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2.
Lancet ; 395(10233): 1345-1360, 2020 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-32171078

RESUMO

BACKGROUND: Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. METHODS: In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2-65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either dihydroartemisinin-piperaquine or dihydroartemisinin-piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate-mefloquine or dihydroartemisinin-piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether-lumefantrine or artemether-lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. FINDINGS: Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either dihydroartemisinin-piperaquine (183 [17%]), dihydroartemisinin-piperaquine plus mefloquine (269 [24%]), artesunate-mefloquine (73 [7%]), artemether-lumefantrine (289 [26%]), or artemether-lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after dihydroartemisinin-piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after dihydroartemisinin-piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p<0·0001). Efficacy of dihydroartemisinin-piperaquine plus mefloquine in the three sites in Myanmar was 91% (42 of 46; 95% CI 79 to 98) versus 100% (42 of 42; 95% CI 92 to 100) after dihydroartemisinin-piperaquine (risk difference 9%, 95% CI 1 to 17; p=0·12). The 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine (96% [68 of 71; 95% CI 88 to 99]) was non-inferior to that of artesunate-mefloquine (95% [69 of 73; 95% CI 87 to 99]) in three sites in Cambodia (risk difference 1%; 95% CI -6 to 8; p=1·00). The overall 42-day PCR-corrected efficacy of artemether-lumefantrine plus amodiaquine (98% [281 of 286; 95% CI 97 to 99]) was similar to that of artemether-lumefantrine (97% [279 of 289; 95% CI 94 to 98]; risk difference 2%, 95% CI -1 to 4; p=0·30). Both TACTs were well tolerated, although early vomiting (within 1 h) was more frequent after dihydroartemisinin-piperaquine plus mefloquine (30 [3·8%] of 794) than after dihydroartemisinin-piperaquine (eight [1·5%] of 543; p=0·012). Vomiting after artemether-lumefantrine plus amodiaquine (22 [1·3%] of 1703) and artemether-lumefantrine (11 [0·6%] of 1721) was infrequent. Adding amodiaquine to artemether-lumefantrine extended the electrocardiogram corrected QT interval (mean increase at 52 h compared with baseline of 8·8 ms [SD 18·6] vs 0·9 ms [16·1]; p<0·01) but adding mefloquine to dihydroartemisinin-piperaquine did not (mean increase of 22·1 ms [SD 19·2] for dihydroartemisinin-piperaquine vs 20·8 ms [SD 17·8] for dihydroartemisinin-piperaquine plus mefloquine; p=0·50). INTERPRETATION: Dihydroartemisinin-piperaquine plus mefloquine and artemether-lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. FUNDING: UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Adolescente , Adulto , Amodiaquina/administração & dosagem , Amodiaquina/uso terapêutico , Antraquinonas/administração & dosagem , Antraquinonas/uso terapêutico , Antimaláricos/administração & dosagem , Combinação Arteméter e Lumefantrina/administração & dosagem , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/administração & dosagem , Resistência a Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Mefloquina/administração & dosagem , Mefloquina/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Reação em Cadeia da Polimerase , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Resultado do Tratamento , Adulto Jovem
3.
PLoS One ; 15(2): e0228190, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023293

RESUMO

BACKGROUND: Mass administrations of antimalarial drugs (MDA) have reduced the incidence and prevalence of P. falciparum infections in a trial in the Greater Mekong Subregion. Here we assess the impact of the MDA on P. vivax infections. METHODS: Between May 2013 and July 2017, four villages in each Myanmar, Vietnam, Cambodia and Lao PDR were selected based on high prevalence of P. falciparum infections. Eight of the 16 villages were randomly assigned to receive MDA consisting of three-monthly rounds of three-day courses of dihydroartemisinin-piperaquine and, except in Cambodia, a single low-dose of primaquine. Cross-sectional surveys were conducted at quarterly intervals to detect Plasmodium infections using ultrasensitive qPCR. The difference in the cumulative incidence between the groups was assessed through a discrete time survival approach, the difference in prevalence through a difference-in-difference analysis, and the difference in the number of participants with a recurrence of P. vivax infection through a mixed-effect logistic regression. RESULTS: 3,790 (86%) residents in the intervention villages participated in at least one MDA round, of whom 2,520 (57%) participated in three rounds. The prevalence of P. vivax infections fell from 9.31% to 0.89% at month 3 but rebounded by six months to 5.81%. There was no evidence that the intervention reduced the cumulative incidence of P.vivax infections (95% confidence interval [CI] Odds ratio (OR): 0.29 to 1.36). Similarly, there was no evidence of MDA related reduction in the number of participants with at least one recurrent infection (OR: 0.34; 95% CI: 0.08 to 1.42). CONCLUSION: MDA with schizontocidal drugs had a lasting effect on P. falciparum infections but only a transient effect on the prevalence of P. vivax infections. Radical cure with an 8-aminoquinoline will be needed for the rapid elimination of vivax malaria.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Vivax/tratamento farmacológico , Primaquina/uso terapêutico , Quinolinas/uso terapêutico , Adolescente , Adulto , Camboja/epidemiologia , Criança , Feminino , Humanos , Malária Falciparum/epidemiologia , Malária Vivax/epidemiologia , Masculino , Administração Massiva de Medicamentos , Mianmar/epidemiologia , Prevalência , Recidiva , Resultado do Tratamento , Vietnã/epidemiologia , Adulto Jovem
4.
Infect Dis Poverty ; 9(1): 21, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32046780

