Browsing by Author "Barnes, Karen I"
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- ItemOpen AccessAbsence of kelch13 artemisinin resistance markers but strong selection for lumefantrine-tolerance molecular markers following 18 years of artemisinin-based combination therapy use in Mpumalanga Province, South Africa (2001–2018)(2019-08-22) Raman, Jaishree; Kagoro, Frank M; Mabuza, Aaron; Malatje, Gillian; Reid, Anthony; Frean, John; Barnes, Karen IAbstract Background The ability of Plasmodium falciparum parasites to develop resistance to widely used anti-malarials threatens malaria control and elimination efforts. Regular drug efficacy monitoring is essential for ensuring effective treatment policies. In low transmission settings where therapeutic efficacy studies are often not feasible, routine surveillance for molecular markers associated with anti-malarial resistance provides an alternative for the early detection of emerging resistance. Such a longitudinal survey of changes in the prevalence of selected molecular markers of resistance was conducted in the malaria-endemic regions of Mpumalanga Province, South Africa, where malaria elimination at a district-level is being pursued. Methods Molecular analyses to determine the prevalence of alleles associated with resistance to lumefantrine (mdr86N, crt76K and mdr1 copy number variation) and sulfadoxine–pyrimethamine (dhfr triple, dhps double, SP quintuple) were conducted between 2001 and 2018, while artemisinin resistance markers (kelch13 mutations) were assessed only in 2018. Results Parasite DNA was successfully amplified from 1667/2393 (70%) of malaria-positive rapid diagnostic tests routinely collected at primary health care facilities. No artemisinin resistance-associated kelch13 mutations nor amplification of the mdr1 gene copy number associated with lumefantrine resistance were observed. However, prevalence of both the mdr86N and crt76K alleles increased markedly over the study period, with all isolates collected in 2018 carrying these markers. SP quintuple mutation prevalence increased steadily from 14% in 2001 to 96% in 2018. Mixed alleles at any of the codons assessed were rare by 2018. Conclusion No kelch13 mutations confirmed or suspected to be associated with artemisinin resistance were identified in 2018. Although parasites carrying the mdr86N and crt76K alleles associated with reduced lumefantrine susceptibility were strongly selected for over the study period, nearing fixation by 2018, the marker for lumefantrine resistance, namely increased mdr1 copy number, was not observed in this study. The increase in mdr86N and crt76K allele prevalence together with intense regional artemether–lumefantrine drug pressure, raises concern regarding the sustained artemether–lumefantrine efficacy. Regular, rigorous anti-malarial resistance marker surveillance across all three South African malaria-endemic provinces to inform case management is recommended.
- ItemOpen AccessAssessment of therapeutic responses to gametocytocidal drugs in Plasmodium falciparum malaria(2014-12-09) White, Nicholas J; Ashley, Elizabeth A; Recht, Judith; Delves, Michael J; Ruecker, Andrea; Smithuis, Frank M; Eziefula, Alice C; Bousema, Teun; Drakeley, Chris; Chotivanich, Kesinee; Imwong, Mallika; Pukrittayakamee, Sasithon; Prachumsri, Jetsumon; Chu, Cindy; Andolina, Chiara; Bancone, Germana; Hien, Tran T; Mayxay, Mayfong; Taylor, Walter R; von Seidlein, Lorenz; Price, Ric N; Barnes, Karen I; Djimdé, Abdoulaye; ter Kuile, Feiko; Gosling, Roly; Chen, Ingrid; Dhorda, Mehul J; Stepniewska, Kasia; Guérin, Philippe; Woodrow, Charles J; Dondorp, Arjen M; Day, Nicholas P; Nosten, Francois HAbstract Indirect clinical measures assessing anti-malarial drug transmission-blocking activity in falciparum malaria include measurement of the duration of gametocytaemia, the rate of gametocyte clearance or the area under the gametocytaemia-time curve (AUC). These may provide useful comparative information, but they underestimate dose-response relationships for transmission-blocking activity. Following 8-aminoquinoline administration P. falciparum gametocytes are sterilized within hours, whereas clearance from blood takes days. Gametocytaemia AUC and clearance times are determined predominantly by the more numerous female gametocytes, which are generally less drug sensitive than the minority male gametocytes, whereas transmission-blocking activity and thus infectivity is determined by the more sensitive male forms. In choosing doses of transmission-blocking drugs there is no substitute yet for mosquito-feeding studies.
