The Experts below are selected from a list of 75 Experts worldwide ranked by ideXlab platform
David S. Hage - One of the best experts on this subject based on the ideXlab platform.
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Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2004Co-Authors: Jianzhong Chen, Corey M. Ohnmacht, David S. HageAbstract:High-performance affinity chromatography was used to study the binding of phenytoin to an immobilized human serum albumin (HSA) column. This was accomplished through frontal analysis and competitive binding zonal elution experiments, the latter of which used four probe compounds for the major and minor binding sites of HSA injected into the presence of mobile phases containing known concentrations of phenytoin. It was found that phenytoin can interact with HSA at the warfarin-Azapropazone, indole-benzodiazepine, tamoxifen, and digitoxin sites of this protein. The association constants for phenytoin at the indole-benzodiazepine and digitoxin sites were determined to be 1.04 (+/-0.05) x 10(4)M(-1) and 6.5 (+/-0.6) x 10(3)M(-1), respectively, at pH 7.4 and 37 degrees C. Both allosteric interactions and direct binding for phenytoin appear to take place at the warfarin-Azapropazone and tamoxifen sites. This rather complex binding system indicates the importance of identifying the binding regions on HSA for specific drugs as a means for understanding the transport of such substances in blood and in characterizing their potential for drug-drug interactions.
Jianzhong Chen - One of the best experts on this subject based on the ideXlab platform.
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Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2004Co-Authors: Jianzhong Chen, Corey M. Ohnmacht, David S. HageAbstract:High-performance affinity chromatography was used to study the binding of phenytoin to an immobilized human serum albumin (HSA) column. This was accomplished through frontal analysis and competitive binding zonal elution experiments, the latter of which used four probe compounds for the major and minor binding sites of HSA injected into the presence of mobile phases containing known concentrations of phenytoin. It was found that phenytoin can interact with HSA at the warfarin-Azapropazone, indole-benzodiazepine, tamoxifen, and digitoxin sites of this protein. The association constants for phenytoin at the indole-benzodiazepine and digitoxin sites were determined to be 1.04 (+/-0.05) x 10(4)M(-1) and 6.5 (+/-0.6) x 10(3)M(-1), respectively, at pH 7.4 and 37 degrees C. Both allosteric interactions and direct binding for phenytoin appear to take place at the warfarin-Azapropazone and tamoxifen sites. This rather complex binding system indicates the importance of identifying the binding regions on HSA for specific drugs as a means for understanding the transport of such substances in blood and in characterizing their potential for drug-drug interactions.
C. J. L. Lock - One of the best experts on this subject based on the ideXlab platform.
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Do you really know what your drug looks like or how it reacts?
InflammoPharmacology, 1996Co-Authors: C. J. L. LockAbstract:Modern spectroscopic and single crystal X-ray diffraction techniques have been applied to the study of drug molecules. Usually drugs are very well characterized but occasionally partial sets of data have been misinterpreted, or the drug has been in use for a long time and was never well characterized. Most of the gold-based drugs used in the treatment of rheumatoid arthritis lie in the latter group. Two drugs will be used as examples, one from each group. From the former group the drug Azapropazone has been chosen. On the basis of proton NMR spectroscopy a non-chiral planar structure has been reported, although three other postulates of the structure have also been reported. X-ray diffraction and variable temperature proton NMR studies show that none of the previous postulates were correct. The molecule is chiral, although inversion takes place rapidly at room temperature in solution. Further studies of chemical transformation products of Azapropazone also show that structural formulations based on proton NMR spectroscopy were incorrect. From the second group the drug gold sodium thiomalate has been chosen. A review of all the work on the structure of this drug will be given. Most techniques are uninformative, in particular proton NMR spectroscopy. A definitive structure has still not been established, although it will be shown that a combination of X-ray diffraction and electrospray mass spectrometry has given considerable insight into what might be the correct structure.
Corey M. Ohnmacht - One of the best experts on this subject based on the ideXlab platform.
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Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2004Co-Authors: Jianzhong Chen, Corey M. Ohnmacht, David S. HageAbstract:High-performance affinity chromatography was used to study the binding of phenytoin to an immobilized human serum albumin (HSA) column. This was accomplished through frontal analysis and competitive binding zonal elution experiments, the latter of which used four probe compounds for the major and minor binding sites of HSA injected into the presence of mobile phases containing known concentrations of phenytoin. It was found that phenytoin can interact with HSA at the warfarin-Azapropazone, indole-benzodiazepine, tamoxifen, and digitoxin sites of this protein. The association constants for phenytoin at the indole-benzodiazepine and digitoxin sites were determined to be 1.04 (+/-0.05) x 10(4)M(-1) and 6.5 (+/-0.6) x 10(3)M(-1), respectively, at pH 7.4 and 37 degrees C. Both allosteric interactions and direct binding for phenytoin appear to take place at the warfarin-Azapropazone and tamoxifen sites. This rather complex binding system indicates the importance of identifying the binding regions on HSA for specific drugs as a means for understanding the transport of such substances in blood and in characterizing their potential for drug-drug interactions.