RESUMO

BACKGROUND: Plasmodium falciparum malaria is endemic in the southern sahelian zone of Mauritania where intense internal and trans-border human and livestock movement occurs. The risk of importation and spread of drug-resistant parasites need to be regularly assessed in this region. The objective of the study was to assess the recent malaria situation near the Mauritania-Mali border. METHODS: Between February 2015 and December 2017, patients with fever or history of fever during the previous 48 h, presenting at the health centre of Kobeni city, were screened for malaria using a rapid diagnostic test (RDT) and microscopic examination of blood smears. The diagnosis was later confirmed by PCR. Cohen's kappa statistics was used to estimate the degree of agreement between diagnostic methods. Fisher's exact test was used to compare proportions. The odds ratio was calculated to measure the association between the use of bed nets and malaria infection. RESULTS: A total of 2326 febrile patients (mean age, 20.2 years) were screened for malaria. The presence of malaria parasites was detected by RDT and microscopy in 53.0% and 49.3% of febrile patients, respectively, and was confirmed by PCR in 59.7% (45 missing data). Of 1361 PCR-positive samples, 1205 (88.5%) were P. falciparum, 47 (3.5%) P. vivax, and 99 (7.3%) P. falciparum-P. vivax mixed infection. Malaria transmission occurred mostly during and shortly after the rainy season. The annual rainfall was relatively low in 2016 (267 mm) and 2017 (274 mm), compared to 2015 (448 mm), and coincided with a decline in malaria prevalence in 2016-2017. Although 71.8% of febrile patients reported to possess at least one bed net in the household in our questionnaire, its reported use was not protective against malaria infection (odds ratio: 1.1, 95% CI: 0.91-1.32). CONCLUSIONS: Our study confirmed that P. falciparum is the dominant species in the sahelian zone and that malaria transmission is seasonal and associated with rainfall in this zone. The application of the current national policy based on rapid and reliable malaria diagnosis, case management with artemisinin-based combination therapy, intermittent preventive treatment for pregnant women, distribution and use of long-lasting insecticide impregnated bed nets, and the planned introduction of seasonal malaria chemoprevention for all children under 6 years old is expected to sustainably reduce malaria transmission in this zone.


Assuntos
Antimaláricos/uso terapêutico , Malária Falciparum/epidemiologia , Malária Vivax/epidemiologia , Adolescente , Artemisininas/uso terapêutico , Criança , Pré-Escolar , Coinfecção/diagnóstico , Coinfecção/tratamento farmacológico , Coinfecção/epidemiologia , Testes Diagnósticos de Rotina/métodos , Quimioterapia Combinada , Feminino , Humanos , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Malária Vivax/diagnóstico , Malária Vivax/tratamento farmacológico , Masculino , Mauritânia/epidemiologia , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/isolamento & purificação , Estações do Ano
5.
Science ; 367(6473): 51-59, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31896710

RESUMO

Artemisinin and its derivatives (ARTs) are the frontline drugs against malaria, but resistance is jeopardizing their effectiveness. ART resistance is mediated by mutations in the parasite's Kelch13 protein, but Kelch13 function and its role in resistance remain unclear. In this study, we identified proteins located at a Kelch13-defined compartment. Inactivation of eight of these proteins, including Kelch13, rendered parasites resistant to ART, revealing a pathway critical for resistance. Functional analysis showed that these proteins are required for endocytosis of hemoglobin from the host cell. Parasites with inactivated Kelch13 or a resistance-conferring Kelch13 mutation displayed reduced hemoglobin endocytosis. ARTs are activated by degradation products of hemoglobin. Hence, reduced activity of Kelch13 and its interactors diminishes hemoglobin endocytosis and thereby ART activation, resulting in parasite resistance.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/genética , Endocitose/genética , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Hemoglobinas/metabolismo , Humanos , Malária Falciparum/tratamento farmacológico , Mutação
6.
BMC Med ; 18(1): 17, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31996199

