Pharmacological Risk Assessment Among Older Patients with Polypharmacy Using the Clinical Decision Support System Janusmed Risk Profile: A Cross-Sectional Register Study.

BACKGROUND: Polypharmacy in older people is steadily increasing and a combination of many medicines may result in adverse effects, especially if the medicines interact pharmacodynamically. Examples are additive or synergistic effects increasing the risk of falls, haemorrhage, serotonin syndrome and torsade de pointes. The clinical decision support system Janusmed Risk Profile has been developed to find such risks based on a patients' medication list. OBJECTIVES: The main aim of this retrospective register-based study was to study what pharmacodynamic risks older patients (aged 65 years or older) on polypharmacy (defined as using five or more medicines) are exposed to. Second, we studied if the introduction of the Janusmed Risk Profile in the main electronic health record system in Region Stockholm influenced the proportion of patients prescribed combinations that increase the risk for the nine adverse-effect categories defined (anticholinergic effects, haemorrhage, constipation, orthostatism, QT prolongation, renal toxicity, sedation, seizures and serotonin syndrome). METHODS: Data on all prescription medicines to individuals aged 65 years or older, and with at least five concomitant medicines were retrieved and analysed for the risk categories in the Janusmed Risk Profile. The proportions of patients with a high/moderate risk during a 4-month period before (period 1) and after (period 2) the introduction were compared. RESULTS: A total of 127,719 patients in period 1 (November 2016-February 2017), and 131,458 patients in period 2 (November 2017-February 2018) were included in the study. The proportion of patients with a high or moderate risk for each of the nine properties (anticholinergic effects, haemorrhage, constipation, orthostatism, QT prolongation, renal toxicity, sedation, seizures and serotonergic effects) were 10.9, 34.7, 32.8, 33.6, 17.2, 0.7, 15.4, 0.5 and 2.4%, respectively, in period 1 and 10.4, 35.5, 32.8, 33.3, 10.8, 0.71, 14.9, 0.5 and 2.3% in period 2. The changes for sedation and QT prolongation were statistically significant, with the most pronounced decrease for QT prolongation from 17.2 to 10.8% (p < 0.001). When analysing patients at a high risk, the decrease was significant for haemorrhage, orthostatism, QT prolongation and sedation. CONCLUSIONS: Older people are exposed to combinations of medications that increase the risk for potentially severe adverse effects. Prescribers seem to respond especially to warnings for QT prolongation, presented in the Janusmed Risk Profile implemented in the electronic health record system.

An in vivo neovascularization assay for screening regulators of angiogenesis and assessing their effects on pre-existing vessels.

Therapeutic regulation of tissue vascularization has appeared as an attractive approach to treat a number of human diseases. In vivo neovascularization assays that reflect physiological and pathological formation of neovessels are important in this effort. In this report we present an assay where the effects of activators and inhibitors of angiogenesis can be quantitatively and qualitatively measured. A provisional matrix composed of collagen I and fibrin was formed in a plastic cylinder and implanted onto the chick chorioallantoic membrane. A nylon mesh separated the implanted matrix from the underlying tissue to distinguish new from pre-existing vessels. Vascularization of the matrix in response to fibroblast growth factor-2 or platelet-derived growth factor-BB was scored in a double-blinded manner, or vessel density was measured using a semi-automated image analysis procedure. Thalidomide, fumagillin, U0126 and TGFß inhibited neovessel growth while hydrocortisone exerted a negative and wortmannin a toxic effect on the pre-existing vasculature. This quantitative, inexpensive and rapid in vivo angiogenesis assay might be a valuable tool in screening and characterizing factors that influence wound or tumor induced vascularization and in assessing their effects on the normal vasculature.

Biomechanical regulation of blood vessel growth during tissue vascularization.

Formation of new vessels in granulation tissue during wound healing has been assumed to occur solely through sprouting angiogenesis. In contrast, we show here that neovascularization can be accomplished by nonangiogenic expansion of preexisting vessels. Using neovascularization models based on the chick chorioallantoic membrane and the healing mouse cornea, we found that tissue tension generated by activated fibroblasts or myofibroblasts during wound contraction mediated and directed translocation of the vasculature. These mechanical forces pulled vessels from the preexisting vascular bed as vascular loops with functional circulation that expanded as an integral part of the growing granulation tissue through vessel enlargement and elongation. Blockade of vascular endothelial growth factor receptor-2 confirmed that biomechanical forces were sufficient to mediate the initial vascular growth independently of endothelial sprouting or proliferation. The neovascular network was further remodeled by splitting, sprouting and regression of individual vessels. This model explains the rapid appearance of large functional vessels in granulation tissue during wound healing.

Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancer.

An in vitro model of VEGF-A-induced angiogenesis was used to generate transcription profiles of human microvascular endothelial cells. Microarray analysis showed increased transcription of genes known to regulate angiogenesis, but also genes that previously have not been firmly associated with angiogenesis such as endocan, pinin, plakophilin, phosphodiesterase 4B and gelsolin. Increased endocan mRNA levels in response to VEGF-A in endothelial cells and in human renal cancer have previously been reported. We now show increased endocan protein levels in VEGF-A treated endothelial cells and in human renal clear cell carcinoma. Increased protein expression was observed both in tumor cells and in a subset of tumor vessels, while expression in normal kidney tissue was low. VEGF-A seemed to be a specific inducer of endocan transcription since FGF-2, PDGF-BB, HGF/SF and EGF did not alter expression levels. Inhibition of PI3K with LY294002 caused a 12-fold increase in endocan transcription suggesting a repressive function of PI3K. In contrast inhibition of Src or MEK, which are signaling pathways activated by VEGF-A, did not influence basal or VEGF-A-induced endocan levels. In conclusion our study shows that, among angiogenic growth factors, VEGF-A is a specific inducer of endocan transcription which is translated into increased protein levels in VEGF-A treated endothelial cells. Increased endocan protein expression in human renal cancer suggests a role in tumor growth.