- ItemOpen AccessCorrection to: Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria(2021-03-19) Anyorigiya, Thomas A; Castel, Sandra; Mauf, Katya; Atuguba, Frank; Ogutu, Bernhards; Oduro, Abraham; Dosoo, David; Asante, Kwaku-Poku; Owusu-Agyei, Seth; Dodoo, Alexander; Hodgson, Abraham; Binka, Fred; Workman, Lesley J; Allen, Elizabeth N; Denti, Paolo; Wiesner, Lubbe; Barnes, Karen IAn amendment to this paper has been published and can be accessed via the original article.
- ItemOpen AccessA cost analysis of the treatment of first-line uncomplicated malaria in the Tonga district of Mpumalanga(1999) Wilkins, Justin; Barnes, Karen I; Folb, Peter IFollowing the completion of a detailed baseline study of malaria in the region, a model was developed to assess the cost-effectiveness of switching from chloroquine to sulfadoxine-pyrimetharnine as first line treatment in the Tonga district of Mpumalanga, South Africa, where malaria is seasonal and the population is non-immune. In vivo drug resistance was used to create a resistance variable, which was used to assess the 1997 relative costs to the health care system of employing the two drugs, analysing factors such as drug costs, staff time, transport costs, maintenance costs, utility costs, training costs and consumables costs to generate an average cost-effectiveness ratio. The model was subsequently used to estimate the average cost-effectiveness ratios of nine other potential agents for the treatment of first line malaria, including artesunate monotherapy, artesunate combinations, pyronaridine, atovaquone-proguanil, co-artemether, halofantrine, amodiaquine, and mefloquine. It was found that sulfadoxinepyrimethamine was 5 times more cost-effective as first line therapy than chloroquine. Of the other modelled drugs, it was recommended that an artesunate combination should be implemented when it becomes necessary to replace sulfadoxine-pyrimethamine; artesunate-mefloquine and artesunate-SP were estimated to be 6 times and 9 times as cost-effective as chloroquine, respectively.
- ItemOpen AccessDevelopment of harmonised approaches for detecting and recording participant-reported anti-malarial drug safety data: The Delphi process(2017) Mandimika, Nyaradzo; Allen, Elizabeth; Barnes, Karen IEliciting adverse event (AE) and non-study medication reports from clinical research participants is integral for evaluating drug safety. However, using different methods to question participants yields inconsistent results, compromising the interpretation, comparison and pooling of data across studies. This is particularly important given the widespread use of antimalarials in vulnerable populations, and their increasing use in healthy but at-risk individuals as preventive treatment or to reduce malaria transmission. Experienced, qualified antimalarial drug clinical researchers were invited to participate in a Delphi process, to facilitate consensus on what panellists consider to be optimal (relevant, important and feasible) methods, tools, and approaches for detecting participant-reported AE and non-study medication data in uncomplicated malaria treatment studies. This Delphi built on a previous survey conducted among malaria clinical researchers about different elicitation methods they used. The findings thereof, and a summary of relevant literature, were presented to Delphi panellists in round one after which they were asked to suggest further questioning methods or approaches that they considered as important and feasible for asking participants (or their caregivers) about their health to collect adverse events, and use of non-study medications to collect previous or concomitant medication data. In round two, the panellists were presented with the collated suggestions from round one to rate each type of question in terms of its relevance, importance and feasibility. Here, panellists would rate methods or approaches as either optimal or not optimal for inclusion in a 'menu' of harmonized or standard types of core questions to be used in a variety of uncomplicated antimalarial treatment studies. In round three, panellists were presented with a summary of items which had achieved consensus in round two and, for items that had not achieved consensus they were asked whether or not they wished to change their response in view of the group's overall response. Of the 72 invited, 25; 16 and 10 panellists responded to the first, second and third rounds of the Delphi process respectively. Overall, 68% of all questioning items presented for rating achieved consensus. When asking general questions about health, panellists agreed to include a question/concept about any change in health, taking care to ensure that such questions/concepts do not imply causality. Eighty-nine percent (39/44) of structured items about specific signs and symptoms, were rated as optimal. For non-study medications, a general question and most structured questioning items were considered an optimal approach. The use of mobile phones, patient diaries, rating scales as well as openly engaging with participants to discuss concerns were also considered optimal complementary data-elicitation tools. This study succeeded in reaching consensus within a section of the antimalarial drug clinical research community about using a general question concept, and some structured questions for eliciting data about AEs and non-study medication reports. The findings suggest that one method of questioning may not be superior to another, or sufficient to fulfil its purpose on its own and that the use of a combination of methods may be optimal. As malaria clinical research is often conducted in children (and other vulnerable groups), this becomes an important consideration in the design of appropriate elicitation methods cognisant of any particular factors that may impede accurate reporting in these groups. The concepts and items found in this Delphi survey to be relevant, important and feasible should be further investigated for potential inclusion in a harmonised approach to collect participant-elicited antimalarial drug safety data. This, in turn, should improve understanding of antimalarial drug safety.
