Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity

Fatty acid amide hydrolase (FAAH) is the primary catabolic regulator of several bioactive lipid amides in vivo, including the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide. Inhibitors of FAAH are considered a potential therapeutic approach for the treatment of several nervous system disorders, including pain, anxiety, and insomnia. However, for FAAH inhibitors to achieve clinical utility, they must not only display efficacy in vivo but also selectivity for this enzyme relative to the numerous other serine hydrolases present in mammalian proteomes. Here, we report a general strategy for evaluating the pharmacological activity and target specificity of FAAH inhibitors and its implementation to develop the first class of selective reversible inhibitors of this enzyme that are highly efficacious in vivo. Using a series of functional proteomics, analytical chemistry, and behavioral pharmacology assays, we have identified a class of alpha-keto-heterocycles that show unprecedented selectivity for FAAH relative to other mammalian hydrolases, and, when administered to rodents, raise central nervous system levels of anandamide and promote cannabinoid receptor 1-dependent analgesia in several assays of pain sensation. These studies provide further evidence that FAAH may represent an attractive therapeutic target and describe a general route by which inhibitors of this enzyme can be optimized to achieve exceptional potency, selectivity, and efficacy in vivo.     

Nitric oxide inhibits ATP release from erythrocytes

Erythrocytes have been reported to release ATP from intracellular stores into the surrounding environment in response to decreased oxygen tension and mechanical deformation. This erythrocyte-derived ATP can then act on purinergic receptors present on vascular endothelial cells, resulting in the synthesis and bidirectional release of nitric oxide (NO). NO released abluminally produces relaxation of vascular smooth muscle, thereby increasing vascular caliber, leading to a decrease in deformation-induced ATP release from erythrocytes. In contrast, NO released into the vascular lumen could interact directly with formed elements in the blood, including the erythrocyte. Here, we investigate the hypothesis that NO functions in a negative-feedback manner to inhibit ATP release from the erythrocyte. The NO donor N-(2-aminoethyl)- N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) decreased total pulmonary resistance in a dose-dependent manner when administered to isolated perfused rabbit lungs. ATP release from rabbit erythrocytes in response to decreased oxygen tension or mechanical deformation was inhibited by preincubation with spermine NONOate (100 nM, 20 min). Importantly, incubating rabbit erythrocytes with spermine (100 nM, 20 min), the polyamine remaining after the liberation of NO from spermine NONOate, did not affect decreased oxygen tension-induced ATP release. Mechanical deformation-induced ATP release was also inhibited when erythrocytes were preincubated with spermine NONOate. However, NO-depleted spermine NONOate had no effect on mechanical deformation-induced ATP release from rabbit erythrocytes. These data provide support for the hypothesis that NO inhibits ATP release from erythrocytes, thereby identifying an additional role of NO in the regulation of vascular resistance.     

Pharmacokinetic interaction between voriconazole and ciclosporin A following allogeneic bone marrow transplantation

Voriconazole is a novel antifungal triazole that undergoes extensive oxidative metabolization involving several CYP450 isoenzymes. We report the case of a 14-year-old patient who received voriconazole concomitant with ciclosporin A as secondary antifungal prophylaxis after bone marrow transplantation. Temporary discontinuation of voriconazole due to worsening liver function tests (LFTs) resulted in a sudden drop of ciclosporin A trough levels in blood. Ciclosporin A trough levels returned to baseline following normalization of LFTs and re-institution of voriconazole. This report emphasizes the need for careful monitoring and dose adjustments of ciclosporin A in patients receiving concomitant voriconazole, and in whom voriconazole is discontinued in order to prevent subtherapeutic ciclosporin A levels with the potential consequence of graft-versus-host disease.     

The impact of abnormalities in IGF and inflammatory systems on the metabolic syndrome

