lumefantrine and Malaria--Vivax

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

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

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

Artemisinin combination therapy is recommended as treatment for uncomplicated Plasmodium falciparum (Pf) malaria, whereas chloroquine is still widely used for non-Pf infections. A common treatment for both vivax and falciparum malaria would be welcome.. A longitudinal prospective effectiveness study of 1682 children aged 3-27 months in outpatient clinics in Papua New Guinea. The main outcome was clinical treatment failure rate following treatment with artemether/lumefantrine (AL).. Among 5670 febrile episodes, 1682 (28%) had positive rapid diagnostic test (RDT) results and were treated with AL. A total of 1261 (22%) had an infection confirmed by blood slide examination. Of these, 594 Pv and 332 Pf clinical malaria cases were included in the primary effectiveness analysis. Clinical treatment failure rates at 7, 28, and 42 days were 0.2%, 2.2%, and 12.0%, respectively, for Pv and 0.3%, 1.2%, and 3.6%, respectively, for Pf. A single malaria-unrelated death occurred within 42 days following treatment with AL, in a child who was aparasitemic by blood slide at reattendance.. AL provides a rapid clinical response against both Pf and Pv malaria, but is associated with a high rate of Pv recurrent clinical episodes between days 28 and 42. In order to prevent relapsing infections from long-lasting hypnozoites, AL should ideally be complemented with a course of primaquine. In the absence of better treatment and diagnostic options, the use of AL in young children in routine practice is an acceptable, interim option in coendemic areas where Pv is resistant to chloroquine and specific treatment for Pv hypnozoites not feasible.

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Child, Preschool; Ethanolamines; Fluorenes; Humans; Infant; Kaplan-Meier Estimate; Lumefantrine; Malaria, Falciparum; Malaria, Vivax; Papua New Guinea; Prospective Studies; Treatment Outcome

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

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

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

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 acquisition of resistance to chloroquine by Plasmodium vivax in parts of the Australasian and Malaysian epidemiological zones and hitherto unconfirmed reports of such resistance in neighbouring zones show the need for monitoring the drug response of P. vivax. In this study, a recently developed in-vitro micro-technique for the assessment of the parasite's sensitivity to chloroquine was adapted to and validated for lumefantrine. In 21 P. vivax isolates tested at Mae Hong Son, northwestern Thailand, in 2001, the mean geometric cut-off concentration for full inhibition for lumefantrine was 2080 nM. The EC50 and EC90 were 12 nM and 237 nM, respectively. The response was well within the putative therapeutic range. Sensitivity to chloroquine was assessed in 18 P. vivax isolates, showing a geometric mean cut-off concentration of 1095 nM and a wider variation of the individual cut-off points compared with lumefantrine. The EC50 and EC90 for chloroquine were 16 nM and 511 nM, respectively. One of the isolates, from Myanmar, showed low sensitivity to chloroquine.

Topics: Adolescent; Adult; Animals; Antimalarials; Cell Proliferation; Child; Child, Preschool; Chloroquine; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation; Ethanolamines; Female; Fluorenes; Humans; Lethal Dose 50; Lumefantrine; Malaria, Vivax; Male; Middle Aged; Parasitic Sensitivity Tests; Plasmodium vivax; Species Specificity; Thailand; Treatment Outcome

Plasmodium Vivax malaria is generally considered as a benign self-limiting illness and is less often associated with more severe disease and complications. Amongst these, acute respiratory distress syndrome (ARDS) is a particularly rare complication. The few cases reported describe the onset of ARDS after initiation of anti-malarial therapy as a post inflammatory response. Here we report the case of a 45 year old male who was a victim of severe Plasmodium vivax malaria culminating into ARDS, prior to the initiation of anti-malarial therapy. He was treated with invasive ventilation and anti-malarial therapy and made a complete and uneventful recovery.

Topics: Adult; Antimalarials; Artemether; Artemisinins; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria, Vivax; Male; Radiography, Thoracic; Respiration, Artificial; Respiratory Distress Syndrome

