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1.
Cochrane Database Syst Rev ; 1: CD004529, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33459345

RESUMO

BACKGROUND: The World Health Organization (WHO) in 2015 stated atovaquone-proguanil can be used in travellers, and is an option in malaria-endemic areas in combination with artesunate, as an alternative treatment where first-line artemisinin-based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005. OBJECTIVES: To assess the efficacy and safety of atovaquone-proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children. SEARCH METHODS: The date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal. SELECTION CRITERIA: Randomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone-proguanil or atovaquone-proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection. DATA COLLECTION AND ANALYSIS: For this update, two review authors re-extracted data and assessed certainty of evidence. We meta-analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)-adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection. MAIN RESULTS: Seventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South-America, and South-East Asia. Eight trials reported PCR-adjusted data to distinguish between new and recrudescent infection during the follow-up period. In this abstract, we report only the comparisons against the three WHO-recommended antimalarials which were included within these trials. There were two comparisons with artemether-lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone-proguanil compared to none with artemether-lumefantrine (PCR-adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR-adjusted treatment failures at day 42). There was only one comparison with artesunate-amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone-proguanil at day 28 and two with artesunate-amodiaquine (PCR-adjusted treatment failures at day 28: 9.4% with atovaquone-proguanil compared to 2.9% with artesunate-amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low-certainty evidence), although there was a similar number of PCR-unadjusted treatment failures (9 (14.1%) with atovaquone-proguanil and 8 (11.8%) with artesunate-amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low-certainty evidence). There were two comparisons with artesunate-mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi-resistant malaria. There were similar numbers of PCR-adjusted treatment failures between groups at day 42 (2.7% with atovaquone-proguanil compared to 2.4% with artesunate-mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high-certainty evidence). There were also similar PCR-unadjusted treatment failures between groups (5.3% with atovaquone-proguanil compared to 6.6% with artesunate-mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low-certainty evidence). When atovaquone-proguanil was combined with artesunate, there were fewer treatment failures with and without PCR-adjustment at day 28 (PCR-adjusted treatment failures at day 28: 2.16% with atovaquone-proguanil compared to no failures with artesunate-atovaquone-proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low-certainty evidence) and day 42 (PCR-adjusted treatment failures at day 42: 3.82% with atovaquone-proguanil compared to 2.05% with artesunate-atovaquone-proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate-certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate-atovaquone-proguanil group compared to the atovaquone-proguanil group at day 42 with PCR-adjustment. Whilst there were some small differences in which adverse events were more frequent in the atovaquone-proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone-proguanil is strongly associated with any specific adverse event. AUTHORS' CONCLUSIONS: Atovaquone-proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone-proguanil may reduce treatment failure rates. Artesunate-atovaquone-proguanil and the development of parasite resistance may represent an area for further research.


Assuntos
Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Malária Falciparum/tratamento farmacológico , Proguanil/uso terapêutico , Adulto , Amodiaquina/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Camarões , Criança , Colômbia , Combinação de Medicamentos , Etiópia , Humanos , Mefloquina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Tailândia , Falha de Tratamento
2.
PLoS Pathog ; 16(12): e1009133, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33320907

RESUMO

The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical samples. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical samples from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants' genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites' drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.


Assuntos
Anti-Infecciosos , Artemisininas , Resistência a Medicamentos/genética , Genes de Protozoários/genética , Plasmodium falciparum/genética , Anti-Infecciosos/uso terapêutico , Artemisininas/uso terapêutico , Estudos Transversais , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Mutação , Papua Nova Guiné
3.
Ann Parasitol ; 63(3): 295-302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33128446

RESUMO

Visceral leishmaniosis is one of the most fatal old-world neglected disease with estimated 90 thousand worldwide cases emerge each year. In Iraq, the cutaneous and visceral form are endemic but available chemotherapies are either toxic with diverse side effects, expensive available drugs or parasite resistant is arising. Artemisinin (ART) is a semi-synthetic compound which proved its effectiveness against protozoan parasites, such as malaria and Leishmania. In this study, the efficacy of different concentrations of pure artemisinin was screened in vitro against promastigotes and axenic amastigotes by MTT assay after 24, 48 and 27 hours follow up. In addition, the infectivity ability and number was investigated of intra-cellular Leishman bodies in treated murine peritoneal macrophages after 24 and 48 hours ART treatment. The results verified ART efficacy against the promastigotes and axenic amastigotes viability with IC50 measured after 24, 48- and 72-hours treatment. Infectivity percentage of murine macrophages and parasite burden were significantly reduced in treated cells. These findings indicate the leishmanicidal activity of ART against the Iraqi isolate of L. donovani and further in vivo study is recommended for assigning ART as a natural anti visceral leishmaniosis compound.


