RESUMEN
The excess of iron in plasma and cellular compartment pose direct and indirect toxic effects. In the present investigation, we proposed additive function of nutritional bioactive ligands in combination which has shown enhanced antioxidant and iron(III) chelation property. The optimal interaction and in vitro antioxidant activity of tertiary mixture comprising of curcumin+quercetin+gallic acid was validated by central composite design (CCD) based on ferric reducing antioxidant power assay (FRAP). The additive denticity of nutritional bioactive ligands was investigated by UV-vis, FTIR & MALDI-TOF-MS analysis, which has given substantial evidence for the formation of tris-bidentate [curcumin-quercetin-gallic acid-Fe(III)] co-ordination complex. The in vivo proof of concept of the hypothesis was tested in iron intoxicated male wistar rats intoxicated with iron dextran. Co-administration curcumin+quercetin+gallic acid (CQG) exhibit dose dependent response & found effective in subsiding acute iron intoxication both at plasma and cellular level, evaluated by studies including serum ferritin, ICP-OES, lipid peroxidation and histopathology studies among others. Thus, we conclude that in vitro and in vivo studies supported our hypothesis to deduce additive function nutritional ligands to counteract direct and indirect effects of iron(III).
Asunto(s)
Antioxidantes/química , Hierro/química , Curcumina/química , Ácido Gálico/química , Hemosiderina/química , Ligandos , Peroxidación de Lípido , Estrés Oxidativo , Quercetina/química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
BACKGROUND: Artemether-lumefantrine (Coartem; AL) is a standard of care for malaria treatment as an oral six-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on patient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two novel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for bioequivalence with their respective number of standard tablets. METHODS: A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study comparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets, and the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed conditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analyses. RESULTS: Adjusted geometric mean AUClast for artemether were 345 and 364 ng·h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 µg·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively. Corresponding Cmax for artemether were 96.8 and 99.7 ng/mL (GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 µg/mL (GMR 0.97; 90% CI 0.89-1.05). For the 60/360 mg tablet versus three standard tablets, adjusted geometric mean AUClast for artemether were 235 and 231 ng·h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 µg·h/mL (GMR 0.89; 90% CI 0.83-0.96), respectively. Corresponding Cmax for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90% CI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 µg/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for Cmax and AUClast for artemether and lumefantrine for all primary comparisons were within the bioequivalence acceptance criteria (0.80-1.25). In addition, secondary PK parameters also met bioequivalence criterion. CONCLUSION: Both of the novel artemether-lumefantrine tablet formulations evaluated are bioequivalent to their respective standard Coartem tablet doses. These novel formulations are easy to administer and may improve adherence in the treatment of uncomplicated malaria caused by Plasmodium falciparum. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2011/12/002256.
Asunto(s)
Antimaláricos/administración & dosificación , Antimaláricos/farmacocinética , Artemisininas/administración & dosificación , Artemisininas/farmacocinética , Etanolaminas/administración & dosificación , Etanolaminas/farmacocinética , Fluorenos/administración & dosificación , Fluorenos/farmacocinética , Comprimidos/administración & dosificación , Comprimidos/farmacocinética , Adolescente , Adulto , Combinación Arteméter y Lumefantrina , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plasma/química , Plasmodium falciparum , Espectrometría de Masas en Tándem , Equivalencia Terapéutica , Adulto JovenRESUMEN
Multiple sequence alignment (MSA) is a vital problem in biology. Optimal alignment of multiple sequences becomes impractical even for a modest number of sequences since the general version of the problem is NP-hard. Because of the high time complexity of traditional MSA algorithms, even today's fast computers are not able to solve the problem for large number of sequences. In this paper we present a randomized algorithm to calculate distance matrices, which is a major step in many multiple sequence alignment algorithms. The basic idea employed is sampling (along the lines of). We also illustrate how to parallelize this algorithm. In Section we introduce the problem of multiple sequence alignments. In Section we provide a discussion on various methods that have been employed in the literature for Multiple Sequence Alignment. In this section we also introduce our new sampling approach. We extend our randomized algorithm to the case of non-uniform length sequences as well. We show that our algorithms are amenable to parallelism in Section. In Section we back up our claim of speedup and accuracy with empirical data and examples. In Section we provide some concluding remarks.