| 1. |
- Blessborn, Daniel, et al.
(författare)
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Assay for screening for six antimalarial drugs and one metabolite using dried blood spot sampling, sequential extraction and ion-trap detection
- 2010
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Ingår i: Bioanalysis. - : Future Science Ltd. - 1757-6180 .- 1757-6199. ; 2:11, s. 1839-1847
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Tidskriftsartikel (refereegranskat)abstract
- Background: More parasites are becoming resistant to antimalarial drugs, and in many areas a change in first-line drug treatment is necessary. The aim of the developed assay is to help determine drug use in these areas and also to be a complement to interviewing patients, which will increase reliability of surveys.Results: This assay detects quinine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, chloroquine and its metabolite desethylchloroquine in a 100-mu l dried blood spot. Most of the drugs also have long half-lives that make them detectable at least 7 days after administration. The drugs are extracted from the dried blood spot with sequential extraction (due to the big differences in physicochemical properties), solid-phase extraction is used as sample clean-up and separation is performed with gradient-LC with MS ion-trap detection.Conclusion: Detection limits (S/N > 5:1) at 50 ng/ml or better were achieved for all drugs except lumefantrine (200 ng/ml), and thus can be used to determine patient compliance. A major advantage of using the ion-trap MS it that it will be possible to go back into the data and look for other drugs as needed.
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| 2. |
- Ngasala, Billy E., et al.
(författare)
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Effectiveness of artemether-lumefantrine provided by community health workers in under-five children with uncomplicated malaria in rural Tanzania : an open label prospective study
- 2011
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 10, s. 64-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Home-management of malaria (HMM) strategy improves early access of anti-malarial medicines to high-risk groups in remote areas of sub-Saharan Africa. However, limited data are available on the effectiveness of using artemisinin-based combination therapy (ACT) within the HMM strategy. The aim of this study was to assess the effectiveness of artemether-lumefantrine (AL), presently the most favoured ACT in Africa, in under-five children with uncomplicated Plasmodium falciparum malaria in Tanzania, when provided by community health workers (CHWs) and administered unsupervised by parents or guardians at home. Methods: An open label, single arm prospective study was conducted in two rural villages with high malaria transmission in Kibaha District, Tanzania. Children presenting to CHWs with uncomplicated fever and a positive rapid malaria diagnostic test (RDT) were provisionally enrolled and provided AL for unsupervised treatment at home. Patients with microscopy confirmed P. falciparum parasitaemia were definitely enrolled and reviewed weekly by the CHWs during 42 days. Primary outcome measure was PCR corrected parasitological cure rate by day 42, as estimated by Kaplan-Meier survival analysis. This trial is registered with ClinicalTrials.gov, number NCT00454961. Results: A total of 244 febrile children were enrolled between March-August 2007. Two patients were lost to follow up on day 14, and one patient withdrew consent on day 21. Some 141/241 (58.5%) patients had recurrent infection during follow-up, of whom 14 had recrudescence. The PCR corrected cure rate by day 42 was 93.0% (95% CI 88.3%-95.9%). The median lumefantrine concentration was statistically significantly lower in patients with recrudescence (97 ng/mL [IQR 0-234]; n = 10) compared with reinfections (205 ng/mL [114-390]; n = 92), or no parasite reappearance (217 [121-374] ng/mL; n = 70; p <= 0.046). Conclusions: Provision of AL by CHWs for unsupervised malaria treatment at home was highly effective, which provides evidence base for scaling-up implementation of HMM with AL in Tanzania.
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| 3. |
- Ngasala, Billy E., et al.
