lumefantrine and Parasitemia

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

The World Health Organization (WHO) is promoting artemether-lumefantrine for treating uncomplicated malaria. The objective of this review is to summarize available evidence of its effects compared with other antimalarial regimens.. We sought randomized and quasi-randomized studies comparing artemether-lumefantrine with any other antimalarial drug regimen. Databases searched were MEDLINE (to February 2003), EMBASE (to February 2003), and the Cochrane Controlled Trials Register (issue 1, 2003). Conference proceedings and reference article lists were searched and malaria researchers and the drug manufacturer were contacted. Two reviewers independently applied inclusion criteria and extracted data.. Six trials (1698 participants) studied the four-dose regimen. Fever and parasite clearance tended to be shorter with artemether-lumefantrine, but parasitological failure on day 28 was more common with artemether-lumefantrine in comparison with mefloquine (one trial, n = 233), halofantrine (one trial, n = 86) and mefloquine-artesunate (one trial, n = 537); but less common with chloroquine (two trials, n = 378). For the six-dose regimen, two studies compared artemether-lumefantrine with mefloquine-artesunate, but there was insufficient data to demonstrate any meaningful comparative effects for day 28 parasitaemia, and no difference in parasite or fever clearance time was detected. There were 11 parasitological failures with artemether-lumefantrine and none with mefloquine-artesunate.. There is no evidence to demonstrate the four-dose regimen of artemether-lumefantrine results in a higher cure rate than other antimalarial regimens against which it has been tested, apart from chloroquine in areas with high chloroquine resistance. Artemether-lumefantrine has potential advantages over non-artemisinin regimens because of the faster clearance time and gametocyte clearance. There is insufficient evidence about the six-dose regimen to know whether it is less or more effective than current antimalarial drug regimens.

Topics: Antimalarials; Artemether; Artemisinins; Drug Administration Schedule; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Parasitemia; Randomized Controlled Trials as Topic; Sesquiterpenes; Treatment Outcome

Artemether-lumefantrine (AL) is the most widely used artemisinin-based combination therapy in Sub-Saharan Africa and is threatened by the emergence of artemisinin resistance. Dosing is suboptimal in young children. We hypothesized that extending AL duration will improve exposure and reduce reinfection risks.. We conducted a prospective, randomized, open-label pharmacokinetic/pharmacodynamic study of extended duration AL in children with malaria in high-transmission rural Uganda. Children received 3-day (standard 6-dose) or 5-day (10-dose) AL with sampling for artemether, dihydroartemisinin, and lumefantrine over 42-day clinical follow-up. Primary outcomes were (1) comparative pharmacokinetic parameters between regimens and (2) recurrent parasitemia analyzed as intention-to-treat.. A total of 177 children aged 16 months to 16 years were randomized, contributing 227 total episodes. Terminal median lumefantrine concentrations were significantly increased in the 5-day versus 3-day regimen on days 7, 14, and 21 (P < .001). A predefined day 7 lumefantrine threshold of 280 ng/mL was strongly predictive of recurrence risk at 28 and 42 days (P < .001). Kaplan-Meier estimated 28-day (51% vs 40%) and 42-day risk (75% vs 68%) did not significantly differ between 3- and 5-day regimens. No significant toxicity was seen with the extended regimen.. Extending the duration of AL was safe and significantly enhanced overall drug exposure in young children but did not lead to significant reductions in recurrent parasitemia risk in our high-transmission setting. However, day 7 levels were strongly predictive of recurrent parasitemia risk, and those in the lowest weight-band were at higher risk of underdosing with the standard 3-day regimen.. ClinicalTrials.gov number NCT03453840.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Malaria, Falciparum; Parasitemia; Prospective Studies; Reinfection; Uganda