RESUMO

BACKGROUND: There has been a successful push towards parasitological diagnosis of malaria in Africa, mainly with rapid diagnostic tests (mRDTs), which has reduced over-prescribing of artemisinin-based combination therapies (ACT) to malaria test-negative patients. The effect on prescribing for test-positive patients has received much less attention. Malaria infection in endemic Africa is often most dangerous for young children and those in low-transmission settings. This study examined non-prescription of antimalarials for patients with malaria infection demonstrated by positive mRDT results, and in particular these groups who are most vulnerable to poor outcomes if antimalarials are not given. METHODS: Analysis of data from 562,762 patients in 8 studies co-designed as part of the ACT Consortium, conducted 2007-2013 in children and adults, in Cameroon, Ghana, Nigeria, Tanzania, and Uganda, in a variety of public and private health care sector settings, and across a range of malaria endemic zones. RESULTS: Of 106,039 patients with positive mRDT results (median age 6 years), 7426 (7.0%) were not prescribed an ACT antimalarial. The proportion of mRDT-positive patients not prescribed ACT ranged across sites from 1.3 to 37.1%. For patients under age 5 years, 3473/44,539 (7.8%) were not prescribed an ACT, compared with 3833/60,043 (6.4%) of those aged ≥ 5 years. The proportion of < 5-year-olds not prescribed ACT ranged up to 41.8% across sites. The odds of not being prescribed an ACT were 2-32 times higher for patients in settings with lower-transmission intensity (using test positivity as a proxy) compared to areas of higher transmission. mRDT-positive children in low-transmission settings were especially likely not to be prescribed ACT, with proportions untreated up to 70%. Of the 7426 mRDT-positive patients not prescribed an ACT, 4121 (55.5%) were prescribed other, non-recommended non-ACT antimalarial medications, and the remainder (44.5%) were prescribed no antimalarial. CONCLUSIONS: In eight studies of mRDT implementation in five African countries, substantial proportions of patients testing mRDT-positive were not prescribed an ACT antimalarial, and many were not prescribed an antimalarial at all. Patients most vulnerable to serious outcomes, children < 5 years and those in low-transmission settings, were most likely to not be prescribed antimalarials, and young children in low-transmission settings were least likely to be treated for malaria. This major public health risk must be addressed in training and practice. TRIAL REGISTRATION: Reported in individual primary studies.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária/tratamento farmacológico , Padrões de Prática Médica , Adolescente , Adulto , Criança , Pré-Escolar , Assistência à Saúde/normas , Feminino , Gana , Humanos , Malária/diagnóstico , Masculino , Pessoa de Meia-Idade , Nigéria , Prescrições , Setor Privado , Tanzânia , Uganda , Adulto Jovem
7.
Parasitol Int ; 74: 101919, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31015034

RESUMO

BACKGROUND: Malaria parasites have developed resistance to most of the known antimalarial drugs in clinical practice, with reports of artemisinin resistance emerging in South East Asia (SEA). We sort to find the status of artemisinin resistance and efficacy of different modalities of the current artemisinin-based combination therapies (ACTs). METHODS: We carried out a systematic search in 11 electronic databases to identify in vivo studies published between 2001 and 2017 that reported artemisinin resistance. This was then followed by A network meta-analysis to compare the efficacy of different ACTs. Quality assessment was performed using the Cochrane Risk of Bias (ROB) tool for randomized controlled trials and National Institute of Health (NIH) tool for cross-sectional studies. The study protocol was registered in PROSPERO under number CRD42018087574. RESULTS: With 8400 studies initially identified, 82 were eligible for qualitative and quantitative analysis. Artemisinin resistance was only reported in South East Asia. K13 mutation C580Y was the most abundant mutation associated with resistance having an abundance of 63.1% among all K13 mutations reported. Although the overall network meta-analysis had shown good performance of dihydroartemisinin piperaquine in the early years, a subgroup analysis of the recent years revealed a poor performance of the drug in relation to recrudescence, clinical failure and parasitological failure especially in the artemisinin resistant regions. CONCLUSION: With report of high resistance and treatment failure against the leading artemisinin combination therapy in South East Asia, it is imperative that a new drug or a formulation is developed before further spread of resistance.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Resistência a Medicamentos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Ásia Sudeste , Estudos Transversais , Quimioterapia Combinada , Humanos , Metanálise em Rede , Falha de Tratamento
8.
BMC Infect Dis ; 19(1): 1025, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31795967

