Comparison of Artemether and Artemether Plus Mefloquine
Comparison of Artemether and Artemether Plus Mefloquine
Objectives: To evaluate the effects of standard parenteral doses of artemether given over 5 days and to compare these effects with those of a single loading dose of artemether followed by a single oral dose of mefloquine on Plasmodium falciparumin vivo and on ex vivo parasite viability, and to assess the relationships between P. falciparum viability ex vivo and the responses in vivo to these regimens in children with severe noncerebral falciparum malaria.
Methods: 19 children with severe noncerebral malaria were randomised to receive therapeutic doses of intramuscular artemether or a single loading dose of intramuscular artemether followed by a single oral dose of mefloquine. Parasitaemia quantification and withdrawal of blood for in vitro culture of P. falciparum were performed before and at specific intervals after drug administration. Therapeutic indices of response were determined by conventional methods, i.e time to 50 or 90% reduction of parasitaemia and parasite clearance time. The corresponding viability estimates ex vivo were derived for each treatment regimen and compared with conventional therapeutic indices.
Results:In vivo responses to both therapeutic regimens were similar. Ex vivo, functional reduction of parasite viability was significant by 8 or 12 hours after administration of both regimens, with no functionally viable parasites by 24 hours after administration. Indices of therapeutic response were significantly higher than those derived from the corresponding functional viability estimates ex vivo for each drug regimen, and were similar for both regimens.
Conclusion: A single loading dose of artemether rapidly reduces parasite viability ex vivo. A single loading dose of artemether followed by a single oral dose of mefloquine produced similar effects to those of a 5-day therapeutic regimen of artemether. The combination of artemether plus mefloquine may be used as an alternative to artemether alone in children with severe noncerebral malaria, and may reduce the chances of development of parasite resistance to both drugs.
Artemether, a methylether derivative of artemisinin, produces accelerated clearing of Plasmodiumfalciparum ring-infected erythrocytes irrespective of other antimalarial drug sensitivity status of the parasites. Despite this effect, recrudescence rates as high as 10 to 20% or more may occur following therapy with artemether alone, and are attributable to the relatively short half-life of artemether of 1to6hours. In order to preserve the effectiveness of artemether or other artemisinin derivatives without compromising their efficacy in areas of multidrug-resistant malaria, for example in Thailand and Vietnam, a sequential therapy comprising an artemisinin derivative and mefloquine has been advocated and proven effective. In these areas, both single-day and 3-day regimens of an artemisinin derivative combined with mefloquine appear to have equal therapeutic efficacy, and are superior to mefloquine alone in the treatment of uncomplicated falciparum malaria.
In West Africa, resistance to chloroquine and pyrimethamine-sulfadoxine is increasing. In addition, innate resistance to artemisinin (the parent drug fromwhich artemether is derived), and to mefloquine in vitro is present in some isolates of P. falciparum in this region. Despite innate resistance in vitro, resistance in vivo to either artemether or artemether and mefloquine has not been detected in the region. However, resistance in vitro and in vivo to mefloquine has been reported in northern Cameroon.
The rapidity of the onset of actions of antimalarial drugs may be assessed by its effects on the viability of P. falciparumex vivo after administration of antimalarial drugs. This is an alternative and complementary method to the conventional indices of therapeutic response. Despite the use of combination or sequential therapy of resistant malaria with an artemisinin derivative and mefloquine, there is little or no published information on the effects of the combination on parasite viability ex vivo. In addition, such effects have not been compared with those of a standard regimen of artemether.
In the present study, we evaluated the effects of standard parenteral doses of artemether given over 5 days and compared these effects with those of a single loading dose of artemether followed by a single oral dose of mefloquine on P. falciparum in vivo and on ex vivo parasite viability.
Objectives: To evaluate the effects of standard parenteral doses of artemether given over 5 days and to compare these effects with those of a single loading dose of artemether followed by a single oral dose of mefloquine on Plasmodium falciparumin vivo and on ex vivo parasite viability, and to assess the relationships between P. falciparum viability ex vivo and the responses in vivo to these regimens in children with severe noncerebral falciparum malaria.
Methods: 19 children with severe noncerebral malaria were randomised to receive therapeutic doses of intramuscular artemether or a single loading dose of intramuscular artemether followed by a single oral dose of mefloquine. Parasitaemia quantification and withdrawal of blood for in vitro culture of P. falciparum were performed before and at specific intervals after drug administration. Therapeutic indices of response were determined by conventional methods, i.e time to 50 or 90% reduction of parasitaemia and parasite clearance time. The corresponding viability estimates ex vivo were derived for each treatment regimen and compared with conventional therapeutic indices.
Results:In vivo responses to both therapeutic regimens were similar. Ex vivo, functional reduction of parasite viability was significant by 8 or 12 hours after administration of both regimens, with no functionally viable parasites by 24 hours after administration. Indices of therapeutic response were significantly higher than those derived from the corresponding functional viability estimates ex vivo for each drug regimen, and were similar for both regimens.
Conclusion: A single loading dose of artemether rapidly reduces parasite viability ex vivo. A single loading dose of artemether followed by a single oral dose of mefloquine produced similar effects to those of a 5-day therapeutic regimen of artemether. The combination of artemether plus mefloquine may be used as an alternative to artemether alone in children with severe noncerebral malaria, and may reduce the chances of development of parasite resistance to both drugs.
Artemether, a methylether derivative of artemisinin, produces accelerated clearing of Plasmodiumfalciparum ring-infected erythrocytes irrespective of other antimalarial drug sensitivity status of the parasites. Despite this effect, recrudescence rates as high as 10 to 20% or more may occur following therapy with artemether alone, and are attributable to the relatively short half-life of artemether of 1to6hours. In order to preserve the effectiveness of artemether or other artemisinin derivatives without compromising their efficacy in areas of multidrug-resistant malaria, for example in Thailand and Vietnam, a sequential therapy comprising an artemisinin derivative and mefloquine has been advocated and proven effective. In these areas, both single-day and 3-day regimens of an artemisinin derivative combined with mefloquine appear to have equal therapeutic efficacy, and are superior to mefloquine alone in the treatment of uncomplicated falciparum malaria.
In West Africa, resistance to chloroquine and pyrimethamine-sulfadoxine is increasing. In addition, innate resistance to artemisinin (the parent drug fromwhich artemether is derived), and to mefloquine in vitro is present in some isolates of P. falciparum in this region. Despite innate resistance in vitro, resistance in vivo to either artemether or artemether and mefloquine has not been detected in the region. However, resistance in vitro and in vivo to mefloquine has been reported in northern Cameroon.
The rapidity of the onset of actions of antimalarial drugs may be assessed by its effects on the viability of P. falciparumex vivo after administration of antimalarial drugs. This is an alternative and complementary method to the conventional indices of therapeutic response. Despite the use of combination or sequential therapy of resistant malaria with an artemisinin derivative and mefloquine, there is little or no published information on the effects of the combination on parasite viability ex vivo. In addition, such effects have not been compared with those of a standard regimen of artemether.
In the present study, we evaluated the effects of standard parenteral doses of artemether given over 5 days and compared these effects with those of a single loading dose of artemether followed by a single oral dose of mefloquine on P. falciparum in vivo and on ex vivo parasite viability.
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