Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum

Basco, Léonardo K.; Pécoulas, Philippe Eldin de; Wilson, Craig M.; Bras, J. Le; Mazabraud, A

doi:10.1016/0166-6851(94)00207-4

Cited by 151 publications

(109 citation statements)

References 9 publications

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“…On the other hand, inasmuch as the Thr-108 genotype in DHFR was not found when analyzing a large number of samples from different geographic areas, [20][21][22] certain authors have suggested that this mutation might occur only in laboratory strains. Nevertheless, the Thr-108 mutation was observed in a high frequency in our study (55%), and it also was found in two Colombian studies in which isolates of different geographic origin were analyzed.…”

Section: Discussionmentioning

confidence: 99%

Genetic diversity of Plasmodium falciparum field samples from an isolated Colombian village.

Gómez¹,

Chaparro²,

Rubiano³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Colombian field isolates of Plasmodium falciparum were analyzed for genetic diversity. Fifty-three samples were collected as thick smears from patients living in Panguí, an isolated area with low migration. While the samples were being collected, Panguí was experiencing an epidemic outbreak of malaria. The samples were typified using nested polymerase chain reaction (PCR) amplification of block 2 of the merozoite surface protein 1 (MSP1) gene and nested PCR with mutation-specific primers for position 108 of the dihydrofolate reductase enzyme gene. The results for the circulating population of parasites in Panguí show low diversity-four allelic forms-using MSP1 as a marker, a fact that contrasts with data reported for certain Asian and African zones. A high percentage of mixed infections was observed, as was high complexity of the infection. No differential distributions were found for any allelic type.

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Section: Discussionmentioning

confidence: 99%

Genetic diversity of Plasmodium falciparum field samples from an isolated Colombian village.

Gómez¹,

Chaparro²,

Rubiano³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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“…In laboratory-cultured parasite lines, a single Asn-108 mutation has resulted in pyrimethamine resistance, whereas the accumulation of mutations (Asn-108, Ile-51, and Arg-59 and/or Leu-164 or Thr-108 and Val-16) was necessary for high levels of cycloguanil resistance. 20,21 In endemic areas, the in vivo effect of chlorproguanil 26 and the in vitro activity of cycloguanil [22][23][24][25][26] have been associated with Asn-108 but generally in combination with Ile-51 and/or Arg-59. However, the importance of these additional mutations is not fully clear.…”

Section: Discussionmentioning

confidence: 99%

Polyclonal Plasmodium falciparum malaria in travelers and selection of antifolate mutations after proguanil prophylaxis.

Färnert¹,

Tengstam²,

Palme³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. The polymorphism of malaria parasites will greatly influence the efficiency of antimalarial drugs and vaccines. This study determined the genetic diversity of Plasmodium falciparum infections in 107 travelers and estimated the importance of mutations in the parasite dihydrofolate reductase (dhfr) gene for clinical breakthrough during proguanil prophylaxis. Genotyping with regards to the three highly polymorphic antigen-coding regions (merozoite surface protein-1 [msp-1], msp-2, and the glutamate-rich protein [glurp]) revealed multiple genotypes (up to five) in 64% of the patients. Single genotype infections were mainly associated with prior intake of antimalarial drugs, but also with a shorter stay in a malaria-endemic area and low parasite density. Malaria breakthrough despite proguanil prophylaxis was always associated with mutations in the dhfr gene; always the Asn-108 mutation and often the Ile-51 and Arg-59 mutations. The Leu-164 mutation was found in four travelers from Africa. Travelers with limited time in an endemic area were often infected with polyclonal P. falciparum infections, which suggests that single mosquito inoculations are often composed of several genetically diverse parasites. Chemoprophylaxis reduces the number of infecting clones and selects for resistant parasites as shown for proguanil through mutations in the dhfr gene.

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“…41,42 Cross-resistance between pyrimethamine and cycloguanil has also been observed in vitro and in vivo. 41,43 Cross-resistance patterns between these drugs may be, at least in part, explained on the basis of similar chemical structures. Our study suggests in vitro cross-resistance between dihydroartemisinin and aminoalcohols (mefloquine and halofantrine), which do not share any similar chemical features.…”

Section: Discussionmentioning

confidence: 99%

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

Ringwald¹,

Bickii²,

Basco³

1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The in vitro activities of dihydroartemisinin (the biologically active metabolite of artemisinin derivatives), chloroquine, monodesethylamodiaquine (the biologically active metabolite of amodiaquine), quinine, mefloquine, halofantrine, and pyrimethamine were assessed in 65 African isolates of Plasmodium falciparum from Yaoundé, Cameroon using an isotopic microtest. The 50% inhibitory concentration (IC 50 ) values for dihydroartemisinin were within a narrow range from 0.25 to 4.56 nM, with a geometric mean of 1.11 nM (95% confidence interval ϭ 0.96-1.28 nM). Dihydroartemisinin was equally active (P Ͼ 0.05) against the chloroquine-sensitive isolates (geometric mean IC 50 ϭ 1.25 nM, 95% confidence interval ϭ 0.99-1.57 nM) and the chloroquine-resistant isolates (geometric mean IC 50 ϭ 0.979 nM, 95% confidence interval ϭ 0.816-1.18 nM). A significant positive correlation was observed between the responses to dihydroartemisinin and mefloquine (r ϭ 0.662) or halofantrine (r ϭ 0.284), suggesting in vitro crossresistance. There was no correlation between the responses to dihydroartemisinin and other antimalarial drugs.Artemisinin (qinghaosu) has been used for centuries in traditional Chinese medicine for antimalarial treatment. 1 In 1972, Chinese scientists isolated the active principle from the plant Artemisia annua. 2 Artemisinin is a sesquiterpene lactone characterized by the presence of an endoperoxide that is associated with a potent antimalarial activity. Because artemisinin is chemically unstable and poorly soluble in water or oil, the carbonyl group at C-10 of the parent compound was reduced to obtain dihydroartemisinin. Several derivatives have been developed by adding an ether, ester, or other substituents to the hydroxyl group of dihydroartemisinin. These semi-synthetic derivatives include the water-soluble derivatives, sodium artesunate and artelinic acid, and the oilsoluble derivatives, artemether and arteether. With the exception of arteether and artelinic acid, these compounds are used to treat malarial infections in endemic countries, mainly in Southeast Asia and, to a lesser extent, in Africa and South America.Artemisinin derivatives are available in different formulations for oral, parenteral, and rectal administration. Clinical studies have shown that artemisinin derivatives are highly potent, rapidly acting, and well-tolerated blood schizontocides, resulting in shorter parasite clearance times than other antimalarial drugs. 3,4 Artemisinin derivatives are highly effective against Plasmodium falciparum isolates that are resistant to other drugs. These derivatives are indicated for the emergency treatment of severe and complicated falciparum malaria by parenteral administration and for the oral treatment of uncomplicated multidrug-resistant malaria. 5 So far, resistance to artemisinin derivatives has not been reported in clinical studies. However, because of the high recrudescence rate when used as monotherapy, many current therapeutic regimens used in Southeast Asia include a combination of o...

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Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum

Cited by 151 publications

References 9 publications

Genetic diversity of Plasmodium falciparum field samples from an isolated Colombian village.

Genetic diversity of Plasmodium falciparum field samples from an isolated Colombian village.

Polyclonal Plasmodium falciparum malaria in travelers and selection of antifolate mutations after proguanil prophylaxis.

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

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