Effects of antifolates - co-trimoxazole and pyrimethamine-sulfadoxine - on gametocytes in children with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria

Sowunmi, A.; Fateye, B. A.; Adedeji, A. A.; Fehintola, F. A.; Bamgboye, Afolabi E.; Babalola, Chinedum P.; Happi, T C; Gbotosho, G. O.

doi:10.1590/s0074-02762005000400019

Cited by 28 publications

(23 citation statements)

References 17 publications

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“…Thus, when normal doses of these drugs are used, the free concentration of TMP is at least five times higher than that of PM, which would compensate for the relatively low activity of TMP, explaining, at least partly, the comparative efficacies of TMP-SMZ and PM-SD. Thus, in areas of high PM-SD efficacy (low rates of dhfr mutants), PM-SD and TMP-SMZ could have comparative efficacies, as supported by in vivo investigations (14,44,50). However, based on our in vitro data, TMP-SMZ, like PM-SD, will be of marginal efficacy in the context of a high rate of dhfr triple mutant parasites.…”

Section: Discussionmentioning

confidence: 62%

“…The data are summarized in Table 2. The median IC 50 for PM was 370 nM in the double mutant group, and this value increased almost twofold in the triple mutant group. Likewise, IC 50 s for TMP increased from 9,308.6 nM in the double mutant group to 33,655 nM in the triple mutant group, a 3.6-fold increase; however, these differences were not significant.…”

Section: Resultsmentioning

confidence: 92%

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In Vitro Activity of Antifolate and Polymorphism in Dihydrofolate Reductase ofPlasmodium falciparumIsolates from the Kenyan Coast: Emergence of Parasites with Ile-164-Leu Mutation

Kiara

Okombo

Masseno

et al. 2009

Antimicrob Agents Chemother

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We have analyzed the activities of the antifolates pyrimethamine (PM), chlorcycloguanil (CCG), WR99210, trimethoprim (TMP), methotrexate (MTX), and trimetrexate (TMX) against Kenyan Plasmodium falciparum isolates adapted in vitro for long-term culture. We have also assessed the relationship between these drug activities and mutations in dihydrofolate reductase (dhfr), a domain of the gene associated with antifolate resistance. As expected, WR99210 was the most potent drug, with a median 50% inhibitory concentration (IC 50 ) of <0.075 nM, followed by TMX, with a median IC 50 of 30 nM. The median IC 50 of CCG was 37.80 nM, and that of MTX was 83.60 nM. PM and TMP were the least active drugs, with median IC 50 s of 733.26 nM and 29,656.04 nM, respectively. We analyzed parasite dhfr genotypes by the PCR-enzyme restriction technique. No wild-type dhfr parasite was found. Twenty-four of 33 parasites were triple mutants (mutations at codons 108, 51, and 59), and only 8/33 were double mutants (mutations at codons 108 and 51 or at codons 108 and 59). IC 50 s were 2.1-fold (PM) and 3.6-fold (TMP) higher in triple than in double mutants, though these differences were not statistically significant. Interestingly, we have identified a parasite harboring a mutation at codon 164 (Ile-164-Leu) in addition to mutations at codons 108, 51, and 59. This quadruple mutant parasite had the highest TMP IC 50 and was in the upper 10th percentile against PM and CCG. We confirmed the presence of this mutation by sequencing. Thus, TMX and MTX are potent against P. falciparum, and quadruple mutants are now emerging in Africa.

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Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 92%

In Vitro Activity of Antifolate and Polymorphism in Dihydrofolate Reductase ofPlasmodium falciparumIsolates from the Kenyan Coast: Emergence of Parasites with Ile-164-Leu Mutation

Kiara

Okombo

Masseno

et al. 2009

Antimicrob Agents Chemother

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“…La mefloquina tampoco elimina los gametocitos maduros de P. falciparum, sino que evita el desarrollo posterior de esas células por su actividad contra sus precursores (46). La sulfadoxina-pirimetamina es un potente esquizonticida sanguíneo y se sospecha que estimula la producción de gametocitos de P. falciparum (47)(48)(49)(50)(51)(52)(53) o eleva la viabilidad de los maduros (36); la sulfadoxina-pirimetamina suprime la capacidad de los gametocitos para infectar los anofelinos (36) y altera las razones de sexo de los gametocitos, lo que influye en la capacidad de causar infección a los mosquitos y la transmisión del paludismo (54); se considera que el efecto neto o global de la sulfadoxinapirimetamina sobre la supresión de la capacidad de infectar es nulo (36).…”

Section: Antipalúdicos Y Gametocitos De P Falciparumunclassified

Gametocitemia en malaria por Plasmodium falciparum tratada con amodiaquina o artesunato

