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 and cycloguanil are competitive inhibitors of the Plasmodium enzyme dihydrofolate reductase (DHFR). They have been effective treatments for malaria, but rapid selection of populations of the parasite resistant to these drugs has compromised their effectiveness. Parasites resistant to either drug usually have point mutations in the dhfr gene, but the frequency of these mutations is unknown. To study drug resistance more effectively, we transferred the DHFR domain of the dhfr-thymidylate synthase gene from a drug-sensitive line of P. falciparum to a strain of the budding yeast, Saccharomyces cerevisiae, that lacks endogenous DHFR activity. Expression of the P. falciparum dhfr is controlled by the yeast dhfr 5' and 3' regulatory regions and the heterologous enzyme provided all of the functions of the yeast dhfr gene. These yeast were susceptible to pyrimethamine and cycloguanil at low concentrations that inhibit P. falciparum (IC50 about 10(-8) and 10(-7) M, respectively). Yeast expressing constructs with dhfr alleles from pyrimethamine-resistant strains were resistant to both pyrimethamine and cycloguanil (IC50 > 10(-6) M); resistance of the yeast depended on the dhfr allele they expressed. The experimental drug WR99210 efficiently killed all three yeast strains (IC50 about 10(-8) M) but the pyrR strains showed collateral hypersensitivity to drug. The yeast transformants carrying the drug-sensitive allele can now be screened quickly and quantitatively to identify new drugs or combinations of drugs and determine which drugs select resistant parasites least efficiently. Such compounds would be excellent candidates for development of treatments with a longer life in clinical practice.
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PMID:Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum. 910 46

The occurrence of an unexpected side effect following the use of Maloprim (pyrimethamine/dapsone) for malaria chemosuppression in 3-59 months old children in Sierra Leone is reported. As part of a trial of chemoprophylaxis and insecticide-impregnated bed nets, 2000 children received either Maloprim or placebo; 4% of children who received Maloprim fortnightly for more than 3 months developed hyperpigmented macules, whereas none of the children who received placebo did so. Histopathological examination of full thickness skin biopsies showed macrophages containing melanin in the dermal layer. Clustering of cases was noted among siblings, suggesting the possible involvement of genetic factors in the pathogenesis of these skin reactions. One child was accidentally re-exposed to Maloprim after the drug had been withdrawn and he developed a severe reaction. No other serious side effect was noted. Hyperpigmented lesions similar to those reported in this study have been described previously in patients with leprosy treated with dapsone, and the dapsone component of Maloprim is the likely cause of the skin reactions seen in children given this drug for malaria chemoprophylaxis.
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PMID:Hyperpigmented dermal macules in children following the administration of Maloprim for malaria chemoprophylaxis. 919 70

Pyrimethamine is an inhibitor of dihydrofolate reductase and is used in the treatment of malaria and toxoplasmosis. We examined the cytogenetic effects of this drug. Adult male mice were given doses of 20, 40, 80, and 120 mg/kg pyrimethamine intraperitoneally. Animals were killed by cervical dislocation on the 3rd, 6th, 9th, and 12th day after treatment, and the primary spermatocytes were harvested from their testes. These cells were analyzed for gaps, breaks, acentric fragments, and exchanges, as well as for numerical aberrations such as univalency. A dose-related increase in chromosomal aberrations was found in the pyrimethamine group compared with the control group. We suspect that pyrimethamine is a possible clastogen that may affect human germ cells.
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PMID:The cytogenetic effects of pyrimethamine on male mouse germ cells. 921 89

