lumefantrine and Malaria

Discovery and development of antimalarial drugs have long been dominated by single-target therapy. Continuous effort has been made to explore and identify different targets in malaria parasite crucial for the malaria treatment. The single-target drug therapy was initially successful, but it was later supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has warranted a review of current antimalarial pharmacotherapy. This has led to the development of the new concept of covalent biotherapy, in which two or more pharmacophores are chemically bound to produce hybrid antimalarial drugs with multi-target functionalities. Herein, the review initially details the current pharmacotherapy for malaria as well as the conventional and novel targets of importance identified in the malaria parasite. Then, the rationale of multi-targeted therapy for malaria, approaches taken to develop the multi-target antimalarial hybrids, and the examples of hybrid molecules are comprehensively enumerated and discussed.

Topics: Animals; Antimalarials; Artemisinins; Drug Discovery; Drug Resistance; Humans; Malaria; Molecular Structure; Paclitaxel; Quinolines

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antimalarials; Antiretroviral Therapy, Highly Active; Artemether, Lumefantrine Drug Combination; Body Weight; Computer Simulation; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Lumefantrine; Malaria; Male; Middle Aged; Monte Carlo Method; Ritonavir; Young Adult

The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.

Topics: Aminoquinolines; Antimalarials; Artemisinins; Drug Discovery; Drug Resistance, Multiple; Ferrous Compounds; Humans; Imidazoles; Lumefantrine; Malaria; Metallocenes; Piperazines; Signal Transduction; Treatment Outcome

Ganaplacide (previously known as KAF156) is a novel antimalarial compound part of the imidazolopiperazine family.. At the time of writing, a total of eight studies addressing its preclinical and clinical development have been published on this compound, which is currently in phase 2 of clinical development, alongside lumefantrine in a novel soluble formulation as combination partner. This review provides an overview and interpretation of the published pre-clinical and clinical data of this possible next-generation antimalarial drug.. In the search for a 'magic bullet' in malaria therapy and prophylaxis facilitating single encounter radical cure and prophylaxis, ganaplacide demonstrates some promising properties toward this ultimate goal. The available data suggest that ganaplacide exerts multi-stage antimalarial activity, and that its pharmacokinetic profile potentially allows for a simplified dosing regimen compared to that of existing antimalarial drug combinations. The first in-patient results demonstrate promising single-dose antimalarial activity, and no serious in-human safety and tolerability concerns have been reported to date.

Topics: Animals; Antimalarials; Drug Administration Schedule; Drug Design; Drug Therapy, Combination; Ethanolamines; Fluorenes; Humans; Imidazoles; Lumefantrine; Malaria; Piperazines

This digest covers some of the most relevant progress in malaria drug discovery published between 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug discovery efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria.

Topics: Animals; Antimalarials; Drug Discovery; Humans; Liver; Liver Transplantation; Malaria; Molecular Structure

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

Topics: Antimalarials; Asia, Southeastern; Chloroquine; Drug Resistance; Drug Tolerance; Ethanolamines; Fluorenes; Genotype; Humans; Lumefantrine; Malaria; Parasitic Sensitivity Tests; Plasmodium

Malaria is a serious parasitic infection, which affects millions of people worldwide. As pregnancy has been shown to alter the pharmacokinetics of many medications, the efficacy and safety of antimalarial drug regimens may be compromised in pregnant women. The objective of this review is to systematically review published literature on the pharmacokinetics of antimalarial agents in pregnant women. A search of MEDLINE (1948-May 2011), EMBASE (1980-May 2011), International Pharmaceutical Abstracts (1970-May 2011), Google and Google Scholar was conducted for articles describing the pharmacokinetics of antimalarials in pregnancy (and supplemented by a bibliographic review of all relevant articles); all identified studies were summarized and evaluated according to the level of evidence, based on the classification system developed by the US Preventive Services Task Force. Identified articles were included in the review if the study had at least one group that reported at least one pharmacokinetic parameter of interest in pregnant women. Articles were excluded from the review if no pharmacokinetic information was reported or if both pregnant and non-pregnant women were analysed within the same group. For quinine and its metabolites, there were three articles (one level II-1 and two level III); for artemisinin compounds, two articles (both level III); for lumefantrine, two articles (both level III); for atovaquone, two articles (both level III); for proguanil, three articles (one level II-1 and two level III); for sulfadoxine, three articles (all level II-1); for pyrimethamine, three articles (all level II-1); for chloroquine and its metabolite, four articles (three level II-1 and one level II-3); for mefloquine, two articles (one level II-1 and one level III); and for azithromycin, two articles (one level II-1 and one level III). Although comparative trials were identified, most of these studies were descriptive and classified as level III evidence. The main findings showed that pharmacokinetic parameters are commonly altered in pregnancy for the majority of recommended agents. Importantly, first-line regimens of artemisinin-based compounds, lumefantrine, chloroquine and pyrimethamine/sulfadoxine may undergo significant changes that could decrease therapeutic efficacy. These changes are usually due to increases in the apparent oral clearance and volume of distribution that commonly occur in pregnant women, and may result in decreased exposure and increased ther

Topics: Anti-Bacterial Agents; Antimalarials; Artemisinins; Atovaquone; Chloroquine; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Mefloquine; Pregnancy; Pregnancy Complications, Parasitic; Proguanil; Pyrimethamine; Quinine; Sulfadoxine

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

Topics: Adult; Antimalarials; Artemether; Artemisinins; Atovaquone; Chloroquine; Climate; Doxycycline; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Male; Mefloquine; Naphthoquinones; Pregnancy; Proguanil; Risk Factors; Self Medication; Sesquiterpenes; Time Factors; Travel

Three new antimalarial drugs have recently been registered in the Netherlands: atovaquone-proguanil, artemether-lumefantrine and artemotil. These drugs are effective against parasites with multiple resistance. Atovaquone-proguanil and artemether-lumefantrine seem in practice to be equivalent for the treatment of non-severe Plasmodium falciparum infections for respectively persons of more than 11 kg and persons aged 12 years and older (35 kg). Artemotil (intramuscular injection) is registered for the treatment of severe malaria in children up to 17 years of age. Atovaquone-proguanil is also registered for prophylactic use in adults. The intravenous administration of quinine is preferable in the case of seriously ill patients. In patients with non-severe malaria for whom parenteral treatment is indicated, artemotil is a good alternative for quinine.

Topics: Antimalarials; Artemether; Artemisinins; Atovaquone; Drug Approval; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Naphthoquinones; Netherlands; Proguanil; Sesquiterpenes; Treatment Outcome

Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.

Topics: Aminoquinolines; Animals; Antimalarials; Artemisinins; Artesunate; Atovaquone; Clinical Trials as Topic; Dapsone; Drug Combinations; Drug Design; Drug Resistance; Ethanolamines; Flavonoids; Fluorenes; Fosfomycin; Global Health; Humans; Lumefantrine; Malaria; Naphthoquinones; Naphthyridines; Plasmodium falciparum; Proguanil; Sesquiterpenes

The combination of artemether and lumefantrine (benflumetol) is a new and very well tolerated oral antimalarial drug effective even against multidrug-resistant falciparum malaria. The artemether component is absorbed rapidly and biotransformed to dihydroartemisinin, and both are eliminated with terminal half-lives of around 1 hour. These are very active antimalarials which give a rapid reduction in parasite biomass and consequent rapid resolution of symptoms. The lumefantrine component is absorbed variably in malaria, and is eliminated more slowly (half-life of 3 to 6 days). Absorption is very dependent on coadministration with fat, and so improves markedly with recovery from malaria. Thus artemether clears most of the infection, and the lumefantrine concentrations that remain at the end of the 3- to 5-day treatment course are responsible for eliminating the residual 100 to 10 000 parasites. The area under the curve of plasma lumefantrine concentrations versus time, or its correlate the plasma concentration on day 7. has proved an important determinant of therapeutic response. Characterisation of these pharmacokinetic-pharmacodynamic relationships provided the basis for dosage optimisation, an approach that could be applied to other antimalarial drugs.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Clinical Trials as Topic; Drug Combinations; Drug Resistance, Microbial; Drug Resistance, Multiple; Ethanolamines; Fluorenes; Food-Drug Interactions; Humans; Lumefantrine; Malaria; Plasmodium falciparum; Sesquiterpenes

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

Malaria in the eastern Greater Mekong subregion has declined to historic lows. Countries in the Greater Mekong subregion are accelerating malaria elimination in the context of increasing antimalarial drug resistance. Infections are now increasingly concentrated in remote, forested foci. No intervention has yet shown satisfactory efficacy against forest-acquired malaria. The aim of this study was to assess the efficacy of malaria chemoprophylaxis among forest goers in Cambodia.. We conducted an open-label, individually randomised controlled trial in Cambodia, which recruited participants aged 16-65 years staying overnight in forests. Participants were randomly allocated 1:1 to antimalarial chemoprophylaxis, a 3-day course of twice-daily artemether-lumefantrine followed by the same daily dosing once a week while travelling in the forest and for a further 4 weeks after leaving the forest (four tablets per dose; 20 mg of artemether and 120 mg of lumefantrine per tablet), or a multivitamin with no antimalarial activity. Allocations were done according to a computer-generated randomisation schedule, and randomisation was in permuted blocks of size ten and stratified by village. Investigators and participants were not masked to drug allocation, but laboratory investigations were done without knowledge of allocation. The primary outcome was a composite endpoint of either clinical malaria with any Plasmodium species within 1-28, 29-56, or 57-84 days, or subclinical infection detected by PCR on days 28, 56, or 84 using complete-case analysis of the intention-to-treat population. Adherence to study drug was assessed primarily by self-reporting during follow-up visits. Adverse events were assessed in the intention-to-treat population as a secondary endpoint from self-reporting at any time, plus a physical examination and symptom questionnaire at follow-up. This trial is registered at ClinicalTrials.gov (NCT04041973) and is complete.. Between March 11 and Nov 20, 2020, 1480 individuals were enrolled, of whom 738 were randomly assigned to artemether-lumefantrine and 742 to the multivitamin. 713 participants in the artemether-lumefantrine group and 714 in the multivitamin group had a PCR result or confirmed clinical malaria by rapid diagnostic test during follow-up. During follow-up, 19 (3%, 95% CI 2-4) of 713 participants had parasitaemia or clinical malaria in the artemether-lumefantrine group and 123 (17%, 15-20) of 714 in the multivitamin group (absolute risk difference 15%, 95% CI 12-18; p<0·0001). During follow-up, there were 166 malaria episodes caused by Plasmodium vivax, 14 by Plasmodium falciparum, and five with other or mixed species infections. The numbers of participants with P vivax were 18 (3%, 95% CI 2-4) in the artemether-lumefantrine group versus 112 (16%, 13-19) in the multivitamin group (absolute risk difference 13%, 95% CI 10-16; p<0·0001). The numbers of participants with P falciparum were two (0·3%, 95% CI 0·03-1·01) in the artemether-lumefantrine group versus 12 (1·7%, 0·9-2·9) in the multivitamin group (absolute risk difference 1·4%, 95% CI 0·4-2·4; p=0·013). Overall reported adherence to the full course of medication was 97% (95% CI 96-98; 1797 completed courses out of 1854 courses started) in the artemether-lumefantrine group and 98% (97-98; 1842 completed courses in 1885 courses started) in the multivitamin group. Overall prevalence of adverse events was 1·9% (355 events in 18 806 doses) in the artemether-lumefantrine group and 1·1% (207 events in 19 132 doses) in the multivitamin group (p<0·0001).. Antimalarial chemoprophylaxis with artemether-lumefantrine was acceptable and well tolerated and substantially reduced the risk of malaria. Malaria chemoprophylaxis among high-risk groups such as forest workers could be a valuable tool for accelerating elimination in the Greater Mekong subregion.. The Global Fund to Fight AIDS, Tuberculosis and Malaria; Wellcome Trust.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Cambodia; Chemoprevention; Drug Combinations; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum

When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response.. Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm. 411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77-86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92-97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52-7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48-231]) than participants who experienced ACPR (190 ng/ml [95% CI 101-378], p-value < 0.008).. Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Fluorenes; HIV Infections; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Malawi; Treatment Outcome

Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria.. This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150 000 parasites per μL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020-003284-25) and ClinicalTrials.gov (NCT03167242).. Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81-98] with 1 day, 47 of 48 [98%, 89-100] with 2 days, and 42 of 43 [98%, 88-100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83-99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93-100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92-100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86-100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83-99] vs 21 of 22 [96%, 77-100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study.. Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633).. Novartis and Medicines for Malaria Venture.

