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Peter Winstanley - One of the best experts on this subject based on the ideXlab platform.
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Measurement of adherence, drug concentrations and the effectiveness of artemether-lumefantrine, Chlorproguanil-dapsone or sulphadoxine-pyrimethamine in the treatment of uncomplicated malaria in Malawi
Malaria journal, 2009Co-Authors: David J. Bell, Dyfrig A. Hughes, Steve A. Ward, Malcolm E. Molyneux, Mavuto Mukaka, Jacqui Montgomery, Noel Kayange, Phillips Chimpeni, Daniel G. Wootton, Peter WinstanleyAbstract:Background Sulphadoxine-pyrimethamine (SP) is the only single dose therapy for uncomplicated malaria, but there is widespread resistance. At the time of this study, artemether-lumefantrine (AL) and Chlorproguanil-dapsone (CPD), both multi-dose regimes, were considered possible alternatives to SP in Malawi. The aim of this study was to investigate the impact of poor adherence on the effectiveness of AL and CPD.
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Effects of genetic variation at the CYP2C19/CYP2C9 locus on pharmacokinetics of chlorcycloguanil in adult Gambians.
Pharmacogenomics, 2009Co-Authors: Ramatoulie E Janha, Fatoumatta Sisay-joof, Majidah Hamid-adiamoh, Archibald Worwui, Hannah L Chapman, Hyginus Opara, Sam Dunyo, Paul Milligan, Kirk A. Rockett, Peter WinstanleyAbstract:Aims: Antimalarial biguanides are metabolized by CYP2C19, thus genetic variation at the CYP2C locus might affect pharmacokinetics and so treatment outcome for malaria. Materials & methods: Polymorphisms in CYP2C19 and CYP2C9 in 43 adult Gambians treated with Chlorproguanil/dapsone for uncomplicated malaria were assessed. Chlorcycloguanil pharmacokinetics were measured and associations with CYP2C19 and CYP2C9 alleles and CYP2C19 metabolizer groups investigated. Results: All CYP2C19/CYP2C9 alleles obeyed Hardy–Weinberg equilibrium. There were 15 CYP2C19/2C9 haplotypes with a common haplotype frequency of 0.23. Participants with the CYP2C19*17 allele had higher chlorcycloguanil area under the concentration versus curve at 24 h (AUC0–24) than those without (geometric means: 317 vs 216 ng.h/ml; ratio of geometric means: 1.46; 95% CI: 1.03 to 2.09; p = 0.0363) and higher Cmax (geometric mean ratio: 1.52; 95% CI: 1.13 to 2.05; p = 0.0071). Conclusion: CYP2C19*17 determines antimalarial biguanide metabolic profil...
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Plasmodium falciparum Strains Harboring Dihydrofolate Reductase with the I164L Mutation Are Absent in Malawi and Zambia Even under Antifolate Drug Pressure
Antimicrobial agents and chemotherapy, 2008Co-Authors: Edwin Ochong, Peter Winstanley, David J. Bell, David J. Johnson, Umberto D'alessandro, Modest Mulenga, Sant Muangnoicharoen, Jean-pierre Van Geertruyden, Patrick G. Bray, Stephen A WardAbstract:The Plasmodium falciparum dihydrofolate reductase (PfDHFR) enzyme is the target of pyrimethamine, a component of the antimalarial pyrimethamine-sulfadoxine. Resistance to this drug is associated primarily with mutations in the Pfdhfr gene. The I164L mutant allele is of particular interest, because strains possessing this mutation are highly resistant to pyrimethamine and to Chlorproguanil, a component of Chlorproguanil-dapsone. A recent study from Malawi reported this mutation at a prevalence of 4.7% in parasites from human immunodeficiency virus-positive pregnant women by using a real-time PCR method. These observations have huge implications for the use of pyrimethamine-sulfadoxine, Chlorproguanil-dapsone, and future antifolate-artemisinin combinations in Africa. It was imperative that this finding be rigorously tested. We identified a number of critical limitations in the original genotyping strategy. Using a refined and validated real-time PCR strategy, we report here that this mutation was absent in 158 isolates from Malawi and 42 isolates from Zambia collected between 2003 and 2005.
