Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
1.
Clin Med (Lond) ; 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727368

RESUMO

BACKGROUND: The seroprevalence of antibodies to SARS-CoV-2 in healthcare workers is variable throughout the world. This study compares the use of two antibody assays among large cohorts of healthcare workers in southern England. METHODS: This cohort study includes data obtained from staff at Western Sussex Hospitals NHS Foundation Trust (WSHT) and Brighton and Sussex University Hospitals (BSUH) during voluntary antibody testing, using Abbott and Roche SARS-CoV-2 antibody assays at each Trust respectively. RESULTS: The observed seroprevalence level was 7.9% for the WSHT/Abbott cohort versus 13% for the BSUH/Roche cohort. Based on a previous positive PCR, we find that the false-negative rate of the Abbott and Roche assays were 60.2% and 19% respectively, implying sensitivity levels of 39.8% and 81%. Within these cohorts, seropositivity was most strongly associated with those of South Asian ethnicity, allied health professionals and male sex (p<0.0001). CONCLUSIONS: In this real-world study, neither antibody test performed to the specification level stated by the manufacturer. More rigorous testing of these and other assays in target populations is recommended prior to widespread usage if they are to provide data that might be useful to control the pandemic.

2.
J Infect Dis ; 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32778875

RESUMO

BACKGROUND: Since the World Health Organization recommended single low-dose (0.25mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant P. falciparum, several single-site studies have been conducted to assess its efficacy. METHODS: An individual patient meta-analysis to assess the gametocytocidal and transmission-blocking efficacy of PQ used in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (i) gametocyte carriage in the first two weeks post-treatment; (ii) the probability of infecting at least one mosquito or of a mosquito becoming infected. RESULTS: In 2,574 participants from fourteen studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytaemia on day 0 (Odds Ratio (OR)=0.22; 95%CI 0.17-0.28 and OR=0.12; 95%CI 0.08-0.16, respectively). The rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (p=0.010 for day 7). Addition of 0.25mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. CONCLUSION: Primaquine's transmission-blocking effects are achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

3.
Clin Med (Lond) ; 20(5): e178-e182, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32694169

RESUMO

BACKGROUND: COVID-19 infection is characterised, among other features, by a prothrombotic state with high rate of venous thromboembolism (VTE), D-dimer, and fibrinogen levels. Clinical observations have also highlighted that these patients have elevated von Willebrand factor (vWF) and factor VIIIc. METHODS: 24 consecutive COVID-19 positive patients were selected from the intensive care unit (ICU) or the high acuity ward of Brighton and Sussex University Hospitals NHS Trust. RESULTS: The rate of VTE was 25% and mortality rate was 16.7%. Fibrinogen and D-Dimers were elevated, 7.9 (1.6) g/L and 2.4 (2.02) ug/ml respectively. Factor VIIIc and von vWF antigen levels were both extremely elevated at 279 (148) u/dL and 350 (131) % respectively, which are comparable to levels seen in ICU patients with severe sepsis. vWF levels were significantly higher in patients that died (p=0.017) and showed a positive correlation with age. There was a statistically significant association between COVID-19 disease and non-O blood group (p=0.02); 80% (4/5) of COVID-19 patients with VTE were blood group A. CONCLUSION: Very high levels of vWF and factor VIIIc are common in COVID-19 patients, comparable to levels in severely septic non-COVID ICU patients. This could contribute to the hypercoagulable state and increased VTE rate in COVID-19. Further studies are needed to evaluate the use of vWF for stratifying thrombotic risk in COVID-19 and to determine if elevated vWF is contributing to disease pathogenesis.


Assuntos
Infecções por Coronavirus/complicações , Endotélio Vascular/patologia , Mortalidade Hospitalar/tendências , Pneumonia Viral/complicações , Síndrome Respiratória Aguda Grave/sangue , Tromboembolia Venosa/etiologia , Fator de von Willebrand/metabolismo , Biomarcadores/sangue , Estudos de Coortes , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/metabolismo , Hospitais Universitários , Humanos , Unidades de Terapia Intensiva , Masculino , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Medição de Risco , Amostragem , Síndrome Respiratória Aguda Grave/diagnóstico , Taxa de Sobrevida , Reino Unido , Tromboembolia Venosa/sangue , Tromboembolia Venosa/mortalidade
4.
Clin Med (Lond) ; 20(4): e76-e81, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32423903

