Kallikrein directly interacts with and activates Factor IX, resulting in thrombin generation and fibrin formation independent of Factor XI.

Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact activation phase of coagulation and functions in the kallikrein-kinin system to generate bradykinin. The general dogma has been that the contribution of PKa to the coagulation cascade is dependent on its action on FXII. Recently this dogma has been challenged by studies in human plasma showing thrombin generation due to PKa activity on FIX and also by murine studies showing formation of FIXa-antithrombin complexes in FXI deficient mice. In this study, we demonstrate high-affinity binding interactions between PK(a) and FIX(a) using surface plasmon resonance and show that these interactions are likely to occur under physiological conditions. Furthermore, we directly demonstrate dose- and time-dependent cleavage of FIX by PKa in a purified system by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and chromogenic assays. By using normal pooled plasma and a range of coagulation factor-deficient plasmas, we show that this action of PKa on FIX not only results in thrombin generation, but also promotes fibrin formation in the absence of FXII or FXI. Comparison of the kinetics of either FXIa- or PKa-induced activation of FIX suggest that PKa could be a significant physiological activator of FIX. Our data indicate that the coagulation cascade needs to be redefined to indicate that PKa can directly activate FIX. The circumstances that drive PKa substrate specificity remain to be determined.

A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers.

BACKGROUND: There is increasing interest in the use of purified cannabidiol (CBD) as a treatment for a wide range of conditions due to its reported anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties. OBJECTIVE: The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single ascending dose of a new lipid-based oral formulation of CBD in healthy volunteers after a high-fat meal. METHODS: A total of 24 eligible healthy volunteers (aged 18-48 years) were randomised to one of three sequential cohorts (each with six active and two placebo subjects). Cohort 1 received 5 mg/kg CBD or placebo, cohort 2 received 10 mg/kg CBD or placebo (cohort 2), and cohort 3 received 20 mg/kg CBD or placebo. Data relating to adverse events, vital signs, clinical laboratory assessments, 12-lead ECGs, physical examinations and concomitant medications were collected to assess safety and tolerability. Blood samples were collected up to 8 days postdose and plasma was analysed by liquid chromatography and mass spectrometry to assess the pharmacokinetics of the CBD formulation. RESULTS: CBD was well tolerated in the healthy volunteers (mean age: 24.0 years) treated with a single oral dose of CBD. There were no safety concerns with increasing the dose and the safety profiles of the CBD-treated and placebo-treated subjects were similar. The most frequently reported treatment emergent adverse events (TEAEs) were headache (17%) and diarrhoea (8%). There were no reported serious adverse events (SAEs) and no clinical laboratory findings, vital signs, ECGs or physical examination findings that were reported as TEAEs or were of clinical significance during the study. After a high-fat meal, CBD was detected in plasma samples at 15 min postdose; the median time to maximum plasma concentration (Tmax) was 4 h across all three CBD dose cohorts. The CBD plasma exposure [maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC)] increased in a dose-proportional manner and declined to levels approaching the lower level of quantification by day 8. The terminal elimination half-life was approximately 70 h, suggesting that 2-3 weeks are needed to fully eliminate CBD. CONCLUSIONS: This new CBD formulation demonstrated a favourable safety and tolerability profile in healthy volunteers that was consistent with the profiles reported for other purified CBD products. No severe or serious AEs were observed in this study and there were no safety concerns. TRIAL REGISTRATION: ACTRN12618001424291. Registered August 2018.

Palliative care in residential aged care: An overview.

OBJECTIVE: To measure how care needs, health and length of stay in permanent residential aged care differs by assessed need for palliative care. METHODS: On entry into permanent residential aged care, people's care needs and health conditions are assessed on the Aged Care Funding Instrument. Data for the period 2008-2009 and 2015-2016 were analysed for trends in care needs, health conditions, length of stay and separation reason across assessed need for palliative care. RESULTS: Assessed care needs have increased for all people in residential aged care over this period, and people appraised for palliative care were more likely to be rated 'high' in need for support in activities of daily living. People appraised for palliative care had a higher prevalence of cancer and shorter length of stays. CONCLUSION: Palliative care appraisal is associated with increased complexity in assessed care needs, different profiles of health and shorter length of stays in permanent residential aged care.