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population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy Chlorproguanil dapsone
British Journal of Clinical Pharmacology, 2006Co-Authors: Julie A. Simpson, Dyfrig A. Hughes, Christine Manyando, Kalifa Bojang, Leon Aarons, Peter Winstanley, Geoffrey EdwardsAbstract:Aims To determine the population pharmacokinetics of Chlorproguanil, dapsone and the active metabolite of Chlorproguanil, chlorcycloguanil; and to estimate the duration of parasitocidal activity for chlorpoguanil/dapsone against Plasmodium falciparum isolates of varying sensitivity. Methods Rich and sparse pharmacokinetic data were collected prospectively from: healthy volunteers (n = 48) and adults (n = 65) and children (n = 68) suffering from P. falciparum malaria. All subjects received 2.0 mg kg−1 of Chlorproguanil and 2.5 mg kg−1 of dapsone. Results The population pharmacokinetic parameter estimates for Chlorproguanil were ka = 00.09 h−1 (intersubject variability was 44%), CL/F = 51.53 l h−1 (57%), CLD/F = 54.67 l h−1, V1/F = 234.40 l (50%) and V2/F = 1612.75 l; for dapsone were ka = 00.93 h−1, CL/F = 1.99 l h−1 (72%) and V/F = 76.96 l (48%); and for chlorcycloguanil were CLm/Fm = 3.72 l h−1 kg−1 (67%) and Vm/Fm = 12.76 l kg−1 (64%). For dapsone, CL/F and V/F were both significantly positively correlated with body weight. For a 10-kg child, the mean duration of parasitocidal activity for Chlorproguanil/dapsone against the three most susceptible P. falciparum strains was 4.5 days [5th and 95th percentiles 2.4, 7.3] for W282; 5.9 days (3.6, 9.7) for ItG2F6; and 6.1 days (3.7, 10.1) for K39. For an isolate with the ile-164-leu mutation, V1/S, activity ranged from 0.8 days (0.0, 3.3) for a 10-kg child to 1.8 days (0.0, 4.0) for a 60-kg adult. Conclusions Plasmodium falciparum malaria has no effect on the pharmacokinetic parameters for Chlorproguanil, dapsone or chlorcycloguanil. Chlorproguanil/dapsone will probably prove to be ineffective against parasite strains with the mutation ile-164-leu, were these to become prevalent in Africa.
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Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy Chlorproguanil/dapsone
British journal of clinical pharmacology, 2006Co-Authors: Julie A. Simpson, Dyfrig A. Hughes, Christine Manyando, Kalifa Bojang, Leon Aarons, Peter Winstanley, Geoffrey Edwards, William A. Watkins, Steve A. WardAbstract:Aims To determine the population pharmacokinetics of Chlorproguanil, dapsone and the active metabolite of Chlorproguanil, chlorcycloguanil; and to estimate the duration of parasitocidal activity for chlorpoguanil/dapsone against Plasmodium falciparum isolates of varying sensitivity. Methods Rich and sparse pharmacokinetic data were collected prospectively from: healthy volunteers (n = 48) and adults (n = 65) and children (n = 68) suffering from P. falciparum malaria. All subjects received 2.0 mg kg−1 of Chlorproguanil and 2.5 mg kg−1 of dapsone. Results The population pharmacokinetic parameter estimates for Chlorproguanil were ka = 00.09 h−1 (intersubject variability was 44%), CL/F = 51.53 l h−1 (57%), CLD/F = 54.67 l h−1, V1/F = 234.40 l (50%) and V2/F = 1612.75 l; for dapsone were ka = 00.93 h−1, CL/F = 1.99 l h−1 (72%) and V/F = 76.96 l (48%); and for chlorcycloguanil were CLm/Fm = 3.72 l h−1 kg−1 (67%) and Vm/Fm = 12.76 l kg−1 (64%). For dapsone, CL/F and V/F were both significantly positively correlated with body weight. For a 10-kg child, the mean duration of parasitocidal activity for Chlorproguanil/dapsone against the three most susceptible P. falciparum strains was 4.5 days [5th and 95th percentiles 2.4, 7.3] for W282; 5.9 days (3.6, 9.7) for ItG2F6; and 6.1 days (3.7, 10.1) for K39. For an isolate with the ile-164-leu mutation, V1/S, activity ranged from 0.8 days (0.0, 3.3) for a 10-kg child to 1.8 days (0.0, 4.0) for a 60-kg adult. Conclusions Plasmodium falciparum malaria has no effect on the pharmacokinetic parameters for Chlorproguanil, dapsone or chlorcycloguanil. Chlorproguanil/dapsone will probably prove to be ineffective against parasite strains with the mutation ile-164-leu, were these to become prevalent in Africa.