RESUMO

BACKGROUND: A possible association between COVID-19 infection and thrombosis, either as a direct consequence of the virus or as a complication of inflammation, is emerging in the literature. Data on the incidence of venous thromboembolism (VTE) are extremely limited. METHODS: We describe three cases of thromboembolism refractory to heparin treatment, the incidence of VTE in an inpatient cohort, and a case-control study to identify risk factors associated with VTE. RESULTS: We identified 274 confirmed (208) or probable (66) COVID-19 patients. 21 (7.7%) were diagnosed with VTE. D-dimer was elevated in both cases (confirmed VTE) and controls (no confirmed VTE) but higher levels were seen in confirmed VTE cases (4.1 vs 1.2 µg/mL, p<0.001). CONCLUSION: Incidence of VTE is high in patients hospitalised with COVID-19. Urgent clinical trials are needed to evaluate the role of anticoagulation in COVID-19. Monitoring of D-dimer and anti-factor Xa levels may be beneficial in guiding management.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Pneumonia Viral/complicações , Tromboembolia Venosa/sangue , Tromboembolia Venosa/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Feminino , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/virologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-31383656

RESUMO

Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of Plasmodium falciparum after artemisinin combination therapy. Genetic variation in CYP2D6, the gene producing the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in Plasmodium vivax malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa (n = 1,076), we were able to genotype CYP2D6 for 774 samples (72%). We determined whether genetic variation in CYP2D6 has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration (n = 554) and for safety in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals treated with PQ (n = 110). Individuals with a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90]; P = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 11.8 g/dl for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dl for CYP2D6 poor/intermediate metabolizers (P = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anemia following PQ treatment (P = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single-low-dose PQ but not with treatment safety.


Assuntos
Antimaláricos/farmacocinética , Citocromo P-450 CYP2D6/genética , Deficiência de Glucosefosfato Desidrogenase/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Polimorfismo Genético , Primaquina/farmacocinética , Adulto , África , Antimaláricos/sangue , Antimaláricos/farmacologia , Combinação Arteméter e Lumefantrina/administração & dosagem , Artemisininas/administração & dosagem , Criança , Citocromo P-450 CYP2D6/deficiência , Esquema de Medicação , Feminino , Expressão Gênica , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Deficiência de Glucosefosfato Desidrogenase/sangue , Deficiência de Glucosefosfato Desidrogenase/parasitologia , Humanos , Estágios do Ciclo de Vida/efeitos dos fármacos , Estágios do Ciclo de Vida/fisiologia , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Masculino , Segurança do Paciente , Plasmodium falciparum/fisiologia , Primaquina/sangue , Primaquina/farmacologia , Quinolinas/administração & dosagem , Resultado do Tratamento
7.
Sci Rep ; 6: 26330, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-27197604

RESUMO

Artemisinin resistance is rapidly spreading in Southeast Asia. The efficacy of artemisinin-combination therapy (ACT) continues to be excellent across Africa. We performed parasite transcriptional profiling and genotyping on samples from an antimalarial treatment trial in Uganda. We used qRT-PCR and genotyping to characterize residual circulating parasite populations after treatment with either ACT or ACT-primaquine. Transcripts suggestive of circulating ring stage parasites were present after treatment at a prevalence of >25% until at least 14 days post initiation of treatment. Greater than 98% of all ring stage parasites were cleared within the first 3 days, but subsequently persisted at low concentrations until day 14 after treatment. Genotyping demonstrated a significant decrease in multiplicity of infection within the first 2 days in both ACT and ACT-primaquine arms. However, multiple clone infections persisted until day 14 post treatment. Our data suggest the presence of genetically diverse persisting parasite populations after ACT treatment. Although we did not demonstrate clinical treatment failures after ACT and the viability and transmissibility of persisting ring stage parasites remain to be shown, these findings are of relevance for the interpretation of parasite clearance transmission dynamics and for monitoring drug effects in Plasmodium falciparum parasites.


