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Bharathi Avula Babu L. Tekwani Narayan D. Chaurasiya NP Dhammika Nanayakkara Yan‐Hong Wang Shabana I. Khan Vijender R. Adelli Rajnish Sahu Mahmoud A. Elsohly James D. McChesney Ikhlas A. Khan Larry A. Walker 《Journal of mass spectrometry : JMS》2013,48(2):276-285
Therapeutic efficiency and hemolytic toxicity of primaquine (PQ), the only drug available for radical cure of relapsing vivax malaria are believed to be mediated by its metabolites. However, identification of these metabolites has remained a major challenge apparently due to low quantities and their reactive nature. Drug candidates labeled with stable isotopes afford convenient tools for tracking drug‐derived metabolites in complex matrices by liquid chromatography‐tandem mass spectrometry (LC‐MS‐MS) and filtering for masses with twin peaks attributable to the label. This study was undertaken to identify metabolites of PQ from an in vitro incubation of a 1:1 w/w mixture of 13C6‐PQ/PQ with primary human hepatocytes. Acquity ultra‐performance LC (UHPLC) was integrated with QTOF‐MS to combine the efficiency of separation with high sensitivity, selectivity of detection and accurate mass determination. UHPLC retention time, twin mass peaks with difference of 6 (originating from 13C6‐PQ/PQ), and MS‐MS fragmentation pattern were used for phenotyping. Besides carboxy‐PQ (cPQ), formed by oxidative deamination of PQ to an aldehyde and subsequent oxidation, several other metabolites were identified: including PQ alcohol, predictably generated by oxidative deamination of PQ to an aldehyde and subsequent reduction, its acetate and the alcohol's glucuronide conjugate. Trace amounts of quinone‐imine metabolites of PQ and cPQ were also detected which may be generated by hydroxylation of the PQ/cPQ quinoline ring at the 5‐position and subsequent oxidation. These findings shed additional light on the human hepatic metabolism of PQ, and the method can be applied for identification of reactive PQ metabolites generated in vivo in preclinical and clinical studies. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
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Wang C Soice NP Ramaswamy S Gagnon BA Umana J Cotoni KA Bian N Cheng KS 《Journal of chromatography. A》2007,1155(1):74-84
Agarose-based anion-exchangers (e.g. quaternary amine, Q) have been widely used in monoclonal antibody flow-through purification to remove trace levels of impurities. Such media are often packed in a large column and the operation is usually robust but with limited throughput due to the compressibility of agarose and consequentially low bed permeability. In order to address this limitation, cored Q beads consisting of a rigid core and a thin agarose gel coating were developed and evaluated for protein flow-through chromatography. Using laboratory-scale columns it was found that, the cored beads indeed provide significantly enhanced rigidity and flow permeability relative to conventional homogeneous agarose resins. Depending on the structure and size of the cored beads, the permeability was 2-4-fold higher than that of a commonly used commercial agarose resin. Good virus and host cell protein clearance was achieved with the cored Q beads even at increased flow velocities. In addition, the impermeable core allows for more efficient use of buffers without loss of useful capacity in polishing applications. Process analyses based upon the experimental data demonstrated that the enhanced permeability achieved with the cored beads can significantly improve process throughput and economics. 相似文献
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Woo M Khan NZ Royce J Mehta U Gagnon B Ramaswamy S Soice N Morelli M Cheng KS 《Journal of chromatography. A》2011,1218(32):5386-5392
A novel anion exchange membrane adsorber is presented which shows excellent impurity removal under different buffer conductivities ranging from 2 to 2 7mS/cm. The membrane utilizes a primary amine ligand (polyallylamine) and was designed specifically to bind impurities at high salt concentrations. Studies with DNA, endotoxin, and virus spiked into buffer at varying salt conditions were done, resulting in clearance of >3, 4, and 4 LRV, respectively, with negligible change on increasing salt up to 27 mS/cm conductivities. Verification of virus removal in mAb feedstocks is also shown. The data are compared with other membrane adsorbers and a conventional resin which utilize traditional chemistries to demonstrate improved purification performance with the primary amine ligand. Additional data on scale-up of the membrane adsorber device is discussed. A stacked flat-sheet design was implemented to ensure linear scale-up of performance using bovine serum albumin (BSA) as a model. The linearly scalable device, coupled with the highly effective membrane for virus, DNA, and endotoxin removal, represents a step forward in polishing technology for the purification of monoclonal antibodies and recombinant proteins. 相似文献
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Unsteady flow in a semi-infinite contracting or expanding pipeis reinvestigated using long series analysis. The proposed seriesmethod is useful in analysing the problem for a moderately largeconstant ( = aa/, where a = a(t), the radius of the pipe isa function of time, a(t) is the velocity of the wall, and iskinematic viscosity). For positive values of (expansion ofthe pipe) accuracy of the series representing shear stress andpressure gradient is increased from = 2.89 to = 6.0 by extractingthe singularity followed by completion of the series. For negativevalues of (contraction of the pipe), we revert the series whichresults into the increase of the region of validity of the transposedseries from = -25.0 to = -2.89. Later we use Padé approximantsfor summing them. Also, the asymptotic solution for large valuesof is obtained and it agrees closely with pure numerical valuesof shear stress at the wall and pressure gradient. 相似文献
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