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Child; Drug Combinations; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Plasmodium falciparum; Treatment Outcome

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

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

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

Most patients with suspected malaria do not receive diagnostic confirmation before beginning antimalarial treatment. We investigated the extent to which uncertainty about malaria diagnosis contributes to patient nonadherence to artemether-lumefantrine (AL) treatment through a randomized controlled trial in central Uganda. Among 1,525 patients purchasing a course of AL at private drug shops, we randomly offered 37.6% a free malaria rapid diagnostic test (RDT) and then assessed adherence through home visits 3 days later. Of these subjects, 68.4% tested positive for malaria and 65.8% adhered overall. Patients who tested positive did not have significantly higher odds of adherence than those who were not offered the test (adjusted odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.734-1.57,P= 0.719). Patients who received a positive malaria test had 0.488 fewer pills remaining than those not offered the test (95% CI: -1.02 to 0.043,P= 0.072). We found that patients who felt relatively healthy by the second day of treatment had lower odds of completing treatment (adjusted OR: 0.532, 95% CI: 0.394-0.719,P< 0.001). Our results suggest that diagnostic testing may not improve artemisinin-based combination therapy adherence unless efforts are made to persuade patients to continue taking the full course of drugs even if symptoms have resolved.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Male; Medication Adherence; Point-of-Care Testing; Uganda

To evaluate the comparative efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and artesunate-amodiaquine-chlorpheniramine (AQC) for the treatment of acute uncomplicated malaria among Southwest Nigerian children.. One hundred and sixty children aged 6 months to 14 years with acute uncomplicated malaria were randomized to AL (n = 53), ASAQ (n = 53), or AQC (n = 54). Enrollees were seen daily on days 0-3 and then on days 7, 14, 21, 28 and 42 for clinical and parasitological evaluations. Paired samples of genomic DNA at enrolment and at the time of recurrent parasitaemia were genotyped using nested PCR to distinguish between reinfection and recrudescence. Detailed haematological and biochemical evaluations were carried out in a subset of enrollees on days 0, 7 and 28 as part of a safety evaluation.. Of the 160 children, 144 (90%) completed the study. The mean fever clearance times and parasite clearance times for AL, ASAQ and AQC were comparable (p = 0.94 and p = 0.122, respectively). On day 14, the adequate clinical and parasitological response (ACPR) for AL and AQC was 100% and for ASAQ it was 90% (p = 0.39). The PCR-uncorrected results on days 28 and 42 and the ACPR-corrected results on day 42 were similar for all drugs (p = 0.62 and p = 0.56, respectively). AQC resulted in the best parasite clearance and haematological recovery on day 2 (p = 0.022 and p = 0.018, respectively). Biochemical parameters were not adversely affected by the three artemisinin-based combination therapies (ACTs) and these were well tolerated.. The three ACTs were efficacious and safe, but AQC resulted in a better haematological recovery on day 2 and higher cure rates throughout the study period.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Chlorpheniramine; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Genome, Protozoan; Humans; Infant; Lumefantrine; Malaria; Male; Nigeria; Polymerase Chain Reaction

Artemisinin combination therapies are available in private outlets, but patient adherence might be compromised by poor advice from dispensers. In this cluster randomized trial in drug shops in Tanzania, 42 of 82 selected shops were randomized to receive text message reminders about what advice to provide when dispensing artemether-lumefantrine (AL). Eligible patients purchasing AL at shops in both arms were followed up at home and questioned about each dose taken. Dispensers were interviewed regarding knowledge of AL dispensing practices and receipt of the malaria-related text messages. We interviewed 904 patients and 110 dispensers from 77 shops. Although there was some improvement in dispenser knowledge, there was no difference between arms in adherence measured as completion of all doses (intervention 68.3%, control 69.8%, p [adjusted] = 0.6), or as completion of each dose at the correct time (intervention 33.1%, control 32.6%, p [adjusted] = 0.9). Further studies on the potential of text messages to improve adherence are needed.

Topics: Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Commerce; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Infant; Lumefantrine; Malaria; Male; Patient Compliance; Plasmodium; Tanzania; Text Messaging

Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine.. This single-centre, randomized, two-way, two-period cross-over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3-day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3-day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given.. Overall, 28 of the 33 volunteers completed the study. Co-administration of etravirine reduced the area under the plasma concentration-time curve (AUC) of artemether [by 38%; 90% confidence interval (CI) 0.48-0.80], dihydroartemisinin (by 15%; 90% CI 0.75-0.97) and lumefantrine (by 13%; 90% CI 0.77-0.98) at steady state. Co-administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69-1.02) and dihydroartemisinin (by 18%; 90% CI 0.74-0.91) but increased lumefantrine (2.75-fold; 90% CI 2.46-3.08) at steady state. Co-administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug-related serious adverse events were reported during the study.. Co-administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co-administered with artemether/lumefantrine without dose adjustment but should be used with caution.

Topics: Adult; Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; Cross-Over Studies; Darunavir; Drug Interactions; Ethanolamines; Fluorenes; Healthy Volunteers; HIV; HIV Infections; Humans; Lumefantrine; Malaria; Middle Aged; Nitriles; Pyridazines; Pyrimidines; Ritonavir; Sulfonamides

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.

Topics: Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Male

Combination therapies are now recommended to treat uncomplicated malaria. We used a longitudinal design to assess the incidence of malaria and compare the efficacies of 3 combination regimens in Kampala, Uganda.. Children aged 1-10 years were enrolled from randomly selected households in 2004-05 and 2007, and were followed at least monthly through 2008. Insecticide-treated bednets (ITNs) were provided in 2006. Children were randomized upon their first episode, and then treated for all episodes of uncomplicated malaria with amodiaquine/sulfadoxine-pyrimethamine (AQ/SP), artesunate/amodiaquine (AS/AQ), or artemether/lumefantrine (AL). Risks of parasitological failure were determined for each episode of uncomplicated malaria and clinical parameters were followed. A total of 690 children experienced 1464 episodes of malaria. 96% of these episodes were uncomplicated malaria and treated with study drugs; 94% were due to Plasmodium falciparum. The rank order of treatment efficacy was AL > AS/AQ > AQ/SP. Failure rates increased over time for AQ/SP, but not the artemisinin-based regimens. Over the 4-year course of the study the prevalence of asymptomatic parasitemia decreased from 11.8% to 1.4%, the incidence of malaria decreased from 1.55 to 0.32 per person year, and the prevalence of anemia (hemoglobin <10 gm/dL) decreased from 5.9% to 1.0%. No episodes of severe malaria (based on WHO criteria) and no deaths were seen.. With ready access to combination therapies and distribution of ITNs, responses were excellent for artemisinin-containing regimens, severe malaria was not seen, and the incidence of malaria and prevalence of parasitemia and anemia decreased steadily over time.. isrctn.org ISRCTN37517549.

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Artesunate; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Incidence; Infant; Lumefantrine; Malaria; Male; Pyrimethamine; Sulfadoxine; Treatment Outcome; Uganda

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

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

We enrolled 382 patients at two hospitals in Uganda in a prospective observational study of severe sepsis. Because artemisinins improve survival in murine sepsis models, we performed a post hoc analysis of the association between the use of artemether-lumefantrine (A-L) and mortality in patients with or without malaria. In patients with negative malaria smears (N = 328 of 379), Kaplan-Meier curves revealed decreased combined inpatient and 30-day mortality among patients receiving A-L versus those who did not (20.6%, SE = 10.6 versus 48.8%, SE = 3.2; Log rank chi(2) = 3.93, P = 0.048). The decrease in mortality associated with A-L was maintained in the most clinically ill patients determined by Karnofsky Performance Scores

Topics: Adult; Anti-Infective Agents; Artemether; Artemisinins; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Male; Middle Aged; Prospective Studies; Sepsis; Uganda; Young Adult

Acute febrile illness is the most common cause of outpatient attendance and mortality for children in Africa. Malaria and bacterial disease are difficult to differentiate with limited diagnostic facilities. Combinations of antibiotics and antimalarials are potentially attractive for treatment of the syndrome. Azithromycin plus artesunate (AT+AS) is an effective antimalarial combination for adults in Asia.. We performed an individually randomized, open-label trial of AZ+AS versus artemether-lumefantrine (AL) involving children (age, 6-59 months) with uncomplicated malaria in Muheza, Tanzania. The primary outcome was parasitological failure by day 28. Parasitological failure by day 42 and failure corrected for reinfection were major secondary outcomes.. Of 2497 children screened, 261 were eligible; 129 were randomized to the AZ+AS arm, and 132 were randomized to the AL arm; 92% and 91%, respectively, underwent follow-up to 28 days. Planned interim analysis was performed after 200 patients reached day 28 follow-up and led the Data and Safety Monitoring Board to halt further recruitment. All children had a complete initial response to treatment, but 69 (58%) of 119 children in the AZ+AS arm and 24 (20%) of 120 in the AL arm had asexual parasites at or by day 28 (adjusted odds ratio for failure with AZ+AS treatment, 6.1; 95% confidence interval, 3.3-11.4; P < .001). When analysis was restricted to children with recrudescence, the parasitological failure rate was 32% in the AZ+AS arm and 9% in the AL arm. This difference was maintained at day 42.. This trial does not support the use of AZ+AS as treatment for malaria or acute febrile illness in children in areas of Africa with high levels of existing antimalarial drug resistance.. ClinicalTrials.gov NCT00694694.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Artesunate; Azithromycin; Child, Preschool; Drug Therapy, Combination; Ethanolamines; Female; Fever of Unknown Origin; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Male; Tanzania; Treatment Outcome

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

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

Artesunate+amodiaquine (AS+AQ) and artemether-lumefantrine (AL) are now the most frequently recommended first line treatments for uncomplicated malaria in Africa. Artesunate+chlorproguanil-dapsone (AS+CD) was a potential alternative for treatment of uncomplicated malaria. A comparison of the efficacy and safety of these three drug combinations was necessary to make evidence based drug treatment policies.. Five hundred and thirty-four, glucose-6-phosphate dehydrogenase (G6PD) normal children were randomised in blocks of 15 to the AS+AQ, AL or AS+CD groups. Administration of study drugs was supervised by project staff and the children were followed up at r home on days 1,2,3,7,14 and 28 post treatment. Parasitological and clinical failures and adverse events were compared between the study groups.. In a per-protocol analysis, the parasitological and clinical failure rate at day 28 post treatment (PCF28) was lower in the AS+AQ group compared to the AL or AS+CD groups (corrected for re-infections: 6.6% vs 13.8% and 13.8% respectively, p = 0.08; uncorrected: 14.6% vs 27.6% and 28.1% respectively, p = 0.005). In the intention to treat analysis, the rate of early treatment failure was high in all three groups (AS+AQ 13.3%; AL 15.2%; and AS+CD 9.3%, p = 0.2) primarily due to vomiting. However, the PCF28 corrected for re-infection was lower, though not significantly, in the AS+AQ group compared to the AL or the AS+CD groups (AS+AQ 18.3%; AL 24.2%; AS+CD 20.8%, p = 0.4) The incidence of adverse events was comparable between the groups.. AS+AQ is an appropriate first line treatment for uncomplicated malaria in Ghana and possibly in the neighbouring countries in West Africa. The effectiveness of AL in routine programme conditions needs to be studied further in West Africa.. ClinicalTrials.gov NCT00119145.

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Artesunate; Child; Child, Preschool; Dapsone; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Male; Polymerase Chain Reaction; Proguanil; Treatment Outcome

To investigate the pharmacokinetic and pharmacodynamic properties of artemether and benflumetol in a fixed combination tablet (CGP 56697) and to offer an explanation for the lower than expected cure rate in a Thai clinical trial.. Two hundred and sixty patients were enrolled into a randomized, double-blind, parallel group, dose-finding trial. CGP 56697 was given orally, either as: A, 4 x 4 tablets over 48 h; B, 4 x 2 tablets over 48 h or C, 3 x 4 tablets over 24 h. Each tablet contained artemether 20 mg amd benflumetol 120 mg. The pharmacokinetics were determined using a population-based approach combining full profiles (42 patients) and sparse data (218 patients). Parasite clearance time and 28 day cure rate were correlated with the derived pharmacokinetic parameters.. The median absorption half-life of benflumetol was 5.3 h, with a tmax of 10 h and terminal elimination half-life of 4.5 days. For artemether (and its metabolite, dihydroartemisinin), the corresponding values were 1.9 (1.9) h, 1.8 (1.2) h, and 0.84 (0.43) h. The variability in bioavailability of artemether and dihydroartemisinin was large both between doses and between patients, but was less pronounced for benflumetol. Compared with the first dose, benflumetol bioavailability was estimated to increase three-fold by the third and fourth doses. Higher artemether or dihydroartemisinin AUC was found to decrease parasite clearance time. Higher benflumetol AUC was found to significantly increase the chance of cure.. Using a population-based approach it was confirmed that the pharmacokinetic and pharmacodynamic properties of benflumetol and artemether differ markedly. Benflumetol AUC is associated with cure and the effect of benflumetol when coadministered with artemether is to prevent recrudescence. The mode of action of benflumetol is consistent with its longer elimination half-life. A short course of low-dose artemether, which is rapidly absorbed and has a short elimination half-life, produced effective parasite clearance. The complementary pharmacokinetic and pharmacodynamic properties of benflumetol and artemether was the main rationale for developing a fixed-dose combination. While the 4 x 4 dose regimen is very effective in most endemic areas, the poorer absorption (2.5 fold lower than in China) and the more resistant parasites in Thailand require higher doses of this drug.

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Double-Blind Method; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Male; Middle Aged; Sesquiterpenes; Treatment Outcome

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Fluorenes; HIV Infections; Humans; Lopinavir; Lumefantrine; Malaria; Malaria, Falciparum; Nevirapine; Ritonavir; Uganda

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

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

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

Lumefantrine (LMN) is one of the first-line drugs in the treatment of malaria due to its long circulation half-life, which results in enhanced effectiveness against drug-resistant strains of malaria. However, LMN's therapeutic efficacy is diminished due to its low bioavailability when dosed as a crystalline solid. The goal of this work was to produce low-cost, highly bioavailable, stable LMN powders for oral delivery that would be suitable for global health applications. We report the development of a LMN nanoparticle formulation and the translation of that formulation from laboratory to industrial scale. We applied Flash NanoPrecipitation (FNP) to develop nanoparticles with 90% LMN loading and sizes of 200-260 nm. The integrated process involves nanoparticle formation, concentration by tangential flow ultrafiltration, and then spray drying to obtain a dry powder. The final powders are readily redispersible and stable over accelerated aging conditions (50°C, 75% RH, open vial) for at least 4 weeks and give equivalent and fast drug release kinetics in both simulated fed and fasted state intestinal fluids, making them suitable for pediatric administration. The nanoparticle-based formulations increase the bioavailability of LMN 4.8-fold in vivo when compared to the control crystalline LMN. We describe the translation of the laboratory-scale process at Princeton University to the clinical manufacturing scale at WuXi AppTec.

