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1.
PLoS Med ; 17(8): e1003203, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32822347

RESUMEN

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).


Asunto(s)
Antiinfecciosos/uso terapéutico , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Malaria Falciparum/sangre , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/metabolismo , Adolescente , Adulto , Animales , Antiinfecciosos/efectos adversos , Antiinfecciosos/farmacología , Antimaláricos/efectos adversos , Antimaláricos/farmacología , Artemisininas/efectos adversos , Artemisininas/farmacología , Artesunato/efectos adversos , Artesunato/farmacología , Artesunato/uso terapéutico , Australia/epidemiología , Femenino , Cefalea/inducido químicamente , Voluntarios Sanos , Humanos , Malaria Falciparum/epidemiología , Masculino , Náusea/inducido químicamente , Parásitos/metabolismo , Proyectos Piloto , Adulto Joven
2.
Nat Commun ; 11(1): 3799, 2020 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-32732892

RESUMEN

Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.


Asunto(s)
Malaria Falciparum/diagnóstico , Malaria Falciparum/prevención & control , Tamizaje Masivo/métodos , Complicaciones Parasitarias del Embarazo/prevención & control , Atención Prenatal/métodos , Antimaláricos/uso terapéutico , Combinación de Medicamentos , Femenino , Política de Salud , Humanos , Malaria Falciparum/tratamiento farmacológico , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/efectos de los fármacos , Embarazo , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Primer Trimestre del Embarazo , Pirimetamina/uso terapéutico , Sulfadoxina/uso terapéutico , Tanzanía , Organización Mundial de la Salud
3.
Nat Commun ; 11(1): 3922, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32764664

RESUMEN

The Plasmodium falciparum chloroquine resistance transporter (PfCRT) is a key contributor to multidrug resistance and is also essential for the survival of the malaria parasite, yet its natural function remains unresolved. We identify host-derived peptides of 4-11 residues, varying in both charge and composition, as the substrates of PfCRT in vitro and in situ, and show that PfCRT does not mediate the non-specific transport of other metabolites and/or ions. We find that drug-resistance-conferring mutations reduce both the peptide transport capacity and substrate range of PfCRT, explaining the impaired fitness of drug-resistant parasites. Our results indicate that PfCRT transports peptides from the lumen of the parasite's digestive vacuole to the cytosol, thereby providing a source of amino acids for parasite metabolism and preventing osmotic stress of this organelle. The resolution of PfCRT's native substrates will aid the development of drugs that target PfCRT and/or restore the efficacy of existing antimalarials.


Asunto(s)
Antimaláricos/farmacología , Cloroquina/farmacología , Proteínas de Transporte de Membrana/metabolismo , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Animales , Transporte Biológico Activo , Resistencia a Medicamentos/genética , Femenino , Interacciones Huésped-Parásitos/genética , Interacciones Huésped-Parásitos/fisiología , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/metabolismo , Malaria Falciparum/parasitología , Proteínas de Transporte de Membrana/genética , Modelos Biológicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Oligopéptidos/metabolismo , Oocitos/metabolismo , Plasmodium falciparum/genética , Transporte de Proteínas , Proteínas Protozoarias/genética , Xenopus laevis
4.
BMC Infect Dis ; 20(1): 533, 2020 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-32698879