Pyrimethamine-sulfadoxine, the first choice for uncomplicated falciparum malaria in Africa, exerts strong selection pressure for resistance because of its slow elimination. It is likely that resistance will emerge rapidly, and there is no widely affordable replacement. Chlorproguanil-dapsone is cheap, rapidly eliminated, more potent than pyrimethamine-sulfadoxine, and could be introduced in the near future to delay the onset of antifolate resistance and as "salvage therapy" for pyrimethamine-sulfadoxine failure. A total of 448 children were randomly allocated (double blind) to either a single dose of pyrimethamine-sulfadoxine or to one of two chlorproguanil-dapsone regimens: a single dose or three doses at 24-h intervals. Reinfections are clinically indistinguishable from recrudescence and are more likely after treatment with rapidly eliminated drugs; we measured the incidence of parasitemia in 205 initially aparasitemic children to allow comparison with the three treatment groups. The patients and a community surveillance group were followed up for 28 days. At the study end point, 31.2% (95% confidence interval, 24.9-38.0) of the community surveillance group subjects were parasitemic, compared with subjects in the treatment groups, whose rates of parasitemia were 40.8% (32.9-49.0; relative risk [RR], 1.31 [0.99-1.73]) after triple-dose chlorproguanil-dapsone, 19.7% (13.5-27.2; RR, 0.63 [0.43-0.93]) after pyrimethamine-sulfadoxine, and 65.6% (57.5-73.0; RR, 2.10 [1.66-2.65]) after single-dose chlorproguanil-dapsone. Pyrimethamine-sulfadoxine and triple-dose chlorproguanil-dapsone were effective treatments. Pyrimethamine-sulfadoxine provided chemoprophylaxis during follow-up because of its slow elimination. Triple-dose chlorproguanil-dapsone should now be developed in an attempt to reduce the rate of emergence of antifolate resistance in Africa and for affordable salvage therapy in cases of pyrimethamine-sulfadoxine failure.
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PMID:Chlorproguanil-dapsone: effective treatment for uncomplicated falciparum malaria. 933 58

To assess pyrimethamine-sulfadoxine (PS) efficacy in Mali, and the role of mutations in Plasmodium falciparum dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) in in vivo PS resistance, 190 patients with uncomplicated P. falciparum malaria were treated with PS and monitored for 56 days. Mutation-specific polymerase chain reactions and digestion with restriction endonucleases were used to detect DHFR and DHPS mutations on filter paper blood samples from pretreatment and post-treatment infections. Only one case each of RI and RII level resistance and no cases of RIII resistance or therapeutic failure were observed. Post-PS treatment infections had significantly higher rates of DHFR mutations at codons 108 and 59. No significant selection for DHPS mutations was seen. Pyrimethamine-sulfadoxine is highly efficacious in Mali, and while the low level of resistance precludes assessing the utility of molecular assays for in vivo PS resistance, rapid selection of DHFR mutations supports their role in PS failure.
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PMID:Pyrimethamine-sulfadoxine efficacy and selection for mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase in Mali. 1046 80

Pyrimethamine is used for treatment of malaria and toxoplasmosis. The embryotoxicity and clastogenicity of pyrimethamine is known and our aim was to investigate its dominant lethal effect in vivo. For this purpose, we used three groups of Swiss-albino male mice and a control group. We injected males with doses of 16, 32 or 64 mg/kg pyrimethamine and housed them with 10 females/male for each mating interval. Females were sacrificed and their uteri were evaluated for dominant lethality. As a result of this study we found that pyrimethamine induced dominant lethal mutations in the third, fourth and sixth weeks at the 64 mg/kg dose level, without the effect being dose-dependent. We conclude that pyrimethamine is a suspected germ cell mutagen.
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PMID:In vivo dominant lethal effect of pyrimethamine in male mouse germ cells. 1047 24

Pyrimethamine, in combination with sulfadoxine, is currently one of the major alternative drugs used for the treatment of chloroquine-resistant Plasmodium falciparum malaria infections in Africa. The mechanism of pyrimethamine resistance has been strongly associated with a single, key point mutation in the dihydrofolate reductase-thymidylate synthase gene, resulting in the substitution of the wild-type allele Ser-108 by either Asn-108 or Thr-108. The pyrimethamine-resistant phenotype and/or genotype were determined in 273 Cameroonian clinical isolates obtained in Yaounde by in vitro assays and polymerase chain reaction-restriction fragment length polymorphism over a 5-year period. The in vitro assays showed that 42% (18 of 43) and 63% (69 of 110) of the isolates obtained in 1994-1995 and 1997-1998, respectively, were resistant to pyrimethamine (50% inhibitory concentration [IC50] > 100 nM). The polymerase chain reaction showed that 43% (55 of 127) and 59% (50 of 85) of the isolates in 1994-1995 and 1997-1998, respectively, had the mutant Asn-108 allele. The pyrimethamine-resistant genotype (Asn-108) corresponded with the pyrimethamine-resistant phenotype (IC50 > or = 100 nM) in a large majority (> 95%) of the isolates. The results of our study suggest an increasing prevalence of pyrimethamine resistance in Yaounde. Our study further suggests that pyrimethamine resistance can be monitored by a technique that can be adopted by malaria research centers in Africa.
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PMID:Molecular epidemiology of malaria in Yaounde, Cameroon IV. Evolution of pyrimethamine resistance between 1994 and 1998. 1058 15