Malcolm E. Molyneux - One of the best experts on this subject based on the ideXlab platform.
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ral ssBioMed CentMalaria Journal
2016Co-Authors: David J. Bell, Dyfrig A. Hughes, Steve A. Ward, Malcolm E. Molyneux, Dan Wootton, Mavuto Mukaka, Jacqui Montgomery, Noel Kayange, Phillips Chimpeni, Peter A WinstanleyAbstract:Measurement of adherence, drug concentrations and the effectiveness of artemether-lumefantrine, Chlorproguanil-dapsone or sulphadoxine-pyrimethamine in the treatment of uncomplicated malaria in Malaw
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Measurement of adherence, drug concentrations and the effectiveness of artemether-lumefantrine, Chlorproguanil-dapsone or sulphadoxine-pyrimethamine in the treatment of uncomplicated malaria in Malawi
Malaria journal, 2009Co-Authors: David J. Bell, Dyfrig A. Hughes, Steve A. Ward, Malcolm E. Molyneux, Mavuto Mukaka, Jacqui Montgomery, Noel Kayange, Phillips Chimpeni, Daniel G. Wootton, Peter WinstanleyAbstract:Background Sulphadoxine-pyrimethamine (SP) is the only single dose therapy for uncomplicated malaria, but there is widespread resistance. At the time of this study, artemether-lumefantrine (AL) and Chlorproguanil-dapsone (CPD), both multi-dose regimes, were considered possible alternatives to SP in Malawi. The aim of this study was to investigate the impact of poor adherence on the effectiveness of AL and CPD.
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mutations associated with sulfadoxine pyrimethamine and Chlorproguanil resistance in plasmodium falciparum isolates from blantyre malawi
Antimicrobial Agents and Chemotherapy, 2005Co-Authors: Alisa P Alker, Malcolm E. Molyneux, Victor Mwapasa, Anne Purfield, Stephen J Rogerson, Deborah D Kamwendo, Eyob Tadesse, Ebbie Chaluluka, Steven R MeshnickAbstract:We conducted a prevalence study of mutations in Plasmodium falciparum that are associated with antifolate resistance in Blantyre, Malawi. The dihydrofolate reductase 164-Leu mutation, which confers resistance to both pyrimethamine and Chlorproguanil, was found in 4.7% of the samples. Previously unreported mutations in dihydropteroate synthase were also found.
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Chlorproguanil-dapsone versus sulfadoxine-pyrimethamine for sequential episodes of uncomplicated falciparum malaria in Kenya and Malawi: a randomised clinical trial
Lancet (London England), 2002Co-Authors: J. Sulo, William M. Watkins, P. Chimpeni, J. Hatcher, James G. Kublin, Christopher V. Plowe, Malcolm E. Molyneux, Kevin Marsh, Terrie E. Taylor, Peter WinstanleyAbstract:Summary Background Chlorproguanil-dapsone exerts lower resistance pressure on Plasmodium falciparum than does sulfadoxine-pyrimethamine, but is rapidly eliminated. We aimed to find out whether Chlorproguanil-dapsone results in a higher retreatment rate for malaria than sulfadoxine-pyrimethamine. Methods In a randomised trial of paediatric outpatients with uncomplicated falciparum malaria, patients received either Chlorproguanil-dapsone or sulfadoxine-pyrimethamine and were followed up for up to 1 year. Sites were in Kenya (n=410) and Malawi (n=500). We used perprotocol analysis to assess the primary outcome of annual malaria incidence. Findings Drop-outs were 117 of 410 (28·5%) in Kenya, and 342 of 500 (68·4%) in Malawi. Follow-up was for a median of 338 days (IQR 128–360) and 342 days (152–359) in Kilifi (Chlorproguanil-dapsone and sulfadoxine-pyrimethamine, respectively), and for 120 days (33–281) and 84 days (26–224) in Blantyre. Mean annual malaria incidence was 2·5 versus 2·1 in Kenya (relative risk 1·16, 95% Cl 0·98–1·37), and 2·2 versus 2·8 in Malawi (0·77, 0·63–0·94). 4·3% versus 12·8%, and 5·4% versus 20·1%, of patients were withdrawn for treatment failure in Kenya and Malawi, respectively. In Kenya haemoglobin concentration of 50 g/L or less caused exit in 6·9% of Chlorproguanil-dapsone patients and 1·5% of sulfadoxine-pyrimethamine patients, but most anaemia occurred before re-treatment. In Malawi only one patient exited because of anaemia. Interpretation Despite the rapid elimination of Chlorproguanil-dapsone, children treated with this drug did not have a higher incidence of malaria episodes than those treated with sulfadoxine-pyrimethamine. Treatment failure was more common with sulfadoxine-pyrimethamine. Cause of anaemia in Kenya was probably not adverse reaction to Chlorproguanil-dapsone, but this observation requires further study.