- ItemOpen AccessEffect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa(Public Library of Science, 2005) Barnes, Karen I; Durrheim, David N; Little, Francesca; Jackson, Amanda; Mehta, Ushma; Allen, Elizabeth; Dlamini, Sicelo S; Tsoka, Joyce; Bredenkamp, Barry; Mthembu, D JothamIn KwaZulu-Natal strengthening of vector control and a change in antimalarial treatment policy to use of artemether-lumefantrine has been associated with a decrease in malaria cases, admissions, and deaths.
- ItemOpen AccessEffect of artemether-lumefantrine policy and improved vector control on malaria burden in KwaZulu-Natal, South Africa(2005) Barnes, Karen I; Durrheim, David N; Little, Francesca; Jackson, Amanda; Mehta, Ushma; Allen, Elizabeth; Dlamini, Sicelo S; Tsoka, Joyce; Bredekamp, Barry; Mthembu, D Jotham; White, Nicholas J; Sharp, Brian LBetween 1995 and 2000, KwaZulu–Natal province, South Africa, experienced a marked increase in Plasmodium falciparum malaria, fuelled by pyrethroid and sulfadoxine-pyrimethamine resistance. In response, vector control was strengthened and artemether-lumefantrine (AL) was deployed in the first Ministry of Health artemisinin-based combination treatment policy in Africa. In South Africa, effective vector and parasite control had historically ensured low-intensity malaria transmission. Malaria is diagnosed definitively and treatment is provided free of charge in reasonably accessible public-sector health-care facilities.
- ItemOpen AccessEfficacy of artemether-lumefantrine in relation to drug exposure in children with and without severe acute malnutrition: an open comparative intervention study in Mali and Niger(BioMed Central, 2016-10-24) Denoeud-Ndam, Lise; Dicko, Alassane; Baudin, Elisabeth; Guindo, Ousmane; Grandesso, Francesco; Diawara, Halimatou; Sissoko, Sibiri; Sanogo, Koualy; Traoré, Seydou; Keita, Sekouba; Barry, Amadou; de Smet, Martin; Lasry, Estrella; Smit, Michiel; Wiesner, Lubbe; Barnes, Karen I; Djimde, Abdoulaye A; Guerin, Philippe J; Grais, Rebecca F; Doumbo, Ogobara K; Etard, Jean-FrançoisBackground: Severe acute malnutrition (SAM) affects almost all organs and has been associated with reduced intestinal absorption of medicines. However, very limited information is available on the pharmacokinetic properties of antimalarial drugs in this vulnerable population. We assessed artemether-lumefantrine (AL) clinical efficacy in children with SAM compared to those without. Methods: Children under 5 years of age with uncomplicated P. falciparum malaria were enrolled between November 2013 and January 2015 in Mali and Niger, one third with uncomplicated SAM and two thirds without. AL was administered under direct observation with a fat intake consisting of ready-to-use therapeutic food (RUTF – Plumpy’Nut®) in SAM children, twice daily during 3 days. Children were followed for 42 days, with PCR-corrected adequate clinical and parasitological response (ACPR) at day 28 as the primary outcome. Lumefantrine concentrations were assessed in a subset of participants at different time points, including systematic measurements on day 7. Results: A total of 399 children (360 in Mali and 39 in Niger) were enrolled. Children with SAM were younger than their non-SAM counterparts (mean 17 vs. 28 months, P < 0.0001). PCR-corrected ACPR was 100 % (95 % CI, 96.8–100 %) in SAM at both day 28 and 42, versus 98.8 % (96.4–99.7 %) at day 28 and 98.3 % (95.6–99.4 %) at day 42 in non-SAM (P = 0.236 and 0.168, respectively). Compared to younger children, children older than 21 months experienced more reinfections and SAM was associated with a greater risk of reinfection until day 28 (adjusted hazard ratio = 2.10 (1.04–4.22), P = 0.038). Day 7 lumefantrine concentrations were significantly lower in SAM than non-SAM (median 251 vs. 365 ng/mL, P = 0.049). Conclusions: This study shows comparable therapeutic efficacy of AL in children without SAM and in those with SAM when given in combination with RUTF, but a higher risk of reinfection in older children suffering from SAM. This could be associated with poorer exposure to the antimalarials as documented by a lower lumefantrine concentration on day 7. Trial registration: ClinicalTrials.gov: NCT01958905, registration date: October 7, 2013.