Topics: Chemistry, Pharmaceutical; Child; Humans; Lumefantrine; Malaria; Nanoparticles; Particle Size; Powders; Solubility

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

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

Substandard anti-malarial agents pose a significant challenge to effective malaria control and elimination efforts especially in sub-Saharan Africa. The quality of anti-malarials in most low-and-middle income countries (LMICs) is affected by several factors including inadequate regulation and limited resources. In this study, the pharmacopeial quality of artemether-lumefantrine (AL) in low and high malaria transmission settings in Uganda was assessed.. This was a cross-sectional study conducted among randomly selected private drug outlets. The AL anti-malarials available in drug outlets were purchased using overt method. The samples were screened for quality using visual inspection, weight uniformity, content assay and dissolution tests. The assay test was done using liquid chromatography-mass spectrometry (LC-MS). The samples were considered substandard if the active pharmaceutical ingredient (API) content was outside 90-110% range of the label claim. Dissolution test was conducted following United States Pharmacopoeia (USP) method. Data was analysed using descriptive statistics and presented as means with standard deviations, frequencies, and proportions. Correlation between medicine quality and independent variables was determined using Fisher's exact test of independence at 95% level of significance.. A total of 74 AL anti-malarial samples were purchased from high (49/74; 66.2%) and low (25/74; 33.8%) malaria transmission settings. The most common batch of AL was LONART, 32.4% (24/74), with 33.8% (25/74) being 'Green leaf'. Overall prevalence of substandard quality artemether-lumefantrine was 18.9% (14/74; 95% CI: 11.4-29.7). Substandard quality AL was significantly associated with setting (p = 0.002). A total of 10 samples (13.5%) failed artemether content assay test while, 4 samples (5.4%, 4/74) failed the lumefantrine assay test. One sample from a high malaria transmission setting failed both artemether and lumefantrine assay content test. Of the samples that failed artemether assay test, 90% had low (< 90%) artemether content. All the samples passed visual inspection and dissolution tests.. Artemether-lumefantrine agents, the recommended first-line treatment for uncomplicated malaria with APIs outside the recommended pharmacopeial content assay limit is common especially in high malaria transmission settings. There is need for continuous surveillance and monitoring of the quality of artemisinin-based anti-malarials across the country by the drug regulatory agency.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Cross-Sectional Studies; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Uganda

Pfcrt gene has been associated with chloroquine resistance and the pfmdr1 gene can alter malaria parasite susceptibility to lumefantrine, mefloquine, and chloroquine. In the absence of chloroquine (CQ) and extensive use of artemether-lumefantrine (AL) from 2004 to 2020 to treat uncomplicated falciparum malaria, pfcrt haplotype, and pfmdr1 single nucleotide polymorphisms (SNPs) were determined in two sites of West Ethiopia with a gradient of malaria transmission.. 230 microscopically confirmed P. falciparum isolates were collected from Assosa (high transmission area) and Gida Ayana (low transmission area) sites, of which 225 of them tested positive by PCR. High-Resolution Melting Assay (HRM) was used to determine the prevalence of pfcrt haplotypes and pfmdr1 SNPs. Furthermore, the pfmdr1 gene copy number (CNV) was determined using real-time PCR. A P-value of less or equal to 0.05 was considered significant.. Of the 225 samples, 95.5%, 94.4%, 86.7%, 91.1%, and 94.2% were successfully genotyped with HRM for pfcrt haplotype, pfmdr1-86, pfmdr1-184, pfmdr1-1042 and pfmdr1-1246, respectively. The mutant pfcrt haplotypes were detected among 33.5% (52/155) and 80% (48/60) of isolates collected from the Assosa and Gida Ayana sites, respectively. Plasmodium falciparum with chloroquine-resistant haplotypes was more prevalent in the Gida Ayana area compared with the Assosa area (COR = 8.4, P = 0.00). Pfmdr1-N86Y wild type and 184F mutations were found in 79.8% (166/208) and 73.4% (146/199) samples, respectively. No single mutation was observed at the pfmdr1-1042 locus; however, 89.6% (190/212) of parasites in West Ethiopia carry the wild-type D1246Y variants. Eight pfmdr1 haplotypes at codons N86Y-Y184F-D1246Y were identified with the dominant NFD 61% (122/200). There was no difference in the distribution of pfmdr1 SNPs, haplotypes, and CNV between the two study sites (P > 0.05).. Plasmodium falciparum with the pfcrt wild-type haplotype was prevalent in high malaria transmission site than in low transmission area. The NFD haplotype was the predominant haplotype of the N86Y-Y184F-D1246Y. A continuous investigation is needed to closely monitor the changes in the pfmdr1 SNPs, which are associated with the selection of parasite populations by ACT.

Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Chloroquine; Drug Resistance; Ethiopia; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Multidrug Resistance-Associated Proteins; Plasmodium falciparum; Polymorphism, Single Nucleotide; Protozoan Proteins

The emergence of resistance to artemisinin derivatives in Southeast Asia constitutes a serious threat for other malaria endemic areas, particularly in Côte d'Ivoire. To delay this resistance, the application of the control measures recommended by the National Malaria Control Programme (NMCP) for a correct management, in the private pharmacies, is a necessity. The purpose of this study was, therefore, to assess the level of knowledge and practices of private pharmacy auxiliary in Abidjan about the management of malaria.. A descriptive cross-sectional study was conducted from April to November 2015. It included auxiliaries of private pharmacies in Abidjan. Data collection material was a structured an open pretested questionnaire. Data analysis was carried out using Package for Social Science (SPSS) software version 21.1. Chi square test was used to compare proportions for a significance threshold of 0.05 for the p value.. A total, 447 auxiliaries from 163 private pharmacies were interviewed. It was noted that the auxiliaries had a good knowledge of clinical signs of uncomplicated malaria (99.1%), biological examinations (54.6% for the thick film and 40.7% for rapid diagnostic tests (RDTs) and anti-malarial drugs (99.3% for artemether + lumefantrine, AL). The strategies of vector control (long-lasting insecticide-treated mosquito nets (LLITNs, Repellent ointments, cleaning gutters, elimination of larvae breeding site and intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) in pregnant women were also known by the auxiliaries, respectively 99.8% and 77.4%. However, the malaria pathogen (25.1%) and the NMCP recommendations (e.g. use of AL or AS + AQ as first-line treatment for uncomplicated malaria and IPTp-SP in pregnant women) were not well known by the auxiliaries (28.2% and 26.9% for uncomplicated and severe malaria). Concerning the practices of the auxiliaries, 91.1% offered anti-malarial drugs to patients without a prescription and 47.3% mentioned incorrect dosages. The combination artemether + lumefantrine was the most recommended (91.3%). The delivery of anti-malarial drugs was rarely accompanied by advice on malaria prevention, neither was it carried out on the result of an RDT.. The epidemiology and the NMCP recommendations for the diagnostic and therapeutic management of malaria, are not well known to auxiliaries, which may have implications for their practices. These results show the need to sensitize and train private pharmacy auxiliaries, and also to involve them in NMCP activities.

Topics: Antimalarials; Artemether; Cote d'Ivoire; Cross-Sectional Studies; Drug Combinations; Female; Humans; Lumefantrine; Malaria; Pharmacies; Pharmacy; Pregnancy; Surveys and Questionnaires

Topics: Anemia, Sickle Cell; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Child; Ethanolamines; Fluorenes; Genotype; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Tanzania

Artemether/lumefantrine is the most commonly used artemisinin-based combination treatment (ACT) for malaria in sub-Saharan Africa. Drug resistance to ACT components is a major threat to malaria elimination efforts. Therefore, rigorous monitoring of drug efficacy is required for adequate management of malaria and to sustain the effectiveness of ACTs.. This study identified and described genomic loci that correlate with differences in ex vivo responses of natural Plasmodium falciparum isolates from The Gambia to antimalarial drugs.. Natural P. falciparum isolates from The Gambia were assayed for IC50 responses to four antimalarial drugs (artemether, dihydroartemisinin, amodiaquine and lumefantrine). Genome-wide SNPs from 56 of these P. falciparum isolates were applied to mixed-model regression and network analyses to determine linked loci correlating with drug responses. Genomic regions of shared haplotypes and positive selection within and between Gambian and Cambodian P. falciparum isolates were mapped by identity-by-descent (IBD) analysis of 209 genomes.. SNPs in 71 genes, mostly involved in stress and drug resistance mechanisms correlated with drug responses. Additionally, erythrocyte invasion and permeability loci, including merozoite surface proteins (Pfdblmsp, Pfsurfin), and high-molecular-weight rhoptry protein 2 (Pfrhops2) were correlated with responses to multiple drugs. Haplotypes of pfdblmsp2 and known drug resistance loci (pfaat1, pfcrt and pfdhfr) from The Gambia showed high IBD with those from Cambodia, indicating co-ancestry, with significant linkage disequilibrium between their alleles.. Multiple linked genic loci correlating with drug response phenotypes suggest a genomic backbone may be under selection by antimalarials. This calls for further analysis of molecular pathways to drug resistance in African P. falciparum.

Topics: Animals; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Drug Resistance; Gambia; Ligands; Lumefantrine; Malaria; Malaria, Falciparum; Merozoites; Plasmodium falciparum; Protozoan Proteins

Therapeutic efficacy of artemether-lumefantrine is highly dependent on adequate systemic exposure to the partner drug lumefantrine particularly day 7 lumefantrine plasma concentration. There has been contradicting findings on the role of the cut-off values in predicting treatment outcomes among malaria patients in malaria endemic regions. This study assesses the day 3 and 7 lumefantrine plasma concentrations including related determinant factors and their influence on treatment outcomes among treated Tanzanian children and adults in uncontrolled conditions (real life condition).. Data was nested from an efficacy study employing the WHO protocol, 2015 for monitoring antimalarial drug efficacy. Lumefantrine plasma concentration was measured by high performance liquid chromatography with ultraviolet (HPLC-UV).. Lumefantrine plasma concentrations below 175ng/ml and 200ng/ml on day 3 and 7 did not affect adequate clinical and parasitological response (ACPR) and recurrence of infection (p = 0.428 and 0.239 respectively). Age and baseline parasitemia were not associated to day 3 median lumefantrine plasma concentrations (p = 0.08 and 0.31 respectively) and day 7 lumefantrine plasma concentrations (p = 0.07 and 0.41 respectively). However, the day 3 and day 7 lumefantrine plasma concentrations were significantly higher in males compared to females (p = 0.03 and 0.042 respectively).. Lumefantrine plasma concentrations below cut-off points (175ng/ml and 200ng/ml) on day 3 and 7 did not influence treatment outcomes.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Male; Plasmodium falciparum; Tanzania; Treatment Outcome

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 (1.7 mg/kg) plus lumefantrine (10 mg/kg) over 3 days. 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.. 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.

Topics: Adult; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Male; Middle Aged; Plasmodium knowlesi

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

Topics: Acridones; Administration, Oral; Animals; Antimalarials; Cell Survival; Disease Models, Animal; Female; Half-Life; Hep G2 Cells; Humans; Life Cycle Stages; Malaria; Male; Mice; Mice, Inbred C57BL; Plasmodium falciparum; Structure-Activity Relationship

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

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

Resource-limited countries face challenges in setting up effective pharmacovigilance systems. This study aimed to monitor the occurrence of adverse events (AEs) after the use of artemisinin-based combination therapies (ACTs), identify potential drivers of reporting suspected adverse drug reactions (ADRs) and monitor AEs among women who were inadvertently exposed to ACTs in the first trimester of pregnancy.. We conducted a prospective observational study from May 2010 to July 2012 in Nanoro Health and Demographic Surveillance System (HDSS), Burkina Faso. The HDSS area was divided into active and passive surveillance areas to monitor AEs among patients (regardless of age or sex) who received a first-line ACT (artemether-lumefantrine or artesunate-amodiaquine). In the active surveillance area, patients were followed up for 28 days, while in the passive surveillance area, patients were encouraged to return voluntarily to the health facility to report any occurrence of AEs until day 28 after drug intake. We assessed the crude incidence rates of AEs in both cohorts and performed Cox regression with mixed random effects to identify potential drivers of ADR occurrence.. In total, 3170 participants were included in the study. Of these, 40.3% had reported at least one AE, with 39.6% and 44.4% from active and passive surveillance groups, respectively. The types of ADRs were similar in both groups. The most frequent reported ADRs were anorexia, weakness, cough, dizziness and pruritus. One case of abortion and eight cases of death were reported, but none of them was related to the ACT. The variance in random factors showed a high variability of ADR occurrence between patients in both groups, whereas variability between health facilities was low in the active surveillance group and high in passive surveillance group. Taking more than two concomitant medications was associated with high hazard in ADR occurrence, whereas the rainy season was associated with low hazard.. This study showed that both passive and active surveillance approaches were useful tools. The HDSS allowed us to capture a few cases of exposure during the first trimester of pregnancy. The passive surveillance approach, which is more likely to be implemented by malaria control programs, seems to be more relevant in the Sub-Saharan African context.

Topics: Adolescent; Amodiaquine; Antimalarials; Artemisinins; Burkina Faso; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Lumefantrine; Malaria; Male; Pharmacovigilance; Pregnancy; Prospective Studies; Structure-Activity Relationship

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure-activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

Topics: Acridones; Animals; Antimalarials; Disease Models, Animal; Drug Discovery; Hep G2 Cells; Humans; Malaria; Mice; Plasmodium; Species Specificity; Structure-Activity Relationship

Combination therapy of artemether (ART) and lumefantrine (LUM) is well-established for the treatment of uncomplicated malaria worldwide. Nanoliposomes (NLs) encapsulating both drugs were prepared and freeze-dried. The lyophilized nanoliposomes exhibited high entrapment efficiency of artemether (66.18%), relatively low entrapment efficiency of lumefantrine (53.46%), low average size diameter (125.3 nm) and found to be stable at 4 °C for 60 days without significant change in mean particle diameter and drug entrapment efficiencies. In vitro drug release study has shown initial burst effect and then sustained release pattern over a time period of 30 h. In vivo toxicity study was examined by liver and kidney function test as well as histopathological examination. Nanoliposomes showed lower hemolytic potential (∼10%) compared to all the components when studied individually. There was no significant change (p > 0.05) in biochemical parametes between control and treated group of animals. Pharmacokinetic data of ART + LUM NLs showed higher the area under the plasma concentration-time curve (AUC) values and prolonged residence time of drug in the blood circulation compared with ART + LUM solution. The tissue distribution demonstrated high uptake of ART + LUM-NLs in RES organs particularly in liver and spleen. Biocompatibility was confirmed by hepato- and nephrotoxicity analysis showed no sign of fibrosis, fatty infiltration, centrilobular necrosis and lymphocyte infiltration confirmed the suitability of developed formulation for treatment of malaria.