Assuntos
Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Primaquina/uso terapêutico , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Criança , Pré-Escolar , DNA de Protozoário/análise , Resistência a Medicamentos , Quimioterapia Combinada , Genótipo , Humanos , Lactente , Malária Falciparum/parasitologia , Plasmodium falciparum/parasitologia , Primaquina/administração & dosagem , Reação em Cadeia da Polimerase em Tempo Real , Uganda
8.
BMC Med ; 14: 40, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26952094

RESUMO

BACKGROUND: A single low dose (0.25 mg/kg) of primaquine is recommended as a gametocytocide in combination with artemisinin-based combination therapies for Plasmodium falciparum but its effect on post-treatment gametocyte circulation and infectiousness to mosquitoes has not been quantified. METHODS: In this randomised, double-blind, placebo-controlled trial, 360 asymptomatic parasitaemic children aged 2-15 years were enrolled and assigned to receive: artemether-lumefantrine (AL) and a dose of placebo; AL and a 0.25 mg/kg primaquine dose; or AL and a 0.40 mg/kg primaquine dose. On days 0, 2, 3, 7, 10 and 14, gametocytes were detected and quantified by microscopy, Pfs25 mRNA quantitative nucleic acid sequence based amplification (QT-NASBA), and quantitative reverse-transcriptase PCR (qRT-PCR). For a subset of participants, pre- and post-treatment infectiousness was assessed by mosquito feeding assays on days -1, 3, 7, 10 and 14. RESULTS: Both primaquine arms had lower gametocyte prevalences after day 3 compared to the placebo arm, regardless of gametocyte detection method. The mean (95% confidence interval) number of days to gametocyte clearance in children with patent gametocytes on day 0 (N = 150) was 19.7 (14.6 - 24.8), 7.7 (6.3 - 9.1) and 8.2 (6.7 - 9.6) for the AL-placebo, the 0.25 mg/kg primaquine dose and the 0.40 mg/kg primaquine dose arms, respectively. While 38.0% (30/79) of selected gametocytaemic individuals were infectious before treatment, only 1/251 participant, from the AL-placebo group, infected mosquitoes after treatment. CONCLUSIONS: We observed similar gametocyte clearance rates after 0.25 and 0.40 mg/kg primaquine doses. Infectivity to mosquitoes after AL was very low and absent in primaquine arms. CLINICALTRIALS. GOV REGISTRATION: NCT01935882.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Etanolaminas/administração & dosagem , Fluorenos/administração & dosagem , Malária Falciparum/tratamento farmacológico , Primaquina/administração & dosagem , Artemeter , Infecções Assintomáticas , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Lactente , Lumefantrina , Malária Falciparum/epidemiologia , Masculino , Plasmodium falciparum , Prevalência
9.
Trials ; 16: 70, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25887344

RESUMO

BACKGROUND: Finding efficacious tools to decrease and interrupt malaria transmission is essential to sustain the gains in malaria control and contain the emergence of artemisinin resistance. Primaquine is effective against Plasmodium falciparum gametocytes and recommended for treatment campaigns in (pre-)elimination settings. Safety concerns preclude its use in endemic African countries with variable proportions of glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The efficacy of the current recommended dose needs to be evaluated, particularly in individuals with an asymptomatic malaria infection. METHODS/DESIGN: This is a four-arm, open label, randomized controlled trial that aims to determine and compare the effect of three different single doses of primaquine combined with dihydroartemisinin-piperaquine, an artemisinin-based combination therapy, on gametocyte carriage in asymptomatic, malaria infected, G6PD-normal individuals. Approximately 1,200 participants are enrolled and followed for 42 days, with the primary endpoint being the prevalence of Plasmodium falciparum gametocyte carriage at day 7 of follow-up determined by quantitative nucleic acid sequence based amplification assay. Direct membrane feeding experiments to determine infectiousness to mosquitoes are conducted as a biological secondary endpoint. DISCUSSION: Sub-Saharan Africa, with a relatively high but poorly characterized G6PD prevalence, could potentially benefit from the use of primaquine to further reduce or interrupt malaria transmission. However, G6PD screening may not be feasible given the cost and difficulties in interpreting test results in terms of risk of haemolysis. Because the haemolytic effect of primaquine is dose-dependent, determining the minimal gametocytocidal and transmission-blocking dose of primaquine is extremely important to help address public health concerns over its safety and validate the efficacy of lower than recommended dosages. By including infectiousness to mosquitoes, the trial provides complementary evidence for the potential of the drug to interrupt transmission to mosquitoes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01838902 (12 April 2013).