Assuntos
Antiprotozoários , Artemisininas , Leishmania donovani , Leishmaniose Visceral , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Iraque , Leishmaniose Visceral/tratamento farmacológico , Macrófagos , Camundongos
4.
BMC Res Notes ; 13(1): 497, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109270

RESUMO

OBJECTIVE: Nigeria bears 25% of global malaria burden despite concerted efforts towards its control and elimination. The emergence of drug resistance to first line drugs, artemisinin combination therapies (ACTs), indicates an urgent need for continuous molecular surveillance of drug resistance especially in high burden countries where drug interventions are heavily relied on. This study describes mutations in Plasmodium falciparum genes associated with drug resistance in malaria; Pfk13, Pfmdr1, PfATPase6 and Pfcrt in isolates obtained from 83 symptomatic malaria patients collected in August 2014, aged 1-61 years old from South-west Nigeria. RESULTS: Two Pfmdr1, N86 and Y184 variants were present at a prevalence of 56% and 13.25% of isolates respectively. There was one synonymous (S679S) and two non-synonymous (M699V, S769M) mutations in the PATPase6 gene, while Pfcrt genotype (CVIET), had a prevalence of 45%. The Pfk13 C580Y mutant allele was suspected by allelic discrimination in two samples with mixed genotypes although this could not be validated with independent isolation or additional methods. Our findings call for robust molecular surveillance of antimalarial drug resistance markers in west Africa especially with increased use of antimalarial drugs as prophylaxis for Covid-19.


Assuntos
Combinação Arteméter e Lumefantrina/uso terapêutico , ATPases Transportadoras de Cálcio/genética , Malária Falciparum/tratamento farmacológico , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mutação , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/genética , Adolescente , Adulto , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Resistência a Medicamentos/genética , Feminino , Expressão Gênica , Genótipo , Humanos , Lactente , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Pessoa de Meia-Idade , Epidemiologia Molecular , Nigéria/epidemiologia , Pandemias/prevenção & controle , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle
5.
Medicine (Baltimore) ; 99(36): e22044, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899064

RESUMO

BACKGROUND: Malaria remains a global health threat for centuries. In recent years, a rising resistance of Plasmodium falciparum to current standard artemisinin-based combination therapies (ACTs) leads to increasing treatment failures and requires for optimized treatment. Here, we intend to make a systematic review and meta-analysis of optimizing treatment for malaria, so as to find a potential optimal treatment. METHODS: We will search electronic databases: the Cochrane Infectious Diseases Group (CIDG) Specialized Register, the Cochrane Central Register of Controlled Trials (CEN-TRAL), PubMed, Embase, Web of Science from their inception to 1 July, 2020. We will also search International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov, and contact with authors when necessary. Two authors will independently collect and select data, and the statistical analyses will be conducted by Revman V.5.3 software. RESULTS: We will evaluate efficacy and safety of modified ACTs for uncomplicate malaria, comparing with standard ACTs in all eligible clinical studies. CONCLUSION: In this study, we will offer clinical evidence for optimizing treatment for malaria. REGISTRATION NUMBER: INPLASY202070115.


