The American journal of tropical medicine and hygiene, 2000
Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination ... more Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination of pyrimethamine/sulfadoxine (PM/SD), as treatment for non-severe falciparum malaria in children at Kilifi, Kenya in 1987-1988 and 1993-1995 have presented an opportunity to assess in vitro the susceptibility trend of Plasmodium falciparum to PM and SD over time on the Kenya coast. The first set of isolates was collected prior to the introduction of PM/SD into the Kenya Medical Research Institute/Wellcome Trust Research unit while the second set was taken soon after PM/SD was introduced in the study area as the first-line treatment drug for uncomplicated falciparum malaria. In the first trial, 69 isolates collected before and after treatment of malaria with PM/SD were tested directly in the field for susceptibility to PM and SD using the standard in vitro micro-test technique, with minimal levels of folate. In the second trial, 97 isolates similarly collected were adapted to culture, and...
Sulfa drugs are well known blockers of folate synthesis, acting as competitive inhibitors of p-am... more Sulfa drugs are well known blockers of folate synthesis, acting as competitive inhibitors of p-aminobenzoate (pABA). Their mimicry of pABA is so complete that they can also condense with 2-amino-4-hydroxy-6-hydroxymethyl-7, 8 dihydropteridine pyrophosphate to form ...
... Giancarlo A. Biagini 1 , Paul M. O'Neill 2 , 3 , Alexis Nzila 3 , 4 , Stephen A. War... more ... Giancarlo A. Biagini 1 , Paul M. O'Neill 2 , 3 , Alexis Nzila 3 , 4 , Stephen A. Ward 1 , Patrick G.Bray 1 , E-mail The ... In terms of antimalarial efficacy and ease of synthesis, the C-14 modified analogues (Figure S2c) prepared by Avery and Jung's groups are attractive alternatives to ...
The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of ma... more The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.
The American journal of tropical medicine and hygiene
Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination ... more Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination of pyrimethamine/sulfadoxine (PM/SD), as treatment for non-severe falciparum malaria in children at Kilifi, Kenya in 1987-1988 and 1993-1995 have presented an opportunity to assess in vitro the susceptibility trend of Plasmodium falciparum to PM and SD over time on the Kenya coast. The first set of isolates was collected prior to the introduction of PM/SD into the Kenya Medical Research Institute/Wellcome Trust Research unit while the second set was taken soon after PM/SD was introduced in the study area as the first-line treatment drug for uncomplicated falciparum malaria. In the first trial, 69 isolates collected before and after treatment of malaria with PM/SD were tested directly in the field for susceptibility to PM and SD using the standard in vitro micro-test technique, with minimal levels of folate. In the second trial, 97 isolates similarly collected were adapted to culture, and...
Resistance to the antifolate sulfadoxine-pyrimethamine (SP), the current mass-treatment antimalar... more Resistance to the antifolate sulfadoxine-pyrimethamine (SP), the current mass-treatment antimalarial drug, is associated with selection of point mutations in dihydrofolate reductase and dihydropteroate synthase. Among these mutations, the leucine 164 dihydrofolate reductase mutation (Leu-164) is associated with higher levels of SP resistance; this mutation is also associated with a decrease in the efficacy of chlorproguanil/dapsone, a newly developed antifolate antimalarial drug. Leu-164 has been detected in Southeast Asia and South America, regions where SP is no longer effective. Surprisingly, this mutation has not yet been detected in Africa, using the standard protocol based on PCR-RFLP, despite high SP resistance. In this paper, we discuss briefly the reasons why Leu-164 has not yet been selected in Africa and we propose a means that may slow down the selection of this mutation.
