Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrimethamine-sulfadoxine (PS) is used as a second-line treatment for P. falciparum malaria patients who fail to respond to chloroquine. Resistance to these drugs has been shown to encode with point mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) genes. Our aim was to assess the comparative rate of point mutation occurring in DHFR and DHPS genes among P. falciparum isolates from India and Thailand where the use of PS is at a different rate. We used the mutation-specific polymerase chain reaction (PCR) technique and mutation-specific restriction digestion to determine the prevalence of DHFR and DHPS gene mutations at codons 16, 51, 59, 108, 164 and at 436, 437, 581 and 613, respectively. In the 89 clinical isolates from India, in the case of the DHFR gene, we found 71 of S108N, 10 of N51I, 28 of C59R and four of I164L types. Among the 50 isolates from Thailand the rate of point mutations in the DHFR gene was higher at four codon positions. We found 47 of S108N, 18 of N51I, 23 of C59R and 12 of I164L types. None of the isolates from either country possessed the paired mutations S108T and A16V. Mutations of the DHPS gene were less frequent among the Indian isolates: 4.5% showed DHPS gene mutation, two of S436F, A437G, A613T and two of S436F, A613T; whereas 66% (33/50) of the Thai isolates had mutated at codons 436, 437, 581 and 613 which include 13 of S436F, 15 of A437G, 19 of A581G and 25 of A613S/T, ranging from single to quadruple mutant types. Among the Indian isolates, DHFR point mutations were very frequent and 85/89 had a wild type DHPS genetic profile. The pattern of mutations in the samples from Thailand was different, as most were associated with point mutations in DHFR and DHPS genes.
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PMID:Prevalence of point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes of Plasmodium falciparum isolates from India and Thailand: a molecular epidemiologic study. 1104 69

Chloroquine has been the mainstay of malaria chemotherapy for the past five decades, but resistance is now widespread. Pyrimethamine or proguanil form an important component of some alternate drug combinations being used for treatment of uncomplicated Plasmodium falciparum infections in areas of chloroquine resistance. Both pyrimethamine and proguanil are dihydrofolate reductase (DHFR) inhibitors, the proguanil acting primarily through its major metabolite cycloguanil. Resistance to these drugs arises due to specific point mutations in the dhfr gene. Cross resistance between cycloguanil and pyrimethamine is not absolute. It is, therefore, important to investigate mutation rates in P. falciparum for pyrimethamine and proguanil so that DHFR inhibitor with less mutation rate is favored in drug combinations. Hence, we have compared mutation rates in P. falciparum genome for pyrimethamine and cycloguanil. Using erythrocytic stages of P. falciparum cultures, progressively drug resistant lines were selected in vitro and comparing their RFLP profile with a repeat sequence. Our finding suggests that pyrimethamine has higher mutation rate compared to cycloguanil. It enhances the degree of genomic polymorphism leading to diversity of natural parasite population which in turn is predisposes the parasites for faster selection of resistance to some other antimalarial drugs.
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PMID:Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone. 1131 56

Drug resistance in Plasmodium falciparum affects prevention of malaria in pregnancy. In a cross-sectional study of 530 pregnant Ghanaian women, P. falciparum dihydrofolate reductase (DHFR) gene mutations linked with pyrimethamine resistance were assessed and associations with pyrimethamine intake were analyzed. P. falciparum infected 69% of women without pyrimethamine use, 59% of those who had a history of pyrimethamine consumption but a negative urine test, and 53% of individuals with a positive urine test. Eighty-one percent, 43%, and 74% of the isolates contained the mutations Asn-108, Ile-51, and Arg-59, respectively. Thr-108 occurred in 8%. Pyrimethamine use was associated with increased frequencies of Asn-108 and Arg-59 but not of Ile-51 or Thr-108. In women with prophylaxis, wild-type parasites were absent and anemia tended to be more common with an increasing number of DHFR gene mutations. Pyrimethamine appears to be not adequately effective in this part of Ghana, most likely due to the predominance of resistant parasites. Selection for resistance following insufficient prophylaxis could possibly affect the efficacy of future intermittent sulfadoxine-pyrimethamine treatment.
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PMID:Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women. 1150 2