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molecular markers for failure of sulfadoxine pyrimethamine and Chlorproguanil dapsone treatment of plasmodium falciparum malaria
The Journal of Infectious Diseases, 2002Co-Authors: James G. Kublin, Stephen J Rogerson, Deborah D Kamwendo, Fraction K Dzinjalamala, Elissa M Malkin, Joseph F Cortese, Lisa M Martino, Rabia A G Mukadam, Andres G Lescano, Malcolm E. MolyneuxAbstract:Molecular assays for monitoring sulfadoxine-pyrimethamine-resistant Plasmodium falciparum have not been implemented because of the genetic and statistical complexity of the parasite mutations that confer resistance and their relation to treatment outcomes. This study analyzed pretreatment dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genotypes and treatment outcomes in a double-blind, placebo-controlled trial of sulfadoxine-pyrimethamine and Chlorproguanildapsone treatment for uncomplicated P. falciparum malaria. Multiple logistic regression was used to identify mutations that were predictive of treatment failure and to identify interactions and confounding factors. Infections caused by parasites with 3 DHFR mutations and 2 DHPS mutations (the "quintuple mutant") were associated with sulfadoxine-pyrimethamine treatment failure but not with Chlorproguanil-dapsone treatment failure. The presence of a single DHFR mutation (Arg-59) with a single DHPS mutation (Glu-540) accurately predicted the presence of the quintuple mutant. If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa.
William M. Watkins - One of the best experts on this subject based on the ideXlab platform.
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Rare, highly pyrimethamine-resistant alleles of the Plasmodium falciparum dihydrofolate reductase gene from 5 African sites.
The Journal of infectious diseases, 2004Co-Authors: Sarah J. Bates, William M. Watkins, Peter Winstanley, James G. Kublin, Ali Alloueche, Zul Premji, Juma Bwika, T. Christian Happi, Peter G. Kremsner, Carol Hopkins SibleyAbstract:In eastern and southern Africa, there has been a rapid increase in the prevalence of alleles with mutations in the Plasmodium falciparum dihydrofolate reductase gene (dhfr) associated with increased risk of clinical failure of sulfadoxine-pyrimethamine (S/P). Molecular methods for surveillance of these mutations are now widespread, but the usual analysis detects only the most prevalent allele in a polyclonal sample. We used a yeast- expression system to identify rare, highly pyrimethamine- resistant alleles of dhfr in isolates from 5 African countries - Kenya, Tanzania, Malawi, Gabon, and Nigeria. Only the isolates from Nigeria yielded significant numbers of novel resistant alleles, and only 1 of the alleles from any location showed a 13-fold increase in resistance to S/P or to Chlorproguanil-dapsone. Overall, these results suggest that dhfr alleles that confer high levels of resistance to antifolates are rare, even in eastern and southern Africa, where pyrimethamine has been intensively used.
