Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

"Stay balanced" - effectiveness of evidence-based balance training for older adults transferred into a physical therapy primary care setting - a pilot study.

Purpose: To evaluate the effects of the Stay Balanced program when this is transferred into a clinical setting regarding balance, gait speed, leg muscle strength, concerns about falling, and physical activity.Method: Implementation pilot study with a pre-post intervention design. Fifteen older adults, 75-91 years of age, participated in a progressive balance training program with a focus on divided attention. The balance training was performed in group sessions twice a week for 10 weeks at a primary care physical therapy clinic. Training efficacy was evaluated after completion of training as well as after 3 months using the Mini-Balance Evaluation Systems Test (Mini-BESTest), 10-meter walk test, 30-s chair stand test, Fall Efficacy Scale-International (FES-I), and steps/day.Results: Significant improvements were shown at the 10-week follow up for balance, gait speed, leg muscle strength, and concerns about falling (p < 0.008). At the 3-month follow-up balance, leg muscle strength and concerns about falling showed persistent improvement compared to baseline (p < 0.045). No significant differences were found for physical activity.Conclusions: This study confirms the results of our previous randomized controlled trials (RCTs), and suggests that the Stay Balanced program can be transferred to clinical physiotherapy practice. The program was appreciated by the participants and proved to be safe, effective, and feasible in primary care.Implication for rehabilitationThe Stay Balance program can easily be transferred to clinical practice without losing the effectiveness of the intervention in older adults with balance problems.The program was appreciated by the participants and proved to be safe, effective, and feasible when executed in primary care.Stay Balance program is an individually adjusted and progressive group balance training including exercises with divided attention that can easily be transferred to tasks in daily life.

Montelukast Disposition: No Indication of Transporter-Mediated Uptake in OATP2B1 and OATP1B1 Expressing HEK293 Cells.

Clinical studies with montelukast show variability in effect and polymorphic OATP2B1-dependent absorption has previously been implicated as a possible cause. This claim has been challenged with conflicting data and here we used OATP2B1-transfected HEK293 cells to clarify the mechanisms involved. For montelukast, no significant difference in cell uptake between HEK-OATP2B1 and empty vector cell lines was observed at pH 6.5 or pH 7.4, and no concentration-dependent uptake was detected. Montelukast is a carboxylic acid, a relatively potent inhibitor of OATP1B1, OATP1B3, and OATP2B1, and has previously been postulated to be actively transported into human hepatocytes. Using OATP1B1-transfected HEK293 cells and primary human hepatocytes in the presence of OATP inhibitors we demonstrate for the first time that active OATP-dependent transport is unlikely to play a significant role in the human disposition of montelukast.

A novel matrix for the short-term storage of cells: utility in drug metabolism and drug transporter studies with rat, dog and human hepatocytes.

1. The SureTran matrix is a novel method facilitating short-term maintenance of fresh primary hepatocyte cellular function and offers the potential use of primary cells "as fresh" for several days post isolation. In the study presented, the maintenance of several key phase I and II drug metabolizing enzyme and drug transporter activities is demonstrated with rat and dog hepatocytes preserved for up to 7 days after cell isolation. 2. Intrinsic clearance values were determined for 60 new chemical entities using rat hepatocytes freshly isolated at AstraZeneca and rat hepatocytes prepared at the facilities of Abcellute Ltd (SureTran purveyors), stored and incubated 24 hours after isolation. A very good correspondence in the intrinsic clearance values underlines the utility of the cell maintenance matrix. 3. For human hepatocytes many of the enzyme activities assayed were well maintained for 7 days of storage but some declined to below 50% of initial values between day 4 and 7 of storage. Human OATP1B1 activity was only determined with one batch and declined to 51% of the initial test value by day 4 and further down to 35% by day 7.