Optimisation of pharmacokinetic properties in a neutral series of 11ß-HSD1 inhibitors.

11ß-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11ß-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.

Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes.

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.

Serious hazards of transfusion: a decade of hemovigilance in the UK.

The Serious Hazards of Transfusion (SHOT) scheme is a UK-wide, independent, professionally led hemovigilance system focused on learning from adverse events. SHOT was established in 1996 as a confidential reporting system for significant transfusion-related events, building an evidence base to support blood safety policy decisions, clinical guidelines, clinician education, and improvements in transfusion practice. Recommendations are formulated by an independent steering group drawn from medical royal colleges and professional bodies. Ten years after its inception, SHOT has analyzed 2630 transfusion safety events, published 8 annual reports with recommendations, and presented data nationally and internationally. These recommendations have underpinned key initiatives, in particular the UK Department of Health "Better Blood Transfusion" strategy. SHOT has encouraged open reporting of adverse events and "near-misses" in a supportive, learning culture, vigilance in hospital transfusion practice, and evaluation of information technology to support this process. The importance of education and training has been emphasized. Detailed analysis of events has identified weaknesses in the transfusion chain. A collaborative initiative between SHOT, the Chief Medical Officer for England's National Blood Transfusion Committee, and the National Patient Safety Agency aims to reduce ABO-incompatible transfusions by improving bedside practice. Cumulative SHOT data have documented the decline in transfusion-related graft vs host disease after implementation of leucodepletion and have highlighted transfusion-related acute lung injury and bacterial contamination of platelets as important causes of death and morbidity. The UK blood services have developed strategies to reduce these risks. Future SHOT data will evaluate the success of these and other blood safety improvements.

Discovery of a potent, selective, and orally bioavailable acidic 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitor: discovery of 2-[(3S)-1-[5-(cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic acid (AZD4017).

Inhibition of 11ß-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11ß-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.

Do we really need to routinely crossmatch blood before primary total knee or hip arthroplasty?

BACKGROUND: A maximum surgical blood ordering schedule may lead to wastage of valuable resources due to over-ordering of blood and/or under-utilisation. We audited the results of a group-and-save (GS) policy for primary hip (THR) and knee (TKR) arthroplasty to evaluate its safety and practicality. PATIENTS AND METHODS: We conducted a retrospective review of consecutive patients attending for THR (177) or TKR (137) over a period of 8 months (phase 1). Following introduction of a limited GS policy, 205 THR and 147 TKR were reviewed prospectively over a corresponding period of 8 months (phase 2). Corresponding THR and TKR groups in each phase were comparable with respect to age, gender, length of stay, operating surgeon, pre- and lowest postoperative hemoglobin, reason for and timing of transfusion. Quantities (units) of blood requested pre- and postoperatively, transfused and returned to the blood bank, were recorded. RESULTS: 77 and 62% of all blood requested for THR and TKR, respectively, in phase 1 was not used. 58 and 21% of patients undergoing THR and TKR, respectively, in phase 2 underwent preoperative GS, with 92% and 100% of all blood requested being used for transfusion. Overall, the quantity of blood returned was reduced by 25% for the THR group. Transfusion rates fell by 9% and 5% for the TKR and THR groups, respectively. We found no adverse events associated with blood from a GS sample. Cost savings of 37 800 euro were calculated estimated for the study period (phase 2). INTERPRETATION: For routine primary THR/TKR, GS policy is a safe procedure. Reduction in non-utilisation of blood has economic and cost-saving implications for limited healthcare resources. Having subsequently introduced a group-and-save policy for all patients undergoing routine THR/TKR, considerable savings have been identified after only 2 months.