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1.  Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda 
Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether–lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether–lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women.
doi:10.1038/psp.2013.59
PMCID: PMC3852159  PMID: 24226803
2.  Field-Based Flow Cytometry for Ex Vivo Characterization of Plasmodium vivax and P. falciparum Antimalarial Sensitivity 
Antimicrobial Agents and Chemotherapy  2013;57(10):5170-5174.
Ex vivo antimalarial sensitivity testing in human malaria parasites has largely depended on microscopic determination of schizont maturation. While this microscopic method is sensitive, it suffers from poor precision and is laborious. The recent development of portable, low-cost cytometers has allowed us to develop and validate a simple, field-optimized protocol using SYBR green and dihydroethidium for the accurate and objective determination of antimalarial drug sensitivity in freshly isolated Plasmodium vivax and Plasmodium falciparum.
doi:10.1128/AAC.00682-13
PMCID: PMC3811473  PMID: 23877705
3.  Population Pharmacokinetics and Pharmacodynamics of Piperaquine in Children With Uncomplicated Falciparum Malaria 
Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight–based oral 3-day fixed-dose dihydroartemisinin-piperaquine regimen. Capillary plasma concentration–time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P < 0.0001) of recurrent malaria infection after treatment. young children (2–5 years of age) received a significantly higher body weight-normalized dose than older children (P = 0.025) but had significantly lower day 7 piperaquine concentrations (P = 0.024) and total piperaquine exposures (P = 0.021), suggesting that an increased dose regimen for young children should be evaluated.
doi:10.1038/clpt.2011.254
PMCID: PMC3736305  PMID: 22258469
4.  pfmdr1 Amplification Is Related to Increased Plasmodium falciparum In Vitro Sensitivity to the Bisquinoline Piperaquine 
The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the Plasmodium falciparum multidrug resistance locus on chromosome 5, containing the pfmdr1 gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC50s) and IC90s for piperaquine and chloroquine in a set of 46 adapted P. falciparum cultures originating from the Thai-Burmese border, we have characterized the regions around the pfmdr1 gene and identified a significant association between the presence of pfmdr1 duplications and enhanced sensitivity to piperaquine (P = 0.005 for IC50 and P = 0.002 for IC90) and chloroquine, reaching statistical significance at IC90s (P = 0.026). These results substantiate the potential importance of pfmdr1 copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations.
doi:10.1128/AAC.06350-11
PMCID: PMC3393437  PMID: 22508315
5.  Obstetric ultrasound scanning by local health workers in a refugee camp on the Thai–Burmese border 
Objectives
Ultrasound examination of the fetus is a powerful tool for assessing gestational age and detecting obstetric problems but is rarely available in developing countries. The aim of this study was to assess the intraobserver and interobserver agreement of fetal biometry by locally trained health workers in a refugee camp on the Thai–Burmese border.
Methods
One expatriate doctor and four local health workers participated in the study, which included examinations performed on every fifth pregnant woman with a singleton pregnancy between 16 and 40 weeks’ gestation, and who had undergone an early dating ultrasound scan, attending the antenatal clinic in Maela refugee camp. At each examination, two examiners independently measured biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), with one of the examiners obtaining duplicate measurements of each parameter. Intraobserver measurement error was assessed using the intraclass correlation coefficient (ICC) and interobserver error was assessed by the Bland and Altman 95% limits of agreement method.
Results
A total of 4188 ultrasound measurements (12 per woman) were obtained in 349 pregnancies at a median gestational age of 27 (range, 16–40) weeks in 2008. The ICC for BPD, HC, AC and FL was greater than 0.99 for all four trainees and the doctor (range, 0.996–0.998). For gestational ages between 18 and 24 weeks, interobserver 95% limits of agreement corresponding to differences in estimated gestational age of less than ± 1 week were calculated for BPD, HC, AC and FL. Measurements by local health workers showed high levels of agreement with those of the expatriate doctor.