Topics: Animals; Antimalarials; Artemether; Drug Liberation; Liposomes; Lumefantrine; Malaria; Mice; Nanoparticles; Tissue Distribution

Study of the clinical effects of combination therapy for malaria is aided by the ability to measure concentrations of individual partner drugs. Existing methods for measurement of the antimalarial drug lumefantrine (LF) in dried blood spots (DBS) on filter paper rely on chemical pretreatment of the paper to facilitate drug elution. However, in the absence of pretreatment, DBS may still offer some utility for semi-quantitative measurements and pharmacokinetic-pharmacodynamic (PK-PD) analyses. We present a method for semi-quantitation of LF in DBS on untreated filter paper using liquid chromatography tandem mass spectrometry. Optimal recovery was achieved by extraction with acetone-water-formic acid (90:5:5). The range of quantitation was 100-20,000ng/ml. Mean intra- and inter-day accuracy values were 86.6% (coefficient of variation [CV]: 10.1%) and 91.8% (CV: 16.1%), therefore we propose the assay as semi-quantitative. Clinical application was demonstrated in exploratory PK-PD analyses of a drug efficacy trial of artemether-lumefantrine in children with uncomplicated falciparum malaria using post-treatment day 7 samples, parasite clearance times estimated from serial blood smears, and recurrence of malaria out to 35days. The median day 7 concentration among children (n=71) was 111ng/ml (interquartile range: 100-194ng/ml). We used a truncated calibration curve of 100-5000ng/ml for calculations due to low observed concentrations. Calculations using the full calibration curve yielded similar values (+1% avg. deviation). Controlling for participant age, sex, and parasite burden, each log increase in LF day 7 concentration corresponded to a decrease of 7.1h in mean parasite clearance time (95% confidence interval: 0.1-14.3h, P=0.05). A nested case-control study of participants (n=18) with and without recurrent malaria showed mean post-treatment day 7 concentrations of 181ng/ml and 235ng/ml, respectively, but the difference was not significant (P=0.64). A method for semi-quantitation of LF from post-treatment day 7 collections of DBS on untreated filter paper demonstrated clinical application in exploratory PK-PD analyses of parasite clearance and reinfection. Use of DBS will endure in certain study settings by virtue of their ease of collection and resilience. Their utility should continue to be explored as our instruments gain in sensitivity and as clinical pharmacology inquiries are pursued to the field.

Topics: Antimalarials; Case-Control Studies; Child, Preschool; Chromatography, Liquid; Dried Blood Spot Testing; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Male; Plasmodium falciparum; Reproducibility of Results; Tandem Mass Spectrometry

Malaria is the most incident parasite infection worldwide. Artemisinin based combination therapy (ACT) has been proposed as a promising treatment for malaria, and artemether + lumefantrine (20 + 120 mg) is the recommended association in endemic areas. Despite its widespread use, there is still scarce information about dissolution of artemether and lumefantrine, reflecting in the absence of a specific method in pharmacopoeias and international compendia. Because the of their low solubility, both artemether and lumefantrine are candidates for in vitro-in vivo correlation (IVIVC) studies. Previous equilibrium solubility studies have been carried out for both drugs using the shake-flask method and dissolution profiles. Experiments were conducted with a range of parameters such as medium composition, pH and surfactants. In vivo data obtained in a previous pharmacokinetic study was used to select the optimum conditions for dissolution test, based on IVIVC. For drug quantitation, a selective method by high performance liquid chromatography was optimized and validated. For this dosage form, the best dissolution conditions found for artemether were: paddles, 900 mL of dissolution medium containing phosphate buffer pH 6.8 with 1.0% sodium lauryl sulfate and rotation speed of 100 rpm. The same was obtained for lumefantrine, except the dissolution medium, which was pH 1.2 with 1.0% polysorbate 80. After obtaining the curve of in vitro dissolved fraction versus in vivo absorbed fraction, the calculated coefficient of determination (R squared) was close to 1.00 for both drugs, indicating a level A correlation. Therefore, a novel method for assessing dissolution of arthemeter and lumefantrine tablets was established and validated.

Topics: Adolescent; Adult; Antimalarials; Artemether; Artemisinins; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Male; Middle Aged; Solubility; Tablets; Young Adult

Parenteral therapy for severe and complicated malaria is necessary, but currently available parenteral antimalarials have their own drawbacks. As for recommended artemisinin-based combination therapy, antimalarial artemether and lumefantrine are limited in parenteral delivery due to their poor water solubility. Herein, the aim of this study was to develop the lipid-based emulsions for intravenous co-delivery of artemether and lumefantrine. The lipid emulsion was prepared by high-speed shear and high-pressure homogenization, and the formulations were optimized mainly by monitoring particle size distribution under autoclaved conditions. The final optimal formulation was with uniform particle size distribution (~ 220 nm), high encapsulation efficiency (~ 99%), good physiochemical stability, and acceptable hemolysis potential. The pharmacokinetic study in rats showed that C

Topics: Administration, Intravenous; Animals; Antimalarials; Artemether; Biological Availability; Drug Delivery Systems; Emulsions; Lumefantrine; Malaria; Male; Particle Size; Rats

In the context of post-marketing surveillance supporting public-health authorities to take evidence-based decisions to fight the spread of poor-quality medicines, the quality of antimalarial artemether-lumefantrine (AL) medicines was assessed in the Democratic Republic of the Congo (DRC). A total of 150 samples of AL-containing products was collected from private pharmaceutical outlets in 8 main cities: Goma, Kikwit, Kinshasa, Kisangani, Lubumbashi, Matadi, Mbandaka, and Mbuji-Mayi. All drug samples were successively analyzed by visual inspection, thin-layer chromatography (TLC), and high-performance liquid chromatography (HPLC) following The International Pharmacopoeia. Of the 150 collected drug samples, 3 (2%) failed the visual inspection as they had shelf lives different from those of other samples with the same brand name. Four samples (2.7%) did not pass the TLC test as they contained only 1 or even none of the 2 declared active pharmaceutical ingredients (APIs). HPLC assays showed that 46 (30.7%) samples had artemether contents below 90% and 17 (11.3%) above 110% of the content claimed on the label. For lumefantrine, 32 (21.7%) samples had contents below 90%, and 8 (5.3%) had contents above 110%. This survey in DRC gives evidence that poor-quality antimalarial medicines are widely present. Based on 3 detection techniques, the study shows the necessity to equip developing countries with modern techniques such as HPLC, which, if combined with affordable techniques like TLC, could provide a pertinent analytical strategy to combat drug counterfeiting and poor manufacturing.

Topics: Antimalarials; Artemether; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Congo; Drug Contamination; Drug Stability; Humans; Lumefantrine; Malaria; Quality Control

Lumefantrine is a long-acting antimalarial drug with an elimination half-life of over 3 days and protein binding of 99 percent. Correlation of lumefantrine concentrations from capillary plasma via fingerprick (Cc) versus venous plasma (Cv) remains to be defined.. Venous and capillary plasma samples were collected simultaneously from children, pregnant women, and non-pregnant adults at 2, 24, 120hr post last dose of a standard 3-day artemether-lumefantrine regimen they received for uncomplicated malaria. Some of the enrolled children and pregnant women were also HIV-infected. Samples were analyzed via liquid chromatography tandem mass spectrometry. Linear regression analysis was performed using the program Stata® SE12.1.. In children, the linear regression equations for Cc vs Cv at 2, 24, and 120hr (day 7) post dose are [Cc] = 1.05*[Cv]+95.0 (n = 142, R2 = 0.977), [Cc] = 0.995*[Cv]+56.7 (n = 147, R2 = 0.990) and [Cc] = 0.958*[Cv]+18.6 (n = 139, R2 = 0.994), respectively. For pregnant women, the equations are [Cc] = 1.04*[Cv]+68.1 (n = 43, R2 = 0.990), [Cc] = 0.997*[Cv]+37.3 (n = 43, R2 = 0.993) and [Cc] = 0.941*[Cv]+11.1 (n = 41, R2 = 0.941), respectively. For non-pregnant adults, the equations are [Cc] = 1.05*[Cv]-117 (n = 32, R2 = 0.958), [Cc] = 0.962*[Cv]+9.21 (n = 32, R2 = 0.964) and [Cc] = 1.04*[Cv]-40.1 (n = 32, R2 = 0.988), respectively. In summary, a linear relationship with a slope of ~1 was found for capillary and venous lumefantrine levels in children, pregnant women and non-pregnant adults at 2hr, 24hr and 120hr post last dose, representing absorption, distribution, and elimination phases.. Capillary and venous plasma concentration of lumefantrine can be used interchangeably at 1:1 ratio. Capillary sampling method via finger prick is a suitable alternative for sample collection in clinical studies.

Topics: Antimalarials; Child; Chromatography, Liquid; Coinfection; Drug Monitoring; Female; HIV Infections; Humans; Lumefantrine; Malaria; Pregnancy; Tandem Mass Spectrometry; Time Factors

Structural optimization of 3-hydroxy-N'-arylidenepropanehydrazonamides provided new analogs with nanomolar to subnanomolar antiplasmodial activity against asexual blood stages of Plasmodium falciparum, excellent parasite selectivity, and nanomolar activity against the earliest forms of gametocyte development. Particularly, derivatives with a 1,3-dihalo-6-trifluoromethylphenanthrene moiety showed outstanding in vivo properties and demonstrated in part curative activity in the Plasmodium berghei mouse model when administered perorally.

Topics: Amides; Animals; Antimalarials; Hep G2 Cells; Humans; Hydrazones; Malaria; Mice; Phenanthrenes; Plasmodium berghei; Stereoisomerism; Structure-Activity Relationship

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

As more and more generics become available in the market place, the safety/efficacy concerns may arise as the result of interchangeably use of approved generics. However, bioequivalence assessment for regulatory approval among generics of the innovative drug product is not required. In practice, approved generics are often used interchangeably without any mechanism of safety monitoring. In this article, based on indirect comparisons, we proposed several methods to assessing bioequivalence and interchangeability between generics. The applicability of the methods and the similarity assumptions were discussed, as well as the inappropriateness of directly adopting adjusted indirect comparison to the field of generics' comparison. Besides, some extensions were given to take into consideration the important topics in clinical trials for bioequivalence assessments, for example, multiple comparisons and simultaneously testing bioequivalence among three generics. Extensive simulation studies were conducted to investigate the performances of the proposed methods. The studies of malaria generics and HIV/AIDS generics prequalified by the WHO were used as real examples to demonstrate the use of the methods. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; Computer Simulation; Confidence Intervals; Drugs, Generic; Ethanolamines; Fluorenes; HIV Infections; Humans; Lamivudine; Lumefantrine; Malaria; Models, Statistical; Therapeutic Equivalency; Zidovudine

Malaria is one of the leading causes of death in sub-Saharan Africa. Artemisinin-based combination therapies are used as first-line treatment drugs, but their market is far from competitive. Market failures include limited availability, low quality, lack of information, and high costs of access. We estimated the theoretical demand for one of the most common artemisinin-based combination therapies, artemether-lumefantrine (AL), and its determinants among caregivers of children with malaria seeking care at public health facilities, thus, entitled to receive drugs for free, in southern Mozambique (year 2012). The predicted theoretical demand was contrasted with international and local private market AL prices. Respondents stated high willingness to pay but lower ability to pay (ATP), which was defined as the theoretical demand. The ATP was on average of 0.94 USD for the treatment of a malaria episode. This implied an average gap of 1.04 USD between average local private prices and theoretical demand. Predicted ATP decreased by 14% for every additional malaria episode that the child had suffered during the malaria season. The market price was unaffordable for a large share of our sample, highlighting an unequal welfare distribution between suppliers and potential consumers, as well as issues of inequity in the private delivery of AL.

Topics: Antimalarials; Artemether; Child; Child, Preschool; Drug Therapy, Combination; Female; Financing, Personal; Health Services Needs and Demand; Humans; Infant; Lumefantrine; Malaria; Male; Mozambique; Outcome Assessment, Health Care; Regression Analysis

Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.

Topics: Amino Acid Sequence; Animals; Anopheles; Antimalarials; CRISPR-Cas Systems; DNA, Protozoan; Drug Combinations; Drug Resistance; Endocytosis; Ethanolamines; Fluorenes; Gene Editing; HEK293 Cells; Heme; Hemoglobins; High-Throughput Screening Assays; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Male; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Mutation; Oocysts; Plasmodium berghei; Plasmodium falciparum; Quinolines

Discovery of novel gametocytocidal molecules is a major pharmacological strategy in the elimination and eradication of malaria. The high patronage of the aqueous root extract of the popular West African anti-malarial plant Cryptolepis sanguinolenta (Periplocaceae) in traditional and hospital settings in Ghana has directed this study investigating the gametocytocidal activity of the plant and its major alkaloid, cryptolepine. This study also investigates the anti-malarial interaction of cryptolepine with standard anti-malarials, as the search for new anti-malarial combinations continues.. The resazurin-based assay was employed in evaluating the gametocytocidal properties of C. sanguinolenta and cryptolepine against the late stage (IV/V) gametocytes of Plasmodium falciparum (NF54). A fixed ratio method based on the SYBR Green I fluorescence-based assay was used to build isobolograms from a combination of cryptolepine with four standard anti-malarial drugs in vitro using the chloroquine sensitive strain 3D7.. Cryptolepis sanguinolenta (IC. The findings of this study shed light on the high gametocytocidal properties of C. sanguinolenta and cryptolepine attributing their potent anti-malarial activity mainly to their effect on both the sexual and asexual stages of the parasite. Amodiaquine is a potential drug partner for cryptolepine in the development of novel fixed dose combinations.