We have studied resistance to sulfadoxine-pyrimethamine (S/P) in the rodent malaria parasite Plasmodium chabaudi. A stable S/P-resistant mutant, AS(50S/P), was selected by drug treatment of a clone, AS(PYR), already resistant to pyrimethamine. The sequences of the P. chabaudi dhfr and dhps genes were obtained and found to be identical in AS(50S/P) and AS(PYR), showing that resistance to S/P in AS(50S/P) was not due to additional mutations in either gene. AS(50S/P) was crossed with a drug-sensitive clone, AJ, and 16 independent recombinant progeny were obtained. These clones were phenotyped for their susceptibility to S/P and to sulfadoxine and pyrimethamine separately. Pyrimethamine resistance was invariably associated with S/P resistance, but no correlation was found between resistance to S/P and resistance to sulfadoxine. Quantitative trait locus analysis of the progeny with 31 chromosome-specific markers showed that mutant P. chabaudi dhfr, or one or more genes closely linked to it, was a major determinant of S/P resistance. In addition, the inheritance of genes on chromosomes 5 and 13 from the sensitive parent appeared to contribute to the level of resistance observed. These results demonstrate that the S/P resistance of the AS(50S/P) mutant of P. chabaudi does not involve mutation in dhps and is not due simply to a combination of two genes determining resistance to pyrimethamine and sulfadoxine separately.
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PMID:Sulfadoxine-pyrimethamine resistance in the rodent malaria parasite Plasmodium chabaudi. 1212 22

Pyrimethamine is used for the treatment of toxoplasmosis and the prophylaxis of malaria. Among the well-documented side effects are megaloblastic anemia, leukopenia, thrombopenia, rash, vomiting, and diarrhea. Hyperpigmentation is a very rare side effect. In some patients, associated HIV infection makes it difficult to distinguish the reasons for the etiology. We herein describe an HIV-negative patient who developed hyperpigmentation after pyrimethamine use.
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PMID:Hyperpigmentation due to pyrimethamine use. 1218 45

Plasmodium vivax is a major public health problem in Asia and South and Central America where it is most prevalent. Until very recently, the parasite has been effectively treated with chloroquine, but resistance to this drug has now been reported in several areas. Affordable alternative treatments for vivax malaria are urgently needed. Pyrimethamine-sulfadoxine is an inhibitor of dihydrofolate reductase (DHFR) that has been widely used to treat chloroquine-resistant Plasmodium falciparum malaria. DHFR inhibitors have not been considered for treatment of vivax malaria, because initial trials showed poor efficacy against P. vivax. P. vivax cannot be grown in culture; the reason for its resistance to DHFR inhibitors is unknown. We show that, like P. falciparum, point mutations in the dhfr gene can cause resistance to pyrimethamine in P. vivax. WR99210 is a novel inhibitor of DHFR, effective even against the most pyrimethamine-resistant P. falciparum strains. We have found that it is also an extremely effective inhibitor of the P. vivax DHFR, and mutations that confer high-level resistance to pyrimethamine render the P. vivax enzyme exquisitely sensitive to WR99210. These data suggest that pyrimethamine and WR99210 would exert opposing selective forces on the P. vivax population. If used in combination, these two drugs could greatly slow the selection of parasites resistant to both drugs. If that is the case, this novel class of DHFR inhibitors could provide effective and affordable treatment for chloroquine- and pyrimethamine-resistant vivax and falciparum malaria for many years to come.
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PMID:Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax. 1237 49

In this study, the anticlastogenic effects of ascorbic acid and the protective effect of folinic acid against the formation of chromosomal aberrations in humans by pyrimethamine were investigated. Pyrimethamine is a folic acid antagonist used for the treatment of malaria and toxoplasmosis. In this study, 18 different healthy people, who do not drink alcohol and are non-smokers, were chosen as an experimental group; 0.025 mg/ml pyrimethamine was given to the lymphocyte culture, which had been prepared with the peripheral blood taken from this group. After that each of the following doses were given to the same culture: 20, 40, and 80 mM of ascorbic acid and 25, 50, and 100 mM of folinic acid. The results of the cytogenetic evaluation showed that the aberrations due to pyrimethamine in the chromosomes were reduced by ascorbic acid and folinic acid significantly, depending on the given dose.
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PMID:Inhibitory effects of ascorbic acid and folinic acid on chromosome aberrations induced by pyrimethamine in vitro. 1221 Apr 98