Day 7 plasma lumefantrine concentration is suggested as a predictor for malaria treatment outcomes and a cut-off of ≥ 200 ng/ml is associated with day 28 cure rate in the general population. However, day 7 lumefantrine plasma concentration can be affected by age, the extent of fever, baseline parasitaemia, and bodyweight. Therefore, this study assessed the usefulness of day 7 lumefantrine plasma concentration as a predictor of malaria treatment outcome in under-fives children treated with generic or innovator drug-containing artemether-lumefantrine (ALu) in Tanzania.. This study was nested in an equivalence prospective study that aimed at determining the effectiveness of a generic ALu (Artefan. The PCR corrected cure rates were 98.7% for children treated with generic and 98.6% for those treated with the innovator product (p = 1.00). The geometric mean (± SD) of day 7 plasma lumefantrine concentration was 159.3 (± 2.4) ng/ml for the generic and 164 (± 2.5) ng/ml for the innovator groups, p = 0.87. Geometric mean (± SD) day 7 lumefantrine plasma concentration between cured and recurrent malaria was not statistically different in both treatment arms [158.5 (± 2.4) vs 100.0 (± 1.5) ng/ml, (p = 0.28) for generic arm and 158.5 (± 2.3) vs 251.2 (± 4.2) ng/ml, (p = 0.24) for innovator arm]. Nutritional status was found to be a determinant of recurrent malaria (adjusted hazardous ratio (95% confidence interval) = 3(1.1-8.2), p = 0.029.. Using the recommended cut-off point of ≥ 200 ng/ml, day 7 plasma lumefantrine concentration failed to predict malaria treatment outcome in children treated with ALu in Tanzania. Further studies are recommended to establish the day 7 plasma lumefantrine concentration cut-off point to predict malaria treatment outcome in children.

Topics: Age Factors; Antimalarials; Artemether, Lumefantrine Drug Combination; Body Weight; Child, Preschool; Female; Hemoglobins; Humans; Infant; Linear Models; Lumefantrine; Malaria; Male; Nutritional Status; Parasitemia; Polymerase Chain Reaction; Recurrence; Sex Factors; Tanzania; Treatment Outcome

The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children.. Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine.. Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations.. We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.

Topics: Antimalarials; Artemether; Artemisinins; Black People; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Recurrence; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda

In vivo efficacy assessments of antimalarials are essential for ensuring effective case management. In Ethiopia, chloroquine (CQ) without primaquine is the first-line treatment for Plasmodium vivax in malarious areas, but artemether-lumefantrine (AL) is also commonly used.. In 2009, we conducted a 42-day efficacy study of AL or CQ for P. vivax in Oromia Regional State, Ethiopia. Individuals with P. vivax monoinfection were enrolled. Primary endpoint was day 28 cure rate. In patients with recurrent parasitemia, drug level and genotyping using microsatellite markers were assessed. Using survival analysis, uncorrected patient cure rates at day 28 were 75.7% (95% confidence interval (CI) 66.8-82.5) for AL and 90.8% (95% CI 83.6-94.9) for CQ. During the 42 days of follow-up, 41.6% (47/113) of patients in the AL arm and 31.8% (34/107) in the CQ arm presented with recurrent P. vivax infection, with the median number of days to recurrence of 28 compared to 35 days in the AL and CQ arm, respectively. Using microsatellite markers to reclassify recurrent parasitemias with a different genotype as non-treatment failures, day 28 cure rates were genotype adjusted to 91.1% (95% CI 84.1-95.1) for AL and to 97.2% (91.6-99.1) for CQ. Three patients (2.8%) with recurrent parasitemia by day 28 in the CQ arm were noted to have drug levels above 100 ng/ml.. In the short term, both AL and CQ were effective and well-tolerated for P. vivax malaria, but high rates of recurrent parasitemia were noted with both drugs. CQ provided longer post-treatment prophylaxis than AL, resulting in delayed recurrence of parasitemia. Although the current policy of species-specific treatment can be maintained for Ethiopia, the co-administration of primaquine for treatment of P. vivax malaria needs to be urgently considered to prevent relapse infections.. ClinicalTrials.gov NCT01052584.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Chloroquine; Ethanolamines; Ethiopia; Female; Fluorenes; Genotype; Humans; Infant; Lumefantrine; Malaria, Vivax; Male; Middle Aged; Parasitemia; Plasmodium vivax; Primaquine; Prospective Studies; Survival Analysis; Treatment Outcome; Young Adult