RESUMO

BACKGROUND: Treatment for severe malaria must be prompt with effective parenteral antimalarial drugs for at least 24 h to achieve fast parasite clearance, and when the patient can tolerate oral therapy, treatment should be completed with effective artemisinin based combination therapy (ACT) for complete parasite clearance and to prevent recrudescence. We evaluated piperaquine concentration and malaria treatment outcomes among Ugandan children treated for severe malaria with intravenous artesunate (AS) or quinine (QN) plus dihydroartemisinin-piperaquine (DP), in Tororo District Hospital in Eastern Uganda. METHODS: Capillary blood piperaquine concentration data were obtained from a randomized clinical trial whose objective was to evaluate parasite clearance, 42-day parasitological treatment outcomes and safety, following treatment of severe malaria with intravenous AS or QN, plus artemether-lumefantrine or DP among children in Tororo District Hospital, in Eastern Uganda. RESULTS: Piperaquine concentration data from 150 participants who received DP were analyzed. Participants with unadjusted treatment failure had lower median day 7 capillary piperaquine concentration than those with treatment success (34.7 (IQR) (17.9-49.1) vs 66.7 (IQR) (41.8-81.9), p < 0.001), and lower than the recommended day 7 cut off level of 57 ng/mL. There was no difference in median capillary piperaquine concentrations among participants with re-infection and recrudescence (35.3 (IQR) (17.9-55.2) vs 34.8 (IQR) (18.1-45.1), p = 0.847). The risk of treatment failure was two times higher among children with low (< 57 ng/mL) day 7 capillary piperaquine concentration (relative risk: 2.1 CI 1.4-3.1), p < 0.001) compared to children with high day 7 capillary piperaquine concentrations (> 57 ng/mL). CONCLUSION: Considering the low day 7 concentrations of piperaquine reported in the patients studied here, we suggest to adopt the recently recommended higher dose of DP in young children or a prolonged 5-day dosing in children living in malaria endemic areas who have suffered an initial episode of severe malaria in order to achieve adequate drug exposures for effective post-treatment prophylactic effects. TRIAL REGISTRATION: The study was registered with the Pan African Clinical Trial Registry (PACTR201110000321348). Registered 7th October 2011.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Artesunato/uso terapêutico , Malária Falciparum/tratamento farmacológico , Quinina/uso terapêutico , Quinolinas/sangue , Quinolinas/uso terapêutico , Administração Intravenosa , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Artesunato/administração & dosagem , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Malária Falciparum/parasitologia , Masculino , Concentração Osmolar , Plasmodium falciparum/isolamento & purificação , Quinina/administração & dosagem , Quinolinas/administração & dosagem , Recidiva , Resultado do Tratamento , Uganda
9.
Malar J ; 18(1): 424, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842893

RESUMO

BACKGROUND: Malaria remains a major public health problem, affecting mainly low-and middle-income countries. The management of this parasitic disease is challenged by ever increasing drug resistance. This study, investigated the therapeutic efficacy, tolerability and safety of artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), used as first-line drugs to treat uncomplicated malaria in Lambaréné, Gabon. METHODS: A non-randomized clinical trial was conducted between October 2017 and March 2018 to assess safety, clinical and parasitological efficacy of fixed-doses of AL and AS-AQ administered to treat uncomplicated Plasmodium falciparum malaria in children aged from 6 months to 12 years. After 50 children were treated with AL, another 50 children received ASAQ. The 2009 World Health Organization protocol for monitoring of the efficacy of anti­malarial drugs was followed. Molecular markers msp1 and msp2 were used to differentiate recrudescence and reinfection. For the investigation of artemisinin resistant markers, gene mutations in Pfk13 were screened. RESULTS: Per-protocol analysis on day 28 showed a PCR corrected cure rate of 97% (95% CI 86-100) and 95% (95% CI 84-99) for AL and AS-AQ, respectively. The most frequent adverse event in both groups was asthenia. No mutations in the kelch-13 gene associated with artemisinin resistance were identified. All participants had completed microscopic parasite clearance by day 3 post-treatment. CONCLUSION: This study showed that AL and AS-AQ remain efficacious, well-tolerated, and are safe to treat uncomplicated malaria in children from Lambaréné. However, a regular monitoring of efficacy and a study of molecular markers of drug resistance to artemisinin in field isolates is essential. Trial registration ANZCTR, ACTRN12616001600437. Registered 18 November, http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12616001600437p&isBasic=True.


Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Monitoramento de Medicamentos/estatística & dados numéricos , Malária Falciparum/tratamento farmacológico , Criança , Pré-Escolar , Combinação de Medicamentos , Feminino , Gabão , Humanos , Lactente , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Proteínas de Protozoários/genética
10.
Malar J ; 18(1): 419, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31843017

RESUMO

BACKGROUND: Although malaria remains one of the major public health threats in inter-tropical areas, there is limited understanding of imported malaria in children by paediatricians and emergency practitioners in non-endemic countries, often resulting in misdiagnosis and inadequate treatment. Moreover, classical treatments (atovaquone-proguanil, quinine, mefloquine) are limited either by lengthy treatment courses or by side effects. Since 2010, the World Health Organization (WHO) has recommended the use of oral artemisinin-based combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria worldwide. The benefits of artenimol-piperaquine in children have been validated in endemic countries but experience remains limited in cases of imported malaria. METHODS: This prospective observational study in routine paediatric care took place at the Emergency Department, Robert-Debré Hospital (Paris, France) from September 2012 to December 2014. Tolerance and efficacy of artenimol-piperaquine in children presenting with the following inclusion criteria were assessed: P. falciparum positive on thin or thick blood smear; and the absence of WHO-defined features of severity. RESULTS: Among 83 children included in this study, treatment with artenimol-piperaquine was successful in 82 children (98.8%). None of the adverse events were severe and all were considered mild with no significant clinical impact. This also applied to cardiological adverse events despite a significant increase of the mean post-treatment QTc interval. CONCLUSION: Artenimol-piperaquine displays a satisfying efficacy and tolerance profile as a first-line treatment for children with imported uncomplicated falciparum malaria and only necessitates three once-daily oral intakes of the medication. Comparative studies versus artemether-lumefantrine or atovaquone-proguanil would be useful to confirm the results of this study.


