Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that degrades the fatty acid amide family of signaling lipids, including the endocannabinoid anandamide. Genetic or pharmacological ...inactivation of FAAH leads to analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes in rodents without showing the undesirable side effects observed with direct cannabinoid receptor agonists, indicating that FAAH may represent an attractive therapeutic target for treatment of pain, inflammation, and other central nervous system disorders. However, the FAAH inhibitors reported to date lack drug-like pharmacokinetic properties and/or selectivity. Herein we describe piperidine/piperazine ureas represented by N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide (PF-750) and N-phenyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide (PF-622) as a novel mechanistic class of FAAH inhibitors. PF-750 and PF-622 show higher in vitro potencies than previously established classes of FAAH inhibitors. Rather unexpectedly based on the high chemical stability of the urea functional group, PF-750 and PF-622 were found to inhibit FAAH in a time-dependent manner by covalently modifying the enzyme's active site serine nucleophile. Activity-based proteomic profiling revealed that PF-750 and PF-622 were completely selective for FAAH relative to other mammalian serine hydrolases. We hypothesize that this remarkable specificity derives, at least in part, from FAAH's special ability to function as a C(O)−N bond hydrolase, which distinguishes it from the vast majority of metabolic serine hydrolases in mammals that are restricted to hydrolyzing esters and/or thioesters. The piperidine/piperazine urea may thus represent a privileged chemical scaffold for the synthesis of FAAH inhibitors that display an unprecedented combination of potency and selectivity for use as potential analgesic and anxiolytic/antidepressant agents.
Background: Peritonitis is the leading cause of morbidity and technique failure in peritoneal dialysis (PD) patients. The International Society for Peritoneal Dialysis (ISPD) recommends each centre ...to monitor the peritonitis rates and the causative organisms in order to guide local empiric antibiotic protocols. The aim of this study was to report on the peritonitis rates and describe the causative microorganisms and the antibiotic susceptibility in continuous ambulatory peritoneal dialysis (CAPD) adult patients at the Universitas Academic Hospital.Methods: A single-centre, retrospective descriptive survey was conducted to determine the peritonitis rates in PD patients (January–December 2016). All CAPD patients aged ≥18 years, who presented with clinical features of PD-associated peritonitis, were included. The peritonitis episodes were studied per patient, and the causative microorganisms and the antibiotic susceptibility of the organisms were described.Results: One hundred and twenty-eight patients underwent CAPD. The peritonitis rate was 1.45 episodes per year at risk. The prevalence of CAPD patients affected by at least one episode of CAPD-associated peritonitis during 2016 was 56.3%. The majority of episodes (76.7%) (n = 122) were mono-microbial. Gram-positive organisms accounted for 73.0% (n = 116) of the peritonitis episodes, coagulase-negative Staphylococcus being the most common. Gram-negative organisms accounted for 15.7% (n = 25) of the peritonitis episodes, and the common pathogens was Enterobacteriaceae. Conclusion: The peritonitis rate was alarmingly high, with 1.45 episodes per year at risk; this is three times more than the recommended 0.5 episodes per year according to the ISPD guidelines. The culture-negative rate of 8.8% is within ISPD-acceptable limits. There is a need to strengthen preventive measures with regard to peritonitis.
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