Plasmodium falciparum parasites resistant to the combination sulfadoxine–pyrimethamine are spread... more Plasmodium falciparum parasites resistant to the combination sulfadoxine–pyrimethamine are spreading in Africa, particularly in East Africa. This is a matter of concern because there are no other affordable drugs available. This article provides the evidence indicating that sulfadoxine–pyrimethamine resistance can be reversed in vitro and discusses how this information might be exploited to extend the therapeutic lifetime of sulfadoxine–pyrimethamine in
At present, artemether/lumefantrine (AL) is the only fixed-dose artemisinin-based combination the... more At present, artemether/lumefantrine (AL) is the only fixed-dose artemisinin-based combination therapy recommended and pre-qualified by WHO for the treatment of uncomplicated malaria caused by Plasmodium falciparum. It has been shown to be effective both in sub-Saharan Africa and in areas with multi-drug resistant P. falciparum in southeast Asia. It is currently recommended as first-line treatment for uncomplicated malaria in several countries. However, AL has a complex treatment regimen and the issues of adherence to treatment with AL by adult patients and real-life effectiveness in resource-poor settings will be critical in determining its useful therapeutic life, especially in Africa, where the major burden of malaria is felt. There are also issues of safety of the artemisinin derivatives, including AL, which will need to be monitored as their use in resource-poor settings becomes more widespread. There are limited pharmacokinetic studies of AL in African patients, and the relationship between plasma drug concentration and efficacy in these patients is unknown. Moreover, the effects of factors such as concurrently administered drugs, malnutrition and co-infections with HIV and helminths in malaria patients are not well understood. These will need to be addressed, although a few studies on possible drug-drug interactions with commonly used drugs, such as quinine, mefloquine and ketoconazole, have been reported. This review focuses on the status of clinical pharmacology, efficacy and real-life effectiveness of AL under a variety of settings, and highlights some of the challenges that face policy makers during the deployment of AL, especially in Africa, with regards to ensuring that those who most need this therapy will not be denied access due to official inefficiency in procurement and distribution processes.
Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plas... more Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum and continues to produce ever-changing landscapes of genetic variation. We performed whole-genome sequencing of 69 P. falciparum isolates from Malawi and used population genetics approaches to investigate genetic diversity and population structure and identify loci under selection. High genetic diversity (Ï€ = 2.4 Ă— 10(-4)), moderately high multiplicity of infection (2.7), and low linkage disequilibrium (500-bp) were observed in Chikhwawa District, Malawi, an area of high malaria transmission. Allele frequency-based tests provided evidence of recent population growth in Malawi and detected potential targets of host immunity and candidate vaccine antigens. Comparison of the sequence variation between isolates from Malawi and those from 5 geographically dispersed countries (Kenya, Burkina Faso, Mali, Cambodia, and Thailand) detected population genetic differences between A...
The mechanisms of drug resistance development in thePlasmodium falciparumparasite to lumefantrine... more The mechanisms of drug resistance development in thePlasmodium falciparumparasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear. We assessed the polymorphisms ofPfmspdbl2for associations with LUM activity in a Kenyan population. MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (P= 0.04). The high frequency ofPfmspdbl2codon 591S in Kenya may be driven by the widespread use of lumefantrine in artemisinin combination therapy (Coartem).
Several strategies to discover new antimalarials have been proposed to augment and complement the... more Several strategies to discover new antimalarials have been proposed to augment and complement the conventional drug-discovery paradigm. One approach, which has not yet been fully exploited, is the use of drug biotransformation to identify new active molecules. This concept rests on the use of the biotransformation of drugs to their pharmacologically active metabolites. This approach has been used successfully in human chemotherapy, with the discovery and development of several metabolite-based drugs. This review looks at the contribution that biotransformations can play in antimalarial drug discovery.
The American journal of tropical medicine and hygiene, 2014
Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artem... more Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 cop...
Drug resistance remains a chief concern for malaria control. In order to determine the genetic ma... more Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.