Assuntos
Artemisininas/uso terapêutico , Doenças Transmissíveis Importadas/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Quinolinas/uso terapêutico , Adolescente , Criança , Pré-Escolar , Doenças Transmissíveis Importadas/parasitologia , Quimioterapia Combinada , Serviço Hospitalar de Emergência , Feminino , Humanos , Lactente , Malária Falciparum/diagnóstico , Masculino , Estudos Prospectivos , Resultado do Tratamento
11.
PLoS Genet ; 15(10): e1008453, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31609965

RESUMO

Determining the genetic basis of fitness is central to understanding evolution and transmission of microbial pathogens. In human malaria parasites (Plasmodium falciparum), most experimental work on fitness has focused on asexual blood stage parasites, because this stage can be easily cultured, although the transmission of malaria requires both female Anopheles mosquitoes and vertebrate hosts. We explore a powerful approach to identify the genetic determinants of parasite fitness across both invertebrate and vertebrate life-cycle stages of P. falciparum. This combines experimental genetic crosses using humanized mice, with selective whole genome amplification and pooled sequencing to determine genome-wide allele frequencies and identify genomic regions under selection across multiple lifecycle stages. We applied this approach to genetic crosses between artemisinin resistant (ART-R, kelch13-C580Y) and ART-sensitive (ART-S, kelch13-WT) parasites, recently isolated from Southeast Asian patients. Two striking results emerge: we observed (i) a strong genome-wide skew (>80%) towards alleles from the ART-R parent in the mosquito stage, that dropped to ~50% in the blood stage as selfed ART-R parasites were selected against; and (ii) repeatable allele specific skews in blood stage parasites with particularly strong selection (selection coefficient (s) ≤ 0.18/asexual cycle) against alleles from the ART-R parent at loci on chromosome 12 containing MRP2 and chromosome 14 containing ARPS10. This approach robustly identifies selected loci and has strong potential for identifying parasite genes that interact with the mosquito vector or compensatory loci involved in drug resistance.


Assuntos
Interações Hospedeiro-Parasita/genética , Estágios do Ciclo de Vida/genética , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Animais , Anopheles/parasitologia , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Mapeamento Cromossômico , Modelos Animais de Doenças , Resistência a Medicamentos/genética , Feminino , Frequência do Gene , Loci Gênicos , Humanos , Malária Falciparum/tratamento farmacológico , Masculino , Camundongos , Mosquitos Vetores/parasitologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Polimorfismo de Nucleotídeo Único , Proteínas Ribossômicas/genética , Seleção Genética , Quimeras de Transplante
12.
Malar J ; 18(1): 338, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31581941

RESUMO

Resistance threatens all our currently available anti-malarial drugs. Triple artemisinin-containing combination anti-malarial treatments (TACTs) combine an artemisinin derivative with two slowly eliminated partner drugs. TACTs are undergoing large-scale trials. If they prove safe, well-tolerated and efficacious then they should be deployed. This is in order to protect and extend the useful therapeutic life of the current generation of anti-malarial drugs, which are so essential for malaria control and elimination.


Assuntos
Antimaláricos/química , Artemisininas/uso terapêutico , Resistência a Medicamentos , Malária/tratamento farmacológico , Combinação de Medicamentos , Humanos , Malária/prevenção & controle , Saúde Pública/legislação & jurisprudência , Saúde Pública/métodos
13.
Malar J ; 18(1): 339, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31581951

RESUMO

Managing multidrug resistant malaria can be problematic if currently available artemisinin-containing anti-malarial combination treatments are not used appropriately. Here, I debate that the best way to manage multidrug resistant malaria is to make best use of existing treatments and to develop new classes of anti-malarial drugs and not to make 'triple combination therapies' when there is already resistance to one or more proposed components.


Assuntos
Antimaláricos/química , Artemisininas/uso terapêutico , Resistência a Medicamentos , Malária/tratamento farmacológico , Antimaláricos/economia , Artemisininas/economia , Combinação de Medicamentos , Humanos , Malária/prevenção & controle , Saúde Pública/legislação & jurisprudência , Saúde Pública/normas
14.
Malar J ; 18(1): 349, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619243