RESUMEN

BACKGROUND: Plasmodium falciparum parasites, which could harbour anti-malaria drug resistance genes, are commonly detected in blood donors in malaria-endemic areas. Notwithstanding, anti-malaria drug resistant biomarkers have not been characterized in blood donors with asymptomatic P. falciparum infection. METHODS: A total of 771 blood donors were selected from five districts in the Greater Accra Region, Ghana. Each donor sample was screened with malaria rapid diagnostic test (RDT) kit and parasitaemia quantified microscopically. Dried blood spots from malaria positive samples were genotyped for P. falciparum chloroquine resistance transporter (Pfcrt), P. falciparum multi-drug resistance (Pfmdr1), P. falciparum dihydropteroate-synthetase (Pfdhps), P. falciparum dihydrofolate-reductase (Pfdhfr) and Kelch 13 propeller domain on chromosome 13 (Kelch 13) genes. RESULTS: Of the 771 blood donors, 91 (11.8%) were positive by RDT. Analysis of sequence reads indicated successful genotyping of Pfcrt, Pfmdr1, Pfdhfr, Pfdhps and Kelch 13 genes in 84.6, 81.3, 86.8, 86.9 and 92.3% of the isolates respectively. Overall, 21 different mutant haplotypes were identified in 69 isolates (75.8%). In Pfcrt, CVIET haplotype was observed in 11.6% samples while in Pfmdr1, triple mutation (resulting in YFN haplotype) was detected in 8.1% of isolates. In Pfdhfr gene, triple mutation resulting in IRNI haplotype and in Pfdhps gene, quintuple mutation resulting in AGESS haplotype was identified in 17.7% parasite isolates. Finally, five non-synonymous Kelch 13 alleles were detected; C580Y (3.6%), P615L (4.8%), A578S (4.8%), I543V (2.4%) and A676S (1.2%) were detected. CONCLUSION: Results obtained in this study indicated various frequencies of mutant alleles in Pfcrt, Pfmdr1, Pfdhfr, Pfdhps and Kelch 13 genes from P. falciparum infected blood donors. These alleles could reduce the efficacy of standard malaria treatment in transfusion-transmitted malaria cases. Incorporating malaria screening into donor screening protocol to defer infected donors is therefore recommended.


Asunto(s)
Donantes de Sangre , Farmacorresistencia Microbiana/genética , Resistencia a Múltiples Medicamentos/genética , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Plasmodium falciparum/genética , Adolescente , Adulto , Alelos , Antimaláricos/uso terapéutico , Enfermedades Asintomáticas , Biomarcadores , Cloroquina/uso terapéutico , Estudios Transversales , Dihidropteroato Sintasa/genética , Femenino , Frecuencia de los Genes , Ghana/epidemiología , Haplotipos , Humanos , Secuencia Kelch/genética , Malaria Falciparum/diagnóstico , Malaria Falciparum/parasitología , Masculino , Proteínas de Transporte de Membrana/genética , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Mutación , Plasmodium falciparum/aislamiento & purificación , Prevalencia , Proteínas Protozoarias/genética , Tetrahidrofolato Deshidrogenasa/genética , Adulto Joven
5.
BMC Infect Dis ; 20(1): 513, 2020 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-32677899

RESUMEN

BACKGROUND: Imported falciparum malaria from Africa has become a key public health challenge in Guizhou Province since 2012. Understanding the polymorphisms of molecular markers of drug resistance can guide selection of antimalarial drugs for the treatment of malaria. This study was aimed to analyze the polymorphisms of pfcrt, pfmdr1, and K13-propeller among imported falciparum malaria cases in Guizhou Province, China. METHOD: Fifty-five imported falciparum malaria cases in Guizhou Province during 2012-2016 were included in this study. Their demographic information and filter paper blood samples were collected. Genomic DNA of Plasmodium falciparum was extracted from the blood samples, and polymorphisms of pfcrt, pfmdr1, and K13-propeller were analyzed with nested PCR amplification followed by sequencing. Data were analyzed with the SPSS17.0 software. RESULTS: The prevalence of pfcrt K76T, pfmdr1 N86Y, and pfmdr1 Y184F mutation was 56.6, 22.2, and 72.2%, respectively, in imported falciparum malaria cases in Guizhou Province. We detected two mutant haplotypes of pfcrt, IET and MNT, with IET being more commonly found (54.7%), and five mutant haplotypes of pfmdr1, of which NFD was the most frequent (53.7%). There were totally 10 combined haplotypes of pfcrt and pfmdr1, of which the haplotype IETNFD possessed a predominance of 28.8%. In addition, three nonsynonymous mutations (S459T, C469F, and V692L) and two synonymous mutations (R471R and V589V) were detected in K13-propeller, all having prevalence less than 6.0%. In particular, a candidate K13 resistance mutation, C469F, was identified for the first time from Democratic Republic of the Congo with the prevalence of 2.0%. CONCLUSIONS: The high prevalence of IET haplotype of pfcrt and NFD haplotype of pfmdr1 suggests the presence of chloroquine, artemether/lumefantrine, and dihydroartemisinin/piperaquine resistance in these cases. Therefore cautions should be made to artemisinin therapy for P. falciparum in Africa. Continuous monitoring of anti-malarial drug efficacy in imported malaria cases is helpful for optimizing antimalarial drug therapy in Guizhou Province, China.