Assuntos
Anti-Infecciosos/uso terapêutico , Artemisininas/uso terapêutico , Malária/tratamento farmacológico , Antimaláricos/uso terapêutico , Terapia Combinada , Feminino , Humanos , Malária/epidemiologia , Malária/parasitologia , Masculino , Plasmodium falciparum/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Segurança , Falha de Tratamento , Resultado do Tratamento
6.
Am J Chin Med ; 48(6): 1315-1330, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907362

RESUMO

Critical care medicine is a medical specialty engaging the diagnosis and treatment of critically ill patients who have or are likely to have life-threatening organ failure. Sepsis, a life-threatening condition that arises when the body responds to infection, is currently the major cause of death in intensive care units (ICU). Although progress has been made in understanding the pathophysiology of sepsis, many drawbacks in sepsis treatment remains unresolved. For example, antimicrobial resistance, controversial of glucocorticoids use, prolonged duration of ICU care and the subsequent high cost of the treatment. Recent years have witnessed a growing trend of applying traditional Chinese medicine (TCM) in sepsis management. The TCM application emphasizes use of herbal formulation to balance immune responses to infection, which include clearing heat and toxin, promoting blood circulation and removing its stasis, enhancing gastrointestinal function, and strengthening body resistance. In this paper, we will provide an overview of the current status of Chinese herbal formulations, single herbs, and isolated compounds, as an add-on therapy to the standard Western treatment in the sepsis management. With the current trajectory of worldwide pandemic eruption of newly identified Coronavirus Disease-2019 (COVID-19), the adjuvant TCM therapy can be used in the ICU to treat critically ill patients infected with the novel coronavirus.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Medicina Tradicional Chinesa , Pneumonia Viral/tratamento farmacológico , Sepse/tratamento farmacológico , Artemisininas/uso terapêutico , Astragalus propinquus , Berberina/uso terapêutico , Betacoronavirus , Estado Terminal , Emodina/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Mucosa Intestinal , Microcirculação , Pandemias , Permeabilidade , Rheum , Salvia miltiorrhiza
7.
PLoS Negl Trop Dis ; 14(9): e0008619, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32966290

RESUMO

BACKGROUND: Despite the reported success in reducing morbidity, praziquantel alone is insufficient for the control and elimination of schistosomiasis, partly due to its poor efficacy against the juvenile worms. Artemisinin derivatives are effective against juvenile worms but are less effective against adult worms. We compared the safety and efficacy of praziquantel and Dihydroartemisinin-piperaquine combination against the standard praziquantel alone for treatment of intestinal schistosomiasis. METHODS: In this randomized, open-label, non-inferiority trial, 639 Schistosoma mansoni infected children were enrolled and randomized to receive either praziquantel alone or praziquantel plus Dihydroartemisinin-piperaquine combination. Two stool samples were collected on consecutive days at baseline, 3 and 8 weeks post-treatment and analyzed using thick smear Kato Katz method. Efficacy was assessed by cure and egg reduction rates at 3 and 8 weeks post-treatment. Adverse events were assessed within four hours of drugs intake. The primary outcome was cure rates at 8 weeks of post-treatment. Secondary outcomes were egg reduction rates at 8 weeks of post-treatment and treatment-associated adverse events. RESULTS: At 3 weeks of post-treatment, cure rates were 88.3% (263/298, 95% CI = 84.1%- 91.4%) and 81.2% (277/341, 95% CI = 76.7%- 85.0%) for the combination therapy and praziquantel alone, respectively (p < 0.01, odds ratio (OR) = 1.74, 95% CI of OR = 1.11 to 2.69). At 8 weeks, there was a significant drop in the cure rates in praziquantel alone group to 63.9% (218/341, 95% CI = 58.7%- 68.8%) compared to 81.9% (244/298, 95% CI = 77.1%- 85.8%) in the combination therapy group (p < 0.0001, OR = 2.55, 95%CI of OR = 1.75 to 3.69). Egg reduction rates at 8 weeks post-treatment were significantly higher in the combination therapy group 93.6% (95% CI = 90.8%- 96.4%) compared to 87.9% (95% CI = 84.4%- 91.4%) in the praziquantel only group (p = 0.01). On both Univariate and Multivariate regression analysis, type of treatment received was a significant predictor of cure at week 8 post-treatment. Overall, 30.8% (95% CI = 27.2%- 34.4%) of the study participants experienced mild and transient treatment-associated adverse events, post-treatment abdominal pain (27.1%) being the most common adverse event observed. There was no significant difference in the overall occurrence of adverse events between the two treatment groups. CONCLUSION: Praziquantel and Dihydroartemisinin piperaquine combination therapy is safe, and more efficacious compared to praziquantel alone for the treatment of intestinal schistosomiasis. Further studies are needed to explore if the combination therapy can be considered as an option for mass drug administration to control and eventually eliminate schistosomiasis.


