Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

At present, in countries of tropical Africa, chemotherapy is the main and often the only operationally, administratively, and financially feasible method of malaria control. This applies particularly in rural areas. This article reviews experience with chemotherapy in Africa since the late 1940s with mepacrine, proguanil, pyrimethamine, chloroquine, amodiaquine, and sulfones and sulfonamides in combination with dihydrofolate reductase inhibitors. Chloroquine has proved to be the most effective compound and it is the drug of choice as long as malarial parasites remain susceptible to it. Because of reports from East Africa of strains of Plasmodium falciparum resistant to 4-aminoquinolines, it is essential that national and regional policies be developed for the rational use of antimalarials.In most of the countries, the scope of activities is still limited to the administration of antimalarial drugs to sick persons through a limited network of health institutions. In some countries, however, attempts have been made to extend the coverage of drug administration by involving voluntary collaborators or through the provision of suppressive treatment to vulnerable groups of the population (such as infants, young children, pregnant women, nursing mothers, and schoolchildren) but the efficacy of such methods depends on the degree of involvement of voluntary collaborators, primary health workers, and communities.
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PMID:Use of drugs for malaria control in tropical Africa. 31 34

Data are presented on the causal prophylactic action of about 100 compounds of various types against Plasmodium yoelii nigeriensis N67 in mice. Examples are given to show how action against pre-erythrocytic schizonts may be differentiated from action on emerging erythrocytic stages. In a series of 35 8-aminoquinolines, all but 10 showed definite causal prophylactic activity at tolerated doses. The data permit the compounds to be ranked in order of activity, and many are shown to be more active in this test system than primaquine. Marked causal prophylactic activity is displayed by a variety of quinone structures, several of which show a significant residual action on blood stages. A high level of activity is found in dihydrofolate reductase inhibitors within several chemical classes. Rorguanil is more effective as a causal prophylactic than a blood schizontocide in the mouse as in man. Sulphonamides and sulphones are also effective in this system. The active levels are influenced by the content of PABA in the diet of the hosts. Causal prophylactic action has been detected in a number of experimental compounds including some antibiotics (such as tetracycline and clindamycin). The pyrocatechol RC 12 shows only slight activity at the maximum tolerated dose. Chloroquine, mepacrine, quinine, quinolinemethanols and phenanthrenemethanols are inactive as causal prophylactics. It is concluded that a rodent malaria-mouse model does provide a relatively simple model for the screening of drugs for causal prophylaxis, and the data so obtained are of relevance to the detection of causal prophylactics against human malaria.
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PMID:The chemotherapy of rodent malaria, XXIII Causal prophylaxis, part II: Practical experience with Plasmodium yoelii nigeriensis in drug screening. 109 90

Resistance to pyrimethamine and proguanil is due to a single point mutation in the gene that codes for dihydrofolate reductase. A single mutation gives rise to resistance to only one of the drugs. Resistance to both drugs results from several mutations. Chloroquine resistance phenotype is due to a rapid efflux of the drug from the parasite's digestive vacuole. This efflux is associated with a transmembrane permeability glycoprotein, or P-gp, which is similar to the protein implicated in the multidrug resistant phenotype of some cancer cells. However, one or several other poorly understood major gene(s) may be involved. Drugs which can inhibit the supposed affinity of P-gp for chloroquine are under study.
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PMID:[Contribution of molecular genetics to the understanding of chemoresistance of Plasmodium falciparum]. 135 39

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

Every year there are 270 million clinical attacks of malaria and 2 million deaths, caused by the protozoan Plasmodium falciparum. Most of these cases occur in Africa. Chloroquine-resistance has led to reliance on anti-malarial antifolates, in particular the synergistic combination sulfadoxine/pyrimethamine (S/P) which targets enzymatic synthesis of folate co-factors through dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Resistance to S/P is now increasing and replacement antimalarials are needed. Crystal structures are not yet available for these key enzymes in the folate pathway. This review focuses on the activity of drugs on DHFR in malaria parasites, attempts to interpret differences in activity of pyrimethamine and its related drugs, and to clarify how residue changes due to point mutations determine the development of resistance. In homology-modelled P. falciparum DHFR (PfDHFR), the typical structure of four alpha-helices, 8-stranded beta-sheet, four Loops and eight Turns is clearly seen. Long polar sequences specific for Plasmodium are inserted in Turns 1 and 2. Structures immediately concerned in drug binding are beta-A, L1, alpha-B, alpha-C, T-3, beta-E, alpha-F, and beta-F. The roles of several mutations associated with resistance are discussed. In view of sequence differences in turn 3 in PfDHFR and in the human enzyme, and the marked interaction with residues of T3 of the experimental flexible antifolate WR99210 effective in pyrimethamine and cycloguanil resistance, further drug development in this area is indicated.
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PMID:Resistance to antifolates in Plasmodium falciparum, the causative agent of tropical malaria. 1196 21

Chloroquine-proguanil combination is one of the options for chemoprophylaxis. The rapid evolution of drug resistance status requires a constant upgrade of epidemiologic data. Due to various difficulties in conducting prospective clinical studies on the prophylactic efficacy of the drug combination, especially in highly chloroquine-resistant zones, in vitro drug sensitivity assays and specific molecular markers for chloroquine (Plasmodium falciparum chloroquine-resistance transporter, pfcrt) and cycloguanil (a biologically active metabolite of proguanil; dihydrofolate reductase, dhfr) resistance were evaluated as an alternative approach in this study. Of 116 isolates, 62 (53.4%) were doubly resistant in vitro to chloroquine (IC50 > or = 100 nM) and cycloguanil (IC50 > or = 15 nM). Likewise, 62 of 118 isolates (52.5%) carried both the mutant Thr-76 pfcrt allele and at least one dhfr mutant allele (1 with a single Asn-108 allele, 8 with double Arg-59 and Asn-108 mutations, and 53 with triple Ile-51, Arg-59, and Asn-108 mutations). The in vitro drug response corresponded with the presence or absence of key mutation(s) in the pfcrt and dhfr genes. These results suggest the high proportion of P. falciparum isolates in southern Cameroon that may not respond to chloroquine-proguanil combination.
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PMID:Molecular epidemiology of malaria in Cameroon. XII. In vitro drug assays and molecular surveillance of chloroquine and proguanil resistance. 1245 95

Chloroquine (CQ) is used as a first-line therapy for the treatment of Plasmodium falciparum malaria in Nicaragua. We investigated the prevalence of molecular markers associated with CQ and sulfadoxine-pyrimethamine (SP) resistance in P. falciparum isolates obtained from the North Atlantic Autonomous Region of Nicaragua. Blood spots for this study were made available from a CQ and SP drug efficacy trial conducted in 2005 and also from a surveillance study performed in 2011. Polymorphisms in P. falciparum CQ resistance transporter, dihydrofolate reductase, and dihydropteroate synthase gene loci that are associated with resistance to CQ, pyrimethamine, and sulfadoxine, respectively, were detected by DNA sequencing. In the 2005 dataset, only 2 of 53 isolates had a CQ resistance allele (CVIET), 2 of 52 had a pyrimethamine resistance allele, and 1 of 49 had a sulfadoxine resistance allele. In the 2011 dataset, none of 45 isolates analyzed had CQ or SP resistance alleles.
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PMID:Molecular analysis of chloroquine and sulfadoxine-pyrimethamine resistance-associated alleles in Plasmodium falciparum isolates from Nicaragua. 2461 26