Asunto(s)
Enfermedades Transmisibles Importadas/parasitología , Resistencia a Medicamentos/genética , Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Polimorfismo Genético , Proteínas Protozoarias/genética , Adulto , África/epidemiología , Sustitución de Aminoácidos/genética , Antimaláricos/uso terapéutico , China/epidemiología , Estudios de Cohortes , Femenino , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Masculino , Proteínas de Transporte de Membrana/genética , Persona de Mediana Edad , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Mutación , Plasmodium falciparum/aislamiento & purificación , Enfermedad Relacionada con los Viajes
6.
Lancet Infect Dis ; 20(8): 943-952, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32530424

RESUMEN

BACKGROUND: Malaria in pregnancy affects both the mother and the fetus. However, evidence supporting treatment guidelines for uncomplicated (including asymptomatic) falciparum malaria in pregnant women is scarce and assessed in varied ways. We did a systematic literature review and individual patient data (IPD) meta-analysis to compare the efficacy and tolerability of different artemisinin-based or quinine-based treatments for malaria in pregnant women. METHODS: We did a systematic review of interventional or observational cohort studies assessing the efficacy of artemisinin-based or quinine-based treatments in pregnancy. Seven databases (MEDLINE, Embase, Global Health, Cochrane Library, Scopus, Web of Science, and Literatura Latino Americana em Ciencias da Saude) and two clinical trial registries (International Clinical Trials Registry Platform and ClinicalTrials.gov) were searched. The final search was done on April 26, 2019. Studies that assessed PCR-corrected treatment efficacy in pregnancy with follow-up of 28 days or more were included. Investigators of identified studies were invited to share data from individual patients. The outcomes assessed included PCR-corrected efficacy, PCR-uncorrected efficacy, parasite clearance, fever clearance, gametocyte development, and acute adverse events. One-stage IPD meta-analysis using Cox and logistic regression with random-effects was done to estimate the risk factors associated with PCR-corrected treatment failure, using artemether-lumefantrine as the reference. This study is registered with PROSPERO, CRD42018104013. FINDINGS: Of the 30 studies assessed, 19 were included, representing 92% of patients in the literature (4968 of 5360 episodes). Risk of PCR-corrected treatment failure was higher for the quinine monotherapy (n=244, adjusted hazard ratio [aHR] 6·11, 95% CI 2·57-14·54, p<0·0001) but lower for artesunate-amodiaquine (n=840, 0·27, 95% 0·14-0·52, p<0·0001), artesunate-mefloquine (n=1028, 0·56, 95% 0·34-0·94, p=0·03), and dihydroartemisinin-piperaquine (n=872, 0·35, 95% CI 0·18-0·68, p=0·002) than artemether-lumefantrine (n=1278) after adjustment for baseline asexual parasitaemia and parity. The risk of gametocyte carriage on day 7 was higher after quinine-based therapy than artemisinin-based treatment (adjusted odds ratio [OR] 7·38, 95% CI 2·29-23·82). INTERPRETATION: Efficacy and tolerability of artemisinin-based combination therapies (ACTs) in pregnant women are better than quinine. The lower efficacy of artemether-lumefantrine compared with other ACTs might require dose optimisation. FUNDING: The Bill & Melinda Gates Foundation, ExxonMobil Foundation, and the University of Oxford Clarendon Fund.


Asunto(s)
Antimaláricos/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Complicaciones Parasitarias del Embarazo/tratamiento farmacológico , Quinina/uso terapéutico , Amodiaquina/uso terapéutico , Antibacterianos/uso terapéutico , Antimaláricos/efectos adversos , Artemisininas/uso terapéutico , Artesunato/uso terapéutico , Atovacuona/uso terapéutico , Clindamicina/uso terapéutico , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Mefloquina/uso terapéutico , Embarazo , Proguanil/uso terapéutico , Pirimetamina/uso terapéutico , Quinina/efectos adversos , Quinolinas/uso terapéutico , Sulfadoxina/uso terapéutico
7.
Rev Med Liege ; 75(5-6): 362-365, 2020 May.
Artículo en Francés | MEDLINE | ID: mdl-32496680

RESUMEN

Malaria is a worldwide public health problem. In Europe, data show an increasing trend of imported cases in the last ten years. Following an alarming observation reporting resistance to anti-malarial drugs, new effective treatments have been developed in early 21st century. These are artemisinin and its derivatives. Artemisinin-based combination therapies (ACT) are now recommended by the World Health Organisation (WHO) since 2006 as the first-line treatment for uncomplicated Plasmodium falciparum malaria. However, resistance phenomena to these new drugs have been described in South-East Asia since 2009. It is thus necessary to use them properly and to monitor their use to preserve their effectiveness in the future.