RESUMO

BACKGROUND: The resistance of Plasmodium falciparum to artemisinin has been identified in Asia and some parts of Africa. The drug resistance of P. falciparum will be an obstacle to the successful elimination of malaria by 2025. Whole-genome sequencing of the artemisinin-resistant parasite line revealed mutations on the k13 gene associated with drug resistance in P. falciparum. To understand the artemisinin resistance of the imported P. falciparum cases from Africa, the mutations in the k13 gene in parasites from imported malaria cases in Guangxi Province were detected and the treatment efficiency of artesunate monotherapy was observed. METHODS: DNA was extracted from 319 blood samples from migrant workers with P. falciparum infection who returned to their hometown in Guangxi Province from Africa between 2014 and 2017. The k13-propeller gene was amplified by nested PCR, and sequencing, gene mutation frequency and geographic difference of imported P. falciparum cases were analysed by comparison with the wild-type strain. Of 319 patients, 158 were P. falciparum-infected and were treated with intravenous injection of artesunate and were observed, including the time of asexual stage clearance and the dose of artesunate used. RESULTS: Of the 319 P. falciparum samples, 12 samples had the k13-propeller mutation, and 11 point mutations were detected; 5 were non-synonymous mutations (T474I, A481T, A578S, V603E, G665S) and were not associated with artemisinin resistance. The clinical treatment observation showed that the median (IQR) dose of artesunate for peripheral blood parasite asexual stage clearance was 407.55 (360-510) mg, and the D3 parasite clearance rate was 70.25%, including the five k13-propeller mutations of P. falciparum. After 7 days of treatment, 98.73% of cases were cleared. Two cases were treated with artemisinin for 8 days with a 960-mg dose to completely clear the asexual parasite, but they did not have a mutation in the k13 gene. CONCLUSIONS: Five mutations of the k13-propeller gene in 319 P. falciparum samples from patients returning from Africa were identified. The frequency of the k13-propeller mutants was low, and the mutations were not strongly associated with artemisinin resistance. The median (IQR) dose of artesunate monotherapy in actual clinical treatment to remove asexual parasite stages was 407.55 (360-510) mg, equivalent to D3-D4. Some P. falciparum cases without a k13-propeller mutation showed obvious delayed clearance of the parasite from peripheral blood. Trial registration The diagnosis of malaria and the treatment of malaria-infected patients are the routine work of Centres for Disease Control and Prevention. Information on the patients was conveyed with the patient's approval, and the research aim, methods, risks and benefits of the study were explained in detail to the patients.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Artesunato/uso terapêutico , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas de Protozoários/genética , China , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo , Migrantes/estatística & dados numéricos
15.
Korean J Parasitol ; 57(4): 369-377, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31533403

RESUMO

Artemisinin-based combination therapy (ACT) resistance is widespread throughout the Greater Mekong Subregion. This raises concern over the antimalarial treatment in Thailand since it shares borders with Cambodia, Laos, and Myanmar where high ACT failure rates were reported. It is crucial to have information about the spread of ACT resistance for efficient planning and treatment. This study was to identify the molecular markers for antimalarial drug resistance: Pfkelch13 and Pfmdr1 mutations from 5 provinces of southern Thailand, from 2012 to 2017, of which 2 provinces on the Thai- Myanmar border (Chumphon and Ranong), one on Thai-Malaysia border (Yala) and 2 from non-border provinces (Phang Nga and Surat Thani). The results showed that C580Y mutation of Pfkelch13 was found mainly in the province on the Thai-Myanmar border. No mutations in the PfKelch13 gene were found in Surat Thani and Yala. The Pfmdr1 gene isolated from the Thai-Malaysia border was a different pattern from those found in other areas (100% N86Y) whereas wild type strain was present in Phang Nga. Our study indicated that the molecular markers of artemisinin resistance were spread in the provinces bordering along the Thai-Myanmar, and the pattern of Pfmdr1 mutations from the areas along the international border of Thailand differed from those of the non-border provinces. The information of the molecular markers from this study highlighted the recent spread of artemisinin resistant parasites from the endemic area, and the data will be useful for optimizing antimalarial treatment based on regional differences.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Marcadores Genéticos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/genética , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Artemisininas/administração & dosagem , Artemisininas/uso terapêutico , Sequência de Bases , DNA de Protozoário/química , Combinação de Medicamentos , Resistência a Medicamentos/genética , Genes MDR/genética , Humanos , Repetição Kelch/genética , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/isolamento & purificação , Reação em Cadeia da Polimerase , Tailândia
16.
Malar J ; 18(1): 318, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533845

