A series of pyrazolo(dihydro)pyridines was synthesized and evaluated for antileishmanial efficacy against experimental visceral leishmaniasis (VL). Among all compounds, 6d and 6j exhibited better activity than miltefosine against intracellular amastigotes. Compound 6j (50 mg/kg/day) was further studied against Leishmania donovani/BALB/c mice via the intraperitoneal route for 5 days and displayed >91 and >93% clearance of splenic and liver parasitic burden, respectively. Combination treatment of 6j with a subcurative dose of miltefosine (5 mg/kg) in BALB/c mice almost completely ameliorated the disease (>97% inhibition) by augmenting nitric oxide generation and shifting the immune response toward Th1. Furthermore, investigating the effect of 6j on Leishmania promastigotes revealed that it induced molecular events, such as a loss in mitochondrial membrane potential, externalization of phosphatidylserine, and DNA fragmentation, that ultimately resulted in the programmed cell death of the parasite. These results along with pharmacokinetic studies suggest that 6j could be a promising lead for treating VL as an adjunct therapy with miltefosine.
Blood and plasma are the biomatrices traditionally used for drug monitoring and their pharmacokinetic profiling. Blood is the circulating fluid in contact with all organs and tissues of body and thus is the most representative fluid for measuring systemic drug levels. However, venipuncture suffers from the caveat of being an invasive technique which often makes people reluctant to participate in clinical studies. Thus, there is a need for noninvasive bio-fluids that are ethically appropriate, cost-efficient and toxicologically relevant. These alternate bio-fluids may prove clinically useful as alternatives to plasma/serum in therapeutic drug monitoring, pharmacokinetic and toxicokinetic studies, doping control in sports medicine and to monitor local adverse effects. These may be of particular interest in the case of special population groups such as neonates, children, the elderly, terminally ill patients and pregnant or lactating women, and offer the advantage of circumvention of the demand for specialized personnel for sample collection. This review describes such noninvasive bio-fluids (saliva, sweat, tears and milk) that have been considered for pharmacokinetic drug analysis, emphasizing their sample preparation, its associated difficulties and their correlation with plasma.
This study identified koenidine (4) as a metabolically stable antidiabetic compound, when evaluated in a rodent type 2 model (leptin receptor-deficient db/db mice), and showed a considerable reduction in the postprandial blood glucose profile with an improvement in insulin sensitivity. Biological studies were directed from the preliminary in vitro evaluation of the effects of isolated carbazole alkaloids (1-6) on glucose uptake and GLUT4 translocation in L6-GLUT4myc myotubes, followed by an investigation of their activity (2-5) in streptozotocin-induced diabetic rats. The effect of koenidine (4) on GLUT4 translocation was mediated by the AKT-dependent signaling pathway in L6-GLUT4myc myotubes. Moreover, in vivo pharmacokinetic studies of compounds 2 and 4 clearly showed that compound 4 was 2.7 times more bioavailable than compound 2, resulting in a superior in vivo efficacy. Therefore, these studies suggested that koenidine (4) may serve as a promising lead natural scaffold for managing insulin resistance and diabetes.
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