Mechanisms of lysophosphatidylcholine-induced demyelination: A primary lipid disrupting myelinopathy.

For decades lysophosphatidylcholine (LPC, lysolecithin) has been used to induce demyelination, without a clear understanding of its mechanisms. LPC is an endogenous lysophospholipid so it may cause demyelination in certain diseases. We investigated whether known receptor systems, inflammation or nonspecific lipid disruption mediates LPC-demyelination in mice. We found that LPC nonspecifically disrupted myelin lipids. LPC integrated into cellular membranes and rapidly induced cell membrane permeability; in mice, LPC injury was phenocopied by other lipid disrupting agents. Interestingly, following its injection into white matter, LPC was cleared within 24 hr but by five days there was an elevation of endogenous LPC that was not associated with damage. This elevation of LPC in the absence of injury raises the possibility that the brain has mechanisms to buffer LPC. In support, LPC injury in culture was significantly ameliorated by albumin buffering. These results shed light on the mechanisms of LPC injury and homeostasis.

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.

Quantifying the intensity of adverse events with ibuprofen and oxycodone: an observational cohort study.

OBJECTIVE: To quantify the frequency and intensity of adverse events (AEs), commonly known as side effects, experienced by children receiving either ibuprofen or oxycodone for pain management following an acute fracture. Secondary objectives were to quantify functional outcome impairment and describe demographic and clinical characteristics associated with AEs. DESIGN: Observational cohort study. SETTING: Paediatric emergency department. PATIENTS: Patients (n=240) aged 4-16 years diagnosed with an acute fracture. INTERVENTION: Prescribed either ibuprofen (n=179) or oxycodone (n=61) for pain. MAIN OUTCOME MEASURES: Families were called for the first 3 days after discharge to report the presence and intensity of AEs and their child's functional outcomes (ability to eat, sleep, play or attend school). RESULTS: On day 1, children using oxycodone were more likely to report any AE (χ2 1=13.5, p<0.001), nausea (χ2 1=17.0, p<0.001), vomiting (χ2 1=11.2, p<0.001), drowsiness (χ2 1=13.7,p<0.001), constipation (χ2 1=8.9, p=0.003) and dizziness (χ2 1=19.1, p<0.001), compared with those using ibuprofen. Children receiving oxycodone reported greater severity of abdominal pain (oxycodone: mean 5.4 SD 3.1; ibuprofen mean 2.5 SD 1.4, F1 13=6.5, p=0.02) on day 1 and worse intensity of constipation (oxycodone: mean 4.9 SD 2.1; ibuprofen mean 3.2 SD 2.2, F1 33=4.5, p=0.04) over all 3 days. Use of oxycodone was associated with an increased odds of experiencing an AE on day 1 (OR=1.31 (95% CI 1.13 to 1.52)). Higher pain scores (OR=1.50 (95% CI 1.12 to 2.01)), lower extremity fracture (OR=1.25 (95% CI 1.07 to 1.47)) and undergoing ED sedation (OR=1.16 (95% CI 1.01 to 1.34)) were associated with missing school. Higher pain scores (OR=1.50 (95% CI 1.14 to 1.97)) and lower extremity fractures (OR=1.23 (95% CI 1.07 to 1.43)) were also associated with less play. CONCLUSIONS: Oxycodone is associated with more frequent AEs overall, higher intensity gastrointestinal AEs and greater functional limitations compared with ibuprofen. Lower extremity fractures cause more functional limitations than upper extremity fractures. Clinicians should consider these differences when providing fracture pain care for children.