- ItemOpen AccessEfficacy of sulphadoxine-pyrimethamine with or without artesunate for the treatment of uncomplicated Plasmodium falciparum malaria in southern Mozambique: a randomized controlled trial(BioMed Central Ltd, 2009) Allen, Elizabeth N; Little, Francesca; Camba, Tunisio; Cassam, Yasmin; Raman, Jaishree; Boulle, Andrew; Barnes, Karen IBACKGROUND: An artemisinin-based combination therapy, artesunate (AS) plus sulphadoxine-pyrimethamine (SP), was compared to SP monotherapy to provide evidence of further treatment options in southern Mozambique. METHODS: Between 2003 and 2005, 411 patients over one year and 10 kg with uncomplicated Plasmodium falciparum malaria were randomly allocated SP (25/1.25 mg per kg day 0) or AS/SP (as above plus 4 mg/kg artesunate days 0, 1 and 2). Allocation was concealed, but treatment was open-label except to microscopists. The primary objective was the relative risk of treatment failure, which was assessed using World Health Organization response definitions modified to a 42-day follow-up. RESULTS: Of the 411 subjects enrolled, 359 (87.3%) completed the follow up period (SP n = 175, AS/SP n = 184). A survival analysis including 408 subjects showed that the polymerase chain reaction-adjusted cure rates were 90.4% (95% confidence interval [CI] 84.9%-93.9%) and 98.0% (95% CI 94.8%-99.3%) for SP and AS/SP respectively. Multivariable analysis showed that treatment with AS/SP decreased the relative hazard of treatment failure by 80% compared to SP (hazard ratio [HR] 0.2; 95% CI 0.1-0.6) and age over seven years decreased the relative hazard of failure by 70% (HR 0.3; 95% CI 0.1-0.9), when compared to younger age. However, having a quintuple dhfr/dhps mutation increased the relative hazard of failure compared to fewer mutations (HR 3.2; 95% CI 1.3-7.5) and baseline axillary temperature increased the relative hazard of failure by 50% for each degreesC increase (HR 1.5; 95% CI 1.1-2.2). CONCLUSION: While both treatments were efficacious, AS plus SP significantly decreased the relative hazard of treatment failure compared to SP monotherapy Artesunate plus sulphadoxine-pyrimethamine, but not sulphadoxine-pyrimethamine monotherapy, met the current WHO criteria of >95% efficacy for policy implementation.TRIAL REGISTRATION:NCT00203736 and NCT00203814
- ItemOpen AccessExploring the seasonality of reported treated malaria cases in Mpumalanga, South Africa(Public Library of Science, 2013) Silal, Sheetal Prakash; Barnes, Karen I; Kok, Gerdalize; Mabuza, Aaron; Little, FrancescaSouth Africa, having met the World Health Organisation's pre-elimination criteria, has set a goal to achieve malaria elimination by 2018. Mpumalanga, one of three provinces where malaria transmission still occurs, has a malaria season subject to unstable transmission that is prone to sporadic outbreaks. As South Africa prepares to intensify efforts towards malaria elimination, there is a need to understand patterns in malaria transmission so that efforts may be targeted appropriately. This paper describes the seasonality of transmission by exploring the relationship between malaria cases and three potential drivers: rainfall, geography (physical location) and the source of infection (local/imported). Seasonal decomposition of the time series by Locally estimated scatterplot smoothing is applied to the case data for the geographical and source of infection sub-groups. The relationship between cases and rainfall is assessed using a cross-correlation analysis. The malaria season was found to have a short period of no/low level of reported cases and a triple peak in reported cases between September and May; the three peaks occurring in October, January and May. The seasonal pattern of locally-sourced infection mimics the triple-peak characteristic of the total series while imported infections contribute mostly to the second and third peak of the season (Christmas and Easter respectively). Geographically, Bushbuckridge municipality, which exhibits a different pattern of cases, contributed mostly to the first and second peaks in cases while Maputo province (Mozambique) experienced a similar pattern in transmission to the imported cases. Though rainfall lagged at 4 weeks was significantly correlated with malaria cases, this effect was dampened due to the growing proportion of imported cases since 2006. These findings may be useful as they enhance the understanding of the current incidence pattern and may inform mathematical models that enable one to predict the impact changes in these drivers will have on malaria transmission.
