Comparison of plasma, venous and capillary blood levels of piperaquine in patients with uncomplicated falciparum malaria

PURPOSE: Dihydroartemisinin-piperaquine (DP) is a fixed-dose artemisinin-based combination treatment. Field pharmacokinetic studies would be simplified and facilitated by being able to use small volume capillary assays rather than venous blood. The aim of this study was to describe the relationship between piperaquine concentrations measured in capillary blood, venous blood and venous plasma. METHODS: Samples of plasma, whole blood obtained by venesection and capillary blood were taken simultaneously from patients with uncomplicated Plasmodium falciparum malaria treated with DP between 0 and 9 weeks after treatment. Piperaquine concentrations in venous and capillary samples were measured using solid phase extraction and analysis by liquid chromatography with ultraviolet detection. RESULTS: A total of 161 sets of the three measures were obtained from 54 patients. Piperaquine concentrations in the venous blood samples were approximately twofold higher and those in the capillary blood samples were threefold higher than the corresponding venous plasma concentrations. Capillary blood piperaquine concentrations were approximately 1.7-fold higher than venous blood concentrations, and this difference also increased with time. CONCLUSION: Differences in whole blood and plasma levels of piperaquine suggest compartmentalisation of the drug within blood cells, as also occurs with the structurally related quinoline chloroquine. The relationship between piperaquine concentrations in the venous plasma, venous blood and capillary blood is variable and unpredictable at low concentrations. However, within the range of concentrations usually present in patients between 3 and 21 days after treatment with currently recommended doses, the relationship between capillary and venous whole blood is predictable; consequently, capillary blood sampling can be used in field assessments

Har du förstått uppgiften? : En studie av gymnasieelevers förståelse av uppgiftsinstruktioner

Sammanfattning Konsten att skriva uppgiftsinstruktioner som alla, eller åtminstone de flesta, elever förstår drömmer många lärare om att behärska. Särskilt lärare som undervisar på distans med få eller inga möjligheter att följa upp elevens läsning med ett snabbt påföljande samtal om innehållet i den text eleven just läst. För hur går det till när elever läser och förstår uppgiftsinstruktioner? Påverkar dessutom elevens uppfattning om hur tydlig uppgiftsinstruktionen är, hur rolig, lätt eller intressant uppgiften verkar vara att genomföra; hur viktigt är det att en instruktion är   tydlig för hur uppgiften förstås eller uppfattas? Genom en empirisk, induktiv studie som följs upp av litteraturstudier för att förklara och tolka resultatet studeras här   tio gymnasieelevers läsning och förståelse av fyra uppgiftsinstruktioner från   kursen Svenska B. Tydlighet står i fokus. Två av uppgifterna är hämtade från Skolverkets nationella prov och två uppgifter är konstruerade av en enskild lärare. Elevernas (mottagarnas) förståelse jämförs med lärarens (sändarens) intention. Uppgiftsinstruktionerna (medierna) analyseras med hjälp av   Hellspong & Ledins textanalysmodeller i Vägar genom texten – Handbok i brukstextanalys från 1997. Resultatet av jämförelsen är att den grupp   elever som har svårast att uttrycka vad uppgifterna innebär med egna ord,   också har svårast att förstå dem. Det hindrar dem däremot inte från att   uppfatta att de förstår och svaret på lärarens vanliga fråga: om eleven har   förstått uppgiften, är enligt den här studien inte mycket värt. Elevens och   lärarens syn på vad kunskap och inlärning innebär påverkar stort, inte bara   svaret på frågan, utan även läsningen och förståelsen av   uppgiftsinstruktionen. Med hjälp av teorier kring läsning, läsbarhet,   hjärnans förmåga och omgivningens påverkan på inlärning diskuteras vad och   hur eleverna förstår och inte förstår i uppgifterna. Genom deras förståelse,   eller brist på sådan, aktualiseras och diskuteras frågor kring vad som är   viktigt vid utformning av text, på såväl ytligare som djupare nivåer, i uppgiftsinstruktioner.