Conclusions
Locally trained health workers working in a well organized unit with ongoing quality control can obtain accurate fetal biometry measurements for gestational age estimation. This experience suggests that training of local health workers in developing countries is possible and could allow effective use of obstetric ultrasound imaging.
doi:10.1002/uog.7350
PMCID: PMC3438883  PMID: 19790099
accuracy; developing country; fetal biometry; reproducibility; ultrasound
6.  The Presence of Leukocytes in Ex Vivo Assays Significantly Increases the 50-Percent Inhibitory Concentrations of Artesunate and Chloroquine against Plasmodium vivax and Plasmodium falciparum ▿  
Plasmodium species ex vivo sensitivity assay protocols differ in the requirement for leukocyte removal before culturing. This study shows that the presence of leukocytes significantly increases the 50% inhibitory concentration (IC50) of P. vivax and P. falciparum to artesunate and chloroquine relative to results with the paired leukocyte-free treatment. Although leukocyte removal is not an essential requirement for the conduct of ex vivo assays, its use has important implications for the interpretation of temporal and spatial antimalarial sensitivity data.
doi:10.1128/AAC.01103-10
PMCID: PMC3067107  PMID: 21189344
7.  The antimalarial ferroquine: from bench to clinic 
Ferroquine (FQ, SSR97193) is currently the most advanced organometallic drug candidate and about to complete phase II clinical trials as a treatment for uncomplicated malaria. This ferrocenecontaining compound is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. This article focuses on the discovery of FQ, its antimalarial activity, the hypothesis of its mode of action, the current absence of resistance in vitro and recent clinical trials.
doi:10.1051/parasite/2011183207
PMCID: PMC3671469  PMID: 21894260
malaria; bioorganometallics; drug candidate; ferroquine; mechanism of action; resistance; paludisme; bio-organométallique; candidat médicament; ferroquine; mécanisme d’action; résistance
8.  Plasmodium vivax Susceptibility to Ferroquine▿ †  
The novel organometallic chloroquine analog ferroquine (SSR 97193) is effective against chloroquine-resistant Plasmodium falciparum. The ex vivo efficacy of ferroquine against Plasmodium vivax isolates was tested. Ferroquine has a potent ex vivo effect on P. vivax schizont maturation (median 50% inhibitory concentration, 15 nM; n = 42). No significant cross-sensitivity between ferroquine and other antimalarials was detected. This drug may be a suitable replacement for chloroquine in the treatment of drug-resistant P. vivax malaria.
doi:10.1128/AAC.01572-09
PMCID: PMC2863649  PMID: 20308387
9.  Multiple Displacement Amplification for Malaria Parasite DNA 
The Journal of parasitology  2009;95(1):253-255.
Multiple displacement amplification (MDA) using Phi29 has proved to be an efficient, high-fidelity method for whole genome amplification in many organisms. This project was designed to evaluate this approach for use with the malaria parasite Plasmodium falciparum. In particular, we were concerned that the AT richness and presence of contaminating human DNA could limit efficiency of MDA in this system. We amplified 60 DNA samples using phi29 and scored 14 microsatellites, 9 single-nucleotide polymorphisms (SNPs), and gene copy number at GTP-cyclohydrolase I both before and after MDA. We observed 100% concordance in 829 microsatellite genotypes and in 499 SNP genotypes. Furthermore, copy number estimates for the GTP-cyclohydrolase I gene were correlated (r2 = 0.67) in pre- and postamplification samples. These data confirm that MDA permits scoring of a range of different types of polymorphisms in P. falciparum malaria and can be used to extend the life of valuable DNA stocks.
doi:10.1645/GE-1706.1
PMCID: PMC2759105  PMID: 18601578
10.  Stronger Activity of Human Immunodeficiency Virus Type 1 Protease Inhibitors against Clinical Isolates of Plasmodium vivax than against Those of P. falciparum▿  
Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax (n = 30) and P. falciparum (n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum, compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter-Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum. PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found.
doi:10.1128/AAC.00169-08
PMCID: PMC2443880  PMID: 18443130
11.  Population Pharmacokinetics of Piperaquine after Two Different Treatment Regimens with Dihydroartemisinin-Piperaquine in Patients with Plasmodium falciparum Malaria in Thailand▿  
The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUCday 0-63]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUCday 3-20) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.
doi:10.1128/AAC.00955-07
PMCID: PMC2258541  PMID: 18180343
12.  Pharmacokinetics and Pharmacodynamics of Lumefantrine (Benflumetol) in Acute Falciparum Malaria 
The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria. Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 h. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) μg/ml after regimen A, 9.0 (1.1 and 19.8) μg/ml after regimen B, and 8 (1.4 and 17.4) μg/ml after regimen C. During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001). The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 μg/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.