- ItemOpen AccessFive years of antimalarial resistance marker surveillance in Gaza Province, Mozambique, following artemisinin-based combination therapy roll out(Public Library of Science, 2011) Raman, Jaishree; Mauff, Katya; Muianga, Pedro; Mussa, Abdul; Maharaj, Rajendra; Barnes, Karen IAntimalarial drug resistance is a major obstacle to malaria control and eventual elimination. The routine surveillance for molecular marker of resistance is an efficient way to assess drug efficacy, which remains feasible in areas where malaria control interventions have succeeded in substantially reducing malaria transmission. Community based asexual parasite prevalence surveys were conducted annually in sentinel sites in Gaza Province, Mozambique from 2006 until 2010, before, during and after antimalarial policy changes to artesunate plus sulfadoxine-pyrimethamine in 2006 and to artemether-lumefantrine in 2008. Genetic analysis of dhfr , dhps , crt , and mdr1 resistant genes was conducted on 3 331 (14.4%) Plasmodium falciparum PCR positive samples collected over the study period from 23 229 children aged 2 to 15 years. The quintuple dhfr/dhps mutation associated with sulfadoxine-pyrimethamine resistance increased from 56.2% at baseline to 75.8% by 2010. At baseline the crt 76T and mdr1 86Y mutants were approaching fixation, 96.1% and 74.7%, respectively. Following the deployment of artemisinin-based combination therapy, prevalence of both these chloroquine-resistance markers began declining, reaching 32.4% and 30.9%, respectively, by 2010. All samples analysed over the 5-year period possessed a single copy of the mdr1 gene. The high and increasing prevalence of the quintuple mutation supports the change in drug policy from artesunate plus sulfadoxine-pyrimethamine to artemether-lumefantrine in Mozambique. As chloroquine related drug pressure decreased in the region, so did the molecular markers associated with chloroquine resistance ( crt 76T and mdr1 86Y). However, this reversion to the wild-type mdr186N predisposes parasites towards developing lumefantrine resistance. Close monitoring of artemether-lumefantrine efficacy is therefore essential, particularly given the high drug pressure within the region where most countries now use artemether-lumefantrine as first line treatment.
- ItemOpen AccessMaking data map-worthy—enhancing routine malaria data to support surveillance and mapping of Plasmodium falciparum anti-malarial resistance in a pre-elimination sub-Saharan African setting: a molecular and spatiotemporal epidemiology study(2022-06-29) Kagoro, Frank M.; Allen, Elizabeth; Mabuza, Aaron; Workman, Lesley; Magagula, Ray; Kok, Gerdalize; Davies, Craig; Malatje, Gillian; Guérin, Philippe J; Dhorda, Mehul; Maude, Richard J; Raman, Jaishree; Barnes, Karen IBackground Independent emergence and spread of artemisinin-resistant Plasmodium falciparum malaria have recently been confirmed in Africa, with molecular markers associated with artemisinin resistance increasingly detected. Surveillance to promptly detect and effectively respond to anti-malarial resistance is generally suboptimal in Africa, especially in low transmission settings where therapeutic efficacy studies are often not feasible due to recruitment challenges. However, these communities may be at higher risk of anti-malarial resistance. Methods From March 2018 to February 2020, a sequential mixed-methods study was conducted to evaluate the feasibility of the near-real-time linkage of individual patient anti-malarial resistance profiles with their case notifications and treatment response reports, and map these to fine scales in Nkomazi sub-district, Mpumalanga, a pre-elimination area in South Africa. Results Plasmodium falciparum molecular marker resistance profiles were linked to 55.1% (2636/4787) of notified malaria cases, 85% (2240/2636) of which were mapped to healthcare facility, ward and locality levels. Over time, linkage of individual malaria case demographic and molecular data increased to 75.1%. No artemisinin resistant validated/associated Kelch-13 mutations were detected in the 2385 PCR positive samples. Almost all 2812 samples assessed for lumefantrine susceptibility carried the wildtype mdr86ASN and crt76LYS alleles, potentially associated with decreased lumefantrine susceptibility. Conclusion Routine near-real-time mapping of molecular markers associated with anti-malarial drug resistance on a fine spatial scale provides a rapid and efficient early warning system for emerging resistance. The lessons learnt here could inform scale-up to provincial, national and regional malaria elimination programmes, and may be relevant for other antimicrobial resistance surveillance.