In recent studies, the combination of azithromycin and artesunate has proven to be a promising alternative for the treatment of uncomplicated falciparum malaria.. We conducted a randomized, controlled clinical trial assessing the efficacy of azithromycin-artesunate combination therapy. The study was conducted involving 228 patients aged 8-65 years. Patients were randomized to 1 of 2 cohorts at a ratio of 2:1, receiving either azithromycin-artesunate once daily for 3 days (30 mg/kg per day of azithromycin plus 4 mg/kg per day of artesunate) or an adult dose of 80 mg of artemether plus 960 mg of lumefantrine (4 tablets Coartem or the equivalent for children weighing <35 kg) twice daily for 3 days.. The 42-day cure rate by Kaplan-Meier analysis was 94.6% (95% confidence interval [CI], 89.38%-97.44%) in the azithromycin-artesunate arm and 97.0% (95% CI, 89.45%-99.40%) in the control arm. Fever clearance times and parasite clearance times did not show any differences between the 2 arms (P=.59 and .95, respectively). No serious adverse events were seen, but the percentage of patients who developed any adverse event was higher in the control group (P=.03).. Our data suggest that azithromycin-artesunate is an efficacious and well-tolerated treatment for patients with uncomplicated falciparum malaria in Bangladesh.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Artemether; Artemisinins; Artesunate; Azithromycin; Bangladesh; Child; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Time Factors; Treatment Outcome; Young Adult

Chloroquine remains the drug of choice for the treatment of vivax malaria in Thailand. Mixed infections of falciparum and vivax malaria are also common in South-East Asia. Laboratory confirmation of malaria species is not generally available. This study aimed to find alternative regimens for treating both malaria species by using falciparum antimalarial drugs. From June 2004 to May 2005, 98 patients with Plasmodium vivax were randomly treated with either artemether-lumefantrine (n = 47) or chloroquine (n = 51). Both treatments were followed by 15 mg of primaquine over 14 days. Adverse events and clinical and parasitological outcomes were recorded and revealed similar in both groups. The cure rate was 97.4% for the artemether-lumefantrine treated group and 100% for the chloroquine treated group. We concluded that the combination of artemether-lumefantrine and primaquine was well tolerated, as effective as chloroquine and primaquine, and can be an alternative regimen for treatment of vivax malaria especially in the event that a mixed infection of falciparum and vivax malaria could not be ruled out.

Topics: Adolescent; Aged; Animals; Antimalarials; Artemether; Artemisinins; Chloroquine; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Vivax; Male; Middle Aged; Parasitemia; Plasmodium vivax; Primaquine; Thailand; Treatment Outcome

The efficacy of the six-dose regimen of artemether-lumefantrine was compared with the combination of artesunate and mefloquine in a randomised, comparative trial in Luang Namtha Province, Northern Laos. Of 1033 screened patients, 201 were positive for Plasmodium falciparum; 108 patients of all age groups (2-66 years) with acute, uncomplicated P. falciparum malaria were enrolled in the study, 100 of whom were followed-up for 42 days. Fifty-three patients received artemether-lumefantrine and 55 received artesunante-mefloquine. Both drug combinations induced rapid clearance of parasites and malaria symptoms; there was no significant difference in the initial therapeutic response parameters. Both regimes were well tolerated. After 42 days, cure rates were 93.6% (95% CI = 82.5-98.7%; 44 of 47 patients) for artemether-lumefantrine and 100% (95% CI = 93.3-100.0%; 53 of 53 patients) for artesunate-mefloquine. The results show the excellent efficacy and tolerability of both artemether-lumefantrine and artesunate-mefloquine in Northern Laos.

