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Philip J Rosenthal - One of the best experts on this subject based on the ideXlab platform.
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prolonged selection of pfmdr1 polymorphisms after treatment of falciparum malaria with artemether lumefantrine in uganda
The Journal of Infectious Diseases, 2011Co-Authors: Frederick N Baliraine, Philip J RosenthalAbstract:We compared the prevalence of key pfmdr1 alleles between pretreatment Plasmodium falciparum parasite isolates and parasites that emerged after treatment of uncomplicated malaria in a longitudinal cohort of Ugandan children. The pfmdr1 86N, 184F, and 1246D alleles were selected after treatment with artemether-lumefantrine, but not after artesunate-Amodiaquine or Amodiaquine-sulfadoxine-pyrimethamine. Remarkably, selection persisted in infections presenting up to about 60 days after treatment with artemether-lumefantrine. Thus, parasites selected for decreased drug sensitivity can appear long after predicted exposure to antimalarial drugs. Continued surveillance of the clinical efficacy and in vitro activity of new combination therapies is warranted.
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randomized comparison of Amodiaquine plus sulfadoxine pyrimethamine artemether lumefantrine and dihydroartemisinin piperaquine for the treatment of uncomplicated plasmodium falciparum malaria in burkina faso
Clinical Infectious Diseases, 2007Co-Authors: Issaka Zongo, Grant Dorsey, Philip J Rosenthal, Christian Dokomajilar, Noel Rouamba, Yves Y Sere, Jean Bosco OuedraogoAbstract:BACKGROUND: Combination antimalarial therapy is advocated to improve treatment efficacy and limit selection of drug-resistant parasites. We compared the efficacies of 3 combination regimens in Bobo-Dioulasso, Burkina Faso: Amodiaquine plus sulfadoxine-pyrimethamine, which was recently shown to be highly efficacious at this site; artemether-lumefantrine, the new national first-line antimalarial regimen; and dihydroartemisinin-piperaquine (DP), a newer regimen. METHODS: We enrolled 559 patients >or=6 months of age with uncomplicated Plasmodium falciparum malaria and randomized them to the 3 regimens. We analyzed the risk of recurrent parasitemia by day 28 and day 42, both unadjusted and adjusted by PCR methods to distinguish recrudescence and new infection. RESULTS: Complete data were available for 517 (92.5%) of the enrolled subjects. Early treatment failures occurred in 5 patients treated with Amodiaquine plus sulfadoxine-pyrimethamine and in 2 patients each treated with the other regimens. The day 28 risk of recurrent parasitemia, unadjusted by genotyping, was significantly higher for patients receiving artemether-lumefantrine than for patients receiving Amodiaquine plus sulfadoxine-pyrimethamine (20.1% vs. 6.2%; risk difference, 13.8%; 95% confidence interval, 7.0%-20.7%) or dihydroartemisinin-piperaquine (20.1% vs. 2.2%; risk difference, 17.9%; 95% confidence interval, 11.6%-24.1%). Similar differences were seen for children <5 years of age (54% of the study population) and when outcomes were extended to 42 days. Significant differences were not seen between outcomes for patients receiving Amodiaquine plus sulfadoxine-pyrimethamine and outcomes for those receiving dihydroartemisinin-piperaquine. Recrudescences were uncommon (occurring in <5% of patients) in all treatment groups. No serious adverse events were noted. CONCLUSIONS: All regimens were highly efficacious in clearing infection, but considering the risks of recurrent malaria after therapy, the Amodiaquine plus sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine regimens were more efficacious than the artemether-lumefantrine regimen (the new national regimen in Burkina Faso) for the treatment of uncomplicated P. falciparum malaria.
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resistance mediating plasmodium falciparum pfcrt and pfmdr1 alleles after treatment with artesunate Amodiaquine in uganda
Antimicrobial Agents and Chemotherapy, 2007Co-Authors: Samuel L Nsobya, Grant Dorsey, Christian Dokomajilar, Moses Joloba, Philip J RosenthalAbstract:Key parasite polymorphisms were assessed in subjects treated for malaria with artesunate-Amodiaquine in Tororo, Uganda. For pfcrt, all of the isolates tested had the CVIET haplotype. For pfmdr1, 86Y and 1246Y were common at baseline and their prevalences were significantly higher in new isolates after therapy, indicating that treatment selected for mutations associated with a decreased response to Amodiaquine.