- ItemOpen AccessMeasuring resistance to malaria(2004) Barnes, Karen I; Folb, Peter IThe paper by Randrianarivelojosia and colleagues in this issue of the Journal (p. 47) describes the in vitro susceptibility of Plasmodium falciparum in Madagascar and the Comoros Union to three of the commonly used antimalarial drugs in the region — quinine, mefloquine and cycloguanil (the active metabolite of proguanil). Severe malaria in the Comoros Union and in Madagascar is invariably caused by P. falciparum, as it is in the rest of sub-Saharan Africa. All of 243 isolates assessed were sensitive to quinine, the drug recommended throughout the region for treatment of severe malaria. With regard to the two chemoprophylactic agents studied, all 67 isolates assessed were sensitive to cycloguanil and only 1 of 128 isolates was mefloquine-resistant. The mefloquine-resistant isolate was 1 of 110 evaluated from Madagascar; none of the 18 isolates from the Comoros Union was resistant. The authors argue that their findings confirm the sensitivity of the parasite to the 3 drugs most commonly used in their countries for both treatment and prophylaxis. They submit, on the basis of their findings, that current policy for treatment of severe malaria with a 7-day course of quinine, and prophylaxis with either mefloquine or cycloguanil-based regimens, is justified by the in vitro laboratory findings that they have shown.
- ItemOpen AccessOptimising methodology for the elicitation of participant-reported data relating to drug safety in resource poor settings(2015) Allen, Elizabeth; Barnes, Karen I; Chandler, Clare I R; Atuyambe, Lynn MIn addition to treating symptomatic patients, malaria prevention and elimination requires giving antimalarial drugs to asymptomatic or uninfected individuals. This shifts the harm-benefit balance and heightens the importance of accurately defining drug safety. Large data sets, including those pooled from multiple sources, are needed to understand uncommon adverse drug reactions. Interpreting individual studies , comparisons between studies and pooled datasets can be compromised, however, by inadequate or varied methods of safety data collection. Specifically, questioning methods may influence participants' reports of medical history, adverse events (AEs) and non-study medications. A Cochrane systematic review synthesised literature on research comparing methods for eliciting AEs from trial participants . A global online survey investigated how antimalarial researchers collect these data, and mixed-methods were used to identify barriers to accurate and complete reporting in South African and Tanzanian antimalarial-antiretroviral drug interaction trials. Focus group discussions were conducted in Ghana, Kenya and Uganda with women in a drugs exposure pregnancy registry to examine barriers to reporting at antenatal clinics, and how they might be overcome. The review included thirty-three studies in various therapeutic areas showing that more specific questioning increases the number of AEs reported by trial participants. Survey responses of 52 antimalarial researchers in 25 countries evidenced a range of methods to obtain AEs, medical histories and non-study drug reports. Qualitative data revealed that the trial context is influential and that detailed questioning facilitated participants' recognition and consideration of what to report. Non-reporting is due to forgetting, not knowing drug names, considering which information is relevant or significant to themselves or trial/healthcare workers, the potential consequences of reporting, and perceiving verbal responses inferior to what blood test results can show. Pregnant women's improved relationship with antenatal staff facilitated information-sharing and registry tools helped overcome problems with recall and naming of medicines. This project provides evidence of the substantial impact of different questioning methods on safety assessments . The results should contribute to developing a framework for researchers when planning globally-relevant, yet context-specific, antimalarial drug safety data collection strategies, and enhance efforts to pool data from multiple sources.