Topics: Acute Disease; Adolescent; Adult; Aged; Antimalarials; Artemether; Artemisinins; Artesunate; Biological Availability; Child; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Korea; Lumefantrine; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Parasitemia; Sesquiterpenes; Treatment Outcome

Uncomplicated malaria is effectively treated with oral artemisinin-based combination therapy (ACT). Yet, there is an unmet clinical need for the intravenous treatment of the more fatal severe malaria. There is no combination intravenous therapy for uncomplicated due to the nonavailability of a water-soluble partner drug for the artemisinin, artesunate. The currently available treatment is a two-part regimen split into an intravenous artesunate followed by the conventional oral ACT . In a novel application of polymer therapeutics, the aqueous insoluble antimalarial lumefantrine is conjugated to a carrier polymer to create a new water-soluble chemical entity suitable for intravenous administration in a clinically relevant formulation . The conjugate is characterized by spectroscopic and analytical techniques, and the aqueous solubility of lumefantrine is determined to have increased by three orders of magnitude. Pharmacokinetic studies in mice indicate that there is a significant plasma release of lumefantrine and production its metabolite desbutyl-lumefantrine (area under the curve of metabolite is ≈10% that of the parent). In a Plasmodium falciparum malaria mouse model, parasitemia clearance is 50% higher than that of reference unconjugated lumefantrine. The polymer-lumefantrine shows potential for entering the clinic to meet the need for a one-course combination treatment for severe malaria.

Topics: Administration, Intravenous; Animals; Antimalarials; Area Under Curve; Disease Models, Animal; Drug Combinations; Lumefantrine; Malaria; Male; Mice; Mice, Inbred BALB C; Parasitemia; Plasmodium falciparum; Polymers; Solubility; Water

Colombia began using artemisinin-based combination therapies for the treatment of uncomplicated Plasmodium falciparum malaria in 2006. It is necessary to implement resistance surveillance to antimalarial drugs in order to promptly detect changes in parasite susceptibility. The aim of this study was to establish a susceptibility baseline of P. falciparum to artemether-lumefantrine using three monitoring tools.. Patients with uncomplicated malaria treated with artemether-lumefantrine underwent clinical and parasitological follow-up over 28 days. Ex vivo test was performed using the microtest technique for chloroquine, arthemeter, dihydroartemisinin and lumefantrine. Pfmdr1 copy number and polymorphisms in Pfk13, Pfatp6, Pfcrt and Pfmdr1 genes were analyzed.. From a total of 150 screened patients, 49 completed follow-up for 28 days. All treated patients had adequate clinical and parasitological responses. Parasitic clearance showed a drastic reduction of parasite biomass at 24 hours and complete elimination at 48 hours. One hundred eleven isolates were processed, all exhibited high susceptibility to artemisinins and a slight decrease in susceptibility to lumefantrine. No genetic polymorphisms associated with resistance to artemisinin were found.. This study generated a susceptibility baseline in response to therapy with Coartem (artemether-lumefantrine) with numerical reference values, which will allow data comparison with future studies to systematically monitor changes in the parasite and to provide an early alert to the health authorities.

Topics: Adolescent; Adult; Aged; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Colombia; DNA Copy Number Variations; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Male; Middle Aged; Parasitemia; Plasmodium falciparum; Polymorphism, Genetic; Protozoan Proteins; Young Adult

Chemotherapy still is the most effective way to control malaria, a major public health problem in sub-Saharan Africa. The large-scale use of the combination therapy artemether-lumefantrine for malaria treatment in Africa predisposes lumefantrine to emergence of resistance. There is need to identify drugs that can be used as substitutes to lumefantrine for use in combination therapy. Methylene blue, a synthetic anti-methemoglobinemia drug, has been shown to contain antimalarial properties, making it a candidate for drug repurposing. The present study sought to determine antiplasmodial effects of methylene blue against lumefantrine- and pyrimethamine-resistant strains of P. berghei.. Activity of methylene blue was assessed using the classical four-day test on mice infected with lumefantrine-resistant and pyrimethamine-resistant P. berghei. A dose of 45 mg/kg/day was effective for testing ED90. Parasitemia and mice survival was determined.. At 45 mg/kg/day, methylene blue sustained significant parasite inhibition, over 99%, for at least 6 days post-treatment against lumefantrine-resistant and pyrimethamine-resistant P. berghei (p = 0.0086 and p = 0.0191, respectively). No serious adverse effects were observed.. Our results indicate that methylene blue at a concentration of 45 mg/kg/day confers over 99% inhibition against lumefantrine- and pyrimethamine-resistant P. berghei for six days. This shows the potential use methylene blue in the development of antimalarials against lumefantrine- and pyrimethamine-resistant parasites.