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combination therapy for uncomplicated falciparum malaria in ugandan children a randomized trial
JAMA, 2007Co-Authors: Grant Dorsey, Sarah G Staedke, Moses R Kamya, Christian Dokomajilar, Tamara D Clark, Denise Njamameya, Bridget Nzarubara, Catherine Maitekisebuguzi, Philip J RosenthalAbstract:ContextCombination therapy is now widely advocated as first-line treatment for uncomplicated malaria in Africa. However, it is not clear which treatment regimens are optimal or how to best assess comparative efficacies in highly endemic areas.ObjectiveTo compare the efficacy and safety of 3 leading combination therapies for the treatment of uncomplicated malaria.Design, Setting, and ParticipantsSingle-blind randomized clinical trial, conducted between November 2004 and June 2006, of treatment for all episodes of uncomplicated malaria in children in an urban community in Kampala, Uganda. A total of 601 healthy children (aged 1-10 years) were randomly selected and were followed up for 13 to 19 months, receiving all medical care at the study clinic.InterventionsStudy participants were randomized to receive 1 of 3 combination therapies (Amodiaquine plus sulfadoxine-pyrimethamine, Amodiaquine plus artesunate, or artemether-lumefantrine) when diagnosed with their first episode of uncomplicated malaria. The same assigned treatment was given for all subsequent episodes.Main Outcome Measure28-Day risk of parasitological failure (unadjusted and adjusted by genotyping to distinguish recrudescence from new infection) for each episode of uncomplicated malaria treated with study drugs.ResultsOf enrolled children, 329 of 601 were diagnosed with at least 1 episode of uncomplicated malaria, and 687 episodes of Plasmodium falciparum malaria were treated with study drugs. The 28-day risk of treatment failure (unadjusted by genotyping) for individual episodes of malaria were 26.1% (95% CI, 21.1%-32.1%) for Amodiaquine plus sulfadoxine-pyrimethamine, 17.4% (95% CI, 13.1%-23.1%) for Amodiaquine plus artesunate, and 6.7% (95% CI, 3.9%-11.2%) for artemether-lumefantrine (P<.05 for all pairwise comparisons). When only recrudescent treatment failures were considered, the risks of failure were 14.1% (95% CI, 10.3%-19.2%), 4.6% (95% CI, 2.5%-8.3%), and 1.0% (95% CI, 0.3%-4.0%) for the same order of study drugs, respectively (P≤.008 for all pairwise comparisons, except Amodiaquine plus artesunate vs artemether-lumefantrine, P = .05). There were no deaths or cases of severe malaria. Significant reductions in anemia (9.3% [95% CI, 7.0%-12.0%] at enrollment vs 0.6% [95% CI, 0.1%-2.2%] during the last 2 months of follow-up; P<.001) and asymptomatic parasitemia (18.6% [95% CI, 15.5%-22.1%] at enrollment vs 2.3% [95% CI, 1.5%-3.5%] during the last 2 months of follow-up; P<.001) were observed according to routine testing.ConclusionsArtemether-lumefantrine was the most efficacious treatment for uncomplicated malaria in the study population. With all study regimens, the provision of prompt and reasonably effective facility-based treatment was associated with good outcomes in long-term health measures.Trial Registrationisrctn.org Identifier: ISRCTN37517549
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artemether lumefantrine versus Amodiaquine plus sulfadoxine pyrimethamine for uncomplicated falciparum malaria in burkina faso a randomised non inferiority trial
The Lancet, 2007Co-Authors: Issaka Zongo, Grant Dorsey, Philip J Rosenthal, Christian Dokomajilar, Noel Rouamba, Halidou Tinto, Robert T Guiguemde, Jean Bosco OuedraogoAbstract:BACKGROUND: Artemisinin-based combination regimens are widely advocated for malarial treatment, but other effective regimens might be cheaper and more readily available. Our aim was to compare the risk of recurrent parasitaemia in patients given artemether-lumefantrine with that in those given Amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated malaria. METHODS: We enrolled 521 patients aged 6 months or older with uncomplicated falciparum malaria in Bobo-Dioulasso, Burkina Faso. Patients were randomly assigned to receive standard doses of either artemether-lumefantrine (261) or Amodiaquine plus sulfadoxine-pyrimethamine (260) for 3 days. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. The study is registered at controlled-trials.gov with the identifier ISRCTN54261005. FINDINGS: Of enrolled patients, 478 (92%) completed the 28-day study. The risk of recurrent symptomatic malaria was lowest in the group given Amodiaquine plus sulfadoxine-pyrimethamine (1.7%vs 10.2%; risk difference 8.5%; 95% CI 4.3-12.6; p=0.0001); as was the risk of recurrent parasitaemia (4.7%vs 15.1%; 10.4%; 5.1-15.6; p=0.0002). Nearly all recurrences were due to new infections. Recrudescences were four late treatment failures with artemether-lumefantrine and one early treatment failure with Amodiaquine plus sulfadoxine-pyrimethamine. Both regimens were safe and well tolerated, with pruritus more common with Amodiaquine plus sulfadoxine-pyrimethamine than with artemether-lumefantrine. Each regimen selected for new isolates with mutations that have been associated with decreased drug susceptibility. INTERPRETATION: Amodiaquine plus sulfadoxine-pyrimethamine was more effective than was artemether-lumefantrine for the treatment of uncomplicated malaria. For regions of Africa where Amodiaquine plus sulfadoxine-pyrimethamine continues to be effective, this less expensive and more available regimen should be considered as an alternative to blanket recommendations for artemisinin-based combination treatment for malaria.