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Protocolos Clínicos , Plasmodium falciparum/efeitos dos fármacos , Primaquina/farmacologia , Quinolinas/farmacologia , Interpretação Estatística de Dados , Combinação de Medicamentos , Humanos , Tamanho da Amostra
10.
Malar J ; 13: 483, 2014 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-25486998

RESUMO

Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies.


Assuntos
Antimaláricos/uso terapêutico , Transmissão de Doença Infecciosa/prevenção & controle , Malária Falciparum/tratamento farmacológico , Malária Falciparum/transmissão , Parasitemia/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Aminoquinolinas/uso terapêutico , Humanos , Fatores de Tempo , Resultado do Tratamento
12.
Antimicrob Agents Chemother ; 58(8): 4971-3, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24913169

RESUMO

Glucose-6-phosphate dehydrogenase (G6PD) enzyme function and genotype were determined in Ugandan children with uncomplicated falciparum malaria enrolled in a primaquine trial after exclusion of severe G6PD deficiency by fluorescent spot test. G6PD A- heterozygotes and hemizygotes/homozygotes experienced dose-dependent lower hemoglobin concentrations after treatment. No severe anemia was observed.


Assuntos
Antimaláricos/uso terapêutico , Glucosefosfato Desidrogenase/genética , Hemoglobinas/metabolismo , Malária Falciparum/tratamento farmacológico , Primaquina/uso terapêutico , Criança , Pré-Escolar , Método Duplo-Cego , Esquema de Medicação , Feminino , Genótipo , Hemólise , Heterozigoto , Homozigoto , Humanos , Malária Falciparum/enzimologia , Malária Falciparum/genética , Malária Falciparum/parasitologia , Masculino , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/fisiologia , Risco , Uganda
13.
Lancet Infect Dis ; 14(2): 130-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24239324

RESUMO

BACKGROUND: Primaquine is the only available drug that clears mature Plasmodium falciparum gametocytes in infected human hosts, thereby preventing transmission of malaria to mosquitoes. However, concerns about dose-dependent haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiencies have limited its use. We assessed the dose-response association of single-dose primaquine for gametocyte clearance and for safety in P falciparum malaria. METHODS: We undertook this randomised, double-blind, placebo-controlled trial with four parallel groups in Jinja district, eastern Uganda. We randomly allocated Ugandan children aged 1-10 years with uncomplicated falciparum malaria and normal G6PD enzyme function to receive artemether-lumefantrine, combined with either placebo or with 0.1 mg/kg, 0.4 mg/kg, or 0.75 mg/kg (WHO reference dose) primaquine base. Randomisation was done with computer-generated four-digit treatment assignment codes allocated to random dose groups in block sizes of 16. Study staff who provided care or assessed outcomes and the participants remained masked to the intervention group after assignment. The primary efficacy endpoint was the non-inferiority of the mean duration of gametocyte carriage in the test doses compared with the reference group of 0.75 mg primaquine per kg, with a non-inferiority margin of 2.5 days. The primary safety endpoint was the superiority of the arithmetic mean maximum decrease in haemoglobin concentration from enrolment to day 28 of follow-up in the primaquine treatment groups compared with placebo, with use of significance testing of pairwise comparisons with a cutoff of p=0.05. The trial is registered with ClinicalTrials.gov, number NCT01365598. FINDINGS: We randomly allocated 468 participants to receive artemether-lumefantrine combined with placebo (119 children) or with 0.1 mg/kg (116), 0.4 mg/kg (116), or 0.75 mg/kg (117) primaquine base. The mean duration of gametocyte carriage was 6.6 days (95% CI 5.3-7.8) in the 0.75 mg/kg reference group, 6.3 days (5.1-7.5) in the 0.4 mg/kg primaquine group (p=0.74), 8.0 days (6.6-9.4) in the 0.1 mg/kg primaquine group (p=0.14), and 12.4 days (9.9-15.0) in the placebo group (p<0.0001). No children showed evidence of treatment-related haemolysis, and the mean maximum decrease in haemoglobin concentration was not associated with the dose of primaquine received-it did not differ significantly compared with placebo (10.7 g/L, SD 11.1) in the 0.1 mg/kg (11.4 g/L, 9.4; p=0.61), 0.4 mg/kg (11.3 g/L, 10.0; p=0.67), or 0.75 mg/kg (12.7 g/L, 8.2; p=0.11) primaquine groups. INTERPRETATION: We conclude that 0.4 mg/kg primaquine has similar gametocytocidal efficacy to the reference 0.75 mg/kg primaquine dose, but a dose of 0.1 mg/kg was inconclusive for non-inferiority. Our findings call for the prioritisation of further trials into the efficacy and safety of doses of primaquine between 0.1 mg/kg and 0.4 mg/kg (including the dose of 0.25 mg/kg recently recommended by WHO), in view of the potential for widespread use of the drug to block malaria transmission. FUNDING: Wellcome Trust and the Bill & Melinda Gates Foundation.