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Chlorproguanil-dapsone versus sulfadoxine-pyrimethamine for sequential episodes of uncomplicated falciparum malaria in Kenya and Malawi: a randomised clinical trial
Lancet (London England), 2002Co-Authors: J. Sulo, William M. Watkins, P. Chimpeni, J. Hatcher, James G. Kublin, Christopher V. Plowe, Malcolm E. Molyneux, Kevin Marsh, Terrie E. Taylor, Peter WinstanleyAbstract:Summary Background Chlorproguanil-dapsone exerts lower resistance pressure on Plasmodium falciparum than does sulfadoxine-pyrimethamine, but is rapidly eliminated. We aimed to find out whether Chlorproguanil-dapsone results in a higher retreatment rate for malaria than sulfadoxine-pyrimethamine. Methods In a randomised trial of paediatric outpatients with uncomplicated falciparum malaria, patients received either Chlorproguanil-dapsone or sulfadoxine-pyrimethamine and were followed up for up to 1 year. Sites were in Kenya (n=410) and Malawi (n=500). We used perprotocol analysis to assess the primary outcome of annual malaria incidence. Findings Drop-outs were 117 of 410 (28·5%) in Kenya, and 342 of 500 (68·4%) in Malawi. Follow-up was for a median of 338 days (IQR 128–360) and 342 days (152–359) in Kilifi (Chlorproguanil-dapsone and sulfadoxine-pyrimethamine, respectively), and for 120 days (33–281) and 84 days (26–224) in Blantyre. Mean annual malaria incidence was 2·5 versus 2·1 in Kenya (relative risk 1·16, 95% Cl 0·98–1·37), and 2·2 versus 2·8 in Malawi (0·77, 0·63–0·94). 4·3% versus 12·8%, and 5·4% versus 20·1%, of patients were withdrawn for treatment failure in Kenya and Malawi, respectively. In Kenya haemoglobin concentration of 50 g/L or less caused exit in 6·9% of Chlorproguanil-dapsone patients and 1·5% of sulfadoxine-pyrimethamine patients, but most anaemia occurred before re-treatment. In Malawi only one patient exited because of anaemia. Interpretation Despite the rapid elimination of Chlorproguanil-dapsone, children treated with this drug did not have a higher incidence of malaria episodes than those treated with sulfadoxine-pyrimethamine. Treatment failure was more common with sulfadoxine-pyrimethamine. Cause of anaemia in Kenya was probably not adverse reaction to Chlorproguanil-dapsone, but this observation requires further study.
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Genetic diversity of Plasmodium falciparum parasites from Kenya is not affected by antifolate drug selection.
International journal for parasitology, 2002Co-Authors: Alexis Nzila, William M. Watkins, E.k. Mberu, Eunice Nduati, Amanda Ross, Carol Hopkins SibleyAbstract:The genotypes of merozoite surface protein-1, merozoite surface protein-2 and glutamine rich protein are frequently used to distinguish recrudescence from reinfection when parasitaemia reappears after antimalarial drug treatment. However, none of the previous reports has clearly assessed the change of genetic diversity following drug treatment. In the present study, we have assessed the impact of pyrimethamine/sulfadoxine and Chlorproguanil/dapsone on the genetic diversity of isolates and the multiplicity of infection in patient isolates from Kilifi, Kenya. We have analysed the length polymorphism of merozoite surface protein-1, merozoite surface protein-2 and glutamine rich protein and the data clearly show that treatment with pyrimethamine/sulfadoxine and Chlorproguanil/dapsone did not change the multiplicity of infection found in patients, in contrast to the selection that these drugs exert on the genes encoded by the target enzymes. In addition, we report that children of less than 2 years tend to have fewer numbers of clones per isolate when compared with older children. Overall, this study shows that the selection for genes that confer drug resistance is not a factor in reducing the genetic diversity of parasite clones in a patient.
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Chlorproguanil-dapsone for treatment of drug-resistant falciparum malaria in Tanzania
Lancet (London England), 2001Co-Authors: Theonest K. Mutabingwa, Peter Winstanley, Alexis Nzila, E.k. Mberu, Eunice Nduati, Elizabeth Hills, William M. WatkinsAbstract:Summary Background Resistance to the affordable malaria treatments chloroquine and pyrimethamine-sulfadoxine is seriously impeding malaria control through treatment in east Africa. We did an open, alternate drug allocation study to assess the efficacy of Chlorproguanil-dapsone in the treatment of falciparum malaria clinically resistant to pyrimethamine-sulfadoxine. Methods Children younger than 5 years with non-severe falciparum malaria, attending Muheza district hospital in Tanzania, were treated with the standard regimen of pyrimethamine-sulfadoxine. Patients whose clinical symptoms resolved but who remained parasitaemic 7 days after pyrimethamine-sulfadoxine were followed up for 1 month. Clinical malaria episodes were retreated with either single dose pyrimethamine-sulfadoxine or a 3-day regimen of Chlorproguanil-dapsone. Those with parasitaemia after 7 days were treated with Chlorproguanil-dapsone. Parasite DNA was collected on day 7 after first treatment with pyrimethamine-sulfadoxine and we looked for point mutations in the genes encoding dihydrofolate reductase ( dhfr ) and dyhydropteroate synthetase ( dhps ). Findings 360 children were enrolled and treated with pyrimethamine-sulfadoxine. On day 7, 192 (55%) of 348 had cleared parasitaemia. Of the remaining 156 parasitaemic children, 140 (90%) were followed up to day 28, and 92 (66%) of 140 developed clinical malaria. These 92 patients were alternately retreated with either pyrimethamine-sulfadoxine (46) or Chlorproguanil-dapsone (46). 28 (61%) of 46 children retreated with pyrimethamine-sulfadoxine were still parasitaemic at day 7, compared with three (15%) of 46 children retreated with Chlorproguanil-dapsone. Resistance to pyrimethamine-sulfadoxine increased from 45% (156/348) at the first treatment to 61% (28/46) after retreatment. 83 of 85 parasite isolates collected after the first pyrimethamine-sulfadoxine treatment, and before and after the second treatments with pyrimethamine-sulfadoxine and Chlorproguanil-dapsone showed triple-mutant dhfr alleles, associated with a variety of dhps mutations. Interpretation Most patients treated with pyrimethamine-sulfadoxine, who remain parasitaemic at day 7, develop new malaria symptoms within 1 month. Chlorproguanil-dapsone was a practicable therapy under these circumstances. Analysis of parasite dhfr and dhps before and after treatment supports the view that pyrimethamine-sulfadoxine resistance in this part of Africa is primarily due to parasites with three mutations in the dhfr domain.