Asunto(s)
Antimaláricos , Malaria Falciparum , Antimaláricos/uso terapéutico , Resistencia a Medicamentos , Europa (Continente) , Humanos , Malaria Falciparum/tratamiento farmacológico
8.
BMC Infect Dis ; 20(1): 363, 2020 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-32448216

RESUMEN

BACKGROUND: Plasmodium vivax rarely develops severe complications when compared to severe falciparum malaria. However, severe vivax malaria also needs urgent, intensive care and treatment as severe falciparum malaria. This systematic review aimed to explore pooled prevalence of severe vivax malaria and to identify factors related to poor outcome of patients who developed severe manifestation. METHODS: The systematic review conducted by two reviewers independently through searching of research publications related to severe P. vivax malaria in three databases including MEDLINE, Web of Science (ISI), and Scopus until October, 22 2019. The pooled prevalence of severe vivax malaria was achieved using STATA and RevMan 5 Software. Factors related to poor outcome of patients with severe vivax malaria were analyzed using SPSS 11.5 Software. RESULTS: Among 2615 research publications retrieved from three databases, 49 articles reporting on 42,325 severity cases were selected for calculating pooled prevalence. Seventy-six patients from case reports, case series, letter to editors, and research communications were collected to identify factors related to poor outcome of patients with severe vivax malaria. The results showed that severe anemia, jaundice, respiratory distress, impaired consciousness, and renal failure were the most common major manifestations of severe malaria guided by the World Health Organization (WHO) criterion. The meta-analysis indicated that severe malaria was less frequent in patient with P. vivax compared to those with P. falciparum (P -value < 0.00001, OR = 0.38, 95% CI = 0.25-0.56, I2 = 87%). In addition, thrombocytopenia, anemia, hepatitis, and severe thrombocytopenia were the most common minor complications. Analysis of cases indicated that convulsion, respiratory distress, renal failure, jaundice, anuria/oliguria, and complication during treatment impacted on longer hospital stays compared to other severe complications (P-value < 0.05). Respiratory distress was frequently found after first treatment with anti-malarial drugs (P-value = 0.002). Renal failure was frequently found before treatment with anti-malarial drugs (P-value = 0.016). Mean days of fever and higher pulse rates at presentation were predictors of poor outcome among patients with severe vivax malaria (P-value < 0.05). CONCLUSIONS: Severe anemia was the most common major manifestation of P. vivax malaria guided by the WHO criterion. Severe anemia was found less frequently in patients with P. vivax than those with P. falciparum. Renal failure, jaundice, anuria/oliguria, and complication during treatment along with, mean days of fever and higher pulse rates at presentation might be predictors of poor outcome of patients with severe vivax malaria.


Asunto(s)
Malaria Falciparum/epidemiología , Malaria Vivax/epidemiología , Plasmodium falciparum , Plasmodium vivax , Índice de Severidad de la Enfermedad , Adulto , Anemia/etiología , Antimaláricos/uso terapéutico , Anuria/etiología , Femenino , Fiebre , Frecuencia Cardíaca , Humanos , Ictericia/etiología , Malaria Falciparum/complicaciones , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Malaria Vivax/complicaciones , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/parasitología , Masculino , Oliguria/etiología , Prevalencia , Insuficiencia Renal/etiología , Factores de Riesgo , Trombocitopenia/etiología , Resultado del Tratamiento , Organización Mundial de la Salud , Adulto Joven
9.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(3): 328-330, 2020 Apr 14.
Artículo en Chino | MEDLINE | ID: mdl-32468804

RESUMEN

The demographic features, epidemiology, diagnosis and treatment of two cases with falciparum malaria imported into Suzhou City in 2019 were reported. These findings indicate a risk of imported malaria in visitors besides high prevalence in migrant labors, and much attention should be paid to children that are at a high risk of infections.


