In aspirin-intolerant subjects, adverse bronchial and nasal reactions to cyclooxygenase (COX) inhibitors are associated with over-production of cysteinyl-leukotrienes (cys-LTs) generated by the 5-lipoxygenase (5-LO) pathway. In the bronchi of patients with aspirin-intolerant asthma, we previously linked cys-LT over-production and aspirin hyper-reactivity with elevated immunoexpression in eosinophils of the terminal enzyme for cys-LT production, LTC4 synthase. We investigated whether this anomaly also occurs in the nasal airways of these patients. Immunohistochemical expression of 5-LO and COX pathway proteins was quantified in nasal polyps from 12 patients with aspirin-intolerant asthma and 13 with aspirin-tolerant asthma. In the mucosa of polyps from aspirin-intolerant asthmatic patients, cells immunopositive for LTC4 synthase were four-fold more numerous than in aspirin-tolerant asthmatic patients (p=0.04). There were also three-fold more cells expressing 5-LO (p=0.037), with no differences in 5-LO activating protein (FLAP), COX-1 or COX-2. LTC4 synthase-positive cell counts correlated exclusively with mucosal eosinophils (r=0.94, p<0.001, n=25). Co-localisation confirmed that five-fold higher eosinophil counts (p=0.007) accounted for the increased LTC4 synthase expression in polyps from aspirin-intolerant asthmatic patients, with no alterations in mast cells or macrophages. Within the epithelium, increased counts of eosinophils (p=0.006), macrophages (p=0.097), and mast cells (p=0.034) in aspirin-intolerant asthmatic polyps were associated only with 2.5-fold increased 5-LO-positive cells (p<0.05), while the other enzymes were not different. Our results indicate that a marked over-representation of LTC4 synthase in mucosal eosinophils is closely linked to aspirin intolerance in the nasal airway, as in the bronchial airways.
The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio. KEYWORDS: FAAH, covalent, ethanolamides, enzyme, anandamide T he fatty acid amide hydrolases 1,2 interrupt the actions, through degradation, of a variety of endogenous lipid signaling molecules.3 FAAH rapidly degrades several fatty acid ethanolamides, including FAAH's primary substrate, AEA (N-arachidonyl ethanolamide or anandamide), 4 PEA (N-palmitoyl ethanolamide), 5,6 and OEA (N-oleoyl ethanolamide).7 In contrast, FAAH-2 catabolizes ethanolamides less efficiently, but will hydrolyze long-chain primary amides. The likely source of AEA's analgesic pharmacology is its ability to agonize the cannabinoid receptor CB 1 .8−10 However, AEA is synthesized on demand and then rapidly broken down locally, which mitigates the side-effects observed as a result of systemic CB 1 agonism (e.g., Δ 9 THC pharmacology). As AEA is synthesized in a localized manner, one might hypothesize that inhibiting FAAH could lead to elevated concentrations of AEA in relevant tissues. Indeed, prior reports have described an increase in AEA levels in the plasma and brains 11−14 of rats and in the plasma of humans upon inhibition of FAAH.Small molecule interruption of FAAH activity has been examined in numerous laboratories (Figure 1)
Quitting smoking is notoriously difficult. Models of nicotine dependence posit that deficits in cognitive control contribute to failures to maintain smoking abstinence during smoking cessation attempts. We examine the role for large-scale functional brain systems associated with cognitive control in smoking lapse. We use data from 70, five-minute functional magnetic resonance imaging (fMRI) scans in 17 daily smokers (5 female) undergoing a smoking lapse paradigm after 12 hours of smoking abstinence. Cox regression results indicate that decreased segregation of the default mode system from the frontoparietal system undermine the ability to resist smoking. Results lend support to the hypothesis that large-scale functional brain systems associated with cognitive control are implicated in smoking lapse behavior and point to the importance of cognitive control as a mechanism underlying smoking relapse.
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