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Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate Pyrimethamine/Sulfadoxine compared with the shorter-acting Chlorproguanil/dapsone on Kenyan Plasmodium falciparum.
The Journal of infectious diseases, 2000Co-Authors: Alexis Nzila, Peter Winstanley, E.k. Mberu, Eunice Nduati, Carol Hopkins Sibley, Stephanie A Monks, William M. WatkinsAbstract:Pyrimethamine (PM) plus sulfadoxine (SD) is the last remaining affordable drug for treating uncomplicated malaria in Africa. The selective pressure exerted by the slowly eliminated combination PM/SD was compared with that exerted by the more rapidly eliminated combination Chlorproguanil/dapsone (CPG/Dap) on Kenyan Plasmodium falciparum. Point mutations were analyzed in dihydrofolate reductase and dihydropteroate synthase and in the genetic diversity of 3 genes in isolates collected before and after CPG/Dap and PM/SD treatments. PM/SD was associated strongly with the disappearance of fully drug-sensitive parasites and with a significant increase in the prevalence of resistant parasites in subsequent parasitemias. However, this was not a characteristic of treatment with CPG/Dap. Moreover, most of the patients who returned with recrudescent infections were in the PM/SD-treated group. The data predict a longer useful therapeutic life for CPG/Dap than for PM/SD, and, thus, CPG/Dap is a preferable alternative for treatment of chloroquine-resistant falciparum malaria in sub-Saharan Africa.
Umberto D'alessandro - One of the best experts on this subject based on the ideXlab platform.
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Demographic and clinical characteristics of children at enrolment according to treatment (AQ+SP: amodiaquine+sulphadoxine-pyrimethamine; CD+A Chlorproguanil-dapsone+artesunate) and presence of the G6PD (A-) deficiency allele (hemizygous males, homozy
2013Co-Authors: Caterina I. Fanello, Umberto D'alessandro, Corine Karema, Pamela Avellino, Germana Bancone, Aline Uwimana, Sue J. Lee, David ModianoAbstract:Demographic and clinical characteristics of children at enrolment according to treatment (AQ+SP: amodiaquine+sulphadoxine-pyrimethamine; CD+A Chlorproguanil-dapsone+artesunate) and presence of the G6PD (A-) deficiency allele (hemizygous males, homozygous and heterozygous females).
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Mean PCV according to treatment group (AQ+SP: amodiaquine+sulphadoxine-pyrimethamine and CD+A: Chlorproguanil-dapsone+artesunate), G6PD status (deficient: hemizygous males and homozygous females) and day of follow-up.
2013Co-Authors: Caterina I. Fanello, Umberto D'alessandro, Corine Karema, Pamela Avellino, Germana Bancone, Aline Uwimana, Sue J. Lee, David ModianoAbstract:Mean PCV according to treatment group (AQ+SP: amodiaquine+sulphadoxine-pyrimethamine and CD+A: Chlorproguanil-dapsone+artesunate), G6PD status (deficient: hemizygous males and homozygous females) and day of follow-up.