Asunto(s)
Malaria Falciparum , Niño , China/epidemiología , Ciudades , Enfermedades Transmisibles Importadas/diagnóstico , Enfermedades Transmisibles Importadas/tratamiento farmacológico , Enfermedades Transmisibles Importadas/epidemiología , Enfermedades Transmisibles Importadas/parasitología , Humanos , Malaria Falciparum/diagnóstico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Malaria Falciparum/prevención & control , Prevalencia
10.
Am J Trop Med Hyg ; 103(1): 359-368, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32431267

RESUMEN

Parasite resistance to antimalarial drugs poses a serious threat to malaria control. The WorldWide Antimalarial Resistance Network (WWARN) aims to provide a collaborative platform to support the global malaria research effort. Here, we describe the "WWARN clinical trials publication library," an open-access, up-to-date resource to streamline the synthesis of antimalarial safety and efficacy data. A series of iteratively refined database searches were conducted to identify prospective clinical trials assessing antimalarial drug efficacy with at least 28 days of follow-up. Of approximately 45,000 articles screened, 1,221 trials published between 1946 and 2018 were identified, representing 2,339 treatment arms and 323,819 patients. In trials from endemic locations, 75.7% (787/1,040) recruited patients with Plasmodium falciparum, 17.0% (177/1,040) Plasmodium vivax, 6.9% (72/1,040) both, and 0.4% (4/1,040) other Plasmodium species; 57.2% (585/1,022) of trials included under-fives and 5.3% (55/1,036) included pregnant women. In Africa, there has been a marked increase in both P. falciparum and P. vivax studies over the last two decades. The WHO-recommended artemisinin-based combination therapies alone or with a gametocidal drug were assessed in 39.5% (705/1,783) of P. falciparum treatment arms and 10.5% (45/429) of P. vivax arms, increasing to 78.0% (266/341) and 22.9% (27/118), respectively, in the last five years. The library is a comprehensive, open-access tool that can be used by the malaria community to explore the collective knowledge on antimalarial efficacy (available at https://www.wwarn.org/tools-resources/literature-reviews/wwarn-clinical-trials-publication-library). It is the first of its kind in the field of global infectious diseases, and lessons learnt in its creation can be adapted to other infectious diseases.


Asunto(s)
Antimaláricos/uso terapéutico , Resistencia a Medicamentos , Malaria/tratamiento farmacológico , Plasmodium/fisiología , Ensayos Clínicos como Asunto , Bases de Datos Bibliográficas , Bases de Datos Factuales , Quimioterapia Combinada , Humanos , Malaria/parasitología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/parasitología , Plasmodium falciparum/fisiología , Plasmodium knowlesi/fisiología , Plasmodium malariae/fisiología , Plasmodium ovale/fisiología , Plasmodium vivax/fisiología
11.
PLoS Negl Trop Dis ; 14(5): e0008295, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32379762

RESUMEN

Genetic epidemiology can provide important insights into parasite transmission that can inform public health interventions. The current study compared long-term changes in the genetic diversity and structure of co-endemic Plasmodium falciparum and P. vivax populations. The study was conducted in Papua Indonesia, where high-grade chloroquine resistance in P. falciparum and P. vivax led to a universal policy of Artemisinin-based Combination Therapy (ACT) in 2006. Microsatellite typing and population genetic analyses were undertaken on available isolates collected between 2004 and 2017 from patients with uncomplicated malaria (n = 666 P. falciparum and n = 615 P. vivax). The proportion of polyclonal P. falciparum infections fell from 28% (38/135) before policy change (2004-2006) to 18% (22/125) at the end of the study (2015-2017); p<0.001. Over the same period, polyclonal P. vivax infections fell from 67% (80/119) to 35% (33/93); p<0.001. P. falciparum strains persisted for up to 9 years compared to 3 months for P. vivax, reflecting higher rates of outbreeding in the latter. Sub-structure was observed in the P. falciparum population, but not in P. vivax, confirming different patterns of outbreeding. The P. falciparum population exhibited 4 subpopulations that changed in frequency over time. Notably, a sharp rise was observed in the frequency of a minor subpopulation (K2) in the late post-ACT period, accounting for 100% of infections in late 2016-2017. The results confirm epidemiological evidence of reduced P. falciparum and P. vivax transmission over time. The smaller change in P. vivax population structure is consistent with greater outbreeding associated with relapsing infections and highlights the need for radical cure to reduce recurrent infections. The study emphasizes the challenge in disrupting P. vivax transmission and demonstrates the potential of molecular data to inform on the impact of public health interventions.