PMCID: PMC89749  PMID: 10681341
13.  The pfmdr1 Gene Is Associated with a Multidrug-Resistant Phenotype in Plasmodium falciparum from the Western Border of Thailand 
Antimicrobial Agents and Chemotherapy  1999;43(12):2943-2949.
On the western border of Thailand, Plasmodium falciparum has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the pfmdr1 gene in 54 parasites collected from the western border of Thailand to determine the relationship of pfmdr1 copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC50) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86. Increased pfmdr1 copy number was associated with higher IC50s of mefloquine (P = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.
PMCID: PMC89592  PMID: 10582887
14.  Randomized Comparison of Artemether-Benflumetol and Artesunate-Mefloquine in Treatment of MultidrugResistant Falciparum Malaria 
An open, randomized comparison of artemether-benflumetol (CGP 56 697; Novartis) with artesunate-mefloquine was conducted in 617 patients with acute uncomplicated multidrug-resistant falciparum malaria on the western border of Thailand. Both treatments rapidly and reliably cleared fever and parasitemia, and there was no significant difference in the initial therapeutic response parameters. Parasite genotyping was used to distinguish recrudescences from new infections. The 63-day cure rate for artesunate-mefloquine (94%) was significantly higher than the cure rate for artemether-benflumetol (81%) (P < 0.001). Both regimens were well tolerated. Nausea, vomiting, dizziness, sleep disorders, and other neurological side effects were between two and four times more common in the artesunate-mefloquine group than in the artemether-benflumetol group (P < 0.001). Artemether-benflumetol is effective and very well tolerated in the treatment of multidrug-resistant falciparum malaria. A higher dose than that used in the present study may improve efficacy.
PMCID: PMC105468  PMID: 9449273
15.  Malaria in pregnancy: the difficulties in measuring birthweight 
Bjog  2011;118(6):671-678.
Recommendations for interventions to control malaria in pregnancy are often based on studies using birthweight as the primary endpoint. Differences in birthweight may be attributable partly to methodological difficulties. We performed a structured search of the literature using ‘malaria’, ‘pregnancy’ and ‘birth weight’ as search terms. Of the clinical trials reporting birthweight, only 33% (14/43) gave information about the timing of the measurement and details on the scales used. Seventy seven per cent explained how gestational age was estimated. We propose a standardised method for the measurement and reporting of birthweight in future studies.
doi:10.1111/j.1471-0528.2010.02880.x
PMCID: PMC3118281  PMID: 21332632
Birthweight; gestational age; malaria; pregnancy
16.  Quality of ultrasound biometry obtained by local health workers in a refugee camp on the Thai–Burmese border 
Objective
In a refugee camp on the Thai–Burmese border, accurate dating of pregnancy relies on ultrasound measurements obtained by locally trained health workers. The aim of this study was to substantiate the accuracy of fetal biometry measurements performed by locally trained health workers by comparing derived reference equations with those published for Asian and European hospitals.
Methods
This prospective observational study included 1090 women who had a dating crown–rump length (CRL) scan and one study-appointed ultrasound biometry scan between 16 and 40 weeks of gestation. The average of two measurements of each of biparietal diameter, head circumference, abdominal circumference and femur length was used in a polynomial regression model for the mean and SD against gestational age (GA). The biometry equations obtained were compared with published equations of professional sonographers from Asian and European hospitals by evaluation of the SD and Z-scores of differences between models.
Results
Reference equations of biometric parameters were found to fit cubic polynomial models. The observed SD values, for any given GA, of fetal biometric measurements obtained by locally trained health workers were lower than those previously reported by centers with professional sonographers. For nearly the entire GA range considered, the mean values of the Asian and European equations for all four biometric measurements were within the 90% expected range (mean ± 1.645 SD) of our equations.