Topics: Animals; Antimalarials; Disease Models, Animal; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Ethanolamines; Female; Fluorenes; Lumefantrine; Malaria; Male; Methylene Blue; Mice; Parasitemia; Plasmodium berghei; Pyrimethamine; Survival Analysis; Treatment Outcome

The present investigation aims at formulating lipid based drug delivery system of β-Artemether and Lumefantrine and comparative pharmacological evaluation with innovator formulation. Commercial modified oil and indigenous natural fatty acids comprised the oily phase in developing lipidic formulation of β-Artemether and Lumefantrine. The developed system was characterized for mean globule size, stability by freeze thaw cycles, and birefringence. Developed formulation and innovator formulation were compared for their in vivo anti-malarial activity at different dose levels in male Swiss mice, infected with lethal ANKA strain of Plasmodium berghei. The percent parasitemia, activity against time and animal survival period were examined. On fourth day of antimalarial studies, at normal and ½ dose levels, formulations revealed zero percent parasitemia while control showed 33.92±6.00% parasitemia. At 1/10 dose level, developed and innovator formulations revealed zero percent parasitemia upto 11th day, however, three mice from innovator formulation demonstrated recrudescence after 12th day. Both the formulations at normal dose and ½ dose levels showed 100% activity and survival whereas at 1/10 dose level, innovator formulation showed, 62.5% survival. The developed lipidic system of β-Artemether and Lumefantrine exhibited excellent antimalarial activity with 100% survival.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Chemistry, Pharmaceutical; Disease Models, Animal; Ethanolamines; Fluorenes; Lipids; Lumefantrine; Malaria; Male; Mice; Parasitemia; Plasmodium berghei

Sixteen new anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in Plasmodium berghei infected mice. Of these 16 new anilides administered orally as one 6 mg/kg dose combined with 18 mg/kg mefloquine hydrochloride, only sulfide 3-arteSanilide 12d was completely curative: on day 30 after infection, all mice in this group had no detectable parasitemia, gained as much weight as the uninfected control mice, and behaved normally.

Topics: Administration, Oral; Anilides; Animals; Antimalarials; Drug Therapy, Combination; Malaria; Mefloquine; Mice; Parasitemia; Plasmodium berghei; Stereoisomerism; Structure-Activity Relationship; Sulfides; Sulfones; Sulfoxides

We report a successful treatment of severe falciparum malaria in a non-immune adult patient with 30% parasitemia treated with the 6-dose oral regimen of artemether plus lumefantrine combination therapy alone. We have also retrospectively searched our tertiary center's database for similar cases and we have found two additional severe malaria cases, resolved uneventfully with oral regimen. These cases might indicate a need to specifically address the definition of severe and complicated malaria in non-immune patients either in designated guidelines or as an explicit addition to the historical World Health Organization criteria.

Topics: Administration, Oral; Adult; Antimalarials; Artemether; Artemisinins; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Retrospective Studies; Treatment Outcome; World Health Organization; Young Adult

We describe a case of severe falciparum malaria with hyperparasitaemia. Treatment with automated erythrocytapheresis, in conjunction with parenteral artesunate, produced a rapid and sustained fall in parasite burden. Several poor prognostic features were present at admission. Despite the development of a severe headache with abnormal cerebrospinal fluid parameters and transient pulmonary oedema, a complete recovery was observed. Erythrocytapheresis can be considered in selected cases where facilities exist and has theoretical and practical advantages over traditional methods of red cell exchange transfusion. The paucity of systematic or trial evidence convincingly demonstrating a benefit in terms of morbidity or mortality has limited its application. However, the lack of robust trial data should not in itself invalidate considering this therapeutic option in the appropriate context.

