433 research outputs found
An aptamer-based sensor for the detection of antimalarial drugs
No full textArtemisinin-based combination therapies (ACTs) have begun to fail as first-line therapies for the treatment of Plasmodium falciparum malaria in Southeast Asia. Preventing the further spread of drug-resistant parasites is a top priority for global malaria elimination campaigns. A low-cost, field-based assay to detect slow clearing ACT compounds from patient samples could allow for improved tracking of antimalarial drug use, monitoring of treatment adherence, and evaluation of therapeutic efficacy and resistance. It could also provide sensitive detection of active components in assessments of tablet quality. This research reports the development of a low-cost, rapid, fluorescent sensor for the specific detection of piperaquine and mefloquine. In order to do this, DNA aptamers were identified that bind and differentiate between small molecule partner drugs. These aptamers were selected from a library of single-stranded DNA molecules for their selectivity and binding affinity. Following their isolation by a capture-SELEX method, a structure-switching aptamer fluorescent sensor was developed.
The sensor performance was optimized for the detection of drug from crushed tablets and from human serum, resulting in two fluorescent sensing platforms. The sensors were evaluated for their sensitivity and specificity in relevant sample matrices and the serum sensor was validated against an LC-MS gold standard drug detection method. Feedback from potential assay end-users was collected to inform the assay development and it is believed that these aptamer sensors will be useful tools for monitoring antimalarial drug quality and studying antimalarial drug use
Box plot for the distribution of PQ concentration by treatment outcome.
No full text<p>The dotted lines represent a previously proposed cut-off for piperaquine concentrations quantified in venous (30 ng/ml) and capillary (57 ng/ml) blood samples (Tarning et al. 2012).</p
Scrub typhus in northern Thailand
No full textScrub typhus, a neglected infectious disease caused by obligate intracellular bacteria Orientia tsutsugamushi, is a major cause of acute non-malarial fever in the tropics. Difficulties surrounding diagnosis have hampered our understanding of disease burden, which in turn negatively impacts awareness. Using national surveillance data, I highlighted the high burden of scrub typhus in Thailand with a substantial rise in cases over time. Spatially, disease burden was greatest in the northern region and geographical and meteorological factors may contribute to disease prevalence. Scrub typhus contributes significantly to the febrile disease burden in Chiangrai, northern Thailand, with 22.5% of adults admitted to hospital with acute undifferentiated fever diagnosed with the disease. I described the disease in adults and found presence of eschar and elevated liver enzymes to be predictive of scrub typhus. Scrub typhus in children remains understudied and in this thesis, I characterised paediatric scrub typhus in Chiangrai, showing that the disease was frequently severe and potentially fatal with complication and treatment failure rates of 40% and 23%, respectively. Severe hepatitis was found to be predictive of treatment failure in this cohort.
In the 1990s, reports of putative drug resistant scrub typhus emerged from northern Thailand. This proved controversial at the time as doxycycline resistant Orientia tsutsugamushi had not been described. Studies on treatment outcome and its determinants were not pursued, leading to uncertainty regarding optimal scrub typhus treatment. I reviewed the evidence on drug resistant scrub typhus extensively and concluded that doxycycline resistance may have been misconceived. Finally, I described my ongoing role as principal investigator for the Scrub Typhus Antibiotic Resistance Trial, a randomised controlled trial comparing the efficacy of 7 days of doxycycline versus 3 days of doxycycline versus 3 days of azithromycin in northern Thailand. Detailed immunological, microbiological and pharmacological analyses are embedded, which should provide clarity on the determinants of treatment outcome and whether drug resistance is illusory
Treatment of malaria in pregnancy