Sulphadoxine/pyrimethamine (SP) is often administered with quinine in the treatment of severe fal... more Sulphadoxine/pyrimethamine (SP) is often administered with quinine in the treatment of severe falciparum malaria to shorten the course of quinine. The efficacy of SP alone in the treatment of non-severe malaria has been declining rapidly in East Africa, raising concerns of the usefulness of a shortened course of quinine followed SP. We audited the efficacy of quinine/SP in the treatment of severe malaria in Kenyan children. Children with severe falciparum malaria were treated with parenteral quinine followed by a single oral dose of SP. A clinical evaluation was performed 3 weeks later in which a blood sample was obtained for full haemogram, blood slide and analysis of the parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) codons, mutations of which are associated with resistance to SP. A total of 452 children were enrolled, of whom 374 completed the study. Fifty-two (13.9%) children were parasitaemic by 3 weeks of whom 17 (4.5%) had fever as well. The treatment failure group had a significantly higher parasitaemia (129 061 vs. 43 339; P&amp;amp;amp;amp;amp;amp;lt;0.001) and haemoglobin on admission, but only admission parasitaemia independently predicted treatment failure. Those with treatment failure had a significantly lower rise in haemoglobin at 3 weeks compared with treatment successes (9.0 vs. 10.0 g/dl). Of the 76 parasite isolates collected before treatment, 40 (53%) were triple mutant DHFR-double DHPS (Tp-Db), the genotype most associated with SP resistance. Three weeks after SP treatment, the proportion of Tp-Db increased to 72% (31/43). The high treatment failure rate and proportion of parasites with Tp-Db negate the use of SP to shorten the course of quinine treatment in East Africa.
The folate pathway represents a powerful target for combating rapidly dividing systems such as ca... more The folate pathway represents a powerful target for combating rapidly dividing systems such as cancer cells, bacteria and malaria parasites. Whereas folate metabolism in mammalian cells and bacteria has been studied extensively, it is understood less well in malaria parasites. In two articles, we attempt to reconstitute the malaria folate pathway based on available information from mammalian and microbial systems, in addition to Plasmodium-genome-sequencing projects. In part I, we focused on folate enzymes that are already used clinically as anticancer drug targets or that are under development in drug-discovery programs. In this article, we discuss mammalian folate enzymes that have not yet been exploited as potential drug targets, and enzymes that function in the de novo folate-synthesis pathway of the parasite--a particularly attractive area of attack because of its absence from the mammalian host.
The American journal of tropical medicine and hygiene, 2000
Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination ... more Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination of pyrimethamine/sulfadoxine (PM/SD), as treatment for non-severe falciparum malaria in children at Kilifi, Kenya in 1987-1988 and 1993-1995 have presented an opportunity to assess in vitro the susceptibility trend of Plasmodium falciparum to PM and SD over time on the Kenya coast. The first set of isolates was collected prior to the introduction of PM/SD into the Kenya Medical Research Institute/Wellcome Trust Research unit while the second set was taken soon after PM/SD was introduced in the study area as the first-line treatment drug for uncomplicated falciparum malaria. In the first trial, 69 isolates collected before and after treatment of malaria with PM/SD were tested directly in the field for susceptibility to PM and SD using the standard in vitro micro-test technique, with minimal levels of folate. In the second trial, 97 isolates similarly collected were adapted to culture, and...
Sulfa drugs are well known blockers of folate synthesis, acting as competitive inhibitors of p-am... more Sulfa drugs are well known blockers of folate synthesis, acting as competitive inhibitors of p-aminobenzoate (pABA). Their mimicry of pABA is so complete that they can also condense with 2-amino-4-hydroxy-6-hydroxymethyl-7, 8 dihydropteridine pyrophosphate to form ...
... Giancarlo A. Biagini 1 , Paul M. O&#x27;Neill 2 , 3 , Alexis Nzila 3 , 4 , Stephen A. War... more ... Giancarlo A. Biagini 1 , Paul M. O&#x27;Neill 2 , 3 , Alexis Nzila 3 , 4 , Stephen A. Ward 1 , Patrick G.Bray 1 , E-mail The ... In terms of antimalarial efficacy and ease of synthesis, the C-14 modified analogues (Figure S2c) prepared by Avery and Jung&#x27;s groups are attractive alternatives to ...
The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of ma... more The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.
