Dihydroartemisinin (DHA)‐piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz‐based antiretroviral therapy on exposure to DHA and ...piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV‐uninfected pregnant women, in 27 HIV‐infected pregnant women receiving efavirenz, and in 30 HIV‐uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC0‐8hr) were 50% and 47% lower, respectively, and piperaquine AUC0‐21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC0‐8hr and piperaquine AUC0‐21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV‐uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed.
•A bioanalytical method for lumefantrine and its main metabolite desbutyl-lumefantrine was developed.•Two isotopically labeled internal standards give robust quantification.•Sensitivite and short ...analysis times is applicable to large volume studies.•The method was successfully applied for clinical samples.
A sensitive liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed for quantification of lumefantrine (LUM) and its metabolite desbutyl-lumefantrine (DBL) in human plasma. Sample preparation was done by protein precipitation using acetonitrile containing deuterated lumefantrine (LUM-d18) and desbutyl-lumefantrine (DBL-d9) as internal standards. Total chromatography time was 2.2min using an Hypersil Gold C18 column (20×2.1mm, 1.9μm), with a gradient using 0.5% formic acid in water (mobile phase A) and 0.5% formic acid in methanol (mobile phase B) at a flow rate of 0.5mL/min. The mass spectrometric quantification was performed in positive electro spray ionization (ESI+) mode using selected reaction monitoring (SRM). Measuring range was 21–529ng/mL for LUM and 1.9–47ng/mL for DBL in plasma. Inter- and intra-assay precision was within 10% coefficient of variation (CV) for all levels of both LUM and DBL. Accuracy was within ±10% for all levels of both LUM and DBL. This method requires 100μL plasma volume and its short retention times allow a high throughput. Samples were stable for a week at +5°C, and up to six months −20°C. The method was successfully applied for plasma LUM and DBL determination in children under 5 years of age with uncomplicated malaria, up to 28 days after a standard 3-day treatment with artemether-lumefantrine.
Artemether‐lumefantrine (AL) is a first‐line treatment for uncomplicated malaria. Absorption of lumefantrine (LUM) is fat dependent, and in children, intake is recommended with milk. We investigated ...whether oil‐fortified maize porridge can be an alternative when milk is not available. In an open‐label pharmacokinetic study, Ugandan children <5 years with uncomplicated Plasmodium falciparum malaria were randomized to receive standard six‐dose AL treatment one tablet (20 mgA/120 mg LUM) if <15 kg and two tablets if >15 kg with milk (A) or maize porridge plus oil (B). Parametric two‐sample t‐test was used to compare relative oral LUM bioavailability. The primary end‐point was LUM exposure till 8 hr after the first dose (AUC0–8 hr). Secondary outcome included day 7 concentrations (d7LUM), LUM exposure between days 7 and 28 (AUCd7–28) and day 28 PCR‐adjusted parasitological response. Evaluable children (n = 33) included 16 in arm A and 17 in arm B. The AUC0–8 hr was comparable between A and B geometric mean (95% CI): 6.01 (3.26–11.1) versus 6.26 (4.5–8.43) hr*μg/mL, p = 0.9. Less interindividual variability in AUC0–8 hr was observed in B (p = 0.01), but d7LUM and AUCd7–28 were comparable. Children receiving two tablets had significantly higher exposure than those receiving one tablet median d7LUM (505 versus 289 ng/mL, p = 0.02) and AUCd7–28 (108 versus 41 hr*μg/mL, p = 0.006). One parasitological failure (d28 recrudescence) was observed. Our findings suggest that oil‐fortified maize porridge can be an alternative to milk in augmenting absorption of LUM. The lower LUM exposure observed in children dosed with one AL tablet needs further attention.
