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1.
BMC Med ; 21(1): 397, 2023 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-37858129

RESUMO

BACKGROUND: Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status. METHODS: This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively. RESULTS: One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo). CONCLUSIONS: In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa. TRIAL REGISTRATION: The trial is registered at ISRCTN 11594437.


Assuntos
Antimaláricos , Deficiência de Glucosefosfato Desidrogenase , Malária Falciparum , Talassemia alfa , Masculino , Feminino , Humanos , Criança , Pré-Escolar , Primaquina , Antimaláricos/efeitos adversos , Talassemia alfa/tratamento farmacológico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemeter/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/induzido quimicamente , Hemoglobinas/análise , Plasmodium falciparum
2.
Lancet Infect Dis ; 23(4): 471-483, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36462528

RESUMO

BACKGROUND: WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. METHODS: We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A- variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether-lumefantrine or dihydroartemisinin-piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants. FINDINGS: Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether-lumefantrine plus single low-dose primaquine group, 286 to the artemether-lumefantrine plus placebo group, 283 to the dihydroartemisinin-piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin-piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study-these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference -0·66%, 95% CI -1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (-0·014%, -0·68 to 0·65; p=0·97). INTERPRETATION: Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa. FUNDING: UK Government Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust Joint Global Health Trials Scheme.


Assuntos
Antimaláricos , Deficiência de Glucosefosfato Desidrogenase , Malária Falciparum , Masculino , Feminino , Humanos , Criança , Lactente , Primaquina/efeitos adversos , Antimaláricos/efeitos adversos , Plasmodium falciparum/genética , Deficiência de Glucosefosfato Desidrogenase/genética , Deficiência de Glucosefosfato Desidrogenase/induzido quimicamente , Deficiência de Glucosefosfato Desidrogenase/tratamento farmacológico , Uganda , República Democrática do Congo/epidemiologia , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/efeitos adversos , Malária Falciparum/epidemiologia , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/uso terapêutico , Hemoglobinas/uso terapêutico , Organização Mundial da Saúde
3.
EBioMedicine ; 96: 104805, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37757570

RESUMO

BACKGROUND: There are no pharmacokinetic data of single low dose primaquine (SLDPQ) as transmission blocking in African children with acute Plasmodium falciparum and glucose-6-phosphate dehydrogenase deficiency (G6PDd). METHODS: Primaquine pharmacokinetics of age-dosed SLDPQ (shown previously to be gametocytocidal with similar tolerability as placebo) were characterised in falciparum-infected Ugandan and Congolese children aged 6 months to 11 years, treated on admission with standard 3-day dihydroartemisinin-piperaquine or artemether-lumefantrine plus SLDPQ: 6 m-<1 y: 1.25 mg, 1-5 y: 2.5 mg, 6-9 y: 5 mg, 10-11 y: 7.5 mg. LC-MS/MS-measured plasma primaquine and carboxyprimaquine (baseline, 1, 1.5, 2, 4, 8, 12, 24 h) were analysed by noncompartmental analysis. Multivariable linear regression modelled associations between covariates, including cytochrome-P450 2D6 metaboliser status, and outcomes. FINDINGS: 258 children (median age 5 [interquartile range (IQR) 3-7]) were sampled; 8 (3.1%) with early vomiting were excluded. Primaquine doses of 0.10-0.40 (median 0.21, IQR 0.16-0.25) mg base/kg resulted in primaquine maximum plasma concentrations (Cmax) of 2.3-447 (median 103.0, IQR 72.1-140.0) ng/mL between 1.0 and 8.0 (median 2) hours (Tmax) and median areas under the drug concentration curves (AUC0-last) 730.2 (6 m-<1 y, n = 12), 582.8 (1-5 y, n = 126), 871.1 (6-9 y, n = 80), and 931.0 (10-11 y, n = 32) ng∗h/mL. Median elimination half-live (T½) was 4.7 (IQR 3.8-5.6) hours. Primaquine clearance/kg peaked at 18 months, plateauing at 4 y. Increasing CYP2D6 metaboliser activity score [poor (3/250), intermediate (52/250), normal (150/250), ultrarapid (5/250), indeterminate (40/250)] and baseline haemoglobin were significantly associated with a lower primaquine AUC0-last,which increased with increasing mg/kg dose and age but was independent of the artemisinin treatment used. INTERPRETATION: Age-dosed SLDPQ resulted in variable primaquine exposure that depended on bodyweight-adjusted dose, age, baseline haemoglobin and CYP2D6 metaboliser status, but not on dihydroartemisinin-piperaquine or artemether-lumefantrine. These data support age-dosed SLDPQ for transmission blocking in sub-Saharan Africa. FUNDING: This work was cofunded by the UK Medical Research Council, Wellcome Trust, and UK Aid through the Global Health Trials (grant reference MR/P006973/1). The funders had no role in the study design, execution, and analysis and decisions regarding publication.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Criança , Humanos , Pré-Escolar , Primaquina/farmacocinética , Primaquina/uso terapêutico , Uganda , Citocromo P-450 CYP2D6/uso terapêutico , Cromatografia Líquida , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Espectrometria de Massas em Tandem , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum , Hemoglobinas
4.
J Int AIDS Soc ; 24(9): e25801, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34496152