K. D. Rainsford - One of the best experts on this subject based on the ideXlab platform.
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Protection from gastrointestinal side-effects by Azapropazone by its incorporation into a glucose-sodium acid citrate formulation.
Alimentary pharmacology & therapeutics, 2007Co-Authors: K. D. Rainsford, F. S. Walker, Paul Dieppe, M. H. Pritchard, John Rhodes, H. Leach, R. I. Russell, R. Upadhyay, J. F. HortAbstract:Addition of glucose and sodium citrate to Azapropazone, in proportions of 1:1:1 by weight reduced gastric mucosal damage in rats and there was a trend towards reduction in radiolabelled faecal red cell loss in human volunteers compared with that with Azapropazone alone. The glucose and citrate did not affect the pharmacokinetics of Azapropazone, or its therapeutic efficacy. While no difference was observed in endoscopic injury and in symptomatic gastrointestinal complaints in a multicentre comparison in rheumatic patients, a striking reduction in symptoms was observed in those patients with a history of severe gastrointestinal intolerance to non-steroidal anti-inflammatory drugs.
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Do NSAIDs Adversely Affect Joint Pathology in Osteoarthritis
Side Effects of Anti-Inflammatory Drugs IV, 1997Co-Authors: F. S. Walker, K. D. RainsfordAbstract:Shortly after the market introduction of NSAIDs in the UK, there were several reports that these drugs accelerate the progression of the osteoarthritis (OA) disease process. There have been suggestions that this effect may be related to dose and to duration of administration. In animal work, it has been shown that NSAIDs have little effect on normal loaded joints but that they diminish cartilage metabolism in diseased joints. Our hypothesis proposes that NSAIDs adversely affect joint pathology in OA by affecting prostaglandin-regulation of cartilage proteoglycans, enhancing interleukin-1 production and attenuating vasodilation, so reducing the OA-enhanced joint perfusion and reducing the repair process. These effects combine to increase the progression of the OA pathology in subjects receiving potent prostaglandin synthesis. To test this hypothesis studies were performed in two phases to examine the long-term effects of treatment of OA patients with NSAIDs of varying potency as prostaglandin-synthesis inhibitors and differing effects on other molecular and cellular events in inflammation. In Phase I, 105 OA patients awaiting hip arthroplasty were treated prospectively with a strong or a weak prostaglandin synthesis inhibitor, indomethacin or Azapropazone respectively. In Phase II subjects received diclofenac, naproxen, piroxicam, tiaprofenic acid or the analgesics, dextropropoxyphene and paracetamol. A few patients elected for no treatment. In both phases, pain and radiological joint space were monitored up to the arthroplasty, following which the histology of the excised femoral head was determined. As judged by histopathological data, the treatment groups in both Phase I and Phase II had similar pain relief from all the drugs and were at a similar pathophysiological end-point when they came to arthroplasty. In the indomethacin group, the ‘affected’ hips lost joint space more rapidly than did the contralateral hips, a difference not seen in the Azapropazone group. The patients receiving Azapropazone who had higher synovial concentrations of vasodilator prostaglandin E2 took longer than the indomethacin group to reach the arthroplasty end-point. The patients in Phase II all appeared to have the same progression in OA as one another, and these appeared similar to those in the indomethacin group in Phase I.
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Studies of nonsteroidal anti-inflammatory drugs: Azapropazone
Canadian Journal of Chemistry, 1994Co-Authors: Theresa Fauconnier, Russell A. Bell, Colin Jl Lock, James F. Britten, K. D. RainsfordAbstract:The structure of Azapropazone, 5-(dimethylamino)-9-methyl-2-propyl-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione, was determined by single crystal X-ray diffraction. Crystals were orthorhombic (P212121), with a = 5.570(1) A, b = 14.593(3) A, c = 19.270(4) A, and Z = 4. Intensities were measured on a Rigaku AFC6-R diffractometer with Cu-Kα radiation and 2316 reflections were used to determine the structure. Contrary to previous postulates, the tricyclic portion of the molecule is not planar. Azapropazone is a zwitterion with the negative charge delocalized over the β-keto-enol system and with the proton on N(6) of the triazine ring. The nonplanarity of the molecule is caused by steric interaction of a methyl group on the exocyclic dimethylamino group with O(3) of the keto-enol system. Bond lengths and angles are normal. NMR studies showed that at room temperature rapid inversion occurs between the two enantiomers, but this inversion slows at low temperatures with ΔG≠ = 44.9(2) kJ mol−1. The product ...