Absence of association between Pfnfs1 mutation and in vitro susceptibility to lumefantrine in Plasmodium falciparum.

Artemether-lumefantrine (AL) is the most widely used antimalarial drug for treating uncomplicated falciparum malaria. This study evaluated whether the K65Q mutation in the Plasmodium falciparum cysteine desulfurase IscS (Pfnfs1) gene was associated with alternated susceptibility to lumefantrine using clinical parasite samples from Ghana and the China-Myanmar border area. Parasite isolates from the China-Myanmar border had significantly higher IC50 values to lumefantrine than parasites from Ghana. In addition, the K65 allele was significantly more prevalent in the Ghanaian parasites (34.5%) than in the China-Myanmar border samples (6.8%). However, no difference was observed in the lumefantrine IC50 value between the Pfnfs1 reference K65 allele and the non reference 65Q allele in parasites from the two regions. These data suggest that the Pfnfs1 K65Q mutation may not be a reliable marker for reduced susceptibility to lumefantrine.

Ex vivo drug susceptibility and resistance mediating genetic polymorphisms of Plasmodium falciparum in Bobo-Dioulasso, Burkina Faso.

Malaria remains a leading cause of morbidity and mortality in Burkina Faso, which utilizes artemether-lumefantrine as the principal therapy to treat uncomplicated malaria and seasonal malaria chemoprevention with monthly sulfadoxine-pyrimethamine plus amodiaquine in children during the transmission season. Monitoring the activities of available antimalarial drugs is a high priority. We assessed the ex vivo susceptibility of Plasmodium falciparum to 11 drugs in isolates from patients presenting with uncomplicated malaria in Bobo-Dioulasso in 2021 and 2022. IC50 values were derived using a standard 72 h growth inhibition assay. Parasite DNA was sequenced to characterize known drug resistance-mediating polymorphisms. Isolates were generally susceptible, with IC50 values in the low-nM range, to chloroquine (median IC5010 nM, IQR 7.9-24), monodesethylamodiaquine (22, 14-46) piperaquine (6.1, 3.6-9.2), pyronaridine (3.0, 1.3-5.5), quinine (50, 30-75), mefloquine (7.1, 3.7-10), lumefantrine (7.1, 4.5-12), dihydroartemisinin (3.7, 2.2-5.5), and atovaquone (0.2, 0.1-0.3) and mostly resistant to cycloguanil (850, 543-1,290) and pyrimethamine (33,200, 18,400-54,200), although a small number of outliers were seen. Considering genetic markers of resistance to aminoquinolines, most samples had wild-type PfCRT K76T (87%) and PfMDR1 N86Y (95%) sequences. For markers of resistance to antifolates, established PfDHFR and PfDHPS mutations were highly prevalent, the PfDHPS A613S mutation was seen in 19% of samples, and key markers of high-level resistance (PfDHFR I164L; PfDHPS K540E) were absent or rare (A581G). Mutations in the PfK13 propeller domain known to mediate artemisinin partial resistance were not detected. Overall, our results suggest excellent susceptibilities to drugs now used to treat malaria and moderate, but stable, resistance to antifolates used to prevent malaria.

Dietary aflatoxin B1 and antimalarial-a lumefantrine/artesunate-therapy perturbs male rat reproductive function via pro-inflammatory and oxidative mechanisms.

We investigated the impact of Coartem™ (COA) and aflatoxin B1 (AFB1) on rats' hypothalamus, epididymis, and testis. Male rats were randomly grouped (n = 5 rats) and treated: control group (corn oil), AFB1 (70 µg/kg), COA (5 mg/kg), COA + AFB1 (5 + 0.035 mg/kg) and COA + AFB1 (5 + 0.07 mg/kg) for 28 days. Blood samples were collected for serum prolactin, testosterone, follicle-stimulating and luteinising hormones (FSH and LH) assay upon sacrifice. The semen, hypothalamus, epididymis, and testes were harvested for morphological, biochemical, and histopathology determination of oxidative, inflammation stress, genomic integrity, and pathological alterations. Exposure to the COA and AFB1 caused the cauda epididymal spermatozoa to display low motility, viability, and volume, with increased abnormalities. Hormonal disruption ensued in animals exposed to COA and AFB1 alone or together, exemplified by increased prolactin, and decreased testosterone, FSH and LH levels. Treatment-related reduction in biomarkers of testicular metabolism-acid and alkaline phosphatases, glucose-6-phosphate dehydrogenase, and lactate dehydrogenase-were observed. Also, COA and AFB1 treatment caused reductions in antioxidant (Glutathione and total thiols) levels and antioxidant enzyme (Catalase, superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase) activities in the examined organs. At the same time, treatment-related increases in DNA damage (p53), oxidative stress (xanthine oxidase, reactive oxygen and nitrogen species and lipid peroxidation), inflammation (nitric oxide and tumour necrosis factor-alpha), and apoptosis (caspase-9, and -3) were observed. Chronic exposure to COA and AFB1 led to oxidative stress, inflammation, and DNA damage in male rats' hypothalamic-reproductive axis, which might potentiate infertility if not contained.