Keywords 1′-hydroxymidazolam, 4-hydroxymidazolam, glucuronidation, in vitro metabolism, in vivo metabolism, midazolam ---------------------------------------------------------------------- Received WHAT THIS STUDY ADDS• N-glucuronide of midazolam has been quantified in human urine, indicating for the first time that this route of metabolism occurs in vivo.• Metabolism of 4-hydroxymidazolam has been compared with that of 1′-hydroxymidazolam in vitro.• This study provides further evidence, in vitro and in vivo, of the importance of N-glucuronidation in the metabolism of midazolam and its metabolites. AIMSMidazolam (MDZ) is a benzodiazepine used as a CYP3A4 probe in clinical and in vitro studies. A glucuronide metabolite of MDZ has been identified in vitro in human liver microsome (HLM) incubations. The primary aim of this study was to understand the in vivo relevance of this pathway. METHODSAn authentic standard of N-glucuronide was generated from microsomal incubations and isolated using solid-phase extraction. The structure was confirmed using proton nuclear magnetic resonance (NMR) and RESULTSNMR data confirmed conjugation of midazolam N-glucuronide (MDZG) standard to be on the a-nitrogen of the imidazole ring. In vivo, MDZG in the urine accounted for 1-2% of the administered dose. In vitro incubations confirmed UGT1A4 as the enzyme of interest. The pathway exhibited atypical kinetics and a substrate inhibitory cooperative binding model was applied to determine Km (46 mM, 64 mM), Vmax (445 pmol min -1 mg -1, 427 pmol min -1 mg -1) and Ki (58 mM, 79 mM) in HLM and rUGT1A4, respectively. From incubations with HLM and rUGT enzymes, N-glucuronidation of 1′-OH MDZ and 4-OH MDZ is also inferred. CONCLUSIONSA more complete picture of MDZ metabolism and the enzymes involved has been elucidated. Direct N-glucuronidation of MDZ occurs in vivo. Pharmacokinetic modelling using Simcyp™ illustrates an increased role for UGT1A4 under CYP3A inhibited conditions.

This article examines diplomatic relations between England and the Italian duchy of Savoy during the 1620s through the Savoyard ambassador, Alessandro Scaglia. Historians have generally viewed England’s participation in the Thirty Year’s War from an essentially English viewpoint, underplaying as a result the critical importance of the Anglo-French and Anglo-Spanish wars to Savoy. The article argues that Scaglia drew upon dynastic affinities between the Stuart and Savoyard ruling families and on his own qualities to cultivate friends at the English court, principally the duke of Buckingham. These friends, in turn, increased Scaglia’s influence which established him as a leading mediator in England’s wars. This was crucial in providing leverage against France and Spain in Savoy’s sphere of territorial interest in north Italy. The article shows how this strategy ultimately broke down with the reconfiguration in English foreign policy following Buckingham’s death, and the impact this had on the war for Mantua and Monferrat in north Italy.

T. (2007) 'Van Dyck, Alessandro Scaglia and the Caroline court : friendship, collecting and diplomacy in the early seventeenth century.', The seventeenth century., 22 . pp. 24-41. Further information on publisher's website: http://journals.mup.man.ac.uk/cgi-bin/MUP?COMval=journalkey=SVCPublisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details.

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The essays in this collection explore diplomacy as a form of cultural translation. Out of necessity, Europeans sought new ways of conducting diplomacy in the changing environment of the early modern world, as they grappled with challenges from within their old but crumbling respublica christiana, and also with changing relations with powers and communities beyond it. Reflecting the current vitality of research into early modern diplomacy and practice that has extended the boundaries of what we consider as constituting “diplomacy,” these essays collectively examine how Europeans, on state and sub-state levels, interacted with powers from the Near East, Asia and Africa. In doing so, they contribute to a more nuanced understanding of how increasingly globalized diplomatic agents deployed symbolic and rhetorical languages that could be shared amongst different participants.