George Miles

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The in vitro metabolism of [(14)C]-gefitinib (1-3 microM) was investigated using human liver microsomes and a range of expressed human cytochrome P450 enzymes, with particular focus on the formation of O-desmethyl-gefitinib (M523595), the major metabolite observed in human plasma. High-performance liquid chromatography with ultraviolet light, radiochemical(More)
The gene encoding hemolysin II (HlyII) was amplified from Bacillus cereus genomic DNA and a truncated mutant, HlyII(DeltaCT), was constructed lacking the 94 amino acid extension at the C terminus. The proteins were produced in an E. coli cell-free in vitro transcription and translation system, and were shown to assemble into SDS-stable oligomers on rabbit(More)
The genes encoding the F and S components of a leukocidin, LukF (HlgB) and LukS (HlgC), a pore-forming binary toxin, were amplified from the Smith 5R strain of Staphylococcus aureus both with and without sequences encoding 3'-hexahistidine tags. The His-tagged components were expressed in Escherichia coli and purified under nondenaturing conditions. In(More)
Staphylococcal alpha-hemolysin (alphaHL) is a beta barrel pore-forming toxin that is secreted by the bacterium as a water-soluble monomeric protein. Upon binding to susceptible cells, alphaHL assembles via an inactive prepore to form a water-filled homoheptameric transmembrane pore. The N terminus of alphaHL, which in the crystal structure of the fully(More)
The in vitro metabolism of gefitinib was investigated by incubating [14C]-gefitinib, as well as M537194, M387783 and M523595 (the main metabolites of gefitinib observed in man), at a concentration of 100 microM with human liver microsomes (4 mg ml(-1)) for 120 min. These relatively high substrate and microsomal protein concentrations were used in an effort(More)
BACKGROUND Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH. OBJECTIVES To identify risk factors associated with mortality and to estimate the expected survival in a(More)
Staphylococcal leukocidin pores are formed by the obligatory interaction of two distinct polypeptides, one of class F and one of class S, making them unique in the family of beta-barrel pore-forming toxins (beta-PFTs). By contrast, other beta-PFTs form homo-oligomeric pores; for example, the staphylococcal alpha-hemolysin (alpha HL) pore is a homoheptamer.(More)
The absorption, metabolism, and excretion of 14C-labeled xamoterol (ICI 118,587) has been examined in mice, rats, rabbits, dogs, and humans. There was incomplete absorption by all species after oral administration, ranging from 9% by humans to 36% by dogs. Most of the absorbed radioactivity was eliminated within 24 hr of administration and the renal route(More)
Staphylococcal leukocidin (Luk) and alpha-hemolysin (alphaHL) are members of the same family of beta barrel pore-forming toxins (betaPFTs). Although the alphaHL pore is a homoheptamer, the Luk pore is formed by the co-assembly of four copies each of the two distantly related polypeptides, LukF and LukS, to form an octamer. Here, we examine N- and C-terminal(More)
1. Xamoterol has been administered both intravenously and orally over a 100-fold dose range to male beagle dogs. 2. Over the dose range examined, sulphation was not saturable, with the proportion of the dose excreted as the sulphate conjugate remaining constant. 3. Extensive first-pass sulphation of an oral dose of xamoterol occurred in the intestine with(More)