Assuntos
Anti-Helmínticos/uso terapêutico , Artemisininas/uso terapêutico , Praziquantel/uso terapêutico , Quinolinas/uso terapêutico , Esquistossomose mansoni/tratamento farmacológico , Adolescente , Animais , Anti-Helmínticos/efeitos adversos , Artemisininas/efeitos adversos , Criança , Quimioterapia Combinada , Fezes/parasitologia , Feminino , Humanos , Intestinos/parasitologia , Masculino , Praziquantel/efeitos adversos , Quinolinas/efeitos adversos , Schistosoma mansoni/efeitos dos fármacos , Tanzânia , Resultado do Tratamento
8.
Lancet Child Adolesc Health ; 4(10): 775-789, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32946831

RESUMO

Malaria disproportionately affects children younger than 5 years. Falciparum malaria is responsible for more than 200 000 child deaths per year in Africa and vivax malaria is well documented as a cause of severe anaemia and excess mortality in children in Asia and Oceania. For the treatment of malaria in children, paediatric dosing recommendations for several agents, including parenteral artesunate and dihydroartemisinin-piperaquine, have belatedly been shown to be suboptimal. Worsening antimalarial resistance in Plasmodium falciparum in the Greater Mekong Subregion threatens to undermine global efforts to control malaria. Triple antimalarial combination therapies are being evaluated to try to impede this threat. The RTS,S/AS01 vaccine gives partial protection against falciparum malaria and is being evaluated in large, pilot studies in Ghana, Malawi, and Kenya as a complementary tool to other preventive measures. Seasonal malaria chemoprevention in west Africa has resulted in declines in malaria incidence and deaths and there is interest in scaling up efforts by expanding the age range of eligible recipients. Preventing relapse in Plasmodium vivax infection with primaquine is challenging because treating children who have G6PD deficiency with primaquine can cause acute haemolytic anaemia. The safety of escalating dose regimens for primaquine is being studied to mitigate this risk.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Bem-Estar da Criança/estatística & dados numéricos , Vacinas Antimaláricas/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Criança , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos , Feminino , Humanos , Malária/epidemiologia , Masculino , Estações do Ano , Vacinação/estatística & dados numéricos
9.
Am J Trop Med Hyg ; 103(5): 1910-1917, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32815508

RESUMO

Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human Plasmodium vivax VISs where subjects were treated with chloroquine (n = 24) or artefenomel (n = 8) and compared them with studies in Thailand (n = 41) and Malaysia (n = 76). In the VISs, alanine transaminase (ALT) increased to ≥ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5-8 days post-treatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ≥ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26-14.59; P = 0.02) for every log10 increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ≥ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91-27.47; P = 0.06), this risk disappeared when corrected for PCB. Peak ALT also correlated with peak C-reactive protein (R = 0.44; P = 0.012). Elevations in ALT (≥ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental P. vivax infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory.


Assuntos
Adamantano/análogos & derivados , Alanina Transaminase/sangue , Antimaláricos/uso terapêutico , Hepatopatias/tratamento farmacológico , Malária Vivax/tratamento farmacológico , Peróxidos/uso terapêutico , Plasmodium vivax/isolamento & purificação , Adamantano/uso terapêutico , Adulto , Artemisininas/uso terapêutico , Cloroquina/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Hepatopatias/sangue , Hepatopatias/parasitologia , Testes de Função Hepática , Malária Vivax/sangue , Malária Vivax/parasitologia , Malásia , Masculino , Parasitemia/tratamento farmacológico , Tailândia , Adulto Jovem
10.
PLoS Med ; 17(8): e1003203, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822347