Asunto(s)
Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Monitoreo Epidemiológico , Lactonas/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Malaria Vivax/tratamiento farmacológico , Malaria Vivax/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada/métodos , Femenino , Variación Genética , Técnicas de Genotipaje , Humanos , Indonesia , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Epidemiología Molecular , Plasmodium falciparum/clasificación , Plasmodium falciparum/genética , Plasmodium falciparum/aislamiento & purificación , Plasmodium vivax/clasificación , Plasmodium vivax/genética , Plasmodium vivax/aislamiento & purificación , Adulto Joven
12.
Med Hypotheses ; 140: 109756, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32344306
13.
Lancet Infect Dis ; 20(8): 964-975, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32275867

RESUMEN

BACKGROUND: (+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. METHODS: The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safety, tolerability, and pharmacokinetics of SJ733, and identification of an SJ733 dose to test in the induced blood-stage malaria model. The phase 1b was a single-centre, open-label, volunteer infection study using the induced blood-stage malaria model in which fasted participants were intravenously infected with blood-stage P falciparum and subsequently treated with a single dose of SJ733. Phase 1b took place at Q-Pharm (Herston, QLD, Australia) and was initiated only after phase 1a showed that exposure exceeding the threshold minimum exposure could be safely achieved in humans. Participants were inoculated on day 0 with P falciparum-infected human erythrocytes (around 2800 parasites in the 150 mg dose cohort and around 2300 parasites in the 600 mg dose cohort), and parasitaemia was monitored before malaria inoculation, after inoculation, immediately before SJ733 dosing, and then post-dose. Participants were treated with SJ733 within 24 h of reaching 5000 parasites per mL or at a clinical score higher than 6. Phase 1b primary endpoints were calculation of a parasite reduction ratio (PRR48) and parasite clearance half-life, and safety and tolerability of SJ733 (incidence, severity, and drug-relatedness of adverse events). In both phases of the trial, SJ733 hydrochloride salt was formulated as a powder blend in capsules containing 75 mg or 300 mg for oral administration. Healthy men and women (of non-childbearing potential) aged 18-55 years were eligible for both studies. Both studies are registered with ClinicalTrials.gov (NCT02661373 for the phase 1a and NCT02867059 for the phase 1b). FINDINGS: In the phase 1a, 23 healthy participants were enrolled and received one to three non-consecutive doses of SJ733 between March 14 and Dec 7, 2016. SJ733 was safe and well tolerated at all doses and in fasted and fed conditions. 119 adverse events were recorded: 54 (45%) were unrelated, 63 (53%) unlikely to be related, and two (2%) possibly related to SJ733. In the phase 1b, 17 malaria-naive, healthy participants were enrolled. Seven participants in the 150 mg dose cohort were inoculated and dosed with SJ733. Eight participants in the 600 mg dose cohort were inoculated, but two participants could not be dosed with SJ733. Two additional participants were subsequently inoculated and dosed with SJ733. SJ733 exposure increased proportional to the dose through to the 600 mg dose, then was saturable at higher doses. Fasted participants receiving 600 mg exceeded the target area under the concentration curve extrapolated to infinity (AUC0-∞) of 13 000 µg × h/L (median AUC0-∞ 24 283 [IQR 16 135-31 311] µg × h/L, median terminal half-life 17·4 h [IQR 16·1-24·0], and median timepoint at which peak plasma concentration is reached 1·0 h [0·6-1·3]), and this dose was tested in the phase 1b. All 15 participants dosed with SJ733 had at least one adverse event. Of the 172 adverse events recorded, 128 (74%) were mild. The only adverse event attributed to SJ733 was mild bilateral foot paraesthesia that lasted 3·75 h and resolved spontaneously. The most common adverse events were related to malaria. Based on parasite clearance half-life, the derived log10PRR48 and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0-2·5) and 6·47 h (95% CI 5·88-7·18) for 150 mg, and 4·1 (3·7-4·4) and 3·56 h (3·29-3·88) for 600 mg. INTERPRETATION: The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy. FUNDING: Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities.


