Fibrosis, the result of excess deposition of extracellular matrix (ECM), in particular collagen, leads to scarring and loss of function in tissues that include the heart, lung, kidney and liver. The second messenger cAMP can inhibit the formation and extent of ECM during this late phase of inflammation, but the mechanisms for these actions of cAMP and of agents that elevate tissue cAMP levels are not well understood. In this article, we review the fibrotic process and focus on two recently recognized aspects of actions of cAMP and its effector Epac (Exchange protein activated by cAMP): (a) blunting of epithelial-mesenchymal transformation (EMT) and (b) down-regulation of Epac expression by profibrotic agents (e.g. TGF-b, angiotensin II), which may promote tissue fibrosis by decreasing Epac-mediated antifibrotic actions. Pharmacological approaches that raise cAMP or blunt the decrease in Epac expression by profibrotic agents may thus be strategies