Identification and Characterization of Novel Receptor-Interacting Serine/Threonine-Protein Kinase 2 Inhibitors Using Structural Similarity Analysis.

Receptor-interacting protein kinase 2 (RIP2 or RICK, herein referred to as RIPK2) is linked to the pathogen pathway that activates nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) and autophagic activation. Using molecular modeling (docking) and chemoinformatics analyses, we used the RIPK2/ponatinib crystal structure and searched in chemical databases for small molecules exerting binding interactions similar to those exerted by ponatinib. The identified RIPK2 inhibitors potently inhibited the proliferation of cancer cells by > 70% and also inhibited NFκB activity. More importantly, in vivo inhibition of intestinal and lung inflammation rodent models suggests effectiveness to resolve inflammation with low toxicity to the animals. Thus, our identified RIPK2 inhibitor may offer possible therapeutic control of inflammation in diseases such as inflammatory bowel disease, asthma, cystic fibrosis, primary sclerosing cholangitis, and pancreatitis.

Effects of pharmacogenetic profiles on pediatric pain relief and adverse events with ibuprofen and oxycodone.

Introduction: Individual genetic variation may influence clinical effects for pain medications. Effects of CYP2C9, CYP3A4, and CYP2D6 polymorphisms on clinical effectiveness and safety for ibuprofen and oxycodone were studied. Objective: Primary objectives were to AU2 evaluate if allelic variations would affect clinical effectiveness and adverse events (AEs) occurrence. Methods: This pragmatic prospective, observational cohort included children aged 4 to 16 years who were seen in a pediatric emergency department with an acute fracture and prescribed ibuprofen or oxycodone for at-home pain management. Saliva samples were obtained for genotyping of allelic variants, and daily telephone follow-up was conducted for 3 days. Pain was measured using the Faces Pain Scale-Revised. Results: We included 210 children (n = 140 ibuprofen and n = 70 oxycodone); mean age was 11.1 (±SD 3.5) years, 33.8% were female. Median pain reduction on day 1 was similar between groups [ibuprofen 4 (IQR 2,4) and oxycodone 4 (IQR 2,6), P = 0.69]. Over the 3 days, the oxycodone group experienced more AE than the ibuprofen group (78.3% vs 53.2%, P < 0.001). Those with a CYP2C9*2 reduced function allele experienced less adverse events with ibuprofen compared with those with a normal functioning allele CYP2C9*1 (P = 0.003). Neither CYP3A4 variants nor CYP2D6 phenotype classification affected clinical effect or AE. Conclusion: Although pain relief was similar, children receiving oxycodone experienced more AE, overall, than those receiving ibuprofen. For children receiving ibuprofen or oxycodone, pain relief was not affected by genetic variations in CYP2C9 or CYP3A4/CYP2D6, respectively. For children receiving ibuprofen, the presence of CYP2C9*2 was associated with less adverse events.

An observational cohort study comparing ibuprofen and oxycodone in children with fractures.

OBJECTIVE: To compare the effectiveness and safety of prescribing ibuprofen and oxycodone for at-home management of children's fracture pain. METHODS: A prospective observational cohort was conducted at the Stollery Children's Hospital pediatric emergency department (June 2010-July 2014). Children aged 4-16 years with an isolated fracture discharged home with advice to use either ibuprofen or oxycodone were recruited. RESULTS: A cohort of 329 children (n = 217 ibuprofen, n = 112 oxycodone) were included. Mean age was 11.1 years (SD 3.5); 68% (223/329) were male. Fracture distribution included 80.5% (264/329) upper limb with 34.3% (113/329) requiring fracture reduction. The mean reduction in Faces Pain Score-Revised score (maximum pain-post-treatment pain) for Day 1 was 3.6 (SD 1.9) (ibuprofen) and 3.8 (SD 2.1) (oxycodone) (p = 0.50); Day 2 was 3.6 (SD 1.8) (ibuprofen) and 3.7 (SD 1.6) (oxycodone) (p = 0.56); Day 3 was 3.7 (SD 1.7) (ibuprofen) and 3.3 (SD 1.7) (oxycodone) (p = 0.24). Children prescribed ibuprofen (51.2%, 109/213) experienced less adverse events compared to those prescribed oxycodone (70.5% 79/112) on Day 1 (p = 0.001). Children prescribed ibuprofen (71.8%, 150/209) had their function (eat, play, school, sleep) affected less than those prescribed oxycodone (83.0%, 93/112) (p = 0.03) on Day 1. CONCLUSION: Children prescribed ibuprofen or oxycodone experienced similar analgesic effectiveness for at-home fracture pain. Oxycodone prescribing was associated with more adverse events and negatively impacted function. Oxycodone use does not appear to confer any benefit over ibuprofen for pain relief and has a negative adverse effect profile. Ibuprofen appears to be a safe option for fracture-related pain.

