Developing a simulation programme to train airway management during the COVID-19 pandemic in a tertiary-level hospital.

Tracheal intubation of a patient with COVID-19 is a high-risk procedure for not only the patient, but all healthcare workers involved, leading to an understandable degree of staff anxiety. We used simulation to help train airway managers to intubate patients with COVID-19. Based on action cards developed by our department, we designed a series of scenarios to simulate airway management during the COVID-19 pandemic.

Emergency Airway Management in Patients with COVID-19: A Prospective International Multicenter Cohort Study.

Background: Tracheal intubation for patients with COVID-19 is required for invasive mechanical ventilation. The authors sought to describe practice for emergency intubation, estimate success rates and complications, and determine variation in practice and outcomes between high-income and low- and middle-income countries. The authors hypothesized that successful emergency airway management in patients with COVID-19 is associated with geographical and procedural factors.

Spontaneous extradural aerocele following cardiopulmonary resuscitation - an unrecognised complication.

We present a case report of a 61-year-old gentleman who had a cardiac arrest and was delivered cardiopulmonary resuscitation (CPR) by a bystander. After resuscitation, he regained cardiac output and was breathing spontaneously. CT scan of the head showed spontaneous right frontal extradural aerocele with fracture of the posterior wall of the frontal sinus with no sign of head injury.

Medicinal chemistry matters - a call for discipline in our discipline.

Medicinal chemistry makes a vital contribution to small molecule drug discovery, and the quality of it contributes directly to research effectiveness as well as to downstream costs, speed and survival in development. In recent years, the discipline of medicinal chemistry has evolved and witnessed many noteworthy contributions that propose and offer potential improvements to medicinal chemistry practice; however, the impact of these ideas is limited by their acceptance and deployment into every-day activity and, as a result, the quality of medicinal chemistry remains variable. For the good of the industry and the medicinal chemistry discipline, there is a need to move from retrospective learning to prospective control of medicinal chemistry practice to improve cost effectiveness, probability of success and survival rates.

Hypothesis driven drug design: improving quality and effectiveness of the design-make-test-analyse cycle.

In drug discovery, the central process of constructing and testing hypotheses, carefully conducting experiments and analysing the associated data for new findings and information is known as the design-make-test-analyse cycle. Each step relies heavily on the inputs and outputs of the other three components. In this article we report our efforts to improve and integrate all parts to enable smooth and rapid flow of high quality ideas.

Design of a potent, soluble glucokinase activator with increased pharmacokinetic half-life.

The continued optimization of a series of glucokinase activators is described, including attempts to understand the interplay between molecular structure and the composite parameter of unbound clearance. These studies resulted in the discovery of a new scaffold for glucokinase activators and further exploration of this scaffold led to the identification of GKA60. GKA60 maintains an excellent balance of potency and physical properties whilst possessing a significantly different, but complimentary, pre-clinical pharmacokinetic profile compared with the previously disclosed compound GKA50.

Creativity, innovation and lean sigma: a controversial combination?

The application of lean sigma is gaining momentum in drug discovery and development but it remains controversial because of perceptions that process improvement will suppress much-needed creativity and innovation. We review the conditions required to support creativity and innovation and the principles and benefits of lean sigma in a drug discovery environment. We conclude that it is desirable to create a unified climate that encourages and enables both innovation and continuous improvement and that this is possible if three key tensions are handled carefully and with due respect to the needs of research.

Discovery of a series of indan carboxylic acid glycogen phosphorylase inhibitors.

A series of carboxylic acid glycogen phosphorylase inhibitors, which have potential as oral antidiabetic agents, is described. Defining and applying simple physicochemical design criteria was used to assess the opportunity and to focus synthetic efforts on compounds with the greatest probability of success. The study led to compound 17, which exhibits a good balance of properties including potent inhibition of recombinant human liver glycogen phosphorylase in vitro, a good DMPK profile including excellent bioavailability and low clearance and good in vivo activity in a glucagon challenge model of diabetes in Zucker rats.

Making medicinal chemistry more effective--application of Lean Sigma to improve processes, speed and quality.

The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made.

A quantitative assessment of hERG liability as a function of lipophilicity.

The impact of lipophilicity as a factor contributing to hERG potency is assessed for a large dataset of compounds of differing ionisation type. This dataset is derived from compounds tested in the IonWorks-based in vitro electrophysiology hERG assay at AstraZeneca. Using logistic regression, a quantification of the risk associated with increasing lipophilicity is presented.

Design of a potent, soluble glucokinase activator with excellent in vivo efficacy.

The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1mg/kg po in an acute rat OGTT model.

Discovery, synthesis and biological evaluation of novel glucokinase activators.

The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.

The application of polymer-bound carbonylcobalt(0) species in linker chemistry and catalysis.

Carbonylcobalt(0) species have been used as linkers between alkynes and a polymer support for the first time. The alkynes may be loaded indirectly onto a phosphine functionalised polymer via their hexacarbonyldicobalt(0) complex, or directly onto a cobalt coated polymer. The alkynes have been released either as alkynes, thus providing a traceless method of immobilising alkynes, or by reaction with an alkene to generate a cyclopentenone via the Pauson-Khand reaction.

A new approach to functionalized spiropiperidines through tandem RCM and nitrogen-directed reactions.

The synthesis of a functionalized spiropiperidine via a tandem ring closing metathesis strategy is described, furthermore, the regio- and stereoselective functionalization of this compound has been achieved through a novel nitrogen-directed epoxidation reaction.

Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors.

We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC(50) 0.