- ItemOpen AccessThe pharmacodynamics and pharmacokenetics of rectal administration of artesunate in the initial treatment of moderately severe and severe malaria in South African adults in northern Kwazulu Natal(2004) Barnes, Karen I; Folb, Peter I; Little, Francesca
- ItemOpen AccessPharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated Falciparum malaria(2017) Anyorigiya, Thomas Atingane; Barnes, Karen I; Wiesner, LubbeRATIONALE: The accurate measurement of antimalarial drug concentrations in key target patient groups is essential to ensure optimal dosing for malaria treatment and to distinguish between inadequate drug exposure and antimalarial resistance. METHODS: A sensitive and selective liquid chromatography-tandem mass spectrophotometric method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine in 20μl heparinised human capillary whole blood and capillary plasma. During validation no significant matrix effects were observed for the analytes or internal standards. This assay method was successfully used to describe the pharmacokinetics of amodiaquine and desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria, who were followed up for 28 days in a therapeutic efficacy study of the fixed-dose combination therapy, artesunate-amodiaquine. RESULTS: The day 28 genotype-adjusted adequate clinical and parasitological response rate of artesunate-amodiaquine combination in 321 patients studied was above 97% in both the intention-to-treat and per protocol analyses in the two study sites. Amodiaquine and desethylamodiaquine pharmacokinetic parameters were defined for 225 patients (7 infants, 127 aged 1-4 years, 91 aged ≥5 years). Multivariate analysis of the effects of pre-defined covariates found that mg/kg dose, female gender, hyperparasitaemia and site of sample collection were independently associated with desethylamodiaquine pharmacokinetic parameters. Although the association between treatment outcome and desethylamodiaquine day 7 concentrations or area under the concentration-time curve could not be established due to high artesunate-amodiquine efficacy, median day 3 amodiaquine concentrations were associated with 13% reduction in the rate of parasite recurrence, p=0.021. Despite the significantly higher amodiaquine exposure (4988ng.h/ml, p<0.001) in infants compared to the older age groups, no significant safety concerns were identified. The ratio of the geometric mean of matched concentrations in capillary whole blood to capillary plasma in a subset of 163 field samples was approximately 2.04 [95% CI 1.90-2.19] for amodiaquine and 2.4 [95%CI 2.14-2.63] for desethylamodiaquine. CONCLUSION: Pharmacokinetic parameters of amodiaquine and desethylamodiaquine were determined in the largest single uncomplicated malaria pharmacokinetic study to date. Although efficacy was high across all age groups with currently recommended dosage regimens, factors were identified as potentially significant covariates that may require further investigation in pooled analyses.
- ItemOpen AccessPopulation pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients(Public Library of Science, 2006) Simpson, Julie A; Agbenyega, Tsiri; Barnes, Karen I; Perri, Gianni Di; Folb, Peter; Gomes, Melba; Krishna, Sanjeev; Krudsood, Srivicha; Looareesuwan, Sornchai; Mansor, SharifA study of the population pharmacokinetics of intra-rectal artesunate in patients with moderately severe falciparum malaria found the pharmacokinetic properties of dihydroartemisinin were affected only by gender and body weight.
- ItemOpen AccessPreventing antimalarial resistance with artemisinin-based combination therapy(2004) Barnes, Karen IMalaria morbidity and mortality is rising, principally as a result of increasing antimalarial resistance. Resistance means that there is a shift to the right in the dose-response (concentration effect) relationship. Plasmodium falciparum has developed clinically significant resistance to all classes of antimalarial drugs, with the possible exception of artemisinin derivatives.
- ItemOpen AccessPreventing antimalarial resistance with artemisinin-based combination therapy(Health and Medical Publishing Group, 2004) Barnes, Karen IMalaria morbidity and mortality is rising, principally as a result of increasing antimalarial resistance. Resistance means that there is a shift to the right in the dose-response (concentration effect) relationship. Plasmodium falciparum has developed clinically significant resistance to all classes of antimalarial drugs, with the possible exception of artemisinin derivatives.
- ItemOpen AccessThe rationale and plan for creating a World Antimalarial Resistance Network (WARN)(BioMed Central Ltd, 2007) Sibley, Carol Hopkins; Barnes, Karen I; Plowe, Christopher VDrug resistant malaria was a major factor contributing to the failure of a worldwide campaign to eradicate malaria in the last century, and now threatens the large investment being made by the global community in the rollout of effective new drug combinations to replace failed drugs. Four related papers in this issue of Malaria Journal make the case for creating the World Antimalarial Resistance Network (WARN), which will consist of four linked open-access global databases containing clinical, in vitro, molecular and pharmacological data, and networks of reference laboratories that will support these databases and related surveillance activities. WARN will serve as a public resource to guide antimalarial drug treatment and prevention policies and to help confirm and characterize the new emergence of new resistance to antimalarial drugs and to contain its spread.