RESUMO

BACKGROUND: Artemisinin resistance is threatening malaria control. We aimed to develop and test a human model of artemisinin-resistant (ART-R) Plasmodium falciparum to evaluate the efficacy of drugs against ART-R malaria. METHODS AND FINDINGS: We conducted 2 sequential phase 1, single-centre, open-label clinical trials at Q-Pharm, Brisbane, Australia, using the induced blood-stage malaria (IBSM) model, whereby healthy participants are intravenously inoculated with blood-stage parasites. In a pilot study, participants were inoculated (Day 0) with approximately 2,800 viable P. falciparum ART-R parasites. In a comparative study, participants were randomised to receive approximately 2,800 viable P. falciparum ART-R (Day 0) or artemisinin-sensitive (ART-S) parasites (Day 1). In both studies, participants were administered a single approximately 2 mg/kg oral dose of artesunate (AS; Day 9). Primary outcomes were safety, ART-R parasite infectivity, and parasite clearance. In the pilot study, 2 participants were enrolled between April 27, 2017, and September 12, 2017, and included in final analyses (males n = 2 [100%], mean age = 26 years [range, 23-28 years]). In the comparative study, 25 participants were enrolled between October 26, 2017, and October 18, 2018, of whom 22 were inoculated and included in final analyses (ART-R infected participants: males n = 7 [53.8%], median age = 22 years [range, 18-40 years]; ART-S infected participants: males n = 5 [55.6%], median age = 28 years [range, 22-35 years]). In both studies, all participants inoculated with ART-R parasites became parasitaemic. A total of 36 adverse events were reported in the pilot study and 277 in the comparative study. Common adverse events in both studies included headache, pyrexia, myalgia, nausea, and chills; none were serious. Seven participants experienced transient severe falls in white cell counts and/or elevations in liver transaminase levels which were considered related to malaria. Additionally, 2 participants developed ventricular extrasystoles that were attributed to unmasking of a predisposition to benign fever-induced tachyarrhythmia. In the comparative study, parasite clearance half-life after AS was significantly longer for ART-R infected participants (n = 13, 6.5 hours; 95% confidence interval [CI] 6.3-6.7 hours) compared with ART-S infected participants (n = 9, 3.2 hours; 95% CI 3.0-3.3 hours; p < 0.001). The main limitation of this study was that the ART-R and ART-S parasite strains did not share the same genetic background. CONCLUSIONS: We developed the first (to our knowledge) human model of ART-R malaria. The delayed clearance profile of ART-R parasites after AS aligns with field study observations. Although based on a relatively small sample size, results indicate that this model can be safely used to assess new drugs against ART-R P. falciparum. TRIAL REGISTRATION: The studies were registered with the Australian New Zealand Clinical Trials Registry: ACTRN12617000244303 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372357) and ACTRN12617001394336 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373637).


Assuntos
Anti-Infecciosos/uso terapêutico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/sangue , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/metabolismo , Adolescente , Adulto , Animais , Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/farmacologia , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Artemisininas/efeitos adversos , Artemisininas/farmacologia , Artesunato/efeitos adversos , Artesunato/farmacologia , Artesunato/uso terapêutico , Austrália/epidemiologia , Feminino , Cefaleia/induzido quimicamente , Voluntários Saudáveis , Humanos , Malária Falciparum/epidemiologia , Masculino , Náusea/induzido quimicamente , Parasitos/metabolismo , Projetos Piloto , Adulto Jovem
11.
PLoS One ; 15(8): e0237791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822392

RESUMO

Artemisinin-based combination therapies (ACTs) have been recommended by the World Health Organization (WHO) as first-line treatment of uncomplicated Plasmodium falciparum (P. falciparum) malaria since 2005 in Democratic Republic of Congo (DRC) and a regular surveillance of the ACT efficacy is required to ensure the treatment effectiveness. Mutations in the propeller domain of the pfk13 gene were identified as molecular markers of artemisinin resistance (ART-R). This study investigated the pfk13-propeller gene polymorphism in clinical isolates of P. falciparum collected in the DRC. In 2017, ten geographical sites across DRC were selected for a cross-sectional study that was conducted first in Kinshasa from January to March, then in the nine other sites from September to December. Dried blood samples were collected from patients attending health centers for fever where diagnosis of Malaria was first made by rapid diagnostic test (RDT) available on site (SD Bioline malaria Ag Pf or CareStart Malaria Pf) or by thick blood smear and then confirmed by a P. falciparum real-time PCR assay. A pfk13-propeller segment containing a fragment that codes for amino acids at positions 427-595 was amplified by conventional PCR before sequencing. In total, 1070 patients were enrolled in the study. Real-time PCR performed confirmed the initial diagnosis of P. falciparum infection in 806 samples (75.3%; 95% CI: 72.6%- 77.9%). Of the 717 successfully sequenced P. falciparum isolates, 710 (99.0%; 95% CI: 97.9% - 99.6) were wild-type genotypes and 7 (1.0%; 95% CI: 0.4% - 2.1%) carried non-synonymous (NS) mutations in pfk13-propeller including 2 mutations (A578S and V534A) previously detected and 2 other (M472I and A569T) not yet detected in the DRC. Mutations associated with ART-R in Southeast Asia were not observed in DRC. However, the presence of other mutations in pfk13-propeller gene calls for further investigations to assess their implication in drug resistance.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Adolescente , Adulto , Idoso , Antimaláricos/farmacologia , Artemisininas/farmacologia , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Resistência a Medicamentos , Feminino , Humanos , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Adulto Jovem
12.
Int J Infect Dis ; 99: 437-440, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32805422