Topics: Alkaloids; Antimalarials; Chloroquine; Ethanolamines; Fluorenes; Gametogenesis; Ghana; Humans; Indole Alkaloids; Life Cycle Stages; Lumefantrine; Malaria; Malaria, Falciparum; Mefloquine; Plant Extracts; Plasmodium falciparum; Quinolines

Topics: Abdomen; Adult; Africa, Central; Antimalarials; Artemether; Artemisinins; Drug Therapy, Combination; Endemic Diseases; Ethanolamines; Fluorenes; Humans; Laparoscopy; Lumefantrine; Malaria; Male; Plasmodium ovale; Splenectomy; Splenic Rupture; Tomography, X-Ray Computed

The objective of the present work was to engineer and characterize stable citric acid cross-linked microcomplex of the inclusion complexes of artemether with β-cyclodextrin and Kollidon VA 64

Topics: Antimalarials; Artemether; Artemisinins; beta-Cyclodextrins; Citric Acid; Drug Carriers; Drug Interactions; Drug Liberation; Ethanolamines; Fluorenes; Lumefantrine; Malaria; Microspheres; Particle Size; Pyrrolidines; Vinyl Compounds

Artemether and lumefantrine combination therapy is well-accepted for uncomplicated malaria treatment. However, the current available formulation has several pharmacokinetic mismatches such as drug degradation in gastrointestinal tract, erratic absorption, etc. Hence, need of the hour is the injectable formulation, which can overcome the pharmacokinetic mismatch associated with current available formulation in the market.. To fabricate artemether and lumefantrine co-loaded injectable nanostructured lipid carriers (NLCs) formulation.. Artemether and lumefantrine co-loaded NLCs were fabricated using homogenization followed by ultra-sonication method. Fabricated NLCs were evalauated for their physicochemical characteristics, and suitability of the formulation for malaria treatment was evaluated using in vivo animal model (Plasmodium berghei-infected mice). Results, discussion and conclusion: Artemether and lumefantrine co-loaded NLCs had a hydrodynamic diameter of ∼ 145 nm with the surface charge of -66 mV. Due to the lipophilic nature of both antimalarial drugs, both single drugs-loaded and co-loaded NLCs have shown high encapsulation efficiency, which is 84% for artemether and 79% for lumefantrine. In vitro drug release study has shown a biphasic drug release pattern, which has shown 63% artemether release and 45% of lumefantrine release over a time period of 30 h. Plasmodium berghei-infected mice treated with artemether and lumefantrine co-loaded NLCs showed better antimalarial activity with respect to parasitemia progression and survivability period.

Topics: Animals; Antimalarials; Artemether; Artemisinins; Drug Carriers; Ethanolamines; Fluorenes; Lipids; Lumefantrine; Malaria; Mice; Nanostructures; Particle Size; Plasmodium berghei

We investigated the influence of efavirenz (EFV)- or nevirapine (NVP)-based antiretroviral therapy (ART) on lumefantrine plasma exposure in HIV-malaria-coinfected patients and implication of pharmacogenetic variations. A total of 269 HIV patients with uncomplicated falciparum malaria on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) or not receiving ART (control-arm) were enrolled and treated with artemether-lumefantrine. Day-7 lumefantrine, baseline EFV and NVP plasma concentrations, and CYP2B6*6,*18, CYP3A4*1B, CYP3A5*3,*6,*7, ABCB1 c.3435C>T and ABCB1 c.4036A>G genotypes were determined. The median day-7 lumefantrine plasma concentration was significantly lower in the EFV-arm compared with that in NVP- and control-arm. High EFV plasma concentrations and CYP2B6*6/*6 genotype significantly correlated with low lumefantrine plasma concentrations and high rate of recurrent parasitemia. No significant effect of NVP-based ART on lumefantrine exposure was observed. In conclusion, owing to long-term CYP3A induction, EFV-based ART cotreatment significantly reduces lumefantrine plasma exposure leading to poor malaria treatment response, which is more pronounced in CYP2B6 slow metabolizers.

Topics: Alkynes; Anti-HIV Agents; Antimalarials; Artemether; Artemisinins; ATP Binding Cassette Transporter, Subfamily B; Benzoxazines; Case-Control Studies; Coinfection; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Drug Antagonism; Drug Therapy, Combination; Ethanolamines; Fluorenes; Genotype; HIV Infections; Humans; Lumefantrine; Malaria; Nevirapine; Prospective Studies

To characterize the impact of widespread inventory management policies on stock-outs of essential drugs in Zambia's health clinics and develop related recommendations.. Daily clinic storeroom stock levels of artemether-lumefantrine (AL) products in 2009-2010 were captured in 145 facilities through photography and manual transcription of paper forms, then used to determine historical stock-out levels and estimate demand patterns. Delivery lead-times and estimates of monthly facility accessibility were obtained through worker surveys. A simulation model was constructed and validated for predictive accuracy against historical stock-outs, then used to evaluate various changes potentially affecting product availability.. While almost no stock-outs of AL products were observed during Q4 2009 consistent with primary analysis, up to 30% of surveyed facilities stocked out of some AL product during Q1 2010 despite ample inventory being simultaneously available at the national warehouse. Simulation experiments closely reproduced these results and linked them to the use of average past monthly issues and failure to capture lead-time variability in current inventory control policies. Several inventory policy enhancements currently recommended by USAID | DELIVER were found to have limited impact on product availability.. Inventory control policies widely recommended and used for distributing medicines in sub-Saharan Africa directly account for a substantial fraction of stock-outs observed in common situations involving demand seasonality and facility access interruptions. Developing central capabilities in peripheral demand forecasting and inventory control is critical. More rigorous independent peer-reviewed research on pharmaceutical supply chain management in low-income countries is needed.

Topics: Antimalarials; Artemether; Artemisinins; Delivery of Health Care; Drugs, Essential; Ethanolamines; Fluorenes; Health Facilities; Health Planning; Humans; Lumefantrine; Malaria; Materials Management, Hospital; Models, Statistical; Pharmaceutical Services; Plasmodium falciparum; Workforce

In 1993, Malawi changed its first-line anti-malarial treatment for uncomplicated malaria from chloroquine to sulfadoxine-pyrimethamine (SP), and in 2007, it changed from SP to lumefantrine-artemether. The change in 1993 raised concerns about whether it had occurred timely and whether it had potentially led to early development of Plasmodium falciparum resistance to SP. This case study examined evidence from Malawi in order to assess if the policy changes were justifiable and supported by evidence.. A systematic review of documents and published evidence between 1984 and 1993, when chloroquine was the first-line drug, and 1994 and 2007, when SP was the first-line drug, was conducted herein. The review was accompanied with key informant interviews.. A total of 1287 publications related to malaria drug policy changes in sub-Saharan Africa were identified. Using the inclusion criteria, four articles from 1984 to 1993 and eight articles from 1994 to 2007 were reviewed. Between 1984 and 1993, three studies reported on chloroquine poor efficacy prompting policy change according to WHO's recommendation. From 1994 to 2007, four studies conducted in the early years of policy change reported a high SP efficacy of above 80%, retaining it as a first-line drug. Unpublished sentinel site studies between 2005 and 2007 showed a reduced efficacy of SP, influencing policy change to lumefantrine-artemether. The views of key informants indicate that the switch from chloroquine to SP was justified based on local evidence despite unavailability of WHO's policy recommendations, while the switch to lumefantrine-artemether was uncomplicated as the country was following the recommendations from WHO.. Ample evidence from Malawi influenced and justified the policy changes. Therefore, locally generated evidence is vital for decision making during policy change.

Topics: Antimalarials; Artemether; Artemisinins; Biomedical Research; Chloroquine; Drug Combinations; Drug Resistance; Ethanolamines; Evidence-Based Medicine; Fluorenes; Health Policy; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Malawi; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Treatment Outcome

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

Artemether-lumefantrine (ARM-LFN) is a World Health Organization (WHO) approved fixed-dose combination having low solubility and poor oral bioavailability. Nanostructured lipid carriers (NLC) were developed to enhance the oral efficacy of this combination using the microemulsion template technique. They were characterized for drug content, entrapment efficiency, size distribution, in vitro release, antimalarial efficacy, and toxicity. The NLC showed sustained drug release. The recommended adult therapeutic dose is 80mg ARM and 480mg LFN (4 tablets) twice a day, which amounts to 160mg ARM and 960mg LFN daily. ARM-LFN NLC given once a day at 1/5 of therapeutic dose (16mg ARM and 96mg LFN) showed complete parasite clearance and 100% survival in Plasmodium berghei-infected mice. 33% of the mice treated with marketed tablets twice a day at the therapeutic dose showed late-stage recrudescence. Thus, NLC showed enhanced efficacy at 1/10 of the daily dose of ARM-LFN. The 10-fold reduced daily dose was formulated in two soft gelatin capsules thus reducing the number of units to be taken at a time by the patient. The capsules showed good stability at room temperature for a year. The NLC were found to be safe in rats. The biocompatible NLC developed using an industrially feasible technique offer a promising solution for oral malaria therapy.

Topics: Administration, Oral; Animals; Antimalarials; Artemether; Artemisinins; Dose-Response Relationship, Drug; Drug Carriers; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Lipids; Lumefantrine; Malaria; Male; Mice; Nanostructures; Plasmodium berghei; Rats; Rats, Wistar; Treatment Outcome

Artemisinin-based combination therapies (ACTs) against malaria are subsidized in many African countries, but the impact of subsidy programs in reducing the sales of concomitantly available antimalarial monotherapies is poorly defined.. Data from The MENTOR initiative, that introduced subsidized artemether-lumefantrine (sAL) in the private sector of Huambo province, Angola, were used. The main response variable was represented by sales of sAL and of monotherapies, measured as number of treatment courses. Sales in private pharmacies of sAL and four antimalarial monotherapies between 2009 and 2013 were organized in four time-periods, and analyzed using generalized linear models for repeated measures. A secondary analysis evaluated changes in relative market share.. We analyzed data from 34 pharmacies at four time points, taken from a larger survey that involved 165 pharmacies between June 2009 and March 2013. The sAL, following its introduction, became the dominant antimalarial treatment in the private sector, usually exceeding the total sales of all antimalarial monotherapies combined (1480/2800 total treatment courses, 52.8% of all sales in March 2013). Sales of monotherapies decreased significantly, but did not stop, representing 36.7% (1028/2800) of sales at the end of the survey.. Subsidized ACTs can attain rapidly a high relative market share. Their introduction reduced, but did not eliminate the demand for less effective monotherapies, that might favor parasite resistance.

Topics: Angola; Antimalarials; Artemether; Artemisinins; Drug Costs; Drug Therapy, Combination; Ethanolamines; Financing, Government; Fluorenes; Health Services Accessibility; Humans; Lumefantrine; Malaria; Marketing of Health Services; Pharmacies; Private Sector

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

Topics: Adamantane; Animals; Anopheles; Antimalarials; Artemether; Artemisinins; Ethanolamines; Female; Fluorenes; Indoles; Insect Vectors; Lumefantrine; Malaria; Mice; Peroxides; Plasmodium berghei; Primaquine; Spiro Compounds

The evolution of drug-resistant parasites is a major hindrance to malaria control, and thus understanding the behaviour of drug-resistant mutants is of clinical relevance. The study aimed to investigate how resistance against lumefantrine (LU) and piperaquine (PQ), anti-malarials used as partner drugs in artemisinin-based combination therapy (ACT), impacts parasite fitness. This is important since resistance to ACT, the first-line anti-malarial regimen is increasingly being reported.. The stability of Plasmodium berghei ANKA strain that was previously selected for LU and PQ resistance was evaluated using the 4-day assay and established infection test in mice. Fitness cost of resistance was determined by comparing parasites proliferation rates in absence of drug pressure for the drug-exposed parasites between day 4 and 7 post-infection (pi), relative to the wild-type. Statistical analysis of data to compare mean parasitaemia and growth rates of respective parasite lines was carried out using student's t-test and one-way analysis of variance, with significance level set at p<0.05.. During serial passaging in the absence of the drug, the PQ-resistant parasite maintained low growth rates at day 7 pi (mean parasitaemia, 5.6% ± 2.3) relative to the wild-type (28.4% ± 6.6), translating into a fitness cost of resistance of 80.3%. Whilst resistance phenotype for PQ was stable, that of LU was transient since after several serial passages in the absence of drug, the LU-exposed line assumed the growth patterns of the wild-type.. The contrasting behaviour of PQ- and LU-resistance phenotypes support similar findings which indicate that even for drugs within the same chemical class, resistance-conferred traits may vary on how they influence parasite fitness and virulence. Resistance-mediating polymorphisms have been associated with less fit malaria parasites. In the absence of drug pressure in the field, it is therefore likely that the wild-type parasite will out-compete the mutant form. This implies the possibility of reintroducing a drug previously lost to resistance, after a period of suspended use. Considering the recent reports of high failure rates associated with ACT, high fitness cost of resistance to PQ is therefore of clinical relevance as the drug is a partner in ACT.

Topics: Animals; Antimalarials; Disease Models, Animal; Drug Resistance; Ethanolamines; Fluorenes; Genetic Fitness; Lumefantrine; Malaria; Male; Mice; Plasmodium berghei; Quinolines

HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation.. This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naïve (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling.. Of the evaluated models, a two-compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080-431,962) versus 784,830 (547,405-1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice daily for five days using the current dose could improve lumefantrine exposure and consequently malaria treatment outcomes.. Co-treatment of AL with EFV-based ART but not NVP-based ART significantly reduces lumefantrine bioavailability and consequently total exposure. To ensure adequate lumefantrine exposure and malaria treatment success in HIV-malaria co-infected patients on EFV-based ART, an extension of the duration of AL treatment to five days using the current dose is proposed.