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Assessing the consistency assumption by exploring treatment by covariate interactions in mixed treatment comparison meta‐analysis: individual patient‐level covariates versus aggregate trial‐level covariates
Statistics in medicine, 2012Co-Authors: Sarah Donegan, Umberto D'alessandro, Paula R Williamson, Catrin Tudur SmithAbstract:Mixed treatment comparison (MTC) meta-analysis allows several treatments to be compared in a single analysis while utilising direct and indirect evidence. Treatment by covariate interactions can be included in MTC models to explore how the covariate modifies the treatment effects. If interactions exist, the assumptions underlying MTCs may be invalidated. For conventional pair-wise meta-analysis, important benefits regarding the investigation of such interactions, gained from using individual patient data (IPD) rather than aggregate data (AD), have been described. We aim to compare IPD MTC models including patient-level covariates with AD MTC models including study-level covariates. IPD and AD random-effects MTC models for dichotomous outcomes are specified. Three assumptions are made regarding the interactions (i.e. independent, exchangeable and common interactions). The models are applied to a dataset to compare four drugs for treating malaria (i.e. amodiaquine-artesunate, dihydroartemisinin-piperaquine (DHAPQ), artemether-lumefantrine and Chlorproguanil-dapsone plus artesunate) using the outcome unadjusted treatment success at day 28. The treatment effects and regression coefficients for interactions from the IPD models were more precise than those from AD models. Using IPD, assuming independent or exchangeable interactions, the regression coefficient for Chlorproguanil-dapsone plus artesunate versus DHAPQ was statistically significant and assuming common interactions, the common coefficient was significant; whereas using AD, no coefficients were significant. Using IPD, DHAPQ was the best drug; whereas using AD, the best drug varied. Using AD models, there was no evidence that the consistency assumption was invalid; whereas, the assumption was questionable based on the IPD models. The AD analyses were misleading.
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Plasmodium falciparum Strains Harboring Dihydrofolate Reductase with the I164L Mutation Are Absent in Malawi and Zambia Even under Antifolate Drug Pressure
Antimicrobial agents and chemotherapy, 2008Co-Authors: Edwin Ochong, Peter Winstanley, David J. Bell, David J. Johnson, Umberto D'alessandro, Modest Mulenga, Sant Muangnoicharoen, Jean-pierre Van Geertruyden, Patrick G. Bray, Stephen A WardAbstract:The Plasmodium falciparum dihydrofolate reductase (PfDHFR) enzyme is the target of pyrimethamine, a component of the antimalarial pyrimethamine-sulfadoxine. Resistance to this drug is associated primarily with mutations in the Pfdhfr gene. The I164L mutant allele is of particular interest, because strains possessing this mutation are highly resistant to pyrimethamine and to Chlorproguanil, a component of Chlorproguanil-dapsone. A recent study from Malawi reported this mutation at a prevalence of 4.7% in parasites from human immunodeficiency virus-positive pregnant women by using a real-time PCR method. These observations have huge implications for the use of pyrimethamine-sulfadoxine, Chlorproguanil-dapsone, and future antifolate-artemisinin combinations in Africa. It was imperative that this finding be rigorously tested. We identified a number of critical limitations in the original genotyping strategy. Using a refined and validated real-time PCR strategy, we report here that this mutation was absent in 158 isolates from Malawi and 42 isolates from Zambia collected between 2003 and 2005.
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A randomised trial to assess the efficacy and safety of Chlorproguanil/dapsone + artesunate for the treatment of uncomplicated Plasmodium falciparum malaria
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2008Co-Authors: Caterina I. Fanello, J. Curtis, Corine Karema, Aline Uwimana, Daniel Ngamije, V. Ndahindwa, C. Van Overmeir, W. Van Doren, Umberto D'alessandroAbstract:Summary We tested the efficacy and safety of Chlorproguanil/dapsone co-administered with artesunate (CD+A) for the treatment of uncomplicated Plasmodium falciparum malaria in children compared with amodiaquine + sulfadoxine/pyrimethamine (AQ+SP) at two different sites in Rwanda. The trial was open label and 800 patients were randomly assigned to AQ+SP ( n = 400) or CD+A ( n = 400). Patients were hospitalised for 3 days and then followed-up weekly until Day 28 after treatment. Clinical and parasitological outcomes were recorded. Results showed that neither treatment was adequately efficacious. At one site, the adequate clinical and parasitological response (ACPR), PCR-adjusted, was 73.3% in the CD+A arm and 87.8% in the AQ+SP arm ( P P NCT00461578 ]
W M Watkins - One of the best experts on this subject based on the ideXlab platform.