Asunto(s)
Antimaláricos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Isoquinolinas/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Plasmodium falciparum/efectos de los fármacos , Inhibidores de la Bomba de Protones/uso terapéutico , Adulto , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , Antimaláricos/farmacocinética , Estudios de Casos y Controles , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Femenino , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Humanos , Isoquinolinas/administración & dosificación , Isoquinolinas/efectos adversos , Isoquinolinas/farmacocinética , Estadios del Ciclo de Vida/efectos de los fármacos , Masculino , Persona de Mediana Edad , Plasmodium falciparum/crecimiento & desarrollo , Plasmodium falciparum/metabolismo , Inhibidores de la Bomba de Protones/administración & dosificación , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/farmacocinética , Resultado del Tratamiento , Adulto Joven
14.
Int J Infect Dis ; 95: 399-405, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32320811

RESUMEN

BACKGROUND: Artemisinin resistance described as increased parasite clearance time (PCT) is rare in Africa. More sensitive methods such as qPCR might better characterize the clearance phenotype in sub-Saharan Africa. METHODS: PCT is explored in Mali using light microscopy and qPCR after artesunate for uncomplicated malaria. In two villages, patients were followed for 28 days. Blood smears and spots were collected respectively for microscopy and qPCR. Parasitemia slope half-life was calculated after microscopy. Patient residual parasitemia were measured by qPCR. RESULTS: Uncorrected adequate clinical and parasitological responses (ACPR) observed in Faladje and Bougoula-Hameau were 78% and 92%, respectively (p=0.01). This reached 100% for both after molecular correction. Proportions of 24H microscopy positive patients in Faladje and Bougoula-Hameau were 97.2% and 72%, respectively (p<0.0001). Slope half-life was 2.8h in Faladje vs 2H in Bougoula-Hameau (p<0.001) and Proportions of 72H patients with residual parasitemia were 68.5% and 40% in Faladje and Bougoula-Hameau, respectively (p=0.003). The mean residual parasitemia was 2.9 in Faladje vs. 0.008 in Bougoula-Hameau (p=0.002). Although artesunate is efficacious in Mali, the longer parasite clearance time with submicroscopic parasitemia observed may represent early signs of developing P. falciparum resistance to artemisinins.


Asunto(s)
Malaria Falciparum/parasitología , Plasmodium falciparum , Antimaláricos/uso terapéutico , Artesunato/uso terapéutico , Niño , Femenino , Humanos , Malaria Falciparum/tratamiento farmacológico , Masculino , Malí , Microscopía , Parasitemia/tratamiento farmacológico , Plasmodium falciparum/genética , Plasmodium falciparum/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa
16.
Am J Trop Med Hyg ; 103(1): 378-393, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32314694

RESUMEN

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum. Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5-5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.


Asunto(s)
Alanina Transaminasa/metabolismo , Antimaláricos/efectos adversos , Aspartato Aminotransferasas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Voluntarios Sanos , Malaria Falciparum/tratamiento farmacológico , Parasitemia/tratamiento farmacológico , Acrilamidas/efectos adversos , Adamantano/efectos adversos , Adamantano/análogos & derivados , Adulto , Aminopiridinas/efectos adversos , Aminoquinolinas/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Transfusión de Eritrocitos , Eritrocitos/parasitología , Femenino , Compuestos Ferrosos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Indoles/efectos adversos , Isoquinolinas/efectos adversos , Masculino , Metalocenos/efectos adversos , Peróxidos/efectos adversos , Piperazinas/efectos adversos , Plasmodium falciparum , Primaquina/efectos adversos , Pirimidinas/efectos adversos , Quinolinas/efectos adversos , Compuestos de Espiro/efectos adversos , Sulfonas/efectos adversos , Triazoles/efectos adversos , Adulto Joven
17.
Am J Trop Med Hyg ; 103(1): 369-377, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32342846