Quantitative magnetic fractionation and a published mathematical model were used to characterize between-treatment differences in gametocyte density and prevalence in 70 Papua New Guinean children with uncomplicated Plasmodium falciparum and/or Plasmodium vivax malaria randomized to one of two artemisinin combination therapies (artemether-lumefantrine or artemisinin-naphthoquine) in an intervention trial. There was an initial rise in peripheral P. falciparum gametocyte density with both treatments, but it was more pronounced in the artemisinin-naphthoquine group. Model-derived estimates of the median pretreatment sequestered gametocyte population were 21/μl for artemether-lumefantrine and 61/μl for artemisinin-naphthoquine (P < 0.001). The median time for P. falciparum gametocyte density to fall to <2.5/μl (below which transmission becomes unlikely) was 16 days in the artemether-lumefantrine group and 20 days in artemisinin-naphthoquine group (P < 0.001). Gametocyte prevalence modeling suggested that artemisinin-naphthoquine-treated children became gametocytemic faster (median, 2.2 days) than artemether-lumefantrine-treated children (median, 5.3 days; P < 0.001) and had a longer median P. falciparum gametocyte carriage time per individual (20 versus 13 days; P < 0.001). Clearance of P. vivax gametocytes was rapid (within 3 days) in both groups; however, consistent with the reappearance of asexual forms in the main trial, nearly 40% of children in the artemether-lumefantrine group developed P. vivax gametocytemia between days 28 and 42 compared with 3% of children in the artemisinin-naphthoquine group. These data suggest that artemisinin is less active than artemether against sequestered gametocytes. Greater initial gametocyte release after artemisinin-naphthoquine increases the period of potential P. falciparum transmission by 4 days relative to artemether-lumefantrine, but the longer elimination half-life of naphthoquine than of lumefantrine suppresses P. vivax recurrence and consequent gametocytemia.

Topics: Antimalarials; Artemether; Artemisinins; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Half-Life; Humans; Kinetics; Lumefantrine; Malaria, Falciparum; Malaria, Vivax; Male; Naphthoquinones; Plasmodium falciparum

Topics: Antimalarials; Artemether; Artemisinins; Artesunate; Biopsy, Needle; Bone Marrow; Child; Ethanolamines; Female; Fluorenes; Humans; India; Liver Function Tests; Lumefantrine; Lymphohistiocytosis, Hemophagocytic; Malaria, Vivax; Plasmodium vivax; Primaquine; Schizonts; Treatment Outcome

The occurrence of chloroquine resistance in Plasmodium vivax underlines the need for monitoring the drug response of this important malaria parasite and for the evaluation of alternative therapeutic agents. In-vitro methods facilitate these tasks. This investigation employed a recently developed in-vitro micro-technique and validated it for lumefantrine and desbutyl-benflumetol, a compound that was initially considered a metabolite of lumefantrine. The studies were conducted in 2001 at Mae Sot, a town situated in northwestern Thailand near the border to Myanmar. Parallel in-vitro tests with lumefantrine and desbutyl-benflumetol were carried out with 53 fresh isolates of P. vivax. For both compounds, the parasite showed a homogenous, log-normal inhibition pattern with nearly parallel log-probit regressions. The geometric mean drug concentrations effecting complete growth inhibition were 2361 nM for lumefantrine and 187 nM for desbutyl-benflumetol. With p=3.264 x 10(-18) the difference was highly significant. The EC50 and EC90 values for lumefantrine, 17.6 nM and 448.5 nM, respectively, were much higher as compared to those determined for desbutyl-benflumetol, with 1.5 nM and 39.7 nM. This difference expressed itself in a highly significant Power Ratio (PR) of 11.0. The activity of desbutyl-benflumetol in P. vivax exceeds that of lumefantrine by one order of magnitude, suggesting a high, hitherto unexploited therapeutic potential of desbutyl-benflumetol.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Chi-Square Distribution; Child; Confidence Intervals; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Vivax; Male; Middle Aged; Plasmodium vivax; Thailand

To observe the efficacy of artemether compound against vivax malaria.. Each artemether compound tablet contains 120 mg benflumetolum and 20 mg artemether. 132 patients with vivax malaria were divided into 3 groups. Group A, 36 patients received 8 tablets as an initial dose, followed by 4 tablets daily for 2 days; group B, 41 patients received 8 tablets as an initial dose, followed by 3 tablets daily for 4 days; group C, 55 patients receiving chloroguine-primaquine served as control. Two patients of group A were voluntarily to be bitten by Anopheles dirus before and after medication to observe the influence of artemether compound on the sporogony.. The average defervescence times for groups A, B and C were 22.3 h, 23.2 h and 25.0 h (P > 0.05), respectively, the average parasite clearance times were 33.5 h, 30.5 h and 44.9 h, respectively, the average parasite clearance times of groups A and B were all significantly shorter than that of group C (P < 0.01). The replase rates of groups A, B and C were 84.9%, 78.8% and 22.9%, respectively, followed-up at nine months, the relapse rates of groups A and B were higher than that of group C(P < 0.01).. Two regimens of artemether compound have the advantage of high efficacy against vivax malaria.

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Lumefantrine; Malaria, Vivax; Male; Middle Aged; Recurrence; Sesquiterpenes