RESUMO

OBJECTIVES: At the end of November 2019, a novel coronavirus responsible for respiratory tract infections (COVID-19) emerged in China. Despite drastic containment measures, this virus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread in Asia and Europe. The pandemic is ongoing with a particular hotspot in Southern Europe and America; many studies predicted a similar epidemic in Africa, as is currently seen in Europe and the United States of America. However, reported data have not confirmed these predictions. One of the hypotheses that could explain the later emergence and spread of COVID-19 pandemic in African countries is the use of antimalarial drugs to treat malaria, and specifically, artemisinin-based combination therapy (ACT). METHODS: The antiviral activity of fixed concentrations of ACT at concentrations consistent with those observed in human plasma when ACT is administered at oral doses for uncomplicated malaria treatment was evaluatedin vitro against a clinically isolated SARS-CoV-2 strain (IHUMI-3) in Vero E6 cells. RESULTS: Mefloquine-artesunate exerted the highest antiviral activity with % inhibition of 72.1 ± 18.3 % at expected maximum blood concentration (Cmax) for each ACT drug at doses commonly administered in malaria treatment. All the other combinations, artesunate-amodiaquine, artemether-lumefantrine, artesunate-pyronaridine, or dihydroartemisinin-piperaquine, showed antiviral inhibition in the same ranges (27.1 to 34.1 %). CONCLUSIONS: Antimalarial drugs for which concentration data in the lungs are available are concentrated from 10 to 160 fold more in the lungs than in blood. Thesein vitro results reinforce the hypothesis that antimalarial drugs could be effective as an anti-COVID-19 treatment.


Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Mefloquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Amodiaquina/farmacologia , Animais , Antimaláricos/farmacologia , Combinação Arteméter e Lumefantrina/farmacologia , Artemisininas/farmacologia , Chlorocebus aethiops , Combinação de Medicamentos , Humanos , Malária/epidemiologia , Malária Falciparum/tratamento farmacológico , Mefloquina/farmacologia , Pandemias , Células Vero
13.
Trends Parasitol ; 36(11): 884-887, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32771284

RESUMO

Resistance to the artemisinin derivatives, our most effective antimalarial drugs, has not manifest as a classical resistance phenotype in which parasites can tolerate higher drug concentrations. Instead, resistant parasites have an altered maturation. We hypothesize that the short half-life of artemisinin concentrations is an unanticipated driver of this novel resistance phenotype.


Assuntos
Artemisininas/farmacologia , Resistência a Medicamentos , Plasmodium/efeitos dos fármacos , Seleção Genética/efeitos dos fármacos , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Humanos , Concentração Inibidora 50
15.
Parasitol Res ; 119(9): 2749-2764, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32638101

RESUMO

The global challenge to the treatment of malaria is mainly the occurrence of resistance of malaria parasites to conventionally used antimalarials. Artesunate, a semisynthetic artemisinin compound, and other artemisinin derivatives are currently used in combination with selected active antimalarial drugs in order to prevent or delay the emergence of resistance to artemisinin derivatives. Several methods, such as preparation of hybrid compounds, combination therapy, chemical modification and the use of synthetic materials to enhance solubility and delivery of artesunate, have been employed over the years to improve the antimalarial activity of artesunate. Each of these methods has advantages it bestows on the efficacy of artesunate. This review discussed the various methods employed in enhancing the antimalarial activity of artesunate and delaying the emergence of resistance of parasite to it.