Summary Background Home management of malaria—the presumptive treatment of febrile children with antimalarial drugs—is advocated to ensure prompt effective treatment of the disease. We assessed the ...effect of home delivery of artemether-lumefantrine on the incidence of antimalarial treatment and on clinical outcomes in children from an urban setting with fairly low malaria transmission. Methods In Kampala, Uganda, 437 children aged between 1 and 6 years from 325 households were randomly assigned by a computer-generated sequence to receive home delivery of prepackaged artemether-lumefantrine for presumptive treatment of febrile illnesses (n=225) or current standard of care (n=212). Randomisation was done by household after a pilot period of 1 month. After randomisation, study participants were followed up for an additional 12 months and information on their health and treatment of illnesses was obtained by use of monthly questionnaires and household diaries, which were completed by the participants' carers. The primary outcome was treatment incidence density per person-year. Analysis of the primary outcome was done on the modified intention-to-treat population, which included all participants apart from those excluded before data collection. This trial is registered with ClinicalTrials.gov , number NCT00115921. Findings Eight participants in the home management group and four in the standard care group were excluded before data collection; therefore, the primary analysis was done in 217 and 208 participants, respectively. The home management group received nearly twice the number of antimalarial treatments as the standard care group (4·66 per person-year vs 2·53 per person-year; incidence rate ratio IRR 1·72, 95% CI 1·43–2·06, p<0·0001), and nearly five times the number given to children with microscopically confirmed malaria in a comparable cohort of children (4·66 per person-year vs 1·03 per person-year, IRR 5·19, 95% CI 4·24–6·35, p<0·0001). Clinical data were available for 189 children in the home management group and 176 in the control group at study end; the main reasons for exclusion were movement out of the study area or loss to follow-up. The proportion of participants with parasitaemia at final assessment in the intervention group was lower than in the control group (four 2% vs 17 10%, p=0·006), but there were no other differences in standard malariometric indices, including anaemia. Serious adverse events were captured retrospectively. One child died in each group (home management—severe pneumonia and possible septicaemia; standard care—presumed respiratory failure). Interpretation Although home management of malaria led to prompt treatment of fever, there was little effect on clinical outcomes. The substantial over-treatment suggests that artemether-lumefantrine provided in the home might not be appropriate for large urban areas or settings with fairly low malaria transmission. Funding Gates Malaria Partnership.
Co‐administration of artemether–lumefantrine with milk is recommended to improve lumefantrine (L) absorption but milk may not be available in resource‐limited settings. This study explored the ...effects of cheap local food in Uganda on oral bioavailability of lumefantrine relative to milk. In an open‐label, four‐period crossover study, 13 healthy adult volunteers were randomized to receive a single oral dose of artemether–lumefantrine (80 mg artemether/480 mg lumefantrine) with water, milk, maize porridge or maize porridge with oil on separate occasions. Plasma lumefantrine was assayed using high‐performance liquid chromatography with ultraviolet detection. Pharmacokinetic exposure parameters were determined by non‐compartmental methods using WinNonlin. Peak concentrations (Cmax) and area under concentration–time curve restricted to 48 hr after single dosing (AUC(0–48)) were selected for relative bioavailability evaluations using confidence interval approach for average bioequivalence. Lumefantrine exposure was comparable in milk and maize porridge plus oil study groups. When artemether–lumefantrine was administered with maize porridge plus oil, average bioequivalence ranges (means ratios 90% CI, 0.84–1.88 and 0.85–1.69 for Cmax and AUC(0–48), respectively) were within and exceeded acceptance ranges relative to milk (90% CI, 0.80–1.25). Both fasted and maize porridge groups demonstrated similarly much lower ranges of lumefantrine exposures (bioinequivalence) relative to milk. If milk is not available, it is thus possible to recommend fortification of carbohydrate‐rich food with little fat (maize porridge plus vegetable oil) to achieve similarly optimal absorption of lumefantrine after artemether–lumefantrine administration.
Home management of malaria/Authors' reply Pagnoni, Franco; Staedke, S G; Mwebaza, N ...
