Treatment of vivax malaria with sulfadoxine-pyrimethamine and with pyrimethamine alone

Doberstyn, E. B.; Teerakiartkamjorn, C.; Andre, Richard G.; Phintuyothin, P; Noeypatimanondh, S.

doi:10.1016/0035-9203(79)90121-4

Cited by 33 publications

(18 citation statements)

References 4 publications

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“…vivax parasites seemed intrinsically resistant to SP. 9,10 However, there is evidence indicating that SP resistance in P. vivax also results from drug selection pressure. Because mixed species infections with P. falciparum and P. vivax are common in many malarious regions, 11 extensive use of SP to treat patients with P. falciparum malaria may have inadvertently exposed P. vivax to these drugs.…”

Section: Introductionmentioning

confidence: 99%

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

Miao

Zhou

Cui

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Abstract. Antifolate resistance in Plasmodium vivax is caused by point mutations in genes encoding dihydrofolate reductase ( pvdhfr ) and dihydropteroate synthase ( pvdhps ). In this study, we used direct sequencing to survey pvdhfr and pvdhps mutations in 122 clinical P. vivax isolates from a central and a southern province of China. For pvdhfr , 36.9% were wild-type, whereas mutations were detected at four codons (57, 58, 61, and 117). The S117N/T mutation was the most prevalent (48.4%), followed by the T61M mutation (18.9%). Six pvdhfr mutant alleles were found, ranging from 37.7% to 0.8%. The dramatically different pvdhfr allele frequencies between the two P. vivax populations might be caused by different drug histories or intrinsic difference between temperate and subtropical strains. In contrast, except polymorphisms within a repeat region, no resistance-conferring mutations were detected in pvdhps . Our result suggests that P. vivax populations in China may be relatively susceptible to sulfadoxine-pyrimethamine.

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Section: Introductionmentioning

confidence: 99%

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

Miao

Zhou

Cui

et al. 2010

The American Society of Tropical Medicine and Hygiene

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“…Fansidar, a fixed combination of sulfadoxine and pyrimethamine (S/P), is most often the alternative chosen when chloroquine-resistant P. falciparum parasites render chloroquine ineffective (4). However, S/P has not been recommended for primary therapy of vivax malaria due to the poor clinical efficacy reported when the drug was introduced in the 1950s (13,14,26,49,64,68).In both P. falciparum and P. vivax, the dihydrofolate reductase (DHFR, E.C. 1.5.1.3) enzyme is the therapeutic target of the pyrimethamine component of S/P (12,18,23,26,27,43,44,60).…”

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Novel Plasmodium vivax dhfr Alleles from the Indonesian Archipelago and Papua New Guinea: Association with Pyrimethamine Resistance Determined by a Saccharomyces cerevisiae Expression System