Malaria parasites (Plasmodium falciparum) provide an excellent system in which to study the genomic effects of strong selection in a recombining eukaryote because the rapid spread of resistance to multiple drugs during the last the past 50 years has been well documented, the full genome sequence and a microsatellite map are now available, and haplotype data can be easily generated. We examined microsatellite variation around the dihydrofolate reductase (dhfr) gene on chromosome 4 of P. falciparum. Point mutations in dhfr are known to be responsible for resistance to the antimalarial drug pyrimethamine, and resistance to this drug has spread rapidly in Southeast (SE) Asia after its introduction in 1970s. We genotyped 33 microsatellite markers distributed across chromosome 4 in 61 parasites from a location on the Thailand/Myanmar border. We observed minimal microsatellite length variation in a 12-kb (0.7-cM) region flanking the dhfr gene and diminished variation for approximately 100 kb (6 cM), indicative of a single origin of resistant alleles. Furthermore, we found the same or similar microsatellite haplotypes flanked resistant dhfr alleles sampled from 11 parasite populations in five SE Asian countries indicating recent invasion of a single lineage of resistant dhfr alleles in locations 2000 km apart. Three features of these data are of especially interest. (1). Pyrimethamine resistance is generally assumed to have evolved multiple times because the genetic basis is simple and resistance can be selected easily in the laboratory. Yet our data clearly indicate a single origin of resistant dhfr alleles sampled over a large region of SE Asia. (2). The wide valley ( approximately 6 cM) of reduced variation around dhfr provides "proof-of-principle" that genome-wide association may be an effective way to locate genes under strong recent selection. (3). The width of the selective valley is consistent with predictions based on independent measures of recombination, mutation, and selection intensity, suggesting that we have reasonable estimates of these parameters. We conclude that scanning the malaria parasite genome for evidence of recent selection may prove an extremely effective way to locate genes underlying recently evolved traits such as drug resistance, as well as providing an opportunity to study the dynamics of selective events that have occurred recently or are currently in progress.
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PMID:A selective sweep driven by pyrimethamine treatment in southeast asian malaria parasites. 1283 43

Studies have been conducted in Liberia on the effect of pyrimethamine on the sporogony and, for the first time, on the pre-erythrocytic schizogony of Laverania falciparum. From the results reported here it is concluded that it may reasonably be assumed that a mass monthly regimen of pyrimethamine in Liberia could afford protection to the individual and to the mosquito and thus to the population at large, provided that resistance to pyrimethamine does not intervene.Pyrimethamine in single doses of 25 mg or 50 mg administered to gametocyte carriers was able to render gametocytes of L. falciparum uninfective to A. gambiae for periods up to 28 days after administration.Mosquitos feeding upon a malaria-free pyrimethamine-treated subject before or after feeding upon a non-treated gametocyte carrier became infected and sporozoites appeared in the salivary glands.Pyrimethamine administered in 12.5-mg doses 13 days before, 6 days before and 2 days after sporozoite infection or administered in 25-mg doses 35 days and 7 days before sporozoite infection disallowed the development of the pre-erythrocytic schizonts of L. falciparum in the livers of two chimpanzees.
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PMID:Effect of pyrimethamine upon sporogony and pre-erythrocytic schizogony of Laverania falciparum. 1380 56

Pyrimethamine resistance in the malaria parasite Plasmodium falciparum is characterized by specific point mutations in the dihydrofolate reductase (DHFR) domain of the bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene. We have previously explored the effect of these mutations by engineering homologous alleles of Toxoplasma gondii DHFR-TS, which can readily be expressed as recombinant protein for enzymatic studies, or as allelic replacements in transgenic parasites. In order to directly assess the costs of pyrimethamine-resistance in vivo, we have carried out competition studies between mixtures of T. gondii tachyzoites harbouring wild-type or mutant DHFR-TS alleles, both in tissue culture and in mice. Arg59+Asn108 mutants (using the P. falciparum numbering system) exhibit no significant fitness defects in vitro, but a fitness defect of 1.8% per generation in mice. Arg59+Ser223 mutants exhibit fitness defects of >2.8% per generation both in vitro and in vivo, which may explain why this highly pyrimethamine-resistant allele has not been observed in the field. It is important to note that long-term propagation of parasites in vitro or in vivo can produce adaptations affecting fitness by >3.7% per generation, necessitating careful attention to background in head-to-head competition studies. A sensitive PCR-based assay permits different growth rates to be assessed even in the absence of a drug resistance marker that can be scored by plaque assay.
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PMID:Fitness effects of DHFR-TS mutations associated with pyrimethamine resistance in apicomplexan parasites. 1462 18


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