Carmona‐Fonseca¹,

Arango²,

Blair³

2008

biomedica

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Introducción. Las relaciones de la gametocitemia de Plasmodium falciparum con el tratamiento antipalúdico han sido poco estudiadas en América. Objetivo. Describir relaciones de la gametocitemia falciparum con el tratamiento con amodiaquina-sulfadoxina-pirimetamina, artesunato-sulfadoxina-pirimetamina o amodiaquinaartesunato. Materiales y métodos. Se usó un diseño experimental, aleatorio, no balanceado, no ciego. El seguimiento fue de 21 a 28 días. La eficacia terapéutica se clasificó según el protocolo de la Organización Mundial de la Salud, 1998. Resultados. Se evaluaron 241 pacientes en Turbo, El Bagre y Zaragoza (Antioquia, Colombia). El esquema de amodiaquina-sulfadoxina-pirimetamina tuvo igual eficacia que el de artesunatosulfadoxina-pirimetamina y amodiaquina-artesunato para controlar las fallas terapéuticas el día 21. Hubo cuatro fallas (1,66%). El esquema de amodiaquina-sulfadoxina-pirimetamina fue menos eficaz que los tratamientos con artesunato para reducir la presencia de gametocitos. Al séptimo día, ninguno de los tres tratamientos había eliminado totalmente los gametocitos. La mayoría (56%) de nuestros pacientes no tenía gametocitos antes del tratamiento y nunca los desarrolló. El tiempo para eliminar los gametocitos que se tenían al iniciar el tratamiento no fue mayor cuando la gametocitemia inicial era mayor. Conclusión. Los tres tratamientos fueron iguales en cuanto a eficacia terapéutica e incapacidad de eliminar los gametocitos en siete días.Palabras clave: malaria/terapia, malaria falciparum, Plasmodium falciparum, antipalúdicos, amodiaquina, sulfadoxina, pirimetamina, Artemisia annua. Gametocytemia in falciparum malaria treated with amodiaquine or artesunateIntroduction. Antimalarial treatment effects on Plasmodium falciparum gametocytemia has been the focus of few studies in the Americas. Objective. Relationships are described that occur between falciparum gametocytemia and the treatment with amodiaquine-sulfadoxine-pyrimethamine, artesunate-sulfadoxinepyrimethamine or amodiaquine-artesunate. Materials and methods. The experimental design consisted of a randomized selection of patients not balanced or blinded. A total of 241 patients were evaluated, residents of Turbo, El Bagre and Zaragoza (Antioquia, Colombia).The follow up occurred 21-28 days after antimalarial treatment. The World Health Organization (1998) protocol was used. Results. The therapeutic efficacy of amodiaquine-sulfadoxine-pyrimethamine, artesunatesulfadoxine-pyrimethamine and amodiaquine-artesunate were equal at day 21 of the follow up. Four cases (1.7%) were therapeutic failures. Amodiaquine-sulfadoxine-pyrimethamine was less effective than the artesunate treatments in reducing the gametocyte load. On day 7, none of the three traetments had eliminated completely the gametocytes. Most patients (56.0%) were observed not to have circulating gametocytes pre-treatment and did not develop them later. Conclusion. The three treatment schemes were similar in their therapeutic efficacy and in their incapacity to eliminate gametocyte...

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“…However, children treated with SP were significantly more likely to have gametocyte carriage on day 14 compared with children treated with TS (65.7% versus 35%, respectively, P = 0.018), suggesting a more marked effect of gametocytemia with SP than TS. 33 The increase in the risk of gametocytemia in children receiving antifolates could be explained by decreased gametocydal activity, drug-induced release of sequestered gametocytes, or development of antifolate drug resistance. In a study of South African patients treated with SP for uncomplicated malaria, increases in the duration of gametocyte carriage after treatment were strongly associated with antifolate resistance markers dhfr and dhps.…”

Section: Discussionmentioning

confidence: 99%

The Effects of ACT Treatment and TS Prophylaxis on Plasmodium falciparum Gametocytemia in a Cohort of Young Ugandan Children

Kakuru

Jagannathan²,

Arinaitwe³

et al. 2013

The American Journal of Tropical Medicine and Hygiene

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Abstract. Artemisinin-based combination therapies (ACTs) and trimethoprim-sulfamethoxazole (TS) prophylaxis are important tools for malaria control, but there are concerns about their effect on gametocytes, the stage of the parasite responsible for transmission. We conducted a longitudinal clinical trial in a cohort of HIV-infected and uninfected children living in an area of high malaria transmission intensity in Uganda. Study participants were randomized to artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) for all treatments of uncomplicated malaria (N = 4,380) as well as TS prophylaxis for different durations. The risks of gametocytemia detected by microscopy in the 28 days after antimalarial therapy were compared using multivariate analyses. The risk of gametocyte detection was significantly higher in patients treated with DP compared with AL (adjusted relative risk = 1.85, P 0.001) and among children prescribed TS prophylaxis (adjusted relative risk = 1.76, P 0.001). The risk of gametocytemia and its potential for increasing transmission should be considered when evaluating different ACTs and TS prophylaxis for malaria control.

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Effects of antifolates - co-trimoxazole and pyrimethamine-sulfadoxine - on gametocytes in children with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria

Cited by 28 publications

References 17 publications

In Vitro Activity of Antifolate and Polymorphism in Dihydrofolate Reductase ofPlasmodium falciparumIsolates from the Kenyan Coast: Emergence of Parasites with Ile-164-Leu Mutation

In Vitro Activity of Antifolate and Polymorphism in Dihydrofolate Reductase ofPlasmodium falciparumIsolates from the Kenyan Coast: Emergence of Parasites with Ile-164-Leu Mutation

Gametocitemia en malaria por Plasmodium falciparum tratada con amodiaquina o artesunato

The Effects of ACT Treatment and TS Prophylaxis on Plasmodium falciparum Gametocytemia in a Cohort of Young Ugandan Children

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