Topics: Adult; Aged; Alkynes; Anti-Retroviral Agents; Antimalarials; Benzoxazines; Cyclopropanes; Drug Interactions; Ethanolamines; Female; Fluorenes; HIV Infections; Humans; Lumefantrine; Malaria; Male; Middle Aged; Nevirapine; Prospective Studies; Tanzania; Young Adult

This study aimed to assess the effect of an integrated community case management of malaria and pneumonia programme (iCCMmp) on the efficacy of artemether-lumefantrine (AL). Thus, we carried out two open label and unique centre clinical trials, before and after the iCCMmp, on the therapeutic efficacy of AL. A total of 210 children aged 6-59 months, were included in the study, 105 before and 105 after the iCCMmp. The adequate clinical and parasitological response was 90.5% and 86.7% respectively before and after the iCCMmp (p value = 0.516). Our findings reported no effect of iCCMmp on the therapeutic efficacy of the AL.

Topics: Antimalarials; Artemether; Artemisinins; Burkina Faso; Child, Preschool; Delivery of Health Care; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria; Male; Population Density; Randomized Controlled Trials as Topic; Rural Population; Sample Size; Treatment Outcome

Access to prompt and effective treatment is the cornerstone for malaria control. Population Services International in collaboration with the Ministry of Health launched a malaria behaviour change communication intervention in Nyanza province, Kenya. The initiative aimed to improve: symptom recognition and prompt access to government health facilities for febrile children; effective treatment with the recommended first-line drug artemether-lumefantrine (AL) in public health facilities and adherence to the AL regimen.. Pre- and post-intervention cross-sectional household surveys were used to evaluate the impact of the intervention on prompt and correct use of AL for febrile children below five years of age. The primary outcome was the proportion of children below five years of age with fever in the last 14 days accessing AL within 48 hours of fever onset.. There was an increase from 62.8% pre-intervention to 79.4% post-intervention (95% CI: 11.1, 22.1) in caregivers who reported seeking formal treatment promptly (on the same day, or next day) for their febrile children. However, there was a decrease in the use of government health facilities in the post-intervention period. There was a small increase in the proportion of children accessing AL within 48 hours of fever onset [18.4% vs 23.5% (0.1-10.0)].. The findings of this evaluation demonstrate that interventions that target only one sector may have a limited impact on improvements in prompt and effective treatment where multiple sources of treatments are sought for febrile illness. Additionally, the context in which an intervention is implemented is likely to influence the process and outcomes.

Topics: Antimalarials; Artemether; Artemisinins; Awareness; Caregivers; Child, Preschool; Community Health Services; Community Participation; Cross-Sectional Studies; Ethanolamines; Family Characteristics; Female; Fever; Fluorenes; Humans; Infant; Infant, Newborn; Kenya; Lumefantrine; Malaria; Male; Patient Acceptance of Health Care

The oral absorption of compounds with low aqueous solubility, such as lumefantrine, is typically limited by the dissolution rate in the gastro-intestinal tract, resulting in erratic absorption and highly variable bioavailability. In previous studies we reported on the ability of Pheroid vesicles to improve the bioavailability of poorly soluble drugs. In the present study a Pro-Pheroid formulation, a modification of the previous formulation, was applied to improve the solubility of lumefantrine after oral administration and compared to lumefantrine in DMSO:water (1:9 v/v) solution (reference solution). A bioavailability study of lumefantrine was conducted in a mouse model in fed and fasted states. When using the reference solution, the bioavailability of the lumefantrine heavily depended on food intake, resulting in a 2.7 times higher bioavailability in the fed state when compared to the fasted state. It also showed large between-subject variability. When formulated using Pro-Pheroid, the bioavailability of lumefantrine was 3.5 times higher as compared to lumefantrine in the reference solution and fasting state. Pro-Pheroid also dramatically reduced the effects of food intake and the between-subject variability for bioavailability observed with the reference. In vivo antimalarial efficacy was also evaluated with lumefantrine formulated using Pro-Pheroid technology compared to the reference solution. The results indicated that lumefantrine in Pro-Pheroid formulation exhibited improved antimalarial activity in vitro by 46.8%, when compared to the reference. The results of the Peters' 4-day suppressive test indicated no significant difference in the efficacy or mean survival time of the mice in the Pro-Pheroid formulation and reference test groups when compared to the positive control, chloroquine. These findings suggest that using the Pro-Pheroid formulation improves the bioavailability of lumefantrine, eliminates the food effect associated with lumefantrine as well as significantly reduces the between subject variability in bioavailability when compared to the reference solution.

Topics: Administration, Oral; Animals; Antimalarials; Biological Availability; Chemistry, Pharmaceutical; Chloroquine; Disease Models, Animal; Drug Stability; Ethanolamines; Fluorenes; Food-Drug Interactions; Lumefantrine; Malaria; Male; Mice; Mice, Inbred C57BL; Solubility; Technology, Pharmaceutical

During a longitudinal study investigating the dynamics of malaria in Ugandan lakeshore communities, a consistently high malaria prevalence was observed in young children despite regular treatment. To explore the short-term performance of artemether-lumefantrine (AL), a pilot investigation into parasite carriage after treatment(s) was conducted in Bukoba village. A total of 163 children (aged 2-7 years) with a positive blood film and rapid antigen test were treated with AL; only 8.7% of these had elevated axillary temperatures. On day 7 and then on day 17, 40 children (26.3%) and 33 (22.3%) were positive by microscopy, respectively. Real-time PCR analysis demonstrated that multi-species Plasmodium infections were common at baseline, with 41.1% of children positive for Plasmodium falciparum/Plasmodium malariae, 9.2% for P. falciparum/ Plasmodium ovale spp. and 8.0% for all three species. Moreover, on day 17, 39.9% of children infected with falciparum malaria at baseline were again positive for the same species, and 9.2% of those infected with P. malariae at baseline were positive for P. malariae. Here, chronic multi-species malaria infections persisted in children after AL treatment(s). Better point-of-care diagnostics for non-falciparum infections are needed, as well as further investigation of AL performance in asymptomatic individuals.

Topics: Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Coinfection; Diagnostic Tests, Routine; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Follow-Up Studies; Humans; Longitudinal Studies; Lumefantrine; Malaria; Male; Plasmodium; Plasmodium falciparum; Plasmodium ovale; Point-of-Care Systems; Prevalence; Uganda

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

Topics: Animals; Antimalarials; Artemether; Artemisinins; Emulsions; Ethanolamines; Female; Fluorenes; Lumefantrine; Malaria; Male; Mice; Plasmodium berghei

A pilot programme of Cohort Event Monitoring (CEM) was conducted across the six geopolitical zones of Nigeria on patients treated for uncomplicated malaria with artemisinin-based combination therapy (ACT). The emergence and spread of malaria parasites resistant to commonly available antimalarial drugs necessitated a shift in policy for malaria treatment by the Federal Government from the use of chloroquine and sulphadoxine-pyrimethamine (SP) as first-line treatments to ACTs. Initial reports following deployment of ACTs in clinical settings raised safety concerns regarding their use. Although artemisinin and its derivatives are generally thought to be safe, there are currently few or no data on their safety among populations in Nigeria.. The main objectives of the CEM programme were to proactively determine the adverse event (AE) profile of artesunate/amodiaquine (AA) and artemether/lumefantrine (AL) in real-life settings and to find out the factors predisposing to AEs.. The CEM study was observational, longitudinal, prospective, and inceptional. Patients were observed in real-life situations. It was conducted in six public health facilities in Nigeria on patients with a clinical diagnosis of uncomplicated malaria treated with ACTs. Patients were prescribed one of the ACTs on an alternate basis as they enrolled into the programme. Follow-up reviews were undertaken on days 3 and 7 following commencement of ACT treatment. At follow-up, patients were evaluated for any clinical event that they might have experienced following the use of the ACTs. We report the result of this initial pilot in which 3,010 patients treated for uncomplicated malaria with AA or AL were enrolled.. The seven most common AEs seen were general body weakness 25.0/36.6% (AL/AA); dizziness 11.9/17.2% (AL/AA); vomiting 8.0/10.2% (AL/AA); abdominal pain 8.5/7.2% (AL/AA); insomnia 6.3/5.9% (AL/AA); body pains 3.4/5.2 (AL/AA) %; anorexia 8.5/4.6% (AL/AA). Most adverse events occurred from day 1 and peaked by day 2 and 3 of medication with the mean duration of events being 3 days. By the end of the follow-up visit on day 7, the AEs had resolved in the majority of patients. Adverse events were more common in the AA group than AL revealing a better safety profile for AL (p < 0.001). Both ACTs demonstrated good ability to resolve the clinical symptoms of uncomplicated malaria.. In conclusion, this pilot CEM programme suggests that adverse events with ACTs were common. However, serious life-threatening events were not common. It appears that ACTs have a tolerable safety profile among Nigerians.

Topics: Adolescent; Adult; Amodiaquine; Anti-Infective Agents; Antimalarials; Artemisinins; Child; Child, Preschool; Cohort Studies; Ethanolamines; Female; Fluorenes; Humans; Infant; Infant, Newborn; Lumefantrine; Malaria; Male; Nigeria; Pregnancy; Prospective Studies; Young Adult

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

Plasmodium knowlesi was known as a plasmodium of macaques until P. knowlesi transmission to humans was recognised in Borneo and later throughout South-East Asia. We describe here a case of a P. knowlesi infection imported to Germany from Thailand. The patient had not taken antimalarial chemoprophylaxis and suffered from daily fever attacks. Microscopy revealed trophozoites and gametocytes resembling P. malariae. P. knowlesi malaria was confirmed by PCR.

Topics: Acute Kidney Injury; Antimalarials; Artemether; Artemisinins; Ethanolamines; Female; Fluorenes; Germany; Humans; Lumefantrine; Malaria; Microscopy; Middle Aged; Plasmodium knowlesi; Polymerase Chain Reaction; Thailand; Travel; Treatment Outcome

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

The World Health Organization aims at universal access to effective antimalarial treatment by the year 2015. Consequently, an enormous financial resource has been invested on Artemisinin Combination Therapy (ACT) subsidy. In Tanzania, strategies to increase access of artemether-lumufantrine (ALu) rural areas, where the burden is highest, includes subsidy to the Faith-based Organisations (FBO) facilities and accredited drug dispensing outlets (ADDOs). This study was done to assess the extent to which children suffering from malaria access ALu from the private sector in rural areas. A total of 1,235 under fives randomly selected from 12 rural villages were followed up at home on weekly basis for six months in Kilosa district in 2008. Using a structured questionnaire, caretakers were interviewed about the child's history of fever in the past 7 days; type of treatment given and the source. Baseline data were obtained on demographic characteristics, caretakers' knowledge about malaria and social economic indicators of the household. Of the 1,235 children followed-up, 740 care-seeking visits were recorded, of which, 264 (35.7%) were made at government health facilities and nearly a quarter (24.1%; 178/740) at ordinary shops that sell general merchandize including rice and sugar. Only 22% of the caretakers sought care from FBO and ADDOs. While 686 (86.6%) of the episodes were treated with antimalarials, only 319 (43%) received ALu, the recommended antimalarial. Majority (83%) of the visits made at government facilities were prescribed with ALu compared to less than half who went to FBO facilities (40.0%) and ADDOs (25.0%). In conclusion, this study has shown that less than a quarter of fever episodes suspected to be malaria in rural areas were made at FBO facilities and ADDOs, of which, less than half were treated with ALu. This shows that ALu subsidy to formal private sector does not adequately reach children in rural areas, where the malaria burden is highest. This cast some doubts if the target of universal access to effective antimalarial, by 2015, will be reached. There is need to consider enlisting the services of community health workers in the efforts to improve access to ALu in rural areas. Further research is needed to explore providers' / dispensers' preference for non-recommended antimalarials in the private sector and caretakers' preference for ordinary shops.

Topics: Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Female; Fever; Fluorenes; Health Services Accessibility; Humans; Infant; Infant, Newborn; Lumefantrine; Malaria; Male; Private Sector; Rural Population; Surveys and Questionnaires; Tanzania

Quartan malaria due to Plasmodium malariae is commonly regarded as being preventable by current antimalarials. A case of P. malariae infection occurred in spite of previous treatment of Plasmodium falciparum malaria 4 months earlier with a full therapy course of intravenous quinine hydrochloride and oral doxycycline followed by artemether + lumefantrine. Since the patient was not anymore exposed to agents of malaria in the meantime, a new infection by P. malariae after therapy is unlikely. The present observation is difficult to explain by the current view on the origin of latent P. malariae infections and recurrences which are thought to arise from intra-erythrocytic development stages susceptible to common antimalarials. The most likely explanation of our observation is a delayed pre-erythrocytic development. The latency between infection by P. malariae and the quartan malaria fever attack might have been extended further by an initial subclinical circulation of a low number of intra-erythrocytic asexual parasites in the blood stream preceeding the clinical quartan malaria breakthrough.

Topics: Adult; Animals; Antibodies, Protozoan; Antimalarials; Artemether; Artemisinins; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria; Plasmodium falciparum; Plasmodium malariae

The combination therapy of the Artemisinin-derivative Artemether (ART) with Lumefantrine (LM) (Coartem®) is an important malaria treatment regimen in many endemic countries. Resistance to Artemisinin has already been reported, and it is feared that LM resistance (LMR) could also evolve quickly. Therefore molecular markers which can be used to track Coartem® efficacy are urgently needed. Often, stable resistance arises from initial, unstable phenotypes that can be identified in vitro. Here we have used the Plasmodium falciparum multidrug resistant reference strain V1S to induce LMR in vitro by culturing the parasite under continuous drug pressure for 16 months. The initial IC(50) (inhibitory concentration that kills 50% of the parasite population) was 24 nM. The resulting resistant strain V1S(LM), obtained after culture for an estimated 166 cycles under LM pressure, grew steadily in 378 nM of LM, corresponding to 15 times the IC(50) of the parental strain. However, after two weeks of culturing V1S(LM) in drug-free medium, the IC(50) returned to that of the initial, parental strain V1S. This transient drug tolerance was associated with major changes in gene expression profiles: using the PFSANGER Affymetrix custom array, we identified 184 differentially expressed genes in V1S(LM). Among those are 18 known and putative transporters including the multidrug resistance gene 1 (pfmdr1), the multidrug resistance associated protein and the V-type H+ pumping pyrophosphatase 2 (pfvp2) as well as genes associated with fatty acid metabolism. In addition we detected a clear selective advantage provided by two genomic loci in parasites grown under LM drug pressure, suggesting that all, or some of those genes contribute to development of LM tolerance--they may prove useful as molecular markers to monitor P. falciparum LM susceptibility.