A randomized trial of robot-based distraction to reduce children's distress and pain during intravenous insertion in the emergency department.

OBJECTIVES: Our objectives were to evaluate the effectiveness of humanoid robot-based distraction on reducing distress and pain in children undergoing intravenous insertion. METHODS: A two-arm, open-label randomized controlled trial was conducted April 2017-May 2018, in a pediatric emergency department (ED). A sample of 86 children aged 6-11 years who required intravenous insertion were recruited. Exclusion criteria included hearing/visual impairments, neurocognitive delay, sensory impairment to pain, previous enrollment, and ED clinical staff discretion. Outcome measures included the Observed Scale of Behavioral Distress-Revised (OSBD-R) (distress) and the Faces Pain Scale-Revised (FPS-R) (pain). RESULTS: Of the 86 children recruited (median age 9 years, IQR 7,10); 55% (47/86) were male, 9% (7/82) were premature, 82% (67/82) had a previous ED visit, 31% (25/82) had a previous hospitalization and 78% (64/82) had previous intravenous insertion. Ninety-six percent (78/81) received topical anesthetic prior to intravenous insertion. Total OSBD-R distress score was 1.49 ± 2.36 (standard care) versus 0.78 ± 1.32 (robot) (p < 0.05). FPS-R pain score was 4 (IQR 2,6) (standard care) versus 2 (IQR 0,4) (robot) (p = 0.13). Parental anxiety immediately after the procedure was 36.7 (11.1) (standard care) versus 31.3 (8.5) (robot) (p = 0.04). Parents were more satisfied with pain management in the robotic distraction group (95% vs 72% very satisfied) (p = 0.002). CONCLUSIONS: Humanoid robot-based distraction therapy is associated with a modest positive impact on child distress for pediatric intravenous insertion, but not pain. It can be considered a potential tool in the ED toolkit for procedural pain-associated distress reduction. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02997631.

RéSUMé: OBJECTIFS: Nos objectifs étaient d'évaluer l'efficacité de la distraction robotique humanoïde pour réduire la détresse et la douleur chez les enfants subissant une insertion intraveineuse. MéTHODES: Un essai contrôlé randomisé ouvert à deux bras a été mené d'avril 2017 à mai 2018, dans un service d'urgence pédiatrique. Un échantillon de 86 enfants âgés de 6 à 11 ans ayant besoin d'une insertion intraveineuse a été recruté. Les critères d'exclusion comprenaient des déficiences auditives / visuelles, un retard neurocognitif, une déficience sensorielle de la douleur, une inscription antérieure et la discrétion du personnel clinique des urgences. Les mesures des résultats comprenaient l'échelle d'hétéro-évaluation comportementale (OSBD-R: Observational Scale of Behavioral Distress ­ Revised) (détresse) et l'échelle de visages (FPS-R: Faces Pain Scale-Revised) (douleur). RéSULTATS: Sur les 86 enfants recrutés (âge médian 9 ans, IQR 7,10) ; 55 % (47/86) étaient de sexe masculin, 9 % (7/82) étaient prématurés, 82 % (67/82) avaient une visite antérieure aux urgences, 31 % (25/82) avaient déjà été hospitalisés et 78 % (64/82) avaient déjà été insérés par voie intraveineuse. Quatre-vingt-seize pour cent (78/81) ont reçu une anesthésie topique avant l'insertion intraveineuse. Le score total de détresse OSBD-R était de 1,49 ± 2,36 (soins standard) contre 0,78 ± 1,32 (robot) (p < 0,05). Le score de douleur FPS-R était de 4 (IQR 2,6) (soins standard) contre 2 (IQR 0, 4) (robot) (p=0,13). L'anxiété parentale immédiatement après l'intervention était de 36,7 (11,1) (soins standard) contre 31,3 (8,5) (robot) (p=0,04). Les parents étaient plus satisfaits de la gestion de la douleur dans le groupe de distraction robotique (95 % vs 72 % très satisfaits) (p = 0,002). CONCLUSIONS: La thérapie de distraction à base de robot humanoïde est associée à un impact positif modeste sur la détresse de l'enfant pour l'insertion intraveineuse pédiatrique, mais pas la douleur. Il peut être considéré comme un outil potentiel dans la boîte à outils des Services d'Urgences pour la réduction de la détresse associée à la douleur procédurale.