Assuntos
Antimaláricos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Primaquina/uso terapêutico , Combinação Arteméter e Lumefantrina , Artemisininas/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Feminino , Fluorenos/uso terapêutico , Seguimentos , Humanos , Lactente , Masculino , Carga Parasitária , Curva ROC , Resultado do Tratamento , Uganda
14.
Malar J ; 12: 210, 2013 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-23782846

RESUMO

BACKGROUND: The distribution of the enzymopathy glucose-6-phosphate dehydrogenase (G6PD) deficiency is linked to areas of high malaria endemicity due to its association with protection from disease. G6PD deficiency is also identified as the cause of severe haemolysis following administration of the anti-malarial drug primaquine and further use of this drug will likely require identification of G6PD deficiency on a population level. Current conventional methods for G6PD screening have various disadvantages for field use. METHODS: The WST8/1-methoxy PMS method, recently adapted for field use, was validated using a gold standard enzymatic assay (R&D Diagnostics Ltd ®) in a study involving 235 children under five years of age, who were recruited by random selection from a cohort study in Tororo, Uganda. Blood spots were collected by finger-prick onto filter paper at routine visits, and G6PD activity was determined by both tests. Performance of the WST8/1-methoxy PMS test under various temperature, light, and storage conditions was evaluated. RESULTS: The WST8/1-methoxy PMS assay was found to have 72% sensitivity and 98% specificity when compared to the commercial enzymatic assay and the AUC was 0.904, suggesting good agreement. Misclassifications were at borderline values of G6PD activity between mild and normal levels, or related to outlier haemoglobin values (<8.0 gHb/dl or >14 gHb/dl) associated with ongoing anaemia or recent haemolytic crises. Although severe G6PD deficiency was not found in the area, the test enabled identification of low G6PD activity. The assay was found to be highly robust for field use; showing less light sensitivity, good performance over a wide temperature range, and good capacity for medium-to-long term storage. CONCLUSIONS: The WST8/1-methoxy PMS assay was comparable to the currently used standard enzymatic test, and offers advantages in terms of cost, storage, portability and use in resource-limited settings. Such features make this test a potential key tool for deployment in the field for point of care assessment prior to primaquine administration in malaria-endemic areas. As with other G6PD tests, outlier haemoglobin levels may confound G6PD level estimation.


Assuntos
Técnicas de Laboratório Clínico/métodos , Ensaios Enzimáticos/métodos , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Programas de Rastreamento/métodos , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Sensibilidade e Especificidade , Manejo de Espécimes/métodos , Uganda
15.
Malar J ; 11: 360, 2012 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-23130957

RESUMO

Following the recent successes of malaria control in sub-Saharan Africa, the gametocytocidal drug primaquine needs evaluation as a tool to further reduce the transmission of Plasmodium falciparum malaria. The drug has scarcely been used in Africa because of concerns about its safety in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The evidence base for the use of primaquine as a transmission blocker is limited by a lack of comparable clinical and parasitological endpoints between trials. In March 2012, a group of experts met in London to discuss the existing evidence on the ability of primaquine to block malaria transmission, to define the roadblocks to the use of primaquine in Africa and to develop a roadmap to enable its rapid, safe and effective deployment. The output of this meeting is a strategic plan to optimize trial design to reach desired goals efficiently. The roadmap includes suggestions for a series of phase 1, 2, 3 and 4 studies to address specific hurdles to primaquine's deployment. These include ex-vivo studies on efficacy, primaquine pharmacokinetics and pharmacodynamics and dose escalation studies for safety in high-risk groups. Phase 3 community trials are proposed, along with Phase 4 studies to evaluate safety, particularly in pregnancy, through pharmacovigilance in areas where primaquine is already deployed. In parallel, efforts need to be made to address issues in drug supply and regulation, to map G6PD deficiency and to support the evaluation of alternative gametocytocidal compounds.


Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Transmissão de Doença Infecciosa/prevenção & controle , Malária Falciparum/tratamento farmacológico , Malária Falciparum/transmissão , Primaquina/administração & dosagem , Primaquina/efeitos adversos , África , Ensaios Clínicos como Assunto , Humanos , Londres , Projetos de Pesquisa
16.
Malar J ; 9: 312, 2010 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-21054863

RESUMO

BACKGROUND: Artemisinin-based combination therapy, currently considered the therapy of choice for uncomplicated Plasmodium falciparum malaria in endemic countries, may be under threat from newly emerging parasite resistance to the artemisinin family of drugs. Studies in Southeast Asia suggest some patients exhibit an extended parasite clearance time in the three days immediately following treatment with artesunate monotherapy. This phenotype is likely to become a more important trial endpoint in studies of anti-malarial drug efficacy, but currently requires frequent, closely spaced blood sampling in hospitalized study participants, followed by quantitation of parasite density by microscopy. METHODS: A simple duplex quantitative PCR method was developed in which distinct fluorescent signals are generated from the human and parasite DNA components in each blood sample. The human amplification target in this assay is the ß tubulin gene, and the parasite target is the unique methionine tRNA gene (pgmet), which exhibits perfect sequence identity in all six Plasmodium species that naturally infect humans. In a small series of malaria cases treated as hospital in-patients, the abundance of pgmet DNA was estimated relative to the human DNA target in daily peripheral blood samples, and parasite clearance times calculated. RESULTS: The qPCR assay was reproducibly able to replicate parasite density estimates derived from microscopy, but provided additional data by quantification of parasite density 24 hours after the last positive blood film. Robust estimates of parasite clearance times were produced for a series of patients with clinical malaria. CONCLUSIONS: Large studies, particularly in Africa where children represent a major proportion of treated cases, will require a simpler blood sample collection regime, and a method capable of high throughput. The duplex qPCR method tested may fulfil these criteria, and should now be evaluated in such field studies.


Assuntos
Antimaláricos/farmacologia , DNA de Protozoário/análise , Plasmodium/efeitos dos fármacos , Plasmodium/crescimento & desenvolvimento , Reação em Cadeia da Polimerase/métodos , DNA de Protozoário/genética , Genes de Protozoários , Humanos , Testes de Sensibilidade Parasitária/métodos , Plasmodium/genética , RNA de Transferência de Metionina/genética
17.
Intensive Care Med ; 34(9): 1703-6, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18500421

RESUMO

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) is a major problem in intensive care units (ICU). International guidelines recommend screening patients for MRSA on admission, although consensus on sites required for optimum detection has not been reached. Our aim was to determine whether throat and rectal swabs identified a significant number of additional MRSA-colonised patients not captured by swabbing at keratinized skin carriage sites (anterior nares, perineum and axillae). DESIGN: Prospective cohort study. SETTING: 30-Bed medical and surgical ICU in a tertiary teaching hospital. PATIENTS: One thousand four hundred and eighty adult patients consecutively admitted over 15 months. MEASUREMENTS AND RESULTS: Swabs from carriage sites (anterior nares, perineum, axillae, throat and rectum), wounds and clinical samples taken within 48 h of ICU admission were analysed to identify patients admitted with MRSA. A complete set of carriage swabs were received from 1,470 patients. 105 (7%) patients were admitted with MRSA of which 63 (60%) were detected by a pooled keratinized skin swab (anterior nares, perineum, axillae). A further 36 (34%) patients were detected only by throat or rectal swabs. Indeed, throat and rectal swabs combined had a higher sensitivity than pooled keratinised skin swabs (76 vs. 60% P = 0.0247). Swabs from all carriage sites together detected 95% (100) of MRSA positive patients, with five patients being positive at wound sites only. CONCLUSIONS: The throat and rectum are important and potentially hidden sites of MRSA carriage in critically ill patients. These findings prompt the need for larger studies to determine the most cost-effective screening strategy for MRSA detection. DESCRIPTOR: Non-pulmonary nosocomial infections.