Topics: Animals; Antimalarials; Drug Design; Erythrocytes; Ethanolamines; Fluorenes; Gene Expression Profiling; Humans; Inhibitory Concentration 50; Likelihood Functions; Linear Models; Lumefantrine; Malaria; Mutation; Oligonucleotide Array Sequence Analysis; Parasites; Phenotype; Plasmodium falciparum; Polymerase Chain Reaction; RNA, Messenger

Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.

Topics: Animals; Antimalarials; Cell Line, Tumor; Drug Discovery; Drug Evaluation, Preclinical; Drug Resistance; Erythrocytes; Humans; Imidazoles; Liver; Malaria; Mice; Mice, Inbred BALB C; Molecular Structure; Piperazines; Plasmodium; Plasmodium berghei; Plasmodium falciparum; Plasmodium yoelii; Polymorphism, Single Nucleotide; Protozoan Proteins; Random Allocation; Small Molecule Libraries; Sporozoites

Naphthoquine (NQ), as a component of ARCO® which composed of NQ and artemisinin, is a new 4-aminoquinoline antimalarial synthesized by our institute. Here, a naphthoquine-resistant line of rodent malaria parasite was selected through exposing Plasmodium berghei Keyberg 173 strain to progressively increased drug pressure. The selected strain showed a more than 200-fold decreased susceptibility to NQ with a stable resistance phenotype after 10 serial passages without drug pressure or when cryopreserved over a period of 12 months. In a cross-resistance assay, the susceptibility of NQ-resistant parasites to chloroquine was decreased by 14.5-fold. These findings imply NQ-resistant parasites might be selected by long-term usage of NQ in epidemic areas and the efficacy of NQ or ARCO® in chloroquine-resistant Plasmodium falciparum epidemic areas should be monitored closely.

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Dose-Response Relationship, Drug; Drug Resistance; Ethanolamines; Fluorenes; Lumefantrine; Malaria; Male; Mice; Naphthoquinones; Plasmodium berghei; Pyrimethamine; Random Allocation

Multidrug-resistant Plasmodium falciparum malaria parasites pose a threat to effective drug control, even to artemisinin-based combination therapies (ACTs). Here we used linkage group selection and Solexa whole-genome resequencing to investigate the genetic basis of resistance to component drugs of ACTs. Using the rodent malaria parasite P. chabaudi, we analyzed the uncloned progeny of a genetic backcross between the mefloquine-, lumefantrine-, and artemisinin-resistant mutant AS-15MF and a genetically distinct sensitive clone, AJ, following drug treatment. Genomewide scans of selection showed that parasites surviving each drug treatment bore a duplication of a segment of chromosome 12 (translocated to chromosome 04) present in AS-15MF. Whole-genome resequencing identified the size of the duplicated segment and its position on chromosome 4. The duplicated fragment extends for ∼393 kbp and contains over 100 genes, including mdr1, encoding the multidrug resistance P-glycoprotein homologue 1. We therefore show that resistance to chemically distinct components of ACTs is mediated by the same genetic mutation, highlighting a possible limitation of these therapies.

Topics: Antimalarials; Artemisinins; Base Sequence; Chromosome Mapping; Drug Resistance, Multiple; Ethanolamines; Fluorenes; Genetic Linkage; Genome, Protozoan; Lumefantrine; Malaria; Mefloquine; Multidrug Resistance-Associated Proteins; Plasmodium chabaudi; Sequence Analysis, DNA

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

Topics: Adult; Antimalarials; Artemether; Artemisinins; Blood Transfusion; Doxycycline; Ethanolamines; Fluorenes; Hemolysis; Humans; Lumefantrine; Malaria; Malaysia; Male; Mefloquine; Microscopy; Phylogeny; Plasmodium knowlesi; Polymerase Chain Reaction; Protozoan Proteins; Quinine; Recurrence

During May 4, 2007-February 29, 2008, the United States resettled 6,159 refugees from Tanzania. Refugees received pre-departure antimalarial treatment with sulfadoxine-pyrimethamine (SP), partially supervised (three/six doses) artemether-lumefantrine (AL), or fully supervised AL. Thirty-nine malaria cases were detected. Disease incidence was 15.5/1,000 in the SP group and 3.2/1,000 in the partially supervised AL group (relative change = -79%, 95% confidence interval = -56% to -90%). Incidence was 1.3/1,000 refugees in the fully supervised AL group (relative change = -92% compared with SP group; 95% confidence interval = -66% to -98%). Among 39 cases, 28 (72%) were in refugees < 15 years of age. Time between arrival and symptom onset (median = 14 days, range = 3-46 days) did not differ by group. Thirty-two (82%) persons were hospitalized, 4 (10%) had severe manifestations, and 9 (27%) had parasitemias > 5% (range = < 0.1-18%). Pre-departure presumptive treatment with an effective drug is associated with decreased disease among refugees.

Topics: Adolescent; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Drug Combinations; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Pyrimethamine; Refugees; Sulfadoxine; Tanzania; United States

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

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

We report a case of Plasmodium falciparum and Plasmodium malariae coinfection with associated failure of clinical response to artemether + lumefantrine therapy. This case highlights the need to consider co-infection in the setting of apparent treatment failure and the impact of mixed species infection upon host dynamics and clinical presentation. Recognition of malarial co-infection is clinically important for determining appropriate therapy and preventing disease sequelae.

Topics: Antimalarials; Artemether; Artemisinins; Australia; Coinfection; Drug Therapy, Combination; Ethanolamines; Fluorenes; Follow-Up Studies; Humans; Lumefantrine; Malaria; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Plasmodium malariae; Travel; Treatment Outcome; Uganda

Malaria transmission is now recognized as a key target for intervention. Evaluation of the Plasmodium oocyst burden in the midguts of Anopheles spp. is important for many of assays investigating transmission. However, current assays are very time-consuming, manually demanding and patently subject to observer-observer variation.. This report presents the development of a method to rapidly, accurately and consistently determine oocyst burdens on mosquito midguts using GFP-expressing Plasmodium berghei and a custom-written macro for ImageJ. The counting macro was optimized and found to be fit-for-purpose by performing gametocyte membrane feeds with parasite infected blood. Dissected midguts were counted both manually and using the automated macro, then compared. The optimized settings for the macro were then validated by using it to determine the transmission blocking efficacies of two anti-malarial compounds - dehydroepiandrosterone sulphate and lumefantrine, in comparison to manually determined analysis of the same experiment.. Concurrence of manual and macro counts was very high (R2 = 0.973) and reproducible. Estimated transmission blocking efficacies between manual and automated analysis were highly concordant, indicating that dehydroepiandrosterone sulphate has little or no transmission blocking potential, whilst lumefantrine strongly inhibits sporogony.. Recognizing a potential five-fold increase in throughput, the resulting reduction in personnel costs, and the absence of inter-operator/laboratory variation possible with this approach, this counting macro may be a benefit to the malaria community.

Topics: Animals; Anopheles; Antimalarials; Automation; Dehydroepiandrosterone Sulfate; Ethanolamines; Female; Fluorenes; Green Fluorescent Proteins; Humans; Image Processing, Computer-Assisted; Lumefantrine; Malaria; Male; Mice; Microscopy; Oocysts; Plasmodium berghei; Reproducibility of Results; Sensitivity and Specificity

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.

Topics: Adult; Antimalarials; Artemisinins; Artesunate; Blood Pressure; Electrocardiography; Ethanolamines; Fluorenes; Glasgow Coma Scale; Heart Rate; Humans; Long QT Syndrome; Lumefantrine; Malaria; Male; Patient Selection

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

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

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

Topics: Administration, Oral; Antimalarials; Artemether; Artemisinins; Drug Approval; Drug Combinations; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Tablets; United States; United States Food and Drug Administration

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of approximately 1.7 million compounds, we identified a diverse collection of approximately 6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 microM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.

Topics: Animals; Antimalarials; Cluster Analysis; Computational Biology; Drug Evaluation, Preclinical; Drug Resistance; Folic Acid Antagonists; Malaria; Models, Molecular; Parasites; Plasmodium falciparum; Reproducibility of Results; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase

Case-management with artemether-lumefantrine (AL) is one of the key strategies to control malaria in many African countries. Yet, the reports on translation of AL implementation activities into clinical practice are scarce. Here the quality of AL case-management is reported from Uganda; approximately one year after AL replaced combination of chloroquine and sulphadoxine-pyrimethamine (CQ+SP) as recommended first line treatment for uncomplicated malaria.. A cross-sectional survey, using a range of quality of care assessment tools, was undertaken at all government and private-not-for-profit facilities in four Ugandan districts. Main outcome measures were AL prescribing, dispensing and counseling practices in comparison with national guidelines, and factors influencing health workers decision to 1) treat for malaria, and 2) prescribe AL.. 195 facilities, 232 health workers and 1,763 outpatient consultations were evaluated. Of 1,200 patients who needed treatment with AL according to guidelines, AL was prescribed for 60%, CQ+SP for 14%, quinine for 4%, CQ for 3%, other antimalarials for 3%, and 16% of patients had no antimalarial drug prescribed. AL was prescribed in the correct dose for 95% of patients. Only three out of seven AL counseling and dispensing tasks were performed for more than 50% of patients. Patients were more likely to be treated for malaria if they presented with main complaint of fever (OR = 5.22; 95% CI: 3.61-7.54) and if they were seen by supervised health workers (OR = 1.63; 95% CI: 1.06-2.50); however less likely if they were treated by more qualified health workers (OR = 0.61; 95% CI: 0.40-0.93) and presented with skin problem (OR = 0.29; 95% CI: 0.15-0.55). AL was more likely prescribed if the appropriate weight-specific AL pack was in stock (OR = 6.15; 95% CI: 3.43-11.05) and when CQ was absent (OR = 2.16; 95% CI: 1.09-4.28). Routine AL implementation activities were not associated with better performance.. Although the use of AL was predominant over non-recommended therapies, the quality of AL case-management at the point of care is not yet optimal. There is an urgent need for innovative quality improvement interventions, which should be rigorously tested. Adequate availability of ACTs at the point of care will, however, ultimately determine the success of any performance interventions and ACT policy transitions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Cross-Sectional Studies; Ethanolamines; Fluorenes; Guideline Adherence; Health Policy; Health Services Research; Humans; Infant; Infant, Newborn; Lumefantrine; Malaria; Middle Aged; Uganda

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

Rapid diagnostic tests (RDTs) for malaria are increasingly being considered for routine use in Africa. However, many RDTs are available and selecting the ideal test for a particular setting is challenging. The appropriateness of RDT choice depends in part on patient population and epidemiological setting, and on decision makers' priorities. The model presented (available online) can be used by decision makers to evaluate alternative RDTs and assess the circumstances under which their use is justified on economic grounds.. An interactive model based on a decision-tree structure and a cost-benefit framework was designed to compare different diagnostic strategies. Variables included in the model can be modified by users, including RDT and treatment costs, test accuracies (sensitivity and specificity), probabilities for developing severe illness, case-fatality rates, and clinician response to negative test results. To illustrate how the model can be used, a comparison is made of presumptive treatment with two available RDTs, one detecting histidine-rich protein-2 (HRP2) and one detecting Plasmodium lactate dehydrogenase (pLDH). Data inputs were obtained from a study comparing the RDTs at seven sites in Uganda.. Applying the model in the illustrative Ugandan context demonstrates that if only direct expenditures are considered, the pLDH test is the preferred option for adult patients except in high transmission settings, while young children are best treated presumptively in all settings. When health outcomes are considered, the HRP2 test gains an advantage in almost all settings and for all age groups. Introducing possible adverse consequences of using an antimalarial into the analysis, such as adverse drug reactions, or the development of resistance, considerably strengthens the case for using RDTs. When the model is adjusted to account for less than complete adherence to test results, the efficiency of using RDTs drops sharply.. Model output demonstrates that which test is preferable varies by location, depending on factors such as malaria transmission intensity and the costs and accuracies of the RDTs under consideration. Despite the uncertainties and complexities involved, adaptable models such as the one presented here can serve as a practical tool to assist policy makers in efficient deployment of new technologies.

Topics: Adolescent; Adult; Animals; Antigens, Protozoan; Antimalarials; Artemether; Artemisinins; Child; Child, Preschool; Cost-Benefit Analysis; Costs and Cost Analysis; Decision Support Techniques; Decision Trees; Diagnostic Tests, Routine; Ethanolamines; Fluorenes; Humans; L-Lactate Dehydrogenase; Lumefantrine; Malaria; Plasmodium; Protozoan Proteins; Sensitivity and Specificity; Uganda; Urban Population

Following the recognition that morbidity and mortality due to malaria had dramatically increased in the last three decades, in 2002 the government of Zambia reviewed its efforts to prevent and treat malaria. Convincing evidence of the failing efficacy of chloroquine resulted in the initiation of a process that eventually led to the development and implementation of a new national drug policy based on artemisinin-based combination therapy (ACT).. All published and unpublished documented evidence dealing with the antimalarial drug policy change was reviewed. These data were supplemented by the authors' observations of the policy change process. The information has been structured to capture the timing of events, the challenges encountered, and the resolutions reached in order to achieve implementation of the new treatment policy.. A decision was made to change national drug policy to artemether-lumefantrine (AL) in the first quarter of 2002, with a formal announcement made in October 2002. During this period, efforts were undertaken to identify funding for the procurement of AL and to develop new malaria treatment guidelines, training materials, and plans for implementation of the policy. In order to avoid a delay in implementation, the policy change decision required a formal adoption within existing legislation. Starting with donated drug, a phased deployment of AL began in January 2003 with initial use in seven districts followed by scaling up to 28 districts in the second half of 2003 and then to all 72 districts countrywide in early 2004.. Drug policy changes are not without difficulties and demand a sustained international financing strategy for them to succeed. The Zambian experience demonstrates the need for a harmonized national consensus among many stakeholders and a political commitment to ensure that new policies are translated into practice quickly. To guarantee effective policies requires more effort and recognition that this becomes a health system and not a drug issue. This case study attempts to document the successful experience of change to ACT in Zambia and provides a realistic overview of some of the painful experiences and important lessons learnt.