RESUMO

INTRODUCTION: Provider-collected swabs are an unappealing procedure for many transgender women and may have led to suboptimal rates of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) testing. Self-collection for CT/NG testing is recommended for men who have sex with men. However, the information on acceptability and clinical performance to support a recommendation for transgender women is lacking. We aimed to determine the acceptability and satisfaction towards self-collection for CT/NG testing among Thai transgender women. METHODS: Thai transgender women who attended Tangerine Clinic (a transgender-led, integrated, gender-affirming care and sexual health services clinic in Bangkok, Thailand) between May and July 2020 and had condomless sexual intercourse within the past six months were offered to collect urine and perform self-swabs of pharyngeal, rectal, and if applicable, neovaginal compartments for pooled nucleic acid amplification testing for CT/NG infections. Participants received a diagram, video and oral instructions about how to perform self-collection procedure. Those who accepted self-collection were also offered to receive provider collection to evaluate the performance between the two methods. Self-administered questionnaires were used to assess satisfaction. RESULTS: Among 216 transgender women enrolled, 142 (65.7%) accepted self-collection. All who accepted had pharyngeal, rectal and urine samples collected. Of 31 transgender women who had undergone genital surgery, 28 (90.3%) accepted neovaginal self-swab. The acceptance rate increased from 46.2% in May to 84.5% in July 2020. One participant had an invalid result. All transgender women who accepted self-collection could perform it without assistance, and 82.8% were highly satisfied with the method. None reported dissatisfaction. Due to the COVID-19 pandemic, provider collection services were discontinued early, and only eight transgender women were able to perform both methods for performance evaluation. The performance agreement was 100%. CONCLUSIONS: Thai transgender women had high acceptability and satisfaction towards self-collection for CT/NG testing. The performance was promising compared to provider collection. Our results support the implementation of self-collection to the sexually transmitted infection services, particularly during the COVID-19 pandemic where physical distancing is the new normal. A larger study is warranted to determine the performance of self-collection for CT/NG testing in each anatomical compartment and confirm the performance between self-collection and provider collection.


Assuntos
Infecções por Chlamydia/diagnóstico , Chlamydia trachomatis/isolamento & purificação , Gonorreia/diagnóstico , Neisseria gonorrhoeae/isolamento & purificação , Aceitação pelo Paciente de Cuidados de Saúde , Satisfação Pessoal , Manejo de Espécimes/métodos , Pessoas Transgênero , Adulto , COVID-19 , Infecções por Chlamydia/epidemiologia , Feminino , Gonorreia/epidemiologia , Humanos , Masculino , Pandemias , SARS-CoV-2 , Autocuidado , Tailândia/epidemiologia
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