The American journal of tropical medicine and hygiene
Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination ... more Two clinical trials that used Falcidin (Cosmos Ltd., Nairobi, Kenya), the antifolate combination of pyrimethamine/sulfadoxine (PM/SD), as treatment for non-severe falciparum malaria in children at Kilifi, Kenya in 1987-1988 and 1993-1995 have presented an opportunity to assess in vitro the susceptibility trend of Plasmodium falciparum to PM and SD over time on the Kenya coast. The first set of isolates was collected prior to the introduction of PM/SD into the Kenya Medical Research Institute/Wellcome Trust Research unit while the second set was taken soon after PM/SD was introduced in the study area as the first-line treatment drug for uncomplicated falciparum malaria. In the first trial, 69 isolates collected before and after treatment of malaria with PM/SD were tested directly in the field for susceptibility to PM and SD using the standard in vitro micro-test technique, with minimal levels of folate. In the second trial, 97 isolates similarly collected were adapted to culture, and...
Resistance to the antifolate sulfadoxine-pyrimethamine (SP), the current mass-treatment antimalar... more Resistance to the antifolate sulfadoxine-pyrimethamine (SP), the current mass-treatment antimalarial drug, is associated with selection of point mutations in dihydrofolate reductase and dihydropteroate synthase. Among these mutations, the leucine 164 dihydrofolate reductase mutation (Leu-164) is associated with higher levels of SP resistance; this mutation is also associated with a decrease in the efficacy of chlorproguanil/dapsone, a newly developed antifolate antimalarial drug. Leu-164 has been detected in Southeast Asia and South America, regions where SP is no longer effective. Surprisingly, this mutation has not yet been detected in Africa, using the standard protocol based on PCR-RFLP, despite high SP resistance. In this paper, we discuss briefly the reasons why Leu-164 has not yet been selected in Africa and we propose a means that may slow down the selection of this mutation.
Plasmodium falciparum parasites resistant to the combination sulfadoxine–pyrimethamine are spread... more Plasmodium falciparum parasites resistant to the combination sulfadoxine–pyrimethamine are spreading in Africa, particularly in East Africa. This is a matter of concern because there are no other affordable drugs available. This article provides the evidence indicating that sulfadoxine–pyrimethamine resistance can be reversed in vitro and discusses how this information might be exploited to extend the therapeutic lifetime of sulfadoxine–pyrimethamine in
At present, artemether/lumefantrine (AL) is the only fixed-dose artemisinin-based combination the... more At present, artemether/lumefantrine (AL) is the only fixed-dose artemisinin-based combination therapy recommended and pre-qualified by WHO for the treatment of uncomplicated malaria caused by Plasmodium falciparum. It has been shown to be effective both in sub-Saharan Africa and in areas with multi-drug resistant P. falciparum in southeast Asia. It is currently recommended as first-line treatment for uncomplicated malaria in several countries. However, AL has a complex treatment regimen and the issues of adherence to treatment with AL by adult patients and real-life effectiveness in resource-poor settings will be critical in determining its useful therapeutic life, especially in Africa, where the major burden of malaria is felt. There are also issues of safety of the artemisinin derivatives, including AL, which will need to be monitored as their use in resource-poor settings becomes more widespread. There are limited pharmacokinetic studies of AL in African patients, and the relationship between plasma drug concentration and efficacy in these patients is unknown. Moreover, the effects of factors such as concurrently administered drugs, malnutrition and co-infections with HIV and helminths in malaria patients are not well understood. These will need to be addressed, although a few studies on possible drug-drug interactions with commonly used drugs, such as quinine, mefloquine and ketoconazole, have been reported. This review focuses on the status of clinical pharmacology, efficacy and real-life effectiveness of AL under a variety of settings, and highlights some of the challenges that face policy makers during the deployment of AL, especially in Africa, with regards to ensuring that those who most need this therapy will not be denied access due to official inefficiency in procurement and distribution processes.
Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plas... more Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum and continues to produce ever-changing landscapes of genetic variation. We performed whole-genome sequencing of 69 P. falciparum isolates from Malawi and used population genetics approaches to investigate genetic diversity and population structure and identify loci under selection. High genetic diversity (Ï€ = 2.4 Ă— 10(-4)), moderately high multiplicity of infection (2.7), and low linkage disequilibrium (500-bp) were observed in Chikhwawa District, Malawi, an area of high malaria transmission. Allele frequency-based tests provided evidence of recent population growth in Malawi and detected potential targets of host immunity and candidate vaccine antigens. Comparison of the sequence variation between isolates from Malawi and those from 5 geographically dispersed countries (Kenya, Burkina Faso, Mali, Cambodia, and Thailand) detected population genetic differences between A...
