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The disposition kinetics study of cefquinome was conducted following single intravenous (IV) administration of 2mg/kg bodyweight in buffalo calves after oral subchronic exposure to flubendiamide and to determine the in vitro plasma protein binding of cefquinome. Plasma concentrations of cefquinome were analyzed using reverse-phase high performance liquid chromatography (HPLC). The results were compared with our earlier study on the pharmacokinetics of cefquinome in untreated buffalo calves. Plasma concentration-time data for cefquinome following IV injection were best fit into a two-compartmental open model in flubendiamide-exposed buffalo calves. Following flubendiamide exposure, most of the pharmacokinetic parameters of cefquinome were significantly altered in buffalo calves. Cefquinome was bound to plasma proteins of buffalo calves to the extent of 11.4±0.66%. In flubendiamide-exposed animals an intravenous dose of 2mg/kg body weight would maintain the therapeutic plasma levels required to be effective against the bacterial pathogens with MIC values ≤0.39μg/mL for only 12h, whereas in untreated buffalo calves the same dose of 2mg/kg body weight would maintain the plasma levels up to 24h, The study revealed that subchronic flubendiamide exposure significantly alters the disposition of cefquinome in buffalo calves., (Copyright © 2014 Elsevier B.V. All rights reserved.)

An optical nanobiosensor is presented using a fluorescent dye and anti-E. coli McAb anchored Ag@Silica core shell nanoparticles, for rapid and sensitive Escherichia coli detection in environmental samples. The synthesized dual labeled core shell (DLCS) nanoparticle shows intense fluorescence at 620 nm in solution, having a narrow emission with full width at half maxima (FWHM) of 10 nm, as a prerequisite to develop a sensitive detection platform for various biosensing applications. The specific E. coli was captured using an anti-E. coli antibody functionalized quartz glass, followed by a treatment with DLCS, where the photoluminescence spectroscopy was used to detect the target pathogen. The fabrication of the quartz glass based optical-immunosensor was monitored, and the results show changes in the photoluminescent patterns, which substantiate that varied species were immobilized on the surface of the antibody modified quartz glass. Consequently, the optical immunosensor demonstrated specificity and improved sensitivity, as compared to the customary methods, and was able to detect as low as 5CFU/mL. The developed DLCS based optical immunosensor was evaluated with environmental water samples, which showed acceptable precision, reproducibility and stability, and could be readily applied to the routine monitoring of pathogenic microorganisms in the environmental samples, and most importantly, demonstrate the potential of a prototype development of a simple and inexpensive diagnostic technique., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Lincomycin 10 mg kg(-1), IV in buffalo calves followed two-compartment open model with high distribution rate constant α (11.2 ± 0.42 h(-1)) and K 12/K 21 ratio (4.40 ± 0.10). Distribution half-life was 0.06 ± 0.01 h and AUC was 41.6 ± 1.73 μg mL(-1) h. Large Vdarea (1.15 ± 0.03 L kg(-1)) indicated good distribution of lincomycin in various body fluids and tissues. Peak plasma level of lincomycin (71.8 ± 1.83 μg mL(-1)) was observed at 1 min as expected by IV route. The elimination half-life and MRT of lincomycin were short (3.30 ± 0.08 and 4.32 ± 0.11 h, respectively). Lincomycin 10 mg kg(-1) IV at 12-h interval would be sufficient to maintain T > MIC above 60 % for bacteria with minimum inhibitory concentrations (MIC) values ≤1.6 μg mL(-1). Favourable pharmacokinetic profile in buffalo calves and a convenient dosing interval suggest that lincomycin may be an appropriate antibacterial in buffalo species for gram-positive and anaerobic bacterial pathogens susceptible to lincomycin.

Previously reported pyrrolones, such as TDR32570, exhibited potential as antimalarial agents; however, while these compounds have potent antimalarial activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure-activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, further modifications to the lead pyrrolone, involving replacement of a phenyl ring with a piperidine and removal of a potentially metabolically labile ester by a scaffold hop, gave rise to derivatives with improved in vitro antimalarial activities against Plasmodium falciparum K1, a chloroquine- and pyrimethamine-resistant parasite strain, with some derivatives exhibiting good selectivity for parasite over mammalian (L6) cells. Three representative compounds were selected for evaluation in a rodent model of malaria infection, and the best compound showed improved ability to decrease parasitaemia and a slight increase in survival., (© 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC(50) ~ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.

Core-shell dendrimers consisting of poly(propyleneimine) (PPI) dendrimer as a core and poly(amidoamine) (PAMAM) dendrons as a shell have been synthesized through the route of Michael addition reaction followed by amidation. These macromolecules were investigated their ability to solubilize a guest molecule, pyrene. The number of encapsulated pyrene molecules per dendrimer increased with pH of a solution and generation (G) of PAMAM dendron, and it reached 2.7 for PPI(G3)-core:PAMAM(G3)-shell dendrimer at pH 11. It was confirmed that the solubilized pyrene located in the hydrophobic nanocavities of the PPI dendrimer core in the dendrimer. The shrunk PAMAM dendron shell should play a role of retention fence of doped molecules.

Several newer 6-fluoro/nitro-4-oxo-7-(sub)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids (10-11a-q) were synthesised from 3,4-difluoro aniline and 3-fluoro-4-nitro aniline by nine-step synthesis. The compounds were evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multidrug-resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) as well as being tested for their ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesised compounds, 7-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-6-nitro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (11l) was found to be the most active compound in vitro, with minimum inhibitory concentrations (MICs) of 0.09 microM and <0.09 microM against MTB and MTR-TB, respectively. Compound 11l was found to be 4 times and >506 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model, 11l decreased the bacterial load in lung and spleen tissues by 30% and 42%, respectively, at a dose of 50 mg/kg body weight.