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• W1990271147 abstract "The rationale for combining drugs with independent modes of action to prevent the emergence of resistance in Plasmodium falciparum in Nick White and colleagues' study (June 5, p 1965)1White NJ Nosten F Looareesuwan S et al.Averting a malaria disaster.Lancet. 1999; 353: 1965-1967Summary Full Text Full Text PDF PubMed Scopus (476) Google Scholar is not new, and had been developed some 30 years ago. On the basis of the same simple calculation and on studies on the development of resistance of P berghei and P gallinaceum to dapsone, pyrimethamine, and sulphadoxine, alone or in combination, we concluded, in 1968, that there was only a minimum risk of emergence of resistant strains with the drug combination. In 1967, however, we reported the resistance of P falciparum to the combination sulphadoxine-pyrimethamine in the Païlin area of Cambodia and confirmed this resistance with cross-resistance to the combination on dapsone-pyrimethamine.2Verdrager J Riche A Cheang GM Action de l'association diaphenylsulfone-pyriméthamine sur le paludisme à P falciparum au Cambodge.Bull World Health Organ. 1969; 40: 319-324PubMed Google Scholar This Thai-Cambodian border area was also the first to be affected by resistance to mefloquine and is now believed to have the most resistant P falciparum in the world.Rapidity of emergence of chloroquine resistance in this area was due to intense drug pressure related to epidemiological factors: a very efficient forest vector, Anopheles dirus, that was exophilic (did not respond to residual spraying) and of limited distribution (jungle) with adjacent hyperendemic and non-endemic areas; and a state of localised permanent epidemics due to a temporary but continuous influx of nonimmune individuals into the Païlin gem mining area. Drug pressure was large: repeated mass drug administration was done, followed by a 3-year (1960–62) WHO-sponsored medicated salt project (Pinotti's method), covering a population of 20 000, first with pyrimethaminised salt and then with chloroquinised salt; and a permanent self-medication programme with intermittent high doses was implemented.3Verdrager J Localized permanent epidemics: the genesis of chloroquine resistance in.Plasmodium falciparum. Southeast Asian J Trop Med Public Health. 1995; 26: 23-38PubMed Google ScholarThe Cambodian chloroquinised salt project showed that resistance to chloroquine can develop rapidly when a large population of P falciparum is exposed to intense drug pressure, with the selection of resistant parasites activated by the introduction of nonimmune groups.4Verdrager J Epidemiology of the emergence and spread of drug-resistant falciparum malaria in South-East Asia and Australasia.J Trop Med Hyg. 1986; 89: 277-289PubMed Google Scholar By the same mechanisms producing the same effects, resistance to quinghaosu derivatives will also develop rapidly once these new drugs (artemisinin, artesunate, artemether) are introduced into this area, even in combination with mefloquine. Results of in-vitro sensitivity of P falciparum to artesunate in Thailand has indicated that combination with mefloquine is not the best way of protecting the usefulness of artemisinin and its derivatives.5Wongsrichanalai C Wimonwattratee T Sookto P et al.In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand.Bull World Health Organ. 1999; 77: 392-397PubMed Google ScholarBecause of the risk that exposure of P falciparum to non-curative doses of artemisinin or its derivatives may lead to the rapid development of resistance, even when these drugs are associated with mefloquine, it is not advisable to use these compounds for mass drug therapy. Their use should be limited to patients infected with multidrug-resistant malaria until the results of further studies are available. The rationale for combining drugs with independent modes of action to prevent the emergence of resistance in Plasmodium falciparum in Nick White and colleagues' study (June 5, p 1965)1White NJ Nosten F Looareesuwan S et al.Averting a malaria disaster.Lancet. 1999; 353: 1965-1967Summary Full Text Full Text PDF PubMed Scopus (476) Google Scholar is not new, and had been developed some 30 years ago. On the basis of the same simple calculation and on studies on the development of resistance of P berghei and P gallinaceum to dapsone, pyrimethamine, and sulphadoxine, alone or in combination, we concluded, in 1968, that there was only a minimum risk of emergence of resistant strains with the drug combination. In 1967, however, we reported the resistance of P falciparum to the combination sulphadoxine-pyrimethamine in the Païlin area of Cambodia and confirmed this resistance with cross-resistance to the combination on dapsone-pyrimethamine.2Verdrager J Riche A Cheang GM Action de l'association diaphenylsulfone-pyriméthamine sur le paludisme à P falciparum au Cambodge.Bull World Health Organ. 1969; 40: 319-324PubMed Google Scholar This Thai-Cambodian border area was also the first to be affected by resistance to mefloquine and is now believed to have the most resistant P falciparum in the world. Rapidity of emergence of chloroquine resistance in this area was due to intense drug pressure related to epidemiological factors: a very efficient forest vector, Anopheles dirus, that was exophilic (did not respond to residual spraying) and of limited distribution (jungle) with adjacent hyperendemic and non-endemic areas; and a state of localised permanent epidemics due to a temporary but continuous influx of nonimmune individuals into the Païlin gem mining area. Drug pressure was large: repeated mass drug administration was done, followed by a 3-year (1960–62) WHO-sponsored medicated salt project (Pinotti's method), covering a population of 20 000, first with pyrimethaminised salt and then with chloroquinised salt; and a permanent self-medication programme with intermittent high doses was implemented.3Verdrager J Localized permanent epidemics: the genesis of chloroquine resistance in.Plasmodium falciparum. Southeast Asian J Trop Med Public Health. 1995; 26: 23-38PubMed Google Scholar The Cambodian chloroquinised salt project showed that resistance to chloroquine can develop rapidly when a large population of P falciparum is exposed to intense drug pressure, with the selection of resistant parasites activated by the introduction of nonimmune groups.4Verdrager J Epidemiology of the emergence and spread of drug-resistant falciparum malaria in South-East Asia and Australasia.J Trop Med Hyg. 1986; 89: 277-289PubMed Google Scholar By the same mechanisms producing the same effects, resistance to quinghaosu derivatives will also develop rapidly once these new drugs (artemisinin, artesunate, artemether) are introduced into this area, even in combination with mefloquine. Results of in-vitro sensitivity of P falciparum to artesunate in Thailand has indicated that combination with mefloquine is not the best way of protecting the usefulness of artemisinin and its derivatives.5Wongsrichanalai C Wimonwattratee T Sookto P et al.In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand.Bull World Health Organ. 1999; 77: 392-397PubMed Google Scholar Because of the risk that exposure of P falciparum to non-curative doses of artemisinin or its derivatives may lead to the rapid development of resistance, even when these drugs are associated with mefloquine, it is not advisable to use these compounds for mass drug therapy. Their use should be limited to patients infected with multidrug-resistant malaria until the results of further studies are available. Averting a malaria disasterAuthors' reply Full-Text PDF" @default.
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