Chromaffin cells from bovine adrenal medulla secrete catecholamines on stimulation with acetylcholine. In addition to the activation of the phosphatidylinositol cycle, arachidonic acid is generated, which was thought to be the result of phospholipase A2 activation. We have demonstrated in isolated plasma membranes of these cells that arachidonic acid is generated by a two-step reaction of diacylglycerol and monoacylglycerol lipase splitting diacylglycerol, which originates from the action of phospholipase C on phosphatidylinositols. No phospholipase A2 activity could be detected in plasma membranes so far. External addition of arachidonic acid increases the release in the absence and in the presence of agonist. Inhibition of the diacylglycerol lipase by RHC 80267 suppresses the catecholamine release, which is restored on addition of arachidonic acid. This effect, however, is reversed by lipoxygenase inhibitors, indicating that it is not arachidonic acid itself, but one of its lipoxygenase products, that is essential for inducing exocytosis.
Introduction: Drug-drug interactions constitute a predictable and in many cases avoidable cause of adverse drug reactions and therapeutic failure. We conducted a register-based study to investigate the prevalence of prescribed combinations of interacting drugs in the whole Swedish population (Holm et al. Eur J Clin Pharmacol. 2014). Material and Methods: A retrospective, cross-sectional register study was conducted, covering four months in 2010. Data from the Prescribed Drug Register on all dispensed drug prescriptions in Swedish pharmacies from January 1 to April 30 were linked to the drug-drug interaction database SFINX. The analysis focused on drug interactions classified in the database as clinically relevant that can be handled, e.g. by dose adjustments (C-interactions), and clinically relevant interactions that should be avoided (D-interactions). Interactions were categorized according to clinical consequence and drug type and prevalences of interacting drug combinations were described. The study was approved by the Regional Ethics Committee. Results: About half of the population were dispensed at least one drug prescription. Mean (SD) number of dispensed drugs was 3.8 (3.4). About 2.5 million potentially interacting drug combinations were identified in the study population of 9.3 million people. Among detected interactions 38% were classified as C-interactions and 3.8% as D-interactions. About half of all C-and D-interactions were combinations of drugs with potential to cause therapeutic failure. The 15 most prevalent combinations accounted for 80% of D-interactions. The 10 most prevalent individual drugs were involved in 94% of all D-interactions. Conclusions: A limited number of drugs and a few specific drug combinations account for the majority of D-interactions, i.e. clinically relevant interactions that should be avoided, in Sweden. About half of interacting drug combinations among C-and D-interactions potentially leads to treatment failure. Uracil catabolism is crucial for the pharmacokinetics of the chemotherapeutic 5-fluorouracil (5-FU) since 5-FU is degraded by the same pathway. Decreased activity of the first catabolizing enzyme, dihydropyrimidine dehydrogenase (DPD), is a major predictor of 5-FU toxicity with known risk variants in the DPD gene (DPYD) accounting for ~30% of toxicities. However, not all toxicity cases can be explained by DPYD risk variants. To date, the phenotypic variability in the catabolism downstream of DPD by dihydropyrimidinase (DHP) and β -ureidopropionase (bUP), potentially contributing to 5-FU toxicity, has not been investigated. Thus, we aimed to characterize the baseline phenotypic variability of endogenous metabolites and metabolic ratios of 5-FU catabolism enzymes and to correlate the phenotype with genetic variation in the DHP and bUP genes (DPYS and UPB1).Material and Methods: Three variants in DPYS and UPB1 previously associated with 5-FU toxicity were genotyped in 320 healthy volunteers and their plasma uracil, dihydrouracil (UH 2 ), β -ureidopropionic acid (UPA)...
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