Hastings

Maguire

Bangs

et al. 2005

Antimicrob Agents Chemother

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In plasmodia, the dihydrofolate reductase (DHFR) enzyme is the target of the pyrimethamine component of sulfadoxine-pyrimethamine (S/P). Plasmodium vivax infections are not treated intentionally with antifolates. However, outside Africa, coinfections with Plasmodium falciparum and P. vivax are common, and P. vivax infections are often exposed to S/P. Cloning of the P. vivax dhfr gene has allowed molecular comparisons of dhfr alleles from different regions. Examination of the dhfr locus from a few locations has identified a very diverse set of alleles and showed that mutant alleles of the vivax dhfr gene are prevalent in Southeast Asia where S/P has been used extensively. We have surveyed patient isolates from six locations in Indonesia and two locations in Papua New Guinea. We sequenced P. vivax dhfr alleles from 114 patient samples and identified 24 different alleles that differed from the wild type by synonymous and nonsynonymous point mutations, insertions, or deletions. Most importantly, five alleles that carried four or more nonsynonymous mutations were identified. Only one of these highly mutant alleles had been previously observed, and all carried the 57L and 117T mutations. P. vivax cannot be cultured continuously, so we used a yeast assay system to determine in vitro sensitivity to pyrimethamine for a subset of the alleles. Alleles with four nonsynonymous mutations conferred very high levels of resistance to pyrimethamine. This study expands significantly the total number of novel dhfr alleles now identified from P. vivax and provides a foundation for understanding how antifolate resistance arises and spreads in natural P. vivax populations.Plasmodium vivax causes a severe and debilitating febrile illness. This mosquito-borne parasite infects an estimated 80 million people each year and is a prevalent cause of malaria outside sub-Saharan Africa (39). Unfortunately, P. vivax cannot be maintained in continuous culture, so despite its prevalence, the study of vivax has lagged markedly behind that of Plasmodium falciparum. This difference is particularly true with respect to the genetics and epidemiology of drug resistance in P. vivax. Chloroquine has been the first-line antimalarial treatment in most areas of endemicity, but resistance to this drug has virtually eliminated its usefulness against P. falciparum (61, 63, 65) and chloroquine resistance has now been observed with P. vivax as well (1,21,34,45,52,55,58,59). Fansidar, a fixed combination of sulfadoxine and pyrimethamine (S/P), is most often the alternative chosen when chloroquine-resistant P. falciparum parasites render chloroquine ineffective (4). However, S/P has not been recommended for primary therapy of vivax malaria due to the poor clinical efficacy reported when the drug was introduced in the 1950s (13,14,26,49,64,68).In both P. falciparum and P. vivax, the dihydrofolate reductase (DHFR, E.C. 1.5.1.3) enzyme is the therapeutic target of the pyrimethamine component of S/P (12,18,23,26,27,43,44,60). A combination of in vitro analysis of cultu...

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“…Since the two species cannot be differentiated on clinical grounds, malaria infections, whether due to P. falciparum or P. vivax, are treated with S-P. Unfortunately, S-P is less effective in clearing fever and parasites in patients infected with P. vivax than in those infected with P. falciparum (9,11). Earlier studies had already shown that sulfa drugs are less active against P. vivax than against P. falciparum (16,18,20).…”

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Sulfadoxine Resistance in Plasmodium vivax Is Associated with a Specific Amino Acid in Dihydropteroate Synthase at the Putative Sulfadoxine-Binding Site

Korsinczky

Fischer

Chen³

et al. 2004

Antimicrob Agents Chemother

106

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Sulfadoxine is predominantly used in combination with pyrimethamine, commonly known as Fansidar, for the treatment of Plasmodium falciparum. This combination is usually less effective against Plasmodium vivax, probably due to the innate refractoriness of parasites to the sulfadoxine component. To investigate this mechanism of resistance by P. vivax to sulfadoxine, we cloned and sequenced the P. vivax dhps (pvdhps) gene. The protein sequence was determined, and three-dimensional homology models of dihydropteroate synthase (DHPS) from P. vivax as well as P. falciparum were created. The docking of sulfadoxine to the two DHPS models allowed us to compare contact residues in the putative sulfadoxine-binding site in both species. The predicted sulfadoxine-binding sites between the species differ by one residue, V585 in P. vivax, equivalent to A613 in P. falciparum. V585 in P. vivax is predicted by energy minimization to cause a reduction in binding of sulfadoxine to DHPS in P. vivax compared to P. falciparum. Sequencing dhps genes from a limited set of geographically different P. vivax isolates revealed that V585 was present in all of the samples, suggesting that V585 may be responsible for innate resistance of P. vivax to sulfadoxine. Additionally, amino acid mutations were observed in some P. vivax isolates in positions known to cause resistance in P. falciparum, suggesting that, as in P. falciparum, these mutations are responsible for acquired increases in resistance of P. vivax to sulfadoxine.

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Treatment of vivax malaria with sulfadoxine-pyrimethamine and with pyrimethamine alone

Cited by 33 publications

References 4 publications

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

Different Allele Prevalence in the Dihydrofolate Reductase and Dihydropteroate Synthase Genes in Plasmodium vivax Populations from China

Novel Plasmodium vivax dhfr Alleles from the Indonesian Archipelago and Papua New Guinea: Association with Pyrimethamine Resistance Determined by a Saccharomyces cerevisiae Expression System

Sulfadoxine Resistance in Plasmodium vivax Is Associated with a Specific Amino Acid in Dihydropteroate Synthase at the Putative Sulfadoxine-Binding Site

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