Jose Pedro Gil - One of the best experts on this subject based on the ideXlab platform.
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Influence of Cytochrome P450 (CYP) 2C8 polymorphisms on the efficacy and tolerability of artesunate-Amodiaquine treatment of uncomplicated Plasmodium falciparum malaria in Zanzibar
Malaria journal, 2021Co-Authors: Leyre Pernaute-lau, Mwinyi I. Msellem, Anders Björkman, Ulrika Morris, Andreas Mårtensson, Jose Pedro GilAbstract:BACKGROUND The anti-malarial drug, Amodiaquine, a commonly used, long-acting partner drug in artemisinin-based combination therapy, is metabolized to active desethyl-Amodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). The CYP2C8 gene carries several polymorphisms including the more frequent minor alleles, CYP2C8*2 and CYP2C8*3. These minor alleles have been associated with decreased enzymatic activity, slowing the Amodiaquine biotransformation towards DEAQ. This study aimed to assess the influence of these CYP2C8 polymorphisms on the efficacy and tolerability of artesunate-Amodiaquine (AS-AQ) treatment for uncomplicated Plasmodium falciparum malaria in Zanzibar. METHODS Dried blood spots on filter paper were collected from 618 children enrolled in two randomized clinical trials comparing AS-AQ and artemether-lumefantrine in 2002-2005 in Zanzibar. Study participant were under five years of age with uncomplicated falciparum malaria. Human CYP2C8*2 and CYP2C8*3 genotype frequencies were determined by PCR-restriction fragment length polymorphism. Statistical associations between CYP2C8*2 and/or CYP2C8*3 allele carriers and treatment outcome or occurrence of adverse events were assessed by Fisher's exact test. RESULTS The allele frequencies of CYP2C8*2 and CYP2C8*3 were 17.5 % (95 % CI 15.4-19.7) and 2.7 % (95 % CI 1.8-3.7), respectively. There was no significant difference in the proportion of subjects carrying either CYP2C8*2 or CYP2C8*3 alleles amongst those with re-infections (44.1 %; 95 % CI 33.8-54.8) or those with recrudescent infections (48.3 %; 95 % CI 29.4-67.5), compared to those with an adequate clinical and parasitological response (36.7 %; 95 % CI 30.0-43.9) (P = 0.25 and P = 0.31, respectively). However, patients carrying either CYP2C8*2 or CYP2C8*3 alleles were significantly associated with an increased occurrence of non-serious adverse events, when compared with CYP2C8 *1/*1 wild type homozygotes (44.9 %; 95 % CI 36.1-54.0 vs. 28.1 %; 95 % CI 21.9-35.0, respectively; P = 0.003). CONCLUSIONS CYP2C8 genotypes did not influence treatment efficacy directly, but the tolerability to AS-AQ may be reduced in subjects carrying the CYP2C8*2 and CYP2C8*3 alleles. The importance of this non-negligible association with regard to Amodiaquine-based malaria chemotherapy warrants further investigation.
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prevalence of cyp2c8 2 and 3 among eritreans and its potential impact on artesunate Amodiaquine treatment
Pharmacogenomics and Personalized Medicine, 2020Co-Authors: Lidia Habtemikael, Andreas Mårtensson, Jose Pedro Gil, Mulugeta Russom, Iyassu Bahta, Selam Mihreteab, Araia BerhaneAbstract:Background: In Eritrea, artesunate–Amodiaquine is the first-line treatment against uncomplicated malaria. Amodiaquine, which is mainly bio-transformed by CYP2C8, is known to be associated with adve ...