Topics: Adult; Antimalarials; Artemether; Artemisinins; Artesunate; Australia; Automation; Blood Component Removal; Cambodia; Combined Modality Therapy; Drug Therapy, Combination; Erythrocyte Transfusion; Erythrocytes; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Parasitemia; Travel

The simian parasite Plasmodium knowlesi causes severe human malaria; the optimal treatment remains unknown. We describe the clinical features, disease spectrum, and response to antimalarial chemotherapy, including artemether-lumefantrine and artesunate, in patients with P. knowlesi malaria diagnosed by PCR during December 2007-November 2009 at a tertiary care hospital in Sabah, Malaysia. Fifty-six patients had PCR-confirmed P. knowlesi monoinfection and clinical records available for review. Twenty-two (39%) had severe malaria; of these, 6 (27%) died. Thirteen (59%) had respiratory distress; 12 (55%), acute renal failure; and 12, shock. None experienced coma. Patients with uncomplicated disease received chloroquine, quinine, or artemether-lumefantrine, and those with severe disease received intravenous quinine or artesunate. Parasite clearance times were 1-2 days shorter with either artemether-lumefantrine or artesunate treatment. P. knowlesi is a major cause of severe and fatal malaria in Sabah. Artemisinin derivatives rapidly clear parasitemia and are efficacious in treating uncomplicated and severe knowlesi malaria.

Topics: Acute Kidney Injury; Adult; Antimalarials; Artemether; Artemisinins; Artesunate; Chloroquine; Ethanolamines; Female; Fluorenes; Hospitals, Urban; Humans; Lumefantrine; Malaria; Malaysia; Microscopy; Middle Aged; Parasitemia; Patient Selection; Plasmodium knowlesi; Polymerase Chain Reaction; Quinine; Respiratory Distress Syndrome; Severity of Illness Index; Shock; Survival Rate

Amodiaquine retains efficacy against infection by chloroquine-resistant Plasmodium falciparum; however, little information is available on its efficacy against infection by chloroquine-resistant Plasmodium vivax. Patients presenting to a rural clinic with a pure P. vivax infection that recurred after recent antimalarial treatment were retreated, this time with amodiaquine monotherapy, and the risk of further recurrence within 4 weeks was assessed. Of the 87 patients with pure P. vivax infection, 15 patients did not complete a full course of treatment, 4 of whom were intolerant to treatment. In the 72 patients completing treatment, 91% (63 of 69) had cleared their parasitemia within 48 h with no early treatment failure. Follow-up to day 28 or recurrent parasitemia was achieved for 56 patients (78%). The cumulative incidence of treatment failure by day 28 was 22.8% (95% confidence interval, 7.3 to 38%). The in vitro sensitivity profile was determined for a separate set of isolates from outpatients with pure P. vivax infection. The median 50% inhibitory concentration of amodiaquine was 11.3 nM (range, 0.37 to 95.8) and was correlated significantly with that of chloroquine (Spearman rank correlation coefficient, 0.602; P < 0.001). Although amodiaquine results in a rapid clinical response, the risk of recurrence by day 28 is unacceptably high, reducing its suitability as an alternative treatment of infection by chloroquine-resistant P. vivax in this region.

Topics: Adolescent; Age Distribution; Amodiaquine; Animals; Antimalarials; Chloroquine; Confidence Intervals; Drug Resistance; Drug Tolerance; Female; Follow-Up Studies; Humans; Inhibitory Concentration 50; Male; Outpatients; Parasitemia; Plasmodium vivax; Prospective Studies; Recurrence; Rural Health; Time Factors; Treatment Failure; Treatment Outcome

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

The correct selection of individuals who will benefit from iron supplements in malaria-endemic regions requires improved insight in the effects of malaria on host iron homeostasis and innovative biomarkers. We assessed sequential changes in serum hepcidin and in traditional biochemical iron status indicators during an experimental Plasmodium falciparum malaria infection with five adult volunteers. The haemoglobin content of reticulocytes (Ret-H(e)) and of mature red blood cells (RBC-H(e)) represented iron incorporation into haemoglobin. Low-density parasitaemia and its treatment induced a mild increase in interleukin (IL)-6 and serum hepcidin concentrations. Despite this only mild increase, a marked hypoferraemia with a strong increase in serum ferritin concentrations developed, which was associated with a sharp fall in Ret-H(e), while RBC-H(e) remained unchanged. The ratio of soluble transferrin receptor (sTfR) to log ferritin concentrations decreased to an average nadir of 63% of the baseline value. We concluded that even mild increases in serum hepcidin and IL-6 concentrations result in a disturbed host iron homeostasis. Serum hepcidin, Ret-H(e) and Delta-H(e) (Ret-H(e) minus RBC-H(e)) are promising biomarkers to select those individuals who will benefit from iron supplements in malaria endemic regions, while the sTfR/log ferritin ratio should be used with caution to assess iron status during malaria.

