rates of 65% to 97% for preventing schistosomiasis, and increased doses and shorter medication intervals improved their efficacies. Praziquantel and artemisinin derivatives (artemether or artesunate) in combination resulted in a higher protection rate of 84% (95% CI: 64%-91%) than praziquantel monotherapy for treatment. praziquantel and artesunate in combination had a great protection rate of 96% (95% CI: 78%-99%) for preventing schistosomes infection.ConclusionsAccording to the results, praziquantel remains effective in schistosomiasis treatment, and multiple doses would improve its efficacy; meanwhile, praziquantel is also a good drug for preventing acute schistosomiasis morbidity. It's better to use multiple doses of artemether or artesunate with 1- or 2-week intervals for prevention against schistosome infection. Praziquantel and artemether or artesunate in combination perform better in treatment than praziquantel monotherapy, and they are especially suitable for treating the patients with repeated exposure to infected water.

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.

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.

Antitumor and immunomodulatory properties of artemether and its ability to reduce CD4+ CD25+ FoxP3+ T reg cells in vivo

BackgroundDevelopment of agents that specifically kill cancer cells and simultaneously elicit antitumor immune response is a step forward in cancer therapy. In the present study, we investigated whether the administration of artemether contributes to the augmentation of antitumor immunity and the regression of tumor tissues in a mouse model of breast cancer. MethodsAn optimal immunostimulatory dose of artemether (ART) was defined by DTH reaction and antibody production in sRBC-challenged mice. Subsequent experiments were carried out on tumor-bearing BALB/c mice. In the first group of tumor-bearing mice, the dose of 10mg/kg/day of artemether were intraperitoneally administered to each animal for six times. The second group was treated with 20mg/kg/day of cyclophosphamide as a positive control, and the last group (negative control) received the ART diluents. Tumor size was measured during the 10-day experiment; on the last day, mice were sacrificed and their splenocytes and tumor infiltrating lymphocytes were harvested. The concentration of IL-4 and IFN-γ cytokines (using ELISA assay) and the percentage of splenic and tumor Treg cells (using Flowcytometry analysis) were measured. ResultsArtemether could increase both DTH reaction and the production of hemagglutinating antibody in normal mice. Administration of ART profoundly suppressed the progression of tumor tissues. As well, it was significantly effective in the depletion of splenic CD4+ CD25+ Foxp3+ Treg cells (p-value>0.05). ART also increased the production of IL-4 (p-value<0.05) and IFN-γ (p-value>0.05). As a conclusion, the cytotoxic and immunomodulatory properties of artemether were acknowledged in vivo

HAEMATOLOGICAL AND PARASITOLOGICAL CHANGES IN EXPERIMENTAL ARTEMETHER-TREATED Trypanosoma brucei INFECTION IN RABBITS

Therapeutic effects and haematological changes by treatment with artemether were investigated and compared with those of diminazene aceturate in Trypanosoma brucei brucei infection of rabbits. Trypanosoma brucei brucei infection of rabbits was characterized by high parasitaemia, acute anaemia and gradual development of leucopenia. T. b. brucei infected rabbits were treated with various doses of artemether, an anti-protozoan drug of malaria and compared with standard dose of diminazene aceturate in other set of rabbits.Though artemether-treated T. b. brucei-infected rabbits were able to survive for 49 to 57 days as against maximum of 39 days in untreated infected group, there was no cure even with high dosage. Diminazene aceturate-treated rabbits were completely cured and had their haematological disorders reversed. Artemether, an anti-protozoan drug against malaria neither could cure the protozoan disease by T. b. brucei in rabbits nor able to reverse the haematological disorder brought about by the parasite but at best slightly prolonged the period of survival of the animals. Â

Does Artesunate Prolong the Electrocardiograph QT Interval in Patients with Severe Malaria?

Several antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular arrhythmias. High doses of artemether and artemotil have been associated with QT prolongation in dogs, raising the possibility of a class effect with the artemisinin derivatives. Serial electrocardiograms were recorded, and QTc interval was calculated before and after administration of artesunate by intravenous injection in patients with severe falciparum malaria in Bangladesh. Of 21 adult patients with severe malaria enrolled, 8 (38%) died. The mean QTc interval was unaffected by bolus intravenous artesunate (2.4 mg/kg). In two patients, the QTc interval exceeded 0.5 seconds, but in both cases, an alternative explanation was plausible. No effect was observed on the JTc or PR interval, QRS width, blood pressure, or heart rate. Intravenous artesunate does not have significant cardiovascular effects in patients with severe falciparum malaria.