Assuntos
Portador Sadio/diagnóstico , Programas de Rastreamento/métodos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Faringe/microbiologia , Reto/microbiologia , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Estudos Prospectivos , Pele/microbiologia , Ferimentos e Lesões/microbiologia
19.
J Infect ; 54(1): 6-11, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16549203

RESUMO

OBJECTIVES: To implement a policy of systematic screening for viral haemorrhagic fever (VHF) among travellers returning from African countries with fever, commencing at initial clinical contact. METHODS: A protocol based on UK Advisory Committee on Dangerous Pathogens guidance was developed collaboratively by medical, nursing and laboratory staff. Audit was carried out to quantify resource demands and effects on time to diagnose malaria, the main differential diagnosis. RESULTS: A protocol is now implemented for all patients presenting to HTD with fever, with clear guidelines for interaction with clinical and laboratory staff at each stage. The protocol required moderate amounts of clinical and laboratory staff time and resulted in some additional hospital admissions. The time to a diagnosis of malaria increased from a median of 90 (range 50-125) min in patients without VHF risk to a median of 140 (range 101-225) min (p=0.0025) in those assessed as at risk. CONCLUSIONS: Although all acute medical services need to have robust procedures for early detection of patients with serious transmissible conditions, few implement such a policy. Our protocol requires increased human and other resources but has no important impact on the rapidity of diagnosis of malaria, and is now embedded in local practice.


Assuntos
Protocolos Clínicos , Febre/etiologia , Febres Hemorrágicas Virais/diagnóstico , Hospitais Especializados/normas , Programas de Rastreamento/normas , Viagem , Medicina Tropical/normas , África , Diagnóstico Diferencial , Testes Diagnósticos de Rotina , Diagnóstico Precoce , Humanos , Londres , Auditoria Médica , Medição de Risco , Medicina Tropical/métodos , Reino Unido
20.
PLoS Clin Trials ; 1(5): e21, 2006 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-16998584

RESUMO

OBJECTIVES: Previous studies have shown that in children with severe malaria, resuscitation with albumin infusion results in a lower mortality than resuscitation with saline infusion. Whether the apparent benefit of albumin is due solely to its colloidal properties, and thus might also be achieved with other synthetic colloids, or due to the many other unique physiological properties of albumin is unknown. As albumin is costly and not readily available in Africa, examination of more affordable colloids is warranted. In order to inform the design of definitive phase III trials we compared volume expansion with Gelofusine (succinylated modified fluid gelatin 4% intravenous infusion) with albumin. DESIGN: This study was a phase II safety and efficacy study. SETTING: The study was conducted at Kilifi District Hospital, Kenya. PARTICIPANTS: The participants were children admitted with severe falciparum malaria (impaired consciousness or deep breathing), metabolic acidosis (base deficit > 8 mmol/l), and clinical features of shock. INTERVENTIONS: The interventions were volume resuscitation with either 4.5% human albumin solution or Gelofusine. OUTCOME MEASURES: Primary endpoints were the resolution of shock and acidosis; secondary endpoints were in-hospital mortality and adverse events including neurological sequelae. RESULTS: A total of 88 children were enrolled: 44 received Gelofusine and 44 received albumin. There was no significant difference in the resolution of shock or acidosis between the groups. Whilst no participant developed pulmonary oedema or fluid overload, fatal neurological events were more common in the group receiving gelatin-based intervention fluids. Mortality was lower in patients receiving albumin (1/44; 2.3%) than in those treated with Gelofusine (7/44; 16%) by intention to treat (Fisher's exact test, p = 0.06), or 1/40 (2.5%) and 4/40 (10%), respectively, for those treated per protocol (p = 0.36). Meta-analysis of published trials to provide a summary estimate of the effect of albumin on mortality showed a pooled relative risk of death with albumin administration of 0.19 (95% confidence interval 0.06-0.59; p = 0.004 compared to other fluid boluses). CONCLUSIONS: In children with severe malaria, we have shown a consistent survival benefit of receiving albumin infusion compared to other resuscitation fluids, despite comparable effects on the resolution of acidosis and shock. The lack of similar mortality benefit from Gelofusine suggests that the mechanism may involve a specific neuroprotective effect of albumin, rather than solely the effect of the administered colloid. Further exploration of the benefits of albumin is warranted in larger clinical trials.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...