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cyp2c8 and antimalaria drug efficacy
Pharmacogenomics, 2007Co-Authors: Jose Pedro Gil, Gil E BerglundAbstract:Malaria is a major infectious disease. In the last 10 years it has killed more than 20 million people, mainly small children in Africa. The highly efficacious artemisinine combination therapy is being launched globally, constituting the main hope for fighting the disease. Amodiaquine is a main partner in these combinations. Amodiaquine is almost entirely metabolized by the polymorphic cytochrome P450 (CYP) isoform 2C8 to the pharmacologically active desethylAmodiaquine. The question remains whether the efficacy of Amodiaquine is affected by the gene polymorphism. Genotype-inferred low metabolizers are found in 1-4% of African populations, which corresponds to millions of expected exposures to the drug. In vivo pharmacokinetic data on Amodiaquine is limited. By combining it with published in vitro pharmacodynamic and drug metabolism information, we review and predict the possible relevance, or lack of, of CYP2C8 polymorphisms in the present and future efficacy of Amodiaquine. Chloroquine and dapsone, both substrates of CYP2C8, are also discussed in the same context.
Grant Dorsey - One of the best experts on this subject based on the ideXlab platform.
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randomized comparison of Amodiaquine plus sulfadoxine pyrimethamine artemether lumefantrine and dihydroartemisinin piperaquine for the treatment of uncomplicated plasmodium falciparum malaria in burkina faso
Clinical Infectious Diseases, 2007Co-Authors: Issaka Zongo, Grant Dorsey, Philip J Rosenthal, Christian Dokomajilar, Noel Rouamba, Yves Y Sere, Jean Bosco OuedraogoAbstract:BACKGROUND: Combination antimalarial therapy is advocated to improve treatment efficacy and limit selection of drug-resistant parasites. We compared the efficacies of 3 combination regimens in Bobo-Dioulasso, Burkina Faso: Amodiaquine plus sulfadoxine-pyrimethamine, which was recently shown to be highly efficacious at this site; artemether-lumefantrine, the new national first-line antimalarial regimen; and dihydroartemisinin-piperaquine (DP), a newer regimen. METHODS: We enrolled 559 patients >or=6 months of age with uncomplicated Plasmodium falciparum malaria and randomized them to the 3 regimens. We analyzed the risk of recurrent parasitemia by day 28 and day 42, both unadjusted and adjusted by PCR methods to distinguish recrudescence and new infection. RESULTS: Complete data were available for 517 (92.5%) of the enrolled subjects. Early treatment failures occurred in 5 patients treated with Amodiaquine plus sulfadoxine-pyrimethamine and in 2 patients each treated with the other regimens. The day 28 risk of recurrent parasitemia, unadjusted by genotyping, was significantly higher for patients receiving artemether-lumefantrine than for patients receiving Amodiaquine plus sulfadoxine-pyrimethamine (20.1% vs. 6.2%; risk difference, 13.8%; 95% confidence interval, 7.0%-20.7%) or dihydroartemisinin-piperaquine (20.1% vs. 2.2%; risk difference, 17.9%; 95% confidence interval, 11.6%-24.1%). Similar differences were seen for children <5 years of age (54% of the study population) and when outcomes were extended to 42 days. Significant differences were not seen between outcomes for patients receiving Amodiaquine plus sulfadoxine-pyrimethamine and outcomes for those receiving dihydroartemisinin-piperaquine. Recrudescences were uncommon (occurring in <5% of patients) in all treatment groups. No serious adverse events were noted. CONCLUSIONS: All regimens were highly efficacious in clearing infection, but considering the risks of recurrent malaria after therapy, the Amodiaquine plus sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine regimens were more efficacious than the artemether-lumefantrine regimen (the new national regimen in Burkina Faso) for the treatment of uncomplicated P. falciparum malaria.
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resistance mediating plasmodium falciparum pfcrt and pfmdr1 alleles after treatment with artesunate Amodiaquine in uganda
Antimicrobial Agents and Chemotherapy, 2007Co-Authors: Samuel L Nsobya, Grant Dorsey, Christian Dokomajilar, Moses Joloba, Philip J RosenthalAbstract:Key parasite polymorphisms were assessed in subjects treated for malaria with artesunate-Amodiaquine in Tororo, Uganda. For pfcrt, all of the isolates tested had the CVIET haplotype. For pfmdr1, 86Y and 1246Y were common at baseline and their prevalences were significantly higher in new isolates after therapy, indicating that treatment selected for mutations associated with a decreased response to Amodiaquine.
