Co-nanoencapsulation of antimalarial drugs increases their in vitro efficacy against Plasmodium falciparum and decreases their toxicity to Caenorhabditis elegans.

Drugs used for the treatment and prevention of malaria have resistance-related problems, making them ineffective for monotherapy. If properly associated, many of these antimalarial drugs may find their way back to the treatment regimen. Among the therapeutic arsenal, quinine (QN) is a second-line treatment for uncomplicated malaria but has side effects that limit its use. Curcumin (CR) is a natural compound with anti-plasmodial activities and low bioavailability. In this context, the aim of this work was to develop and characterize co-encapsulated QN + CR-loaded polysorbate-coated polymeric nanocapsules (NC-QC) to evaluate their activity on Plasmodium falciparum and the safety of the nanoformulations for Caenorhabditis elegans. NC-QC displayed a diameter of approximately 200 nm, a negative zeta potential and a slightly basic pH. The drugs are homogeneously distributed in the NCs in the amorphous form. Co-encapsulated NCs exhibited a significant reduction in P. falciparum parasitemia, better than QN/CR. The worms exposed to NC-QC showed higher survival and longevity and no decrease in their reproductive capacity compared to free and associated drugs. It was possible to prove that the NCs were absorbed orally by the worms using fluorescence microscopy. Co-encapsulation of QN and CR was effective against P. falciparum, minimizing the toxic effects caused by chronic exposure of the free drugs in C. elegans.

Optimization of Curcuma Oil/Quinine-Loaded Nanocapsules for Malaria Treatment.

Quinine, a treatment used in chloroquine-resistant falciparum malaria, was loaded into poly(ɛ-caprolactone) or Eudragit® RS100 nanocapsules using Curcuma oil as the oil-based core. Until now, the effect of cationic nanocapsules on malaria has not been reported. A 24 factorial design was adopted using, as independent variables, the concentration of Curcuma oil, presence of quinine, type of polymer, and aqueous surfactant. Diameter, zeta potential, and pH were the responses studied. The formulations were also evaluated for drug content, encapsulation efficiency, photostability, and antimalarial activity against Plasmodium berghei-infected mice. The type of polymer influenced all of the responses studied. Quinine-loaded Eudragit® RS100 (F13) and PCL nanocapsules (F9), both with polysorbate 80 coating, showed nanometric particle size, positive zeta potential, neutral pH, high drug content, and quinine photoprotection ability; thus, these nanocapsules were selected for in vivo tests. Both formulations showed lower levels of parasitemia from the beginning of the experiment (5.78 ± 3.60 and 4.76 ± 3.46% for F9 and F13, respectively) and highest survival mean time (15.3 ± 2.0 and 14.9 ± 5.6 days for F9 and F13, respectively). F9 and F13 showed significant survival curve compared to saline, thus demonstrating that nanoencapsulation improved bioefficacy of QN and co-encapsulated curcuminoids, regardless of the surface charge.

Hydrochlorothiazide and high-fat diets reduce plasma magnesium levels and increase hepatic oxidative stress in rats.

This study was designed to develop a rodent model of hydrochlorothiazide (HCTZ) toxicity by associating its intake with a high-fat (HF) diet. Rats were fed for 16 weeks with a control diet or with an HF diet supplemented or not with different doses of HCTZ. HCTZ, in a similar way to the HF diet, caused a significant increase in fructosamine levels. HCTZ and HF diet intake caused a significant reduction in magnesium and potassium levels, as well as an increase in lipid peroxidation and vitamin C in liver. Importantly, negative correlations were found between magnesium and glucose levels as well as between magnesium and fructosamine levels. The association between HCTZ and the HF diet caused additional worsening of biochemical parameters related to glucose homeostasis, and further increased hepatic oxidative stress. Our results suggest that chronic intake of HCTZ or an HF diet causes metabolic changes that are consistent with the development of insulin resistance. In addition, the association of an HF diet and HCTZ treatment can exacerbate some of these biochemical alterations, suggesting that this model might be useful for studying HCTZ metabolic toxicity.