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molecular evidence of greater selective pressure for drug resistance exerted by the long acting antifolate pyrimethamine sulfadoxine compared with the shorter acting Chlorproguanil dapsone on kenyan plasmodium falciparum
The Journal of Infectious Diseases, 2000Co-Authors: W M Watkins, Peter Winstanley, Alexis Nzila, E.k. Mberu, Eunice Nduati, Carol Hopkins Sibley, Stephanie A MonksAbstract:Pyrimethamine (PM) plus sulfadoxine (SD) is the last remaining affordable drug for treating uncomplicated malaria in Africa. The selective pressure exerted by the slowly eliminated combination PM/SD was compared with that exerted by the more rapidly eliminated combination Chlorproguanil/dapsone (CPG/Dap) on Kenyan Plasmodium falciparum. Point mutations were analyzed in dihydrofolate reductase and dihydropteroate synthase and in the genetic diversity of 3 genes in isolates collected before and after CPG/Dap and PM/SD treatments. PM/SD was associated strongly with the disappearance of fully drug-sensitive parasites and with a significant increase in the prevalence of resistant parasites in subsequent parasitemias. However, this was not a characteristic of treatment with CPG/Dap. Moreover, most of the patients who returned with recrudescent infections were in the PM/SD-treated group. The data predict a longer useful therapeutic life for CPG/Dap than for PM/SD, and, thus, CPG/Dap is a preferable alternative for treatment of chloroquine-resistant falciparum malaria in sub-Saharan Africa.
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the efficacy of antifolate antimalarial combinations in africa a predictive model based on pharmacodynamic and pharmacokinetic analyses
Parasitology Today, 1997Co-Authors: W M Watkins, Peter Winstanley, E.k. Mberu, Christopher V. PloweAbstract:Abstract At present, effective treatment for non-severe malaria is the most important malaria control strategy in Africa. Pyrimethamine—sulfadoxine (PSD) is rapidly becoming the first-line treatment in areas of chloroquine resistance, although the parasite chemoresistance factors that dispose towards clinical failure with PSD are still unclear. Here, Bill Watkins and colleagues analyse the relationship between the pharmacokinetic properties of two treatment combinations (PSD and Chlorproguanil—dapsone) in vivo and the respective in vitro isobolograms for parasites with specific drug-resistance patterns. From this relationship, they develop a hypothesis that may explain clinical drug failure and differential efficacy between treatments. The deductions can be tested in field studies to validate or refute the model.
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Chlorproguanil dapsone for uncomplicated plasmodium falciparum malaria in young children pharmacokinetics and therapeutic range
Transactions of The Royal Society of Tropical Medicine and Hygiene, 1997Co-Authors: W M Watkins, Peter Winstanley, Kevin Marsh, Evans Amukoye, David Muhia, Simon SzwandtAbstract:Abstract The disposition of Chlorproguanil/dapsone (one daily dose for 3 d of 1·2 and 2·4 mg/kg respectively) has been studied in young children with Plasmodium falciparum malaria, to provide data complementary to a clinical trial of this drug combination. Unbound concentrations of chlorcycloguanil (the active metabolite of Chlorproguanil) and dapsone in clinical samples have been related to the unbound drug concentrations which produced defined outcomes in tests in vitro of drug efficacy and toxicity. Twelve children with uncomplicated malaria were treated: all cleared parasitaemia within 72 h and made uneventful recoveries. After the first dose of Chlorproguanil/dapsone the maximum unbound chlorcycloguanil concentration in clinical samples (19 ng/mL [about 60 nM]) was 2 orders of magnitude above the 50% inhibitory concentration (IC 50 ) value for this drug against the K39 strain of P falciparum , while falling 2 orders of magnitude below its IC 50 against human bone marrow cells; the maximum unbound dapsone concentration in clinical samples (160 ng/mL [about 645 nM]) was 10-fold higher than its IC 50 against the K39 strain. However, because of the rapid elimination of Chlorproguanil from the body (half-life 12·6 ± 6·3 h), the minimum fractional inhibitory concentrations of unbound chlorcycloguanil/dapsone against the K39 strain were probably exceeded for no more than 6 d. These data, together with the clinical trial, will be helpful in deciding whether current Chlorproguanil/dapsone doses are optimal for the treatment of falciparum malaria.