Topics: Adult; Antimalarials; Antimicrobial Cationic Peptides; Artemether; Artemisinins; Biomarkers; C-Reactive Protein; Cell Count; Erythrocytes; Ethanolamines; Female; Ferritins; Fluorenes; Hemoglobins; Hepcidins; Homeostasis; Humans; Interleukin-6; Iron; Iron, Dietary; Linear Models; Lumefantrine; Malaria, Falciparum; Male; Parasitemia; Reticulocytes; Young Adult

A 20 year-old healthy female volunteer participated in a clinical Phase I and IIa safety and efficacy trial with candidate malaria vaccine PfLSA-3-rec adjuvanted with aluminium hydroxide. Eleven weeks after the third and last immunization she was experimentally infected by bites of Plasmodium falciparum-infected mosquitoes. When the thick blood smear became positive, at day 11, she was treated with artemether/lumefantrine according to protocol. On day 16 post-infection i.e. two days after completion of treatment, she woke up with retrosternal chest pain. She was diagnosed as acute coronary syndrome and treated accordingly. She recovered quickly and her follow-up was uneventful. Whether the event was related to the study procedures such as the preceding vaccinations, malaria infection or antimalarial drugs remains elusive. However, the relation in time with the experimental malaria infection and apparent absence of an underlying condition makes the infection the most probable trigger. This is in striking contrast, however, with the millions of malaria cases each year and the fact that such complication has never been reported in the literature. The rare occurrence of cardiac events with any of the preceding study procedures may even support a coincidental finding. Apart from acute coronary syndrome, myocarditis can be considered as a final diagnosis, but the true nature and patho-physiological explanation of the event remain unclear.

Topics: Acute Coronary Syndrome; Adult; Animals; Antimalarials; Artemether; Artemisinins; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Human Experimentation; Humans; Insect Bites and Stings; Lumefantrine; Malaria Vaccines; Malaria, Falciparum; Parasitemia; Plasmodium falciparum; Treatment Outcome; Vaccination

Within the context of increasing antimalarial costs and or decreasing malaria transmission, the importance of limiting antimalarial treatment to only those confirmed as having malaria parasites becomes paramount. This motivates for this assessment of the cost-effectiveness of routine use of rapid diagnostic tests (RDTs) as an integral part of deploying artemisinin-based combination therapies (ACTs).. The costs and cost-effectiveness of using RDTs to limit the use of ACTs to those who actually have Plasmodium falciparum parasitaemia in two districts in southern Mozambique were assessed. To evaluate the potential impact of introducing definitive diagnosis using RDTs (costing $0.95), five scenarios were considered, assuming that the use of definitive diagnosis would find that between 25% and 75% of the clinically diagnosed malaria patients are confirmed to be parasitaemic. The base analysis compared two ACTs, artesunate plus sulfadoxine/pyrimethamine (AS+SP) costing $1.77 per adult treatment and artemether-lumefantrine (AL) costing $2.40 per adult treatment, as well as the option of restricting RDT use to only those older than six years. Sensitivity analyses considered lower cost ACTs and RDTs and different population age distributions.. Compared to treating patients on the basis of clinical diagnosis, the use of RDTs in all clinically diagnosed malaria cases results in cost savings only when 29% and 52% or less of all suspected malaria cases test positive for malaria and are treated with AS+SP and AL, respectively. These cut-off points increase to 41.5% (for AS+SP) and to 74% (for AL) when the use of RDTs is restricted to only those older than six years of age. When 25% of clinically diagnosed patients are RDT positive and treated using AL, there are cost savings per malaria positive patient treated of up to $2.12. When more than 29% of clinically diagnosed cases are malaria test positive, the incremental cost per malaria positive patient treated is less than US$1. When relatively less expensive ACTs are introduced (e.g. current WHO preferential price for AL of $1.44 per adult treatment), the RDT price to the healthcare provider should be $0.65 or lower for RDTs to be cost saving in populations with between 30 and 52% of clinically diagnosed malaria cases being malaria test positive.. While the use of RDTs in all suspected cases has been shown to be cost-saving when parasite prevalence among clinically diagnosed malaria cases is low to moderate, findings show that targeting RDTs at the group older than six years and treating children less than six years on the basis of clinical diagnosis is even more cost-saving. In semi-immune populations, young children carry the highest risk of severe malaria and many healthcare providers would find it harder to deny antimalarials to those who test negative in this age group.