Assuntos
Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Artemisininas/química , Artemisininas/uso terapêutico , Resistência a Medicamentos/fisiologia , Quimioterapia Combinada , Humanos , Malária Falciparum/parasitologia
16.
Am J Trop Med Hyg ; 103(2_Suppl): 28-36, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618242

RESUMO

From 2014 to 2016, a community-randomized controlled trial in Southern Province, Zambia, compared mass drug administration (MDA) and focal MDA (fMDA) with the standard of care. Acceptability of the intervention was assessed quantitatively using closed-ended and Likert scale-based questions posed during three household surveys conducted from April to May in 2014, 2015, and 2016 in 40 health catchments that implemented MDA and fMDA and 20 catchments that served as trial controls. In 2014 and 2015, 47 households per catchment were selected, targeting 1,880 households in MDA and fMDA trial arms; in 2016, 55 households per catchment were selected for a target of 2,200 households in MDA and fMDA trial arms. Concurrently, 27 focus group discussions and 23 in-depth interviews with 248 participants were conducted on reasons for testing and treatment refusal, reasons for nonadherence, and community perception of the MDA campaign. Results demonstrated that the MDA campaign was highly accepted with more than 99% of respondents stating that they would take treatment if positive for malaria. High acceptability at baseline could be associated with test-and-treat campaigns recently conducted in the study area. There was a large increase in the acceptability of prophylactic treatment if negative for malaria from the baseline to follow-up survey for adults and children, from 62% to 96% for each. This likely resulted from an intensive community-wide sensitization program that occurred before the first treatment round at each household during community health worker visits.


Assuntos
Artemisininas/administração & dosagem , Atitude Frente a Saúde , Malária Falciparum/prevenção & controle , Administração Massiva de Medicamentos , Aceitação pelo Paciente de Cuidados de Saúde , Quinolinas/administração & dosagem , Adulto , Artemisininas/uso terapêutico , Erradicação de Doenças/métodos , Quimioterapia Combinada , Feminino , Grupos Focais , Humanos , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Quinolinas/uso terapêutico , Zâmbia/epidemiologia
17.
Am J Trop Med Hyg ; 103(2_Suppl): 54-65, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618245

RESUMO

Rigorous evidence of effectiveness is needed to determine where and when to apply mass drug administration (MDA) or focal MDA (fMDA) as part of a malaria elimination strategy. The Zambia National Malaria Elimination Centre recently completed a community-randomized controlled trial in Southern Province to evaluate MDA and fMDA for transmission reduction. To assess the role of MDA and fMDA on infection incidence, we enrolled a longitudinal cohort for an 18-month period of data collection including monthly malaria parasite infection detection based on polymerase chain reaction and compared time to first infection and cumulative infection incidence outcomes across study arms using Cox proportional hazards and negative binomial models. A total of 2,026 individuals from 733 households were enrolled and completed sufficient follow-up for inclusion in analysis. Infection incidence declined dramatically across all study arms during the period of study, and MDA was associated with reduced risk of first infection (hazards ratio: 0.36; 95% CI: 0.16-0.80) and cumulative infection incidence during the first rainy season (first 5 months of follow-up) (incidence rate ratio: 0.34; 95% CI: 0.12-0.95). No significant effect was found for fMDA or for either arm over the full study period. Polymerase chain reaction infection status at baseline was strongly associated with follow-up infection. The short-term effects of MDA suggest it may be an impactful accelerator of transmission reduction in areas with high coverage of case management and vector control and should be considered as part of a malaria elimination strategy.


Assuntos
Malária Falciparum/epidemiologia , Administração Massiva de Medicamentos , Adolescente , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Artemisininas/administração & dosagem , Artemisininas/uso terapêutico , Criança , Pré-Escolar , Erradicação de Doenças/métodos , Erradicação de Doenças/estatística & dados numéricos , Quimioterapia Combinada , Características da Família , Feminino , Humanos , Incidência , Estudos Longitudinais , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Masculino , Administração Massiva de Medicamentos/métodos , Administração Massiva de Medicamentos/estatística & dados numéricos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Adulto Jovem , Zâmbia/epidemiologia
18.
Am J Trop Med Hyg ; 103(2_Suppl): 7-18, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618247