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combination therapy for uncomplicated falciparum malaria in ugandan children a randomized trial
JAMA, 2007Co-Authors: Grant Dorsey, Sarah G Staedke, Moses R Kamya, Christian Dokomajilar, Tamara D Clark, Denise Njamameya, Bridget Nzarubara, Catherine Maitekisebuguzi, Philip J RosenthalAbstract:ContextCombination therapy is now widely advocated as first-line treatment for uncomplicated malaria in Africa. However, it is not clear which treatment regimens are optimal or how to best assess comparative efficacies in highly endemic areas.ObjectiveTo compare the efficacy and safety of 3 leading combination therapies for the treatment of uncomplicated malaria.Design, Setting, and ParticipantsSingle-blind randomized clinical trial, conducted between November 2004 and June 2006, of treatment for all episodes of uncomplicated malaria in children in an urban community in Kampala, Uganda. A total of 601 healthy children (aged 1-10 years) were randomly selected and were followed up for 13 to 19 months, receiving all medical care at the study clinic.InterventionsStudy participants were randomized to receive 1 of 3 combination therapies (Amodiaquine plus sulfadoxine-pyrimethamine, Amodiaquine plus artesunate, or artemether-lumefantrine) when diagnosed with their first episode of uncomplicated malaria. The same assigned treatment was given for all subsequent episodes.Main Outcome Measure28-Day risk of parasitological failure (unadjusted and adjusted by genotyping to distinguish recrudescence from new infection) for each episode of uncomplicated malaria treated with study drugs.ResultsOf enrolled children, 329 of 601 were diagnosed with at least 1 episode of uncomplicated malaria, and 687 episodes of Plasmodium falciparum malaria were treated with study drugs. The 28-day risk of treatment failure (unadjusted by genotyping) for individual episodes of malaria were 26.1% (95% CI, 21.1%-32.1%) for Amodiaquine plus sulfadoxine-pyrimethamine, 17.4% (95% CI, 13.1%-23.1%) for Amodiaquine plus artesunate, and 6.7% (95% CI, 3.9%-11.2%) for artemether-lumefantrine (P<.05 for all pairwise comparisons). When only recrudescent treatment failures were considered, the risks of failure were 14.1% (95% CI, 10.3%-19.2%), 4.6% (95% CI, 2.5%-8.3%), and 1.0% (95% CI, 0.3%-4.0%) for the same order of study drugs, respectively (P≤.008 for all pairwise comparisons, except Amodiaquine plus artesunate vs artemether-lumefantrine, P = .05). There were no deaths or cases of severe malaria. Significant reductions in anemia (9.3% [95% CI, 7.0%-12.0%] at enrollment vs 0.6% [95% CI, 0.1%-2.2%] during the last 2 months of follow-up; P<.001) and asymptomatic parasitemia (18.6% [95% CI, 15.5%-22.1%] at enrollment vs 2.3% [95% CI, 1.5%-3.5%] during the last 2 months of follow-up; P<.001) were observed according to routine testing.ConclusionsArtemether-lumefantrine was the most efficacious treatment for uncomplicated malaria in the study population. With all study regimens, the provision of prompt and reasonably effective facility-based treatment was associated with good outcomes in long-term health measures.Trial Registrationisrctn.org Identifier: ISRCTN37517549
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artemether lumefantrine versus Amodiaquine plus sulfadoxine pyrimethamine for uncomplicated falciparum malaria in burkina faso a randomised non inferiority trial
The Lancet, 2007Co-Authors: Issaka Zongo, Grant Dorsey, Philip J Rosenthal, Christian Dokomajilar, Noel Rouamba, Halidou Tinto, Robert T Guiguemde, Jean Bosco OuedraogoAbstract:BACKGROUND: Artemisinin-based combination regimens are widely advocated for malarial treatment, but other effective regimens might be cheaper and more readily available. Our aim was to compare the risk of recurrent parasitaemia in patients given artemether-lumefantrine with that in those given Amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated malaria. METHODS: We enrolled 521 patients aged 6 months or older with uncomplicated falciparum malaria in Bobo-Dioulasso, Burkina Faso. Patients were randomly assigned to receive standard doses of either artemether-lumefantrine (261) or Amodiaquine plus sulfadoxine-pyrimethamine (260) for 3 days. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. The study is registered at controlled-trials.gov with the identifier ISRCTN54261005. FINDINGS: Of enrolled patients, 478 (92%) completed the 28-day study. The risk of recurrent symptomatic malaria was lowest in the group given Amodiaquine plus sulfadoxine-pyrimethamine (1.7%vs 10.2%; risk difference 8.5%; 95% CI 4.3-12.6; p=0.0001); as was the risk of recurrent parasitaemia (4.7%vs 15.1%; 10.4%; 5.1-15.6; p=0.0002). Nearly all recurrences were due to new infections. Recrudescences were four late treatment failures with artemether-lumefantrine and one early treatment failure with Amodiaquine plus sulfadoxine-pyrimethamine. Both regimens were safe and well tolerated, with pruritus more common with Amodiaquine plus sulfadoxine-pyrimethamine than with artemether-lumefantrine. Each regimen selected for new isolates with mutations that have been associated with decreased drug susceptibility. INTERPRETATION: Amodiaquine plus sulfadoxine-pyrimethamine was more effective than was artemether-lumefantrine for the treatment of uncomplicated malaria. For regions of Africa where Amodiaquine plus sulfadoxine-pyrimethamine continues to be effective, this less expensive and more available regimen should be considered as an alternative to blanket recommendations for artemisinin-based combination treatment for malaria.