The available antimalarial drugs for the treatment of Plasmodium falciparum malaria during pregnancy are potentially toxic, especially in the presence of red blood cells (RBC) defects. We describe a case of chloroquine-resistant malaria by P. falciparum in a pregnant woman with glucose-6-phosphate dehydrogenase (G6PD) deficiency successfully treated with pyrimethamine followed by mefloquine administration. The susceptibility of P. falciparum to chloroquine and mefloquine was assessed by an in vitro test before treatment. Pyrimethamine and mefloquine were administered at the 18th and 22nd week of pregnancy, respectively. Mefloquine concentrations were monitored in the mother's blood at 2, 4, 8, 12, 24 and 48 hr after the administration to define effective blood-drug concentrations. Blood smear examination was negative after 48 hr post mefloquine treatment. No histologic lesions of the placenta were observed. The newborn presented normal clinical parameters. The administration of pyrimethamine prevented massive placental infection, thus permitting the fetus to achieve suitable gestational age for further treatment with mefloquine to eradicate P. falciparum malaria without deleterious effects to the newborn. Subsequent studies could contribute to define safe administration of mefloquine in G6PD-deficient pregnant woman.
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PMID:Management of a case of chloroquine-resistant falciparum malaria in a pregnant woman with glucose-6-phosphate dehydrogenase (G6PD) deficiency. 1077 4

Pyrimethamine (PM) plus sulfadoxine (SD) is the last remaining affordable drug for treating uncomplicated malaria in Africa. The selective pressure exerted by the slowly eliminated combination PM/SD was compared with that exerted by the more rapidly eliminated combination chlorproguanil/dapsone (CPG/Dap) on Kenyan Plasmodium falciparum. Point mutations were analyzed in dihydrofolate reductase and dihydropteroate synthase and in the genetic diversity of 3 genes in isolates collected before and after CPG/Dap and PM/SD treatments. PM/SD was associated strongly with the disappearance of fully drug-sensitive parasites and with a significant increase in the prevalence of resistant parasites in subsequent parasitemias. However, this was not a characteristic of treatment with CPG/Dap. Moreover, most of the patients who returned with recrudescent infections were in the PM/SD-treated group. The data predict a longer useful therapeutic life for CPG/Dap than for PM/SD, and, thus, CPG/Dap is a preferable alternative for treatment of chloroquine-resistant falciparum malaria in sub-Saharan Africa.
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PMID:Molecular evidence of greater selective pressure for drug resistance exerted by the long-acting antifolate Pyrimethamine/Sulfadoxine compared with the shorter-acting chlorproguanil/dapsone on Kenyan Plasmodium falciparum. 1083 85

The pattern of antimalarial dispensing by Patent Medicine Dealers (PMD) was studied in 17 villages of Gokana (Ogoni Land) in Rivers State of Nigeria. Of the 40 PMDs studied only eight (20%) had had formal health training and only eight could understand doctor's prescriptions. In total, 19 different types of antimalarials could be obtained from the individual ranges of antimalarials displayed by the 40 PMDs in the study. Chloroquine phosphate was the most frequently available. Twenty-three (57.5%) of PMDs administered Chloroquine at below the recommended dose of this drug. Twelve (30%) PMDs, eight with formal training and four others, administered the correct dose whilst five (12.5%) gave too much. All 40 of the PMDs studied knew how to dispense Daraprim and Fansidar correctly. We conclude that malaria control through prevention and treatment would be more effective if PMDs were to receive training on antimalarial dispensing alongside Community Health Workers.
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PMID:Antimalarials dispensing pattern by patent medicine dealers in rural settlements in Nigeria. 1096 92


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