RESUMO

Over the past decade, Zambia has made substantial progress against malaria and has recently set the ambitious goal of eliminating by 2021. In the context of very high vector control and improved access to malaria diagnosis and treatment in Southern Province, we implemented a community-randomized controlled trial to assess the impact of four rounds of community-wide mass drug administration (MDA) and household-level MDA (focal MDA) with dihydroartemisinin-piperaquine (DHAP) implemented between December 2014 and February 2016. The mass treatment campaigns achieved relatively good household coverage (63-79%), were widely accepted by the community (ranging from 87% to 94%), and achieved very high adherence to the DHAP regimen (81-96%). Significant declines in all malaria study end points were observed, irrespective of the exposure group, with the overall parasite prevalence during the peak transmission season declining by 87.2% from 31.3% at baseline to 4.0% in 2016 at the end of the trial. Children in areas of lower transmission (< 10% prevalence at baseline) that received four MDA rounds had a 72% (95% CI = 12-91%) reduction in malaria parasite prevalence as compared with those with the standard of care without any mass treatment. Mass drug administration consistently had the largest short-term effect size across study end points in areas of lower transmission following the first two MDA rounds. In the context of achieving very high vector control coverage and improved access to diagnosis and treatment for malaria, our results suggest that MDA should be considered for implementation in African settings for rapidly reducing malaria outcomes in lower transmission settings.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Malária Falciparum/prevenção & controle , Administração Massiva de Medicamentos/métodos , Quinolinas/administração & dosagem , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Erradicação de Doenças/métodos , Quimioterapia Combinada , Humanos , Incidência , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Avaliação de Programas e Projetos de Saúde , Quinolinas/uso terapêutico , Zâmbia/epidemiologia
20.
Am J Trop Med Hyg ; 103(2_Suppl): 46-53, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32618249

RESUMO

Community-wide administration of antimalarial drugs in therapeutic doses is a potential tool to prevent malaria infection and reduce the malaria parasite reservoir. To measure the effectiveness and cost of using the antimalarial drug combination dihydroartemisinin-piperaquine (DHAp) through different community-wide distribution strategies, Zambia's National Malaria Control Centre conducted a three-armed community-randomized controlled trial. The trial arms were as follows: 1) standard of care (SoC) malaria interventions, 2) SoC plus focal mass drug administration (fMDA), and 3) SoC plus MDA. Mass drug administration consisted of offering all eligible individuals DHAP, irrespective of a rapid diagnostic test (RDT) result. Focal mass drug administration consisted of offering DHAP to all eligible individuals who resided in a household where anyone tested positive by RDT. Results indicate that the costs of fMDA and MDA per person targeted and reached are similar (US$9.01 versus US$8.49 per person, respectively, P = 0.87), but that MDA was superior in all cost-effectiveness measures, including cost per infection averted, cost per case averted, cost per death averted, and cost per disability-adjusted life year averted. Subsequent costing of the MDA intervention in a non-trial, operational setting yielded significantly lower costs per person reached (US$2.90). Mass drug administration with DHAp also met the WHO thresholds for "cost-effective interventions" in the Zambian setting in 90% of simulations conducted using a probabilistic sensitivity analysis based on trial costs, whereas fMDA met these criteria in approximately 50% of simulations. A sensitivity analysis using costs from operational deployment and trial effectiveness yielded improved cost-effectiveness estimates. Mass drug administration may be a cost-effective intervention in the Zambian context and can help reduce the parasite reservoir substantially. Mass drug administration was more cost-effective in relatively higher transmission settings. In all scenarios examined, the cost-effectiveness of MDA was superior to that of fMDA.


Assuntos
Antimaláricos/economia , Artemisininas/economia , Erradicação de Doenças/economia , Malária Falciparum/prevenção & controle , Administração Massiva de Medicamentos/economia , Quinolinas/economia , Antimaláricos/administração & dosagem , Antimaláricos/uso terapêutico , Artemisininas/administração & dosagem , Artemisininas/uso terapêutico , Análise Custo-Benefício , Erradicação de Doenças/métodos , Custos de Medicamentos , Quimioterapia Combinada/economia , Quimioterapia Combinada/métodos , Custos de Cuidados de Saúde , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/economia , Malária Falciparum/epidemiologia , Administração Massiva de Medicamentos/métodos , Plasmodium falciparum/efeitos dos fármacos , Anos de Vida Ajustados por Qualidade de Vida , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Zâmbia/epidemiologia
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