RESUMO

BACKGROUND: Intermittent preventive treatment (IPT) of malaria is recommended as policy for certain high-risk populations, but not currently for schoolchildren. A cluster-randomized trial was conducted to evaluate the effect of IPT with dihydroartemisinin-piperaquine (DP) on primary schoolchildren in Jinja, Uganda. Results of the impact of IPT of schoolchildren on community-level transmission have been reported previously. Here, secondary outcomes from a school-based survey are presented. METHODS: Eighty-four clusters (one primary school plus 100 households) were randomized to intervention and control (1:1 ratio). Participants from intervention schools received monthly IPT with DP for up to 6 rounds (June-December 2014). At endline (November-December 2014), randomly selected children from all 84 schools were surveyed (13 per school) and thick blood smears were done. Those with fever or history of fever were tested with rapid diagnostic tests (RDTs) for malaria. Haemoglobin was measured in every fifth participant. Outcome measures included prevalence of asexual parasites and gametocytes (by microscopy), and prevalence of anaemia. Prevalence outcomes were analysed using generalized linear Poisson models with log link function, incorporating a cluster-level random intercept and quantified using prevalence risk ratios. RESULTS: Among 23,280 students listed on the 42 intervention school registers, 10,079 (43.3%) aged 5-20 years were enrolled into the IPT intervention and received at least one dose of DP; of these, 9286 (92.1%) received at least one full (3-day) course. In total, 1092 children were enrolled into the final school survey (546 per arm) and had a thick blood smear done; of these, 255 had haemoglobin measured (129 intervention, 126 control). Children in the intervention arm were less likely to have asexual parasites (9.2% intervention vs 44.1% control, adjusted risk ratio [aRR] 0.22 [95% CI 0.16-0.30] p < 0.001), gametocytes (3.1% intervention vs 9.5% control, aRR 0.34 [95% CI 0.20-0.56] p < 0.001), fever (20.2% intervention vs 56.2% control, aRR 0.35 [95% CI 0.25-0.50] p < 0.001), or symptomatic malaria (5.1% intervention vs 35.7% control, aRR 0.14 [95% CI 0.08-0.26] p < 0.001). Prevalence of anaemia and mean haemoglobin were similar in both study arms. CONCLUSIONS: School-aged children are a major reservoir of malaria parasites. Delivering IPT to schoolchildren would benefit individual children and may reduce transmission. School-based IPT could help to intensify malaria control toward elimination, and should be considered for policies and programmes. Trial registration Clinicaltrials.gov (NCT02009215), Registered 11 December 2013. https://clinicaltrials.gov/ct2/show/NCT02009215.


Assuntos
Anemia/epidemiologia , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária/prevenção & controle , Quinolinas/uso terapêutico , Adolescente , Criança , Pré-Escolar , Análise por Conglomerados , Combinação de Medicamentos , Feminino , Humanos , Malária/epidemiologia , Masculino , Prevalência , Estudantes , Uganda/epidemiologia
17.
Am J Chin Med ; 47(6): 1325-1343, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488031

RESUMO

Artemisinin and its analogues (ARTs) are currently the most effective anti-malarial drugs, but the precise mechanism of action is still highly controversial. Effects of ARTs on Plasmodium genes expression are studied in our Lab. The overexpression of an interesting amidotransferase, NADH-dependent glutamate synthase (NADH-GltS) was found in treated by dihydroartemisinin (DHA). The increased expression occurred not only from global transcriptomics analysis on the human malaria parasite Plasmodium falciparum (P. falciparum) 3D7 and gene expression screening on all of iron-sulphur cluster proteins from P.f. 3D7 in vitro but also from Plasmodium berghei (P. berghei) ANKA in mice. Influence of DHA on NADH-GltS was specifically at trophozoite stage of P. falciparum and in a dose-dependent manner below the effective doses. L-glutamine (Gln) and L-glutamate (Glu) are the substrate and product of NADH-GltS respectively. Azaserine (Aza) is specific inhibitor for NADH-GltS. Experimental data showed that Glu levels were significantly decreasing with DHA dose increasing but NADH-GltS enzyme activities were still remained at higher levels in parasites, and appropriate amount of exogenous Glu could significantly reduce anti-malarial action of DHA but excessive amount lost the above effect. Aza alone could inhibit proliferation of P. falciparum and had an additive effect in combination with DHA. Those results could suggest that: Glutamate depletion is one of the anti-malarial actions of DHA; overexpression of NADH-GltS would be a feedback pattern of parasite itself due to glutamate depletion, but not a direct action of DHA; the "feedback pattern" is one of protective strategies of Plasmodium to interfere with the anti-malarial actions of DHA; and specific inhibitor for NADH-GltS as a new type of anti-malarial agents or new partner in ACT might provide a potential.


Assuntos
Antimaláricos , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Glutamato Sintase (NADH)/genética , Glutamato Sintase (NADH)/metabolismo , Malária/tratamento farmacológico , Fitoterapia , Plasmodium falciparum/enzimologia , Plasmodium falciparum/genética , Animais , Azasserina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glutamato Sintase (NADH)/antagonistas & inibidores , Ácido Glutâmico/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Plasmodium falciparum/fisiologia
18.
Biomed Pharmacother ; 118: 109383, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31545251

RESUMO

Given studies have shown that Artemisinin (ART) reduces cancer cell proliferation, migration, invasion, tumorigenesis and metastasis. In this study, we evaluated the roles of ART in clear cell renal cell carcinoma (ccRCC) progression. We measured the eff ;ects of ART on cancer cell proliferation, colony formation, migration, invasion and tumorigenesis. CCK-8 assay demonstrated that ART inhibited cell growth with IC50 values 31.30 ±â€¯0.73 µM in UMRC-2 and 23.97 ±â€¯0.92 µM in CAKI-2, respectively. Colony formation assay shown that ART inhibited cell colony formation. Transwell migration and invasion assay shown that ART inhibited RCC migration and invasion. Realtime-qPCR assay shown that ART decreased the mRNA levels of proliferation related genes c-Myc, cyclin D1 and PCNA, and reduced the mRNA levels of mesenchymal genes N-cadherin, Vimentin and Snail, but increased the mRNA levels of epithelial marker E-cadherin. Moreover, ART inhibited AKT signaling pathway. In the presence of AKT inhibitor VIII, a pan-AKT inhibitor, ART reduced more cell proliferation, migration and invasion than in the absence of AKT inhibitor VIII, suggesting combination of ART and AKT inhibitor enhanced the anti-cancer effects of ART. Furthermore, the in vivo xenograft tumor model results suggested that ART decreased tumor size and weight, and suppressed AKT signaling. Taken together, our results indicated that ART inhibited ccRCC cell proliferation, colony formation, migration, invasion and tumorigenesis. Combination of ART and AKT inhibitor enhanced the anti-cancer cell proliferation, migration and invasion.