The mechanisms of drug resistance development in thePlasmodium falciparumparasite to lumefantrine... more The mechanisms of drug resistance development in thePlasmodium falciparumparasite to lumefantrine (LUM), commonly used in combination with artemisinin, are still unclear. We assessed the polymorphisms ofPfmspdbl2for associations with LUM activity in a Kenyan population. MSPDBL2 codon 591S was associated with reduced susceptibility to LUM (P= 0.04). The high frequency ofPfmspdbl2codon 591S in Kenya may be driven by the widespread use of lumefantrine in artemisinin combination therapy (Coartem).
Several strategies to discover new antimalarials have been proposed to augment and complement the... more Several strategies to discover new antimalarials have been proposed to augment and complement the conventional drug-discovery paradigm. One approach, which has not yet been fully exploited, is the use of drug biotransformation to identify new active molecules. This concept rests on the use of the biotransformation of drugs to their pharmacologically active metabolites. This approach has been used successfully in human chemotherapy, with the discovery and development of several metabolite-based drugs. This review looks at the contribution that biotransformations can play in antimalarial drug discovery.
The American journal of tropical medicine and hygiene, 2014
Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artem... more Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 cop...
Drug resistance remains a chief concern for malaria control. In order to determine the genetic ma... more Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.
Sulphadoxine/pyrimethamine (SP) is often administered with quinine in the treatment of severe fal... more Sulphadoxine/pyrimethamine (SP) is often administered with quinine in the treatment of severe falciparum malaria to shorten the course of quinine. The efficacy of SP alone in the treatment of non-severe malaria has been declining rapidly in East Africa, raising concerns of the usefulness of a shortened course of quinine followed SP. We audited the efficacy of quinine/SP in the treatment of severe malaria in Kenyan children. Children with severe falciparum malaria were treated with parenteral quinine followed by a single oral dose of SP. A clinical evaluation was performed 3 weeks later in which a blood sample was obtained for full haemogram, blood slide and analysis of the parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) codons, mutations of which are associated with resistance to SP. A total of 452 children were enrolled, of whom 374 completed the study. Fifty-two (13.9%) children were parasitaemic by 3 weeks of whom 17 (4.5%) had fever as well. The treatment failure group had a significantly higher parasitaemia (129 061 vs. 43 339; P&amp;amp;amp;amp;amp;amp;lt;0.001) and haemoglobin on admission, but only admission parasitaemia independently predicted treatment failure. Those with treatment failure had a significantly lower rise in haemoglobin at 3 weeks compared with treatment successes (9.0 vs. 10.0 g/dl). Of the 76 parasite isolates collected before treatment, 40 (53%) were triple mutant DHFR-double DHPS (Tp-Db), the genotype most associated with SP resistance. Three weeks after SP treatment, the proportion of Tp-Db increased to 72% (31/43). The high treatment failure rate and proportion of parasites with Tp-Db negate the use of SP to shorten the course of quinine treatment in East Africa.
The folate pathway represents a powerful target for combating rapidly dividing systems such as ca... more The folate pathway represents a powerful target for combating rapidly dividing systems such as cancer cells, bacteria and malaria parasites. Whereas folate metabolism in mammalian cells and bacteria has been studied extensively, it is understood less well in malaria parasites. In two articles, we attempt to reconstitute the malaria folate pathway based on available information from mammalian and microbial systems, in addition to Plasmodium-genome-sequencing projects. In part I, we focused on folate enzymes that are already used clinically as anticancer drug targets or that are under development in drug-discovery programs. In this article, we discuss mammalian folate enzymes that have not yet been exploited as potential drug targets, and enzymes that function in the de novo folate-synthesis pathway of the parasite--a particularly attractive area of attack because of its absence from the mammalian host.
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Papers by Alexis Nzila