RESUMEN

Progress with malaria control in western Kenya has stagnated since 2007. Additional interventions to reduce the high burden of malaria in this region are urgently needed. We conducted a two-arm, community-based, cluster-randomized, controlled trial of active case detection and treatment of malaria infections in all residents mass testing and treatment (MTaT) of 10 village clusters (intervention clusters) for two consecutive years to measure differences in the incidence of clinical malaria disease and malaria infections compared with 20 control clusters where MTaT was not implemented. All residents of intervention clusters, irrespective of history of fever or other malaria-related symptoms, were tested three times per year before the peak malaria season using malaria rapid diagnostic tests. All positive cases were treated with dihydroartemisinin-piperaquine. The incidence of clinical malaria was measured through passive surveillance, whereas the cumulative incidence of malaria infection was measured using active surveillance in a cohort comprising randomly selected residents. The incidence of clinical malaria was 0.19 cases/person-year (p-y, 95% CI: 0.13-0.28) in the intervention arm and 0.24 cases/p-y (95% CI: 0.15-0.39) in the control arm (incidence rate ratio [IRR] 0.79, 95% CI: 0.61-1.02). The cumulative incidence of malaria infections was similar between the intervention (2.08 infections/p-y, 95% CI: 1.93-2.26) and control arms (2.19 infections/p-y, 95% CI: 2.02-2.37) with a crude IRR of 0.95 (95% CI: 0.87-1.04). Six rounds of MTaT over 2 years did not have a significant impact on the incidence of clinical malaria or the cumulative incidence of malaria infection in this area of high malaria transmission.


Asunto(s)
Antimaláricos/uso terapéutico , Malaria Falciparum/diagnóstico , Adolescente , Artemisininas/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Incidencia , Kenia/epidemiología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Malaria Falciparum/transmisión , Masculino , Tamizaje Masivo/métodos , Quinolinas/uso terapéutico
18.
PLoS One ; 15(4): e0232171, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32324826

RESUMEN

There is great concern regarding the rapid emergence and spread of drug-resistance in Plasmodium falciparum, the parasite responsible for the most severe form of human malaria. Parasite populations resistant to some or all the currently available antimalarial treatments are present in different world regions. Considering the need for novel and integrated approaches to control malaria, combinations of drugs were tested on P. falciparum. The primary focus was on doxycycline, an antibiotic that specifically targets the apicoplast of the parasite. In combination with doxycycline, three different drugs known to inhibit efflux pumps (verapamil, elacridar and ivermectin) were tested, with the assumption that they could increase the intracellular concentration of the antibiotic and consequently its efficacy against P. falciparum. We emphasize that elacridar is a third-generation ABC transporters inhibitor, never tested before on malaria parasites. In vitro experiments were performed on asexual stages of two strains of P. falciparum, chloroquine-sensitive (D10) and chloroquine-resistant (W2). Incubation times on asynchronous or synchronous cultures were 72h or 96h, respectively. The antiplasmodial effect (i.e. the IC50) was determined by measuring the activity of the parasite lactate dehydrogenase, while the interaction between drugs was determined through combination index (CI) analyses. Elacridar achieved an IC50 concentration comparable to that of ivermectin, approx. 10-fold lower than that of verapamil, the other tested ABC transporter inhibitor. CI results showed synergistic effect of verapamil plus doxycycline, which is coherent with the starting hypothesis, i.e. that ABC transporters represent potential targets, worth of further investigations, towards the development of companion molecules useful to enhance the efficacy of antimalarial drugs. At the same time, the observed antagonistic effect of doxycycline in combination with ivermectin or elacridar highlighted the importance of drug testing, to avoid the de-facto generation of a sub-dosage, a condition that facilitates the development of drug resistance.


Asunto(s)
Antimaláricos/uso terapéutico , Doxiciclina/uso terapéutico , Ivermectina/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Cloroquina/uso terapéutico , Resistencia a Medicamentos/efectos de los fármacos , Quimioterapia Combinada/métodos , Humanos , Malaria Falciparum/parasitología
19.
Lancet ; 395(10233): 1345-1360, 2020 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-32171078

RESUMEN

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.


Asunto(s)
Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Adolescente , Adulto , Amodiaquina/administración & dosificación , Amodiaquina/uso terapéutico , Antraquinonas/administración & dosificación , Antraquinonas/uso terapéutico , Antimaláricos/administración & dosificación , Combinación Arteméter y Lumefantrina/administración & dosificación , Combinación Arteméter y Lumefantrina/uso terapéutico , Artemisininas/administración & dosificación , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Masculino , Mefloquina/administración & dosificación , Mefloquina/uso terapéutico , Plasmodium falciparum/efectos de los fármacos , Reacción en Cadena de la Polimerasa , Quinolinas/administración & dosificación , Quinolinas/uso terapéutico , Resultado del Tratamiento , Adulto Joven
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