Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signaling through ERK1/2. Here, we describe the fragment-based generation of ERK1/2 inhibitors that block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells, the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization toward clinical pERK1/2 modulating ERK1/2 inhibitors.
Background: Vancomycin is the primary treatment for methicillin-resistant Staphylococcus aureus infections. Hospital audits have showed that dosing and therapeutic drug monitoring practices for vancomycin are suboptimal. Limited studies have examined the current educational resources used to support vancomycin use.Aims: To explore and compare the perceptions of health educators and recipients of education on the methods currently used to educate health professionals about vancomycin and to identify ideal methods of education.Methods: Semi-structured interviews were conducted with health educators around Australia and with recipients of education (doctors and nurses). Interview questions explored previous experiences of education and perceptions of ideal methods of education. Interviews were audio-taped, transcribed and thematically analysed.Results: Health educators explained that current vancomycin education comprises large-scale presentations, but they perceived these to be ineffective. The recipients of vancomycin education reported a lack of formal education on vancomycin. Despite this, both educators and recipients agreed on the ideal methods of education: nurses are reported to be protocol driven, and education for nurses should be through in-services or e-learning modules, while doctors require an evidenced-based approach. Senior doctors initially require convincing that education is needed. Once convinced, they respond well to brief emails and case-based and one-on-one education strategies. Technologybased strategies and problem-based learning were observed to be effective methods for junior doctors.Conclusions: Vancomycin dosing and therapeutic drug monitoring involves multiple health professionals, but current education strategies do not take this into account. Ideal education strategies need to be multimodal and targeted to specific health profession groups. AbstractBackground: Dedicated geriatric models of care are becoming more prevalent due to the complexity of, and increase in, acute healthcare presentations for older patients. For older people, a long stay in the emergency department (ED) may reflect the complexity of their presentation, or deficiencies in systems that manage these complexities.Aims: To identify predictors of a long ED length of stay (LLoS) for patients ≥65 years old. Methods: Linked hospital information systems data from a large, public Australian ED were analysed in this retrospective cohort study. LLoS was defined as the 75th percentile (617 min). Multivariate regression identified LLoS predictors for admissions and discharges separately.Results: Of 16 791 ED presentations made by older people, 4192 experienced a LLoS; 55% were admitted. Increasing age was associated with an increasing ED LoS. Factors most predictive of LLoS for both admitted and discharged patients included: investigations (both pathology and imaging), less urgent Australasian triage scale categories and after-hours arrival. Ambulance arrival did not increase the risk of a LLoS for patients eventually admitted...
Background:The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning.Aims: To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD). Methods:Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross-sectional survey of patients already prescribed metformin (n = 34), and by a prospective study where metformin (500 mg, immediate release, twice daily) for up to 6 weeks was prescribed (n = 24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD.Results: All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5 mg/L; lactate, 5 mmol/L). Lactate concentrations were unrelated to average steady-state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P < 0.0001). CLD patients with cirrhosis had 23% higher lactate concentrations than those without cirrhosis (P = 0.01). The pharmacokinetics of metformin in CLD patients were similar to patients with T2DM and no liver disease. The ratio of apparent metformin clearance (CL Met /F) to creatinine clearance was marginally lower in CLD patients compared to healthy subjects (median, interquartile range; 12.6, 9.5-15.9 vs 14.9, 13.4-16.4; P = 0.03). Conclusions:The pharmacokinetics of metformin are not altered sufficiently in CLD patients to raise concerns regarding unsafe concentrations of metformin. There were no unsafe plasma lactate concentrations observed in CLD patients receiving metformin (ACTRN12619001292167; ACTRN12619001348145).
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