Conclusion
Locally trained health workers in a refugee camp on the Thai–Burmese border can obtain measurements that are associated with low SD values and within the normal limits of published Asian and European equations. The fact that the SD values were lower than in other studies may be explained by the use of the average of two measurements, CRL dating or motivation of the locally trained sonographers. Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.
doi:10.1002/uog.11091
PMCID: PMC3443371  PMID: 22262286
developing country; fetal biometry; health workers; quality; reference equations; standard deviation; Thai–Burmese border; ultrasound; Z-score
17.  Assessment of Streptococcus pneumoniae pilus islet-1 prevalence in carried and transmitted isolates from mother–infant pairs on the Thailand–Burma border 
Clinical Microbiology and Infection  2011;18(10):970-975.
Streptococcus pneumoniae pilus islet-1 (PI-1)-encoded pilus enhances in vitro adhesion to the respiratory epithelium and may contribute to pneumococcal nasopharyngeal colonization and transmission. The pilus subunits are regarded as potential protein vaccine candidates. In this study, we sought to determine PI-1 prevalence in carried pneumococcal isolates and explore its relationship with transmissibility or carriage duration. We studied 896 pneumococcal isolates collected during a longitudinal carriage study that included monthly nasopharyngeal swabbing of 234 infants and their mothers between the ages of 1 and 24 months. These were cultured according to the WHO pneumococcal carriage detection protocol. PI-1 PCR and genotyping by multilocus sequence typing were performed on isolates chosen according to specific carriage and transmission definitions. Overall, 35.2% of the isolates were PI-1-positive, but PI-1 presence was restricted to ten of the 34 serotypes studied and was most frequently associated with serotypes 19F and 23F; 47.5% of transmitted and 43.3% of non-transmitted isolates were PI-1-positive (OR 1.2; 95% CI 0.8–1.7; p 0.4). The duration of first-ever infant pneumococcal carriage was significantly longer with PI-1-positive organisms, but this difference was not significant at the individual serotype level. In conclusion, PI-1 is commonly found in pneumococcal carriage isolates, but does not appear to be associated with pneumococcal transmissibility or carriage duration.
doi:10.1111/j.1469-0691.2011.03711.x
PMCID: PMC3469734  PMID: 22092910
Carriage; carriage duration; colonization; PI-1; pilus-1; Streptococcus pneumoniae; transmission
18.  Obstetric ultrasound scanning by local health workers in a refugee camp on the Thai–Burmese border 
Objectives
Ultrasound examination of the fetus is a powerful tool for assessing gestational age and detecting obstetric problems but is rarely available in developing countries. The aim of this study was to assess the intraobserver and interobserver agreement of fetal biometry by locally trained health workers in a refugee camp on the Thai–Burmese border.
Methods
One expatriate doctor and four local health workers participated in the study, which included examinations performed on every fifth pregnant woman with a singleton pregnancy between 16 and 40 weeks' gestation, and who had undergone an early dating ultrasound scan, attending the antenatal clinic in Maela refugee camp. At each examination, two examiners independently measured biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), with one of the examiners obtaining duplicate measurements of each parameter. Intraobserver measurement error was assessed using the intraclass correlation coefficient (ICC) and interobserver error was assessed by the Bland and Altman 95% limits of agreement method.
Results
A total of 4188 ultrasound measurements (12 per woman) were obtained in 349 pregnancies at a median gestational age of 27 (range, 16–40) weeks in 2008. The ICC for BPD, HC, AC and FL was greater than 0.99 for all four trainees and the doctor (range, 0.996–0.998). For gestational ages between 18 and 24 weeks, interobserver 95% limits of agreement corresponding to differences in estimated gestational age of less than ± 1 week were calculated for BPD, HC, AC and FL. Measurements by local health workers showed high levels of agreement with those of the expatriate doctor.
Conclusions
Locally trained health workers working in a well organized unit with ongoing quality control can obtain accurate fetal biometry measurements for gestational age estimation. This experience suggests that training of local health workers in developing countries is possible and could allow effective use of obstetric ultrasound imaging. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.
doi:10.1002/uog.7350
PMCID: PMC3438883  PMID: 19790099
accuracy; developing country; fetal biometry; reproducibility; ultrasound

Results 1-18 (18)