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artemisinin combination therapies for treatment of uncomplicated malaria in uganda
PLOS Clinical Trials, 2006Co-Authors: Hasifa Bukirwa, Moses R Kamya, Philip J Rosenthal, Nathan Bakyaita, Adoke Yeka, Kristin Banek, Ambrose O Talisuna, John B Rwakimari, Fred Wabwiremangen, Grant DorseyAbstract:OBJECTIVES: To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda. DESIGN: Randomized single-blind controlled trial. SETTING: Tororo, Uganda, an area of high-level malaria transmission. PARTICIPANTS: Children aged one to ten years with confirmed uncomplicated P. falciparum malaria. INTERVENTIONS: Amodiaquine + artesunate or artemether-lumefantrine. OUTCOME MEASURES: Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. RESULTS: Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with Amodiaquine + artesunate, and only two occurred in those treated with artemether-lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether-lumefantrine than for those treated with Amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%-24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether-lumefantrine versus 66% Amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%-25.2%). Amodiaquine + artesunate and artemether-lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens. CONCLUSIONS: Amodiaquine + artesunate and artemether-lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether-lumefantrine was superior to Amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.
Sue J. Lee - One of the best experts on this subject based on the ideXlab platform.
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the cardiovascular effects of Amodiaquine and structurally related antimalarials an individual patient data meta analysis
PLOS Medicine, 2021Co-Authors: Sue J. Lee, Xin Hui S Chan, Ilsa L Haeusler, Yan Naung Win, James Pike, Borimas Hanboonkunupakarn, Maryam Hanafiah, Abdoulaye DjimdeAbstract:BACKGROUND: Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of Amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of Amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. METHODS AND FINDINGS: Studies of Amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing Amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, Amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of Amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. CONCLUSIONS: While caution is advised in the use of Amodiaquine in patients aged ≥12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after Amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.
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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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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).
Xin Hui S Chan - One of the best experts on this subject based on the ideXlab platform.
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the cardiovascular effects of Amodiaquine and structurally related antimalarials an individual patient data meta analysis
PLOS Medicine, 2021Co-Authors: Sue J. Lee, Xin Hui S Chan, Ilsa L Haeusler, Yan Naung Win, James Pike, Borimas Hanboonkunupakarn, Maryam Hanafiah, Abdoulaye DjimdeAbstract:BACKGROUND: Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of Amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of Amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. METHODS AND FINDINGS: Studies of Amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing Amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (-1.2 ms, -3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, Amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of Amodiaquine on the heart rate of children aged <12 years compared with other antimalarials was not clinically significant. Study limitations include the unavailability of individual patient-level adverse event data for most included participants, but no serious complications were documented. CONCLUSIONS: While caution is advised in the use of Amodiaquine in patients aged ≥12 years with concomitant use of heart rate-reducing medications, serious cardiac conduction disorders, or risk factors for torsade de pointes, there have been no serious cardiovascular events reported after Amodiaquine in widespread use over 7 decades. Amodiaquine and structurally related antimalarials in the World Health Organization (WHO)-recommended dose regimens alone or in ACTs are safe for the treatment and prevention of malaria.