Appraisal of Australian and New Zealand paediatric sepsis guidelines.

OBJECTIVE: Clinical practice guidelines (CPGs) are an important tool for the management of children with sepsis. The quality, consistency and concordance of Australian and New Zealand (ANZ) childhood sepsis CPGs with the Australian Commission on Safety and Quality in Healthcare (ACSQHC) sepsis clinical care standards and international sepsis guidelines is unclear. METHODS: We accessed childhood sepsis CPGs for all ANZ states and territories through Paediatric Research in Emergency Departments International Collaborative members. The guidelines were assessed for quality using the AGREE-II instrument. Consistency between CPG treatment recommendations was assessed, as was concordance with the ACSQHC sepsis clinical care standards and international sepsis guidelines. RESULTS: Overall, eight CPGs were identified and assessed. CPGs used a narrative and pathway format, with those using both having the highest quality overall. CPG quality was highest for description of scope and clarity of presentation, and lowest for editorial independence. Consistency between guidelines for initial treatment recommendations was poor, with substantial variation in the choice and urgency of empiric antimicrobial administration; the choice, volume and urgency of fluid resuscitation; and the choice of first-line vasoactive agent. Most CPGs were concordant with time-critical components of the ACSQHC sepsis clinical care standard, although few addressed post-acute care. Concordance with international sepsis guidelines was poor. CONCLUSION: Childhood sepsis CPGs in current use in ANZ are of variable quality and lack consistency with key treatment recommendations. CPGs are concordant with the ACSQHC care standard, but not with international sepsis guidelines. A bi-national sepsis CPG may reduce unnecessary variation in care.

Confidential consultations with adolescents: an exploration of Australian parents' perspectives.

PURPOSE: Extensive literature documents the high value adolescents place on seeing doctors alone for confidential health care. This is articulated in clinical guidelines that promote confidentiality for adolescents. However, little research has explored parents' views and beliefs regarding their adolescent children seeing doctors alone for confidential care. METHOD: A qualitative study was undertaken to investigate the beliefs and opinions of parents about confidential care for adolescents. In-depth semi-structured interviews were conducted with 17 parents of adolescents recruited through the Centre for Adolescent Health at the Royal Children's Hospital in Melbourne, Australia. Interviews were audio-recorded and transcribed verbatim. Transcripts were analyzed using content and thematic analyses. RESULTS: Parents demonstrated a wide variety of opinions about confidentiality for adolescents in the health setting, with several expressing concern about not being involved in their children's care. Parents' opinions appeared to be underpinned by two key factors; the way in which they perceived their role as a parent and the level of trust they held in health professionals generally but also, specifically, their child's doctor. CONCLUSION: In this study, parental desires regarding confidentiality for their adolescent children in the health setting were not always in accordance with current guidance provided to health professionals. Consequently, the provision of confidential care for young people may be more successful if health professionals invest in building trust with parents, as well as with adolescents, to facilitate parental acceptance of confidential health care for adolescents.

Discovery of GSK1997132B a novel centrally penetrant benzimidazole PPARγ partial agonist.

The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.

Structure guided design of 5-arylindazole glucocorticoid receptor agonists and antagonists.

Glucocorticoid receptor (GR) agonists have been used for more than half a century as the most effective treatment of acute and chronic inflammatory conditions despite serious side effects that accompany their extended use that include glucose intolerance, muscle wasting, skin thinning, and osteoporosis. As a starting point for the identification of GR ligands with an improved therapeutic index, we wished to discover selective nonsteroidal GR agonists and antagonists with simplified structure compared to known GR ligands to serve as starting points for the optimization of dissociated GR modulators. To do so, we selected multiple chemical series by structure guided docking studies and evaluated GR agonist activity. From these efforts we identified 5-arylindazole compounds that showed moderate binding to the glucocorticoid receptor (GR) with clear opportunities for further development. Structure guided optimization was used to design arrays that led to potent GR agonists and antagonists. Several in vitro and in vivo experiments were utilized to demonstrate that GR agonist 23a (GSK9027) had a profile similar to that of a classical steroidal GR agonist.

The identification a novel, selective, non-steroidal, functional glucocorticoid receptor antagonist.

The identification of novel, potent, non-steroidal/small molecule functional GR antagonist GSK1564023A selective over PR is described. Associated structure-activity relationships and the process of optimisation of an initial HTS hit are also described.

Piperidine-derived gamma-secretase modulators.

This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.

Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.

Aryl aminopyrazole benzamides as oral non-steroidal selective glucocorticoid receptor agonists.

Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).