Topics: Antimalarials; Artemisinins; Chloroquine; Drug Therapy, Combination; Ethanolamines; Fluorenes; Health Planning Guidelines; Health Policy; Humans; Lumefantrine; Malaria; Zambia

Kenya recently changed its antimalarial drug policy to a specific artemisinin-based combination therapy (ACT), artemether-lumefantrine (AL). New national guidelines on the diagnosis, treatment and prevention were developed and disseminated to health workers together with in-service training.. Between January and March 2007, 36 in-depth interviews were conducted in five rural districts with health workers who attended in-service training and were non-adherent to the new guidelines. A further 20 interviews were undertaken with training facilitators and members of District Health Management Teams (DHMTs) to explore reasons underlying health workers' non-adherence.. Health workers generally perceived AL as being tolerable and efficacious as compared to amodiaquine and sulphadoxine-pyremethamine. However, a number of key reasons for non-adherence were identified. Insufficient supply of AL was a major issue and hence fears of stock outs and concern about AL costs was an impediment to AL prescription. Training messages that contradicted the recommended guidelines also led to health worker non-adherence, compounded by a lack of follow-up supervision. In addition, the availability of non-recommended antimalarials such as amodiaquine caused prescription confusion. Some health workers and DHMT members maintained that shortage of staff had resulted in increased patient caseload affecting the delivery of the desirable quality of care and adherence to guidelines.. The introduction of free efficacious ACTs in the public health sector in Kenya and other countries has major potential public health benefits for Africa. These may not be realized if provider prescription practices do not conform to the recommended treatment guidelines. It is essential that high quality training, drug supply and supervision work synergistically to ensure appropriate case management.

Topics: Adult; Antimalarials; Artemether; Artemisinins; Case Management; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Government Programs; Guideline Adherence; Health Personnel; Humans; Kenya; Lumefantrine; Malaria; Male; Middle Aged; Rural Population; Surveys and Questionnaires

Combination drug therapy for malaria is recommended both to prevent and to overcome drug resistance. Drug combinations developed for use in Asia are being deployed in Africa, where higher rates of malaria affect the therapeutic and public health objectives of malaria chemotherapy as well as drug safety. Rational consideration of drug mechanisms, pharmacokinetics (PK), pharmacodynamics (PD), and malaria epidemiology should result in more effective combination regimens that retain therapeutic and prophylactic efficacy in the face of resistance.

Topics: Amodiaquine; Antimalarials; Artemether; Artemisinins; Artesunate; Chloroquine; Dapsone; Drug Design; Drug Resistance; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Global Health; Half-Life; Humans; Lumefantrine; Malaria; Mefloquine; Pregnancy; Pregnancy Complications, Infectious; Proguanil; Pyrimethamine; Quinine; Sesquiterpenes; Sulfadoxine

Topics: Antimalarials; Artemether; Artemisinins; Child; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Safety

Humanitarian medical programmes in the tropics have the opportunity to provide beacons of good practice. The use of modern drugs and diagnostics, a lack of bureaucracy, adequate budgets, motivated staff and well-functioning supply lines all contribute to the success of this approach. At a joint meeting of the Royal Society of Tropical Medicine, the London School of Hygiene and Tropical Medicine, Médecins Sans Frontières and Merlin, new data were presented on the outcomes of recent humanitarian programmes to control malaria (Ethiopia), human African trypanosomiasis (south Sudan), Lassa fever (Sierra Leone) and tuberculosis (Tomsk, former USSR).

Topics: Antimalarials; Artemether; Artemisinins; Attitude to Health; Child; Child, Preschool; Communicable Disease Control; Cross Infection; Eflornithine; Ethanolamines; Ethiopia; Female; Fluorenes; Humans; Lassa Fever; Lumefantrine; Malaria; Medical Missions; Pregnancy; Sierra Leone; Sudan; Trypanocidal Agents; Trypanosomiasis, African; Tuberculosis, Pulmonary; USSR

Artemether-lumefantrine is the first registered, fixed, artemisinin-based combination treatment. Artemisinin derivatives are highly effective antimalarials with a favorable safety profile. Concerns remain over their potential neurotoxicity, although there has been no clinical evidence of this in humans. In animals (rats, dogs, and monkeys) artemether, a derivative of artemisinin is associated with an unusual toxicity pattern in specific brain nuclei involving the auditory and vestibular pathways. A recent report from Mozambique described a small but significant and irreversible hearing loss in patients exposed to artemether-lumefantrine. To explore this issue, we conducted a case-control study using tympanometry, audiometry and auditory brain-stem responses. We assessed 68 subjects who had been treated with artemether-lumefantrine within the previous five years and 68 age- and sex-matched controls living in the malarious region along the Thailand-Myanmar border. There were no differences in the test results between cases and controls. There was no neurophysiologic evidence of auditory brainstem toxicity that could be attributed to artemether-lumefantrine in this study population.

Topics: Acoustic Impedance Tests; Adolescent; Adult; Aged; Antimalarials; Artemether; Artemisinins; Audiometry; Case-Control Studies; Child; Drug Therapy, Combination; Ethanolamines; Evoked Potentials, Auditory, Brain Stem; Female; Fluorenes; Hearing Loss; Humans; Lumefantrine; Malaria; Male; Middle Aged; Treatment Outcome

Topics: Anti-Infective Agents; Artemisinins; Audiometry; Auditory Threshold; Case-Control Studies; Ethanolamines; Fluorenes; Hearing Loss; Humans; Lumefantrine; Malaria; Research; Sesquiterpenes; Time Factors

We assessed the feasibility and acceptability of and the willingness to use artemether-lumefantrine (Coartem) during early, appropriate treatment of malaria/fever in children aged 6-59 months at the community and household level in a rural malaria-endemic area in Ghana.. In this descriptive study with a pre- post-evaluation of an intervention, community perceptions of fever, health-seeking behaviour and current treatment practices for children aged 6-59 months were ascertained through qualitative research and surveys. The children were counted in a household census and given identification cards. Community-based agents (who were supervised monthly) dispensed a 6-dose-treatment formulation of Coartem over a 4 months period and counseled caregivers on case management and referral. Caregivers who consulted were followed up after 4 days to determine adherence to the treatment regimen. Blister packs of the drugs were inspected where available. The performance of the agents in terms of counselling, advising on referral and reporting was evaluated. Community satisfaction was also assessed qualitatively through focus group discussions and interviews.. Three hundred and sixty-three children sought care during the intervention period. All 235 children aged 6-35 months were correctly provided the one tablet per dose per treatment package compared with 119 of 125 children 36-59 months (95.2%). Only 5 of 17 children were referred appropriately. All 334 caregivers followed the correct drug administration schedule, i.e. twice a day for 3 days. Validation of drugs received indicates that all 204 children aged 6-35 months and 103/118 (87.3%) children aged 36-59 months received the correct drug dose. Adherence of agents and caregivers to the treatment was 308/334 (92.5%). Delay in seeking care was reduced from 3 to 2 days. No serious adverse drug reactions were reported. Community members were enthusiastic about the performance of the agents.. A Home Management of Malaria (HMM) strategy with Coartem using trained community-based agents supervised monthly is feasible, acceptable, and can achieve high levels of compliance within Dangme, West District of Ghana. However, if the intervention is to be sustainable, the agents need to be paid.

Topics: Antimalarials; Artemether; Artemisinins; Caregivers; Child, Preschool; Clinical Competence; Community Health Services; Drug Administration Schedule; Drug Combinations; Ethanolamines; Feasibility Studies; Female; Fluorenes; Ghana; Home Nursing; Humans; Infant; Lumefantrine; Malaria; Male; Patient Acceptance of Health Care; Patient Compliance

Topics: Animals; Antimalarials; Artemether; Artemisinins; Brazil; Drug Combinations; Ethanolamines; Fluorenes; Humans; Lumefantrine; Malaria; Time Factors; World Health Organization

A recent observational study undertaken at 17 health facilities with microscopy in Kenya revealed that potential benefits of malaria microscopy are not realized because of irrational clinical practices and the low accuracy of routine microscopy. Using these data, we modelled financial and clinical implications of revised clinical practices and improved accuracy of malaria microscopy among adult outpatients under the artemether-lumefantrine (AL) treatment policy for uncomplicated malaria in Kenya.. The cost of AL, antibiotics and malaria microscopy and the expected number of malaria diagnosis errors were estimated per 1,000 adult outpatients presenting at a facility with microscopy under three scenarios: (1) current clinical practice and accuracy of microscopy (option A), (2) revised clinical practice with current accuracy of microscopy (option B) and (3) revised clinical practice with improved accuracy of microscopy (option C). Revised clinical practice was defined as performing a blood slide for all febrile adults and prescribing antimalarial treatment only for positive results. Improved accuracy of routine microscopy was defined as 90% sensitivity and specificity. In the sensitivity analysis, the implications of changes in the cost of drugs and malaria microscopy and changes in background malaria prevalence were examined for each option.. The costs of AL, antibiotics and malaria microscopy decreased from 2,154 dollars under option A to 1,254 dollars under option B and 892 dollars under option C. Of the cost savings from option C, 72% was from changes in clinical practice, while 28% was from improvements in the accuracy of microscopy. Compared with 638 malaria overdiagnosis errors per 1,000 adults under option A, 375 and 548 fewer overdiagnosis errors were estimated, respectively, under options B and C. At the same time, the number of missed malaria diagnoses remained generally low under all options. Sensitivity analysis showed that both options B and C are robust to a wide range of assumptions on the costs of drugs, costs of blood slides and malaria prevalence.. Even with the imperfect microscopy conditions at Kenyan facilities, implementation of revised clinical practice (option B) would substantially reduce the costs and errors from malaria overdiagnosis. Additional interventions to improve the accuracy of microscopy (option C) can achieve further benefits; however, improved microscopy in the absence of revised clinical practice is unlikely to generate significant cost savings. Revision of guidelines to state explicitly age-specific indications for the use and interpretation of malaria microscopy is urgently needed. Further prospective studies are required to evaluate the effectiveness and costs of interventions to improve clinical practice and the accuracy of malaria microscopy.

Topics: Adolescent; Adult; Anti-Infective Agents; Antimalarials; Artemether; Artemisinins; Diagnostic Errors; Ethanolamines; Fever; Fluorenes; Health Care Costs; Humans; Kenya; Lumefantrine; Malaria; Microscopy; Models, Economic; Prevalence; Sensitivity and Specificity

Fever is the clinical hallmark of malaria disease. The Roll Back Malaria (RBM) movement promotes prompt, effective treatment of childhood fevers as a key component to achieving its optimistic mortality reduction goals by 2010. A neglected concern is how communities will access these new medicines promptly and the costs to poor households when they are located in rural areas distant to health services.. We assemble data developed between 2001 and 2002 in Kenya to describe treatment choices made by rural households to treat a child's fever and the related costs to households. Using a cost-of-illness approach, we estimate the expected cost of a childhood fever to Kenyan households in 2002. We develop two scenarios to explore how expected costs to households would change if more children were treated at a health care facility with an effective antimalarial within 48 hours of fever onset.. 30% of uncomplicated fevers were managed at home with modern medicines, 38% were taken to a health care facility (HCF), and 32% were managed at home without the use of modern medicines. Direct household cash expenditures were estimated at $0.44 per fever, while the total expected cost to households (cash and time) of an uncomplicated childhood fever is estimated to be $1.91. An estimated mean of 1.42 days of caretaker time devoted to each fever accounts for the majority of household costs of managing fevers. The aggregate cost to Kenyan households of managing uncomplicated childhood fevers was at least $96 million in 2002, equivalent to 1.00% of the Kenyan GDP. Fewer than 8% of all fevers were treated with an antimalarial drug within 24 hours of fever onset, while 17.5% were treated within 48 hours at a HCF. To achieve an increase from 17.5% to 33% of fevers treated with an antimalarial drug within 48 hours at a HCF (Scenario 1), children already being taken to a HCF would need to be taken earlier. Under this scenario, direct cash expenditures would not change, and total household costs would fall slightly to $1.86 because caretakers also save time with prompt treatment if the child has malaria.. The management of uncomplicated childhood fevers imposes substantial costs on Kenyan households. Achieving substantial improvements in the numbers of fevers treated within 48 hours at a HCF with an effective antimalarial drug (Scenario 1) will not impose additional costs on households. Achieving additional improvements in fevers treated promptly at a HCF (Scenario 2) will impose additional costs on some households roughly equal to average cash expenses for transportation to a HCF. Additional financing mechanisms that further reduce the costs of accessing care at a HCF and/or that make artemisinin-based combination therapies (ACTs) accessible for home management need to be developed and evaluated as a top priority.

Topics: Antimalarials; Artemisinins; Caregivers; Child, Preschool; Cost of Illness; Drug Therapy, Combination; Ethanolamines; Family Characteristics; Fever; Fluorenes; Health Care Surveys; Health Expenditures; Health Services Accessibility; Home Nursing; Humans; Infant; Kenya; Lactones; Lumefantrine; Malaria; Models, Econometric; Rural Health Services; Sesquiterpenes; Time Factors