OBJECTIVE: Low plasma levels of IGF-I, particularly when coupled with low levels of the potentially inhibitory IGF binding protein (IGFBP)-1 and higher levels of C-reactive protein (CRP), have been implicated in the pathogenesis of metabolic syndrome X and cardiovascular disease. We report the relative contributions of IGFBP-1 and CRP to the occurrence of the metabolic syndrome in a healthy population cohort to establish the extent to which these factors may contribute to subsequent risk of cardiovascular disease. RESEARCH DESIGN AND METHODS: The volunteers in the study were all participants in the Ely study, a continuing population-based cohort in Ely, Cambridgeshire, U.K. Of 839 individuals studied, 154 (18.4%) fulfilled criteria for the metabolic syndrome. RESULTS: Subjects with the metabolic syndrome had lower IGFBP-1 (14.4 microg/l [95% CI 12.9-16.0] vs. 25.4 [24.1-26.7], P < 0.001) and higher CRP (1.9 mg/l [1.6-2.2] vs. 1.0 [0.9-1.1], P < 0.001). Logistic regression, adjusted for age, sex, fasting insulin, and IGF-I, demonstrated a striking 14-fold increased risk for the metabolic syndrome (odds ratio 14.1 [4.1-48.4], P < 0.001) in individuals with a CRP value in the highest tertile and IGFBP-1 levels below the median. CONCLUSIONS: The combination of a high CRP concentration coupled with a low IGFBP-1 results in a dramatic increase in an individual's risk of having the metabolic syndrome. Further elucidation of the biological processes linking the IGF and inflammatory systems may allow the identification of novel therapeutic targets for cardiovascular risk reduction.     

Do the residents in the emergency department appropriately manage patients with acute asthma attack? A study of self-criticism

The objective of this study was to investigate the management of patients with asthma attack admitted to the emergency department (ED) in terms of compliance with international guidelines. The records of patients with asthma who were admitted to a university-based ED between December 2001 and December 2002 were evaluated. A total of 72 cases with available data were evaluated retrospectively. Twenty-six patients (36.1%) were admitted more than once during the study period. The number of multiple admissions ranged from 2 (15 patients, 20.0%) to 11 (2 patients, 2.8%). Peak expiratory flow (PEF) measurements were recorded in 17 patients (23.6%) on presentation. Pulse and respiratory rates were recorded in 70 (97.0%) and 67 patients (93.0%), respectively. Thirty-four patients (47.2%) underwent chest x-ray; results were normal in most patients. Salbutamol was the most commonly used drug as first-line therapy. Ipratropium bromide (inhaled) and systemic corticosteroids were added to the salbutamol in 47 (65.2%), 42 (58.4%), and 32 patients (44%), respectively. Pulmonologists were consulted in only 7 cases (9.7%). Thirty patients (43.4%) were prescribed corticosteroids on discharge. The role of functional parameters in determining asthma severity and monitoring treatment effects should be emphasized in clinical practice. Finally, more prevalent use of management guidelines will help determine their usefulness.     

Pulque intake during pregnancy and lactation in rural Mexico: alcohol and child growth from 1 to 57 months

OBJECTIVE: To examine maternal intake of a mildly alcoholic beverage (pulque) during pregnancy and lactation, and its potential effect on postpartum child growth and attained size. DESIGN: A prospective cohort study that followed mothers (during pregnancy and lactation) and their offspring (from birth to approximately 57 months of age). SETTING: Six villages in rural, central Mexico. SUBJECTS: Subjects are 58 mother-child pairs. Pulque intake was measured as part of a dietary assessment that was conducted for 2days/month during pregnancy and early lactation. RESULTS: Most mothers consumed pulque during pregnancy (69.0%) and lactation (72.4%). Among pulque drinkers, the average ethanol intake was 125.1 g/week during pregnancy and 113.8 g/week during lactation. Greater pulque intake during lactation, independent of intake during pregnancy, was associated with slower weight and linear growth from 1 to 57 months, and smaller attained size at 57 months. Low-to-moderate pulque intake during pregnancy, in comparison to either nonconsumption or heavy intake, was also associated with greater stature at 57 months. CONCLUSIONS: Pulque intake during lactation may have adversely influenced postnatal growth in this population. Public health interventions are urgently needed in Mexico to reduce heavy intake of pulque by pregnant and lactating women, and to replace intake with foods that provide the vitamins and minerals present in the traditional alcoholic beverage.     

Empirical assessment of the economic behaviour of Dutch general hospitals

We study the cost structure and efficiency of Dutch general hospitals over the period 1985-1995. Several studies on the efficiency of hospitals now exist. Most of them start from the assumption that hospital management attempts to minimize cost. We went beyond this assumption by trying to collect empirical evidence on management behaviour with respect to patient selection. We did so by estimating both the direct cost function and the indirect cost function as proposed by F?re and Primont and compared the results. We found that acknowledging the possibility of output reallocation increases the validity of optimizing models in the hospital sector but a complete indirect optimizing model ignores that some output categories are less flexible especially in the short run. Endogenous shifts in the allocation of patients appear to be realized through time by increased specialization of hospitals. We suggest that a mixed direct-indirect cost model is probably preferable.