RESUMEN
BACKGROUND: Sulphadoxine-pyrimethamine (SP) has been and is currently used for treatment of uncomplicated Plasmodium falciparum malaria in many African countries. Nevertheless, the response of parasites to SP treatment has shown significant variation between individuals. METHODS: The genes for dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) were used as markers, to investigate parasite resistance to SP in 141 children aged less than 5 years. Parasite DNA was extracted by Chelex method from blood samples collected and preserved on filter papers. Subsequently, polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) were applied to detect the SP resistance-associated point mutations on dhfr and dhps. Commonly reported point mutations at codons 51, 59, 108 and 164 in the dhfr and codons 437, 540 and 581 in the dhps domains were examined. RESULTS: Children infected with parasites harbouring a range of single to quintuple dhfr/dhps mutations were erratically cured with SP. However, the quintuple dhfr/dhps mutant genotypes were mostly associated with treatment failures. High proportion of SP resistance-associated point mutations was detected in this study but the adequate clinical response (89.4%) observed clinically at day 14 of follow up reflects the role of semi-immunity protection and parasite clearance in the population. CONCLUSION: In monitoring drug resistance to SP, concurrent studies on possible confounding factors pertaining to development of resistance in falciparum malaria should be considered. The SP resistance potential detected in this study, cautions on its useful therapeutic life as an interim first-line drug against malaria in Tanzania and other malaria-endemic countries.
Asunto(s)
Antimaláricos/farmacología , Dihidropteroato Sintasa/genética , Resistencia a Medicamentos , Plasmodium falciparum/efectos de los fármacos , Pirimetamina/farmacología , Sulfadoxina/farmacología , Tetrahidrofolato Deshidrogenasa/genética , Animales , Antimaláricos/uso terapéutico , Preescolar , Combinación de Medicamentos , Resistencia a Medicamentos/genética , Femenino , Humanos , Lactante , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/epidemiología , Malaria Falciparum/parasitología , Masculino , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/enzimología , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Pirimetamina/uso terapéutico , Sulfadoxina/uso terapéutico , Tanzanía/epidemiologíaRESUMEN
Alpha+-thalassaemia is well known for conferring partial protection to severe malaria. On the other, Glutathione-S-transferase (GST) polymorphism has recently been associated to severe malaria in children. A retrospective cross sectional study was carried out to determine the relationship between genotypic polymorphisms of alpha+-thalassaemia and glutathione-S-transferase in children with severe malaria. A total of 148 DNA samples from children aged between 3 and 15 years with mild and severe malaria were retrieved and determined by polymerase chain reaction. Children with Glutathione-S-transferase-pil (GSTP1)-polymorphism were observed to have three fold risk (OR = 2.9; 95% CI =1.3- 6.1; P = 0.006) of developing severe malaria compared to mild malaria in Mnyuzi in Korogwe District, north-eastern, Tanzania. In the presence of Glutathione-S-transferase-pil polymorphism, children were found to have 3% decreased protective effect of alpha+-thalassaemia polymorphisms (homozygotes and heterozygotes) against severe malaria although this was not statistically significant [OR = 0.81 (95% CI = 0.5-1.5; P = 0.5) to OR =0.78(95% CI = 0.4-1.5; P = 0.44)]. We conclude that Glutathione-S-transferase-pil polymorphism increases risk of developing severe malaria due to Plasmodium falciparum in children. The observed inverse relationship between GSTP1 polymorphisms and alpha-thalassaemia to children with severe malaria need further investigation.