Assuntos
Antineoplásicos/uso terapêutico , Artemisininas/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Renais/patologia , Masculino , Camundongos Nus , Invasividade Neoplásica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaio Tumoral de Célula-Tronco
19.
Malar J ; 18(1): 331, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31558149

RESUMO

BACKGROUND: Febrile children seen in malaria hypo-endemic settings, such as the Greater Accra region (GAR) of Ghana are more likely to be suffering from a non-malarial febrile illness compared to those seen in hyper-endemic settings. The need for prescribers to rely on malaria test results to guide treatment practices in the GAR is even greater. This study was designed to investigate the factors associated with inappropriate artemisinin-based combination therapy (ACT) prescription. METHODS: A survey was conducted in six health facilities in the region in 2015. Treatment practices for febrile outpatient department (OPD) patients were obtained from their records. Prescribers were interviewed and availability of malaria commodities were assessed. The primary outcome was the proportion of patients prescribed ACT inappropriately. Independent variables included patient age and access to care, prescriber factors (professional category, work experience, access to guidelines, exposure to training). Data were analysed using Stata at 95% CI (α-value of 0.05). Frequencies and means were used to describe the characteristics of patients and prescribers. To identify the predictors of inappropriate ACT prescription, regression analyses were performed accounting for clustering. RESULTS: Overall, 2519 febrile OPD records were analysed; 45.6% (n = 1149) were younger than 5 years. Only 40.0% of patients were tested. The proportion of patients who were prescribed ACT inappropriately was 76.4% (n = 791 of 1036). Of these 791 patients, 141 (17.8%) were prescribed anti-malarial injections. Patients seen in facilities with rapid diagnostic tests (RDT) in stock were less likely to be prescribed ACT inappropriately, (AOR: 0.04, 95% CI 0.01-0.14, p < 0.001) compared to those seen in facilities with RDT stock-outs. Prescribers who had been trained on malaria case management within the past year were 4 times more likely to prescribe ACT inappropriately compared to those who had not been trained (AOR: 4.1; 95% CI (1.5-11.6); p < 0.01). Patients seen by prescribers who had been supervised were 8 times more likely to be  prescribed ACT inappropriately. CONCLUSION: Inappropriate ACT prescription to OPD febrile cases was high. Training and supervision of health workers appears not to be yielding the desired outcomes. Further research is needed to understand this observation.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Febre/tratamento farmacológico , Febre/parasitologia , Prescrição Inadequada/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos Transversais , Feminino , Febre/epidemiologia , Gana/epidemiologia , Pessoal de Saúde , Humanos , Lactente , Injeções , Malária/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Inquéritos e Questionários , Adulto Jovem
20.
BMC Res Notes ; 12(1): 490, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391102

RESUMO

OBJECTIVE: To investigate the influence of socioeconomic household characteristics on access to paediatric malaria treatment in Homa Bay County, Kenya. RESULTS: From univariate analysis, treatment with analgesics only in a community health center or a faith-based organization, self-employment, urban residence and residing in a sub-county other than Suba or Mbita showed significant association with access to paediatric antimalarial treatment. However, on multivariate analysis, urban residence, education, income of 10,000 to 30,000 and information from peers were the most statistically significant predictors of access to treatment. Urban households were 0.37 times more likely to access treatment than rural ones. Having primary, secondary or post-secondary education conferred 0.25, 0.14 and 0.28 higher chance of access to paediatric malaria treatment respectively compared to those with no formal education. Those with monthly income levels of 10,000 to 30,000 shillings had 0.32 higher chance of accessing treatment compared to those with less than 5000 shillings.


Assuntos
Analgésicos/economia , Antimaláricos/economia , Artemisininas/economia , Acesso aos Serviços de Saúde/economia , Disparidades em Assistência à Saúde/economia , Malária/economia , Adulto , Analgésicos/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Criança , Pré-Escolar , Centros Comunitários de Saúde , Estudos Transversais , Combinação de Medicamentos , Características da Família , Feminino , Acesso aos Serviços de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Humanos , Quênia , Malária/tratamento farmacológico , Malária/fisiopatologia , Masculino , Análise Multivariada , População Rural , Fatores Socioeconômicos , População Urbana
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