Topics: Adolescent; Animals; Artemisinins; Child; Child, Preschool; Cost-Benefit Analysis; Diagnostic Tests, Routine; Ethanolamines; Fluorenes; Health Policy; Humans; Infant; Lumefantrine; Malaria, Falciparum; Mozambique; Parasitemia; Plasmodium falciparum; Pyrimethamine; Sulfadoxine

Adequate malaria diagnosis and treatment remain major difficulties in rural sub-Saharan Africa. These issues deserve renewed attention in the light of first-line treatment with expensive artemisinin-combination therapy (ACT) and changing patterns of transmission intensity. This study describes diagnostic and treatment practices in Mto wa Mbu, an area that used to be hyperendemic for malaria, but where no recent assessments of transmission intensity have been conducted.. Retrospective and prospective data were collected from the two major village health clinics. The diagnosis in prospectively collected data was confirmed by microscopy. The level of transmission intensity was determined by entomological assessment and by estimating sero-conversion rates using anti-malarial antibody responses.. Malaria transmission intensity by serological assessment was equivalent to < 1 infectious bites per person per year. Despite low transmission intensity, > 40% of outpatients attending the clinics in 2006-2007 were diagnosed with malaria. Prospective data demonstrated a very high overdiagnosis of malaria. Microscopy was unreliable with < 1% of slides regarded as malaria parasite-positive by clinic microscopists being confirmed by trained research microscopists. In addition, many 'slide negatives' received anti-malarial treatment. As a result, 99.6% (248/249) of the individuals who were treated with ACT were in fact free of malaria parasites.. Transmission intensity has dropped considerably in the area of Mto wa Mbu. Despite this, most fevers are still regarded and treated as malaria, thereby ignoring true causes of febrile illness and over-prescribing ACT. The discrepancy between the perceived and actual level of transmission intensity may be present in many areas in sub-Saharan Africa and calls for greater efforts in defining levels of transmission on a local scale to help rational drug-prescribing behaviour.

Topics: Adolescent; Adult; Age Distribution; Animals; Anopheles; Antibodies, Protozoan; Artemisinins; Child; Child, Preschool; Drug Therapy, Combination; Endemic Diseases; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Male; Middle Aged; Parasitemia; Rain; Rural Health Services; Seroepidemiologic Studies; Tanzania; Young Adult

Artemisinin-containing therapies are highly effective against Plasmodium falciparum malaria. Insufficient numbers of tablets and inadequate package inserts result in sub-optimal dosing and possible treatment failure. This study reports the case of three, non-immune, expatriate workers with P. falciparum acquired in Africa, who failed to respond to artemisinin-based therapy. Sub-therapeutic dosing in accordance with the manufacturers' recommendations was the probable cause.. Manufacturers information and drug content included in twenty-five artemisinin-containing specialities were reviewed.. A substantial number of manufacturers do not follow current WHO recommendations regarding treatment duration and doses.. This study shows that drug packaging and their inserts should be improved.

Topics: Adult; Antimalarials; Artemether; Artemisinins; Artesunate; Cote d'Ivoire; Dose-Response Relationship, Drug; Drug Labeling; Ethanolamines; Female; Fluorenes; Guidelines as Topic; Guinea; Humans; Lactones; Lumefantrine; Malaria, Falciparum; Parasitemia; Recurrence; Risk; Sesquiterpenes; Sudan; Switzerland; Treatment Failure; World Health Organization