Gymnasielärares skrivpraktiker : Skrivande som professionell handling i en digitaliserad skola

The aim of this thesis is to contribute to deeper knowledge about the writing practices of teachers in upper secondary school. Schools are under constant pressure to respond to the needs and expectations of an ever-changing society and political intentions. A major factor in this change which is taking place in schools is digitalization. Another factor is the adoption of new governing principles for schools involving management by goals and results, which brings increased demands for written documentation of teachers' work. In order to describe and problematize this development the thesis is based on a combination of Critical Discourse Analysis and New Literacy (Clark and Ivanič, 1997). The theoretical framework rests upon an understanding of writing as social action and the idea that texts both affect and are affected by the social environment. The empirical study focuses on twelve teachers and their writing practices, analyzed during week-long field visits over three years. The teachers' talk about their writing is used together with analyses of texts and images to investigate parts of teachers' writing which, according to the teachers, are considered complex and problematic. The findings indicate significant differences between the writing practices of the individual teachers, where each teacher has his or her own system of texts fulfilling different purposes. Despite these differences it is still possible to identify recurrent themes in the discursive conditions for teachers' writing: efficiency, reuse, authority, audit, relationships to addressees, and room to maneuver. The study illustrates possible dilemmas for teachers' writing at the intersection of teachers' professional responsibility and demands for accountability

Att vetenskapligt förankra ett yrkeslärarprogram: Erfarenheter från ett utvecklingsprojekt [Developing a scientific foundation in vocational teacher education: Experiences from a Swedish project]

Demands on the scientific foundation of Swedish Vocational Teacher Education has led to a development project on academic competence at Dalarna University in 2018. The project contained two sub-projects; the construction of a matrix, to display the progression of students' academic competence; and the implementation of a series of seminars on VET research. This article presents the point of departure and the methods used, together with the results of mappings and analysis of four different aspects of academic competence. This inventory of features of academic competence in teacher education, evokes a wide range of questions on the meaning and consequence of scientific foundation, the research-practice relationship and concrete questions concerning course content

Pitfalls in Estimating Piperaquine Elimination

By using a sensitive new assay, the terminal elimination half-life of the antimalarial piperaquine in a healthy volunteer was estimated to be 33 days, which is longer than estimated previously. This result illustrates the importance of extended sampling duration and sensitive assay methodologies in characterizing the disposition of slowly eliminated antimalarial drugs

Population Pharmacokinetics and Pharmacodynamics of Artemether and Lumefantrine during Combination Treatment in Children with Uncomplicated Falciparum Malaria in Tanzania▿

The combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model

Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria▿

Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed

A Small Amount of Fat Does Not Affect Piperaquine Exposure in Patients with Malaria▿†

Dihydroartemisinin-piperaquine is a new, highly effective, and well-tolerated combination treatment for uncomplicated falciparum malaria. The lipophilic characteristic of piperaquine suggests that administration together with fat will increase the oral bioavailability of the drug, and this has been reported for healthy volunteers. This pharmacokinetic study monitored 30 adult patients with uncomplicated falciparum malaria for 4.5 months to evaluate the effects of the concomitant intake of fat on the total piperaquine exposure. The fixed-drug combination of dihydroartemisinin-piperaquine was given with water to fasting patients (n = 15) or was coadministered with 200 ml milk containing 6.4 g fat (n = 15). The drug combination was generally well tolerated, and there were no severe adverse effects reported for either group during the study. Total piperaquine exposure (area under the concentration-time curve from zero to infinity [AUC0-∞]; results are given as medians [ranges]) were not statistically different between fed (29.5 h · μg/ml [20.6 to 58.7 h · μg/ml]) and fasting (23.9 h · μg/ml [11.9 to 72.9 h · μg/ml]) patients, but the interindividual variation was reduced in the fed group. Overall, none of the pharmacokinetic parameters differed statistically between the groups. Total piperaquine exposure correlated well with the day 7 concentrations in the fasted group, but the fed group showed a poor correlation. In conclusion, the coadministration of 6.4 g fat did not have any significant effect on piperaquine pharmacokinetics in the treatment of uncomplicated malaria