No full textPregnant women are particularly susceptible to the complications of malaria infections, and therefore must be treated promptly and effectively. Unfortunately, the number of antimalarial drugs that are know to be both safe and effective in pregnancy is very limited. Antimalarial recommendations commonly exclude use in pregnant women owing to concerns about fetal toxicity. In uncomplicated Plasmodium falciparum infections, the objective of treatment is to eradicate parasitaemia, and the available drugs include chloroquine, amodiaquine, sulfadoxine-pyrimethamine, quinine, chlorproguanil-dapsone, mefloquine and the artemisinin derivatives. In severe and complicated malaria the objective is to save the mother's life. The drugs of choice are quinine and the artemisinins. Studies are urgently needed to define the best therapeutic options and to develop new treatments, especially in Africa where drug resistance already compromises all strategies of control
Supplementary files
No full textSupplementary files for the manuscript "Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Burkina Faso" submitted to Wellcome Open Research.Supplementary file 1 shows the CONSORT checklist.Supplementary file 2 shows the CONSORT flowchart.</div
Lancet Infect Dis
No full textOver the past 10 years, the available evidence on the treatment of malaria during pregnancy has increased substantially. Owing to their relative ease of use, good sensitivity and specificity, histidine rich protein 2 based rapid diagnostic tests are appropriate for symptomatic pregnant women; however, such tests are less appropriate for systematic screening because they will not detect an important proportion of infections among asymptomatic women. The effect of pregnancy on the pharmacokinetics of antimalarial drugs varies greatly between studies and class of antimalarial drugs, emphasising the need for prospective studies in pregnant and non-pregnant women. For the treatment of malaria during the first trimester, international guidelines are being reviewed by WHO. For the second and third trimester of pregnancy, results from several trials have confirmed that artemisinin-based combination treatments are safe and efficacious, although tolerability and efficacy might vary by treatment. It is now essential to translate such evidence into policies and clinical practice that benefit pregnant women in countries where malaria is endemic. Access to parasitological diagnosis or appropriate antimalarial treatment remains low in many countries and regions. Therefore, there is a pressing need for research to identify quality improvement interventions targeting pregnant women and health providers. In addition, efficient and practical systems for pharmacovigilance are needed to further expand knowledge on the safety of antimalarial drugs, particularly in the first trimester of pregnancy.CC999999/Intramural CDC HHS/United States2019-06-24T00:00:00Z29395998PMC65900696419vault:3245
A LC-MS/MS Assay for Quantification of Amodiaquine and Desethylamodiaquine in Dried Blood Spots on Filter Paper
No full textArtesunate-amodiaquine (ARS-AQ) is a first-line antimalarial treatment recommended by the World Health Organization. AQ is the long acting partner drug in this combination, and therapeutic success is correlated with the terminal exposure to AQ. Dried blood spot (DBS) sampling for AQ is a convenient and minimally invasive technique, especially suitable for clinical studies in resource limited settings and pediatric studies. Our primary aim was to develop and validate a bioanalytical method for quantification of AQ and its active metabolite in capillary blood applied onto filter paper as a DBS sample. The separation was achieved using a reverse phase column (Zorbax SB-CN 50 × 4.6 mm, I.D. 3.5 μm) and a mobile phase consisting of acetonitrile:ammonium formate 20 mM with 0.5% formic acid (15:85, v/v). A 50 μL DBS was punctured with five 3.2 mm punches from the filter paper, and the punches collected correspond to approximately 15 μL of dried blood. The blood was then extracted using a mixture of 0.5% formic acid in water:acetonitrile (50:50, v/v), along with stable isotope-labeled internal standards (AQ-D10 and desethylamodiaquine [DAQ]-D5). Mass spectrometry was used for quantification over the range of 2.03-459 ng/mL for AQ and 3.13-1570 ng/mL for DAQ. The validation of the method was carried out in compliance with regulatory requirements. The intra- and interbatch precisions were below 15% and passed all validation acceptance criteria. No carryover and no matrix effects were detected. Normalized matrix factors (analyte/internal standard) ranged from 0.96 to 1.03 for all analytes, hence no matrix effects. AQ and DAQ were stable in all conditions evaluated. Long-term stability in DBS samples was demonstrated for up to 10 years when stored at -80°C and for 15 months when stored at room temperature. The developed method was demonstrated to be reliable and accurate. This assay may be particularly useful in the context of resource limited settings and in pediatric field studies
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