The Lancet (British edition),
07/2009, Letnik:
374, Številka:
9686
Journal Article
Recenzirano
With the exception of our study, all published studies to assess the health effects of home management of malaria in Africa were done in rural areas.1 The epidemiology of malaria in rural and urban ...areas is different, and interventions appropriate for rural settings might not be transferable to urban areas, or vice versa. Practising in rural west Africa, it becomes galling to see the Abuja target of treating 80% of malaria patients presented as if its goals are a stark contrast with the "percentage of febrile children given any form of malaria treatment".1 Have people forgotten that malarious areas are also overwhelmed by numerous other real causes of fever, including viruses, teething, otitis, urinary-tract infections, and pneumonia?
Background Multiple host blood transcriptional signatures have been developed as non-sputum triage tests for tuberculosis (TB). We aimed to compare the diagnostic performance of 20 blood ...transcriptomic TB signatures for differentiating between symptomatic patients who have TB versus other respiratory diseases (ORD). Methods As part of a nested case-control study, individuals presenting with respiratory symptoms at primary health care clinics in Ethiopia, Malawi, Namibia, Uganda, South Africa, and The Gambia were enrolled. TB was diagnosed based on clinical, microbiological, and radiological findings. Transcriptomic signatures were measured in whole blood using microfluidic RT-qPCR. Diagnostic performance was benchmarked against the WHO Target Product Profile (TPP) for a non-sputum TB triage test. Results Among 541 participants, 158 had definite, microbiologically-confirmed TB, 32 had probable TB, while 389 participants had ORD. Nine signatures differentiated between ORD and TB with equivalent performance (Satproedprai7: area under the curve 0.83 95% CI 0.79–0.87, Jacobsen3: 0.83 0.79–0.86; Suliman2: 0.82 0.78–0.86; Roe1: 0.82 0.78–0.86; Kaforou22: 0.82 0.78–0.86; Sambarey10: 0.81 0.77–0.85; Duffy9: 0.81 0.76–0.86; Gliddon3: 0.8 0.75–0.85; and Suliman4 0.79 0.75–0.84. Benchmarked against a 90% sensitivity, these signatures achieved specificities between 44% (95% CI 38–49) and 54% (49–59), not meeting the TPP criteria. Signature scores significantly varied by HIV status and country. In country-specific analyses several signatures, such as Satproedprai7 and Penn-Nicholson6, met the minimal TPP criteria for a triage test in Ethiopia, Malawi, and South Africa. Conclusion No signatures met the TPP criteria in a pooled analysis of all countries, but several signatures met the minimum criteria for a non-sputum TB triage test in some countries.
Dried blood spots (DBS) are an alternative specimen type for HIV drug resistance genotyping in resource-limited settings. Data relating to the impact of DBS storage and shipment conditions on ...genotyping efficiency under field conditions are limited. We compared the genotyping efficiencies and resistance profiles of DBS stored and shipped at different temperatures to those of plasma specimens collected in parallel from patients receiving antiretroviral therapy in Uganda. Plasma and four DBS cards from anti-coagulated venous blood and a fifth card from finger-prick blood were prepared from 103 HIV patients with a median viral load (VL) of 57,062 copies/ml (range, 1,081 to 2,964,191). DBS were stored at ambient temperature for 2 or 4 weeks or frozen at -80 °C and shipped from Uganda to the United States at ambient temperature or frozen on dry ice for genotyping using a broadly sensitive in-house method. Plasma (97.1%) and DBS (98.1%) stored and shipped frozen had similar genotyping efficiencies. DBS stored frozen (97.1%) or at ambient temperature for 2 weeks (93.2%) and shipped at ambient temperature also had similar genotyping efficiencies. Genotyping efficiency was reduced for DBS stored at ambient temperature for 4 weeks (89.3%, P = 0.03) or prepared from finger-prick blood and stored at ambient temperature for 2 weeks (77.7%, P < 0.001) compared to DBS prepared from venous blood and handled similarly. Resistance profiles were similar between plasma and DBS specimens. This report delineates the optimal DBS collection, storage, and shipping conditions and opens a new avenue for cost-saving ambient-temperature DBS specimen shipments for HIV drug resistance (HIVDR) surveillances in resource-limited settings.
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