(författare)
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Efficacy and Effectiveness of Artemether-Lumefantrine after Initial and Repeated Treatment in Children < 5 Years of Age with Acute Uncomplicated Plasmodium falciparum Malaria in Rural Tanzania : A Randomized Trial
- 2011
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 52:7, s. 873-882
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Tidskriftsartikel (refereegranskat)abstract
- Background. We assessed the efficacy, effectiveness and safety of artemether-lumefantrine, which is the most widely used artemisinin-based combination therapy in Africa, against Plasmodium falciparum malaria during an extended follow-up period after initial and repeated treatment. Methods. We performed an open-label randomized trial of artemether-lumefantrine with supervised (n 5 180) and unsupervised intake (n = 179) in children <5 years of age with uncomplicated falciparum malaria in rural Tanzania. Recurrent infections between day 14 and day 56 were retreated within the same study arm. Main end points were polymerase chain reaction (PCR)-corrected cure rates by day 56 and day 42 after initial and repeated treatment, respectively, as estimated by survival analysis. Results. The PCR-corrected cure rate after initial treatment was 98.1% (95% confidence interval [CI], 94.2%-99.4%) after supervised and 95.1% (95% CI, 90.7%-98.1%) after unsupervised intake (P = .29). After retreatment of recurrent infections, the cure rates were 92.9% (95% CI, 81.8%-97.3%) and 97.6% (95% CI, 89.3%-98.8%), respectively (P = .58). Reinfections occurred in 46.9% (82 of 175) versus 50.9 % of the patients (relative risk [RR], 0.92 [95% CI, 0.74-1.14]; P 5.46) after initial therapy and 32.4% (24 of 74) versus 39.0% (32 of 82) (RR, 0.83 [95% CI, 0.54-1.27]; P 5.39) after retreatment. Median blood lumefantrine concentrations in supervised and unsupervised patients on day 7 were 304 versus 194 ng/ mL (P <.001) after initial treatment and 253 versus 164 ng/ mL (P 5.001) after retreatment. Vomiting was the most commonly reported drug-related adverse event (in 1% of patients) after both initial and repeated treatment. Conclusions. Artemether-lumefantrine was highly efficacious even after unsupervised administration, despite significantly lower lumefantrine concentrations, compared with concentration achieved with supervised intake, and was well-tolerated and safe after initial and repeated treatment.
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| 4. |
- Ursing, Johan, et al.
(författare)
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Chloroquine is grossly under dosed in young children with malaria : implications for drug resistance
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations.Methods and Findings: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10-14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent.Conclusions: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.
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| 5. |
- Ursing, Johan, et al.
(författare)
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Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in Guinea-Bissau : a randomized trial
- 2011
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 203:1, s. 109-116
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Tidskriftsartikel (refereegranskat)abstract
- Background. In 2008. Guinea-Bissau introduced artemether-lumefantrine for treatment of uncomplicated malaria. Previously, 3 times the standard dose of chloroquine, that was probably efficacious against Plasmodium falciparum with the resistance-associated chloroquine-resistance transporter (pfcrt) 76T allele, was routinely used. The present study compared the efficacy and tolerability of a double standard dose of chloroquine with the efficacy and tolerability of artemether-lumefantrine.Methods. In a randomized open-label clinical trial, artemether-lumefantrine or chloroquine (50 mg/kg) were given as 6 divided doses over 3 days to children aged 6 months - 15 years who had uncomplicated P. falciparum monoinfection. Drug concentrations were measured on day 7. P. falciparum multidrug resistance gene N86Y and pfcrt K76T alleles were identified.Results. The polymerase chain reaction adjusted day 28 and 42 treatment efficacies were 162 (97%) of 168 and 155 (97%) of 161, respectively, for artemether-lumefantrine and 150 (95%) of 158 and 138 (94%) of 148, respectively, for chloroquine. When parasites with resistance-associated pfcrt 76T were treated, the day 28 efficacy of chloroquine was 87%. No severe drug-related adverse events were detected. Symptom resolution was similar with both treatments.Conclusions. Both treatments achieved the World Health Organization recommended efficacy for antimalarials that will be adopted as policy. High-dose chloroquine treatment regimes should be further evaluated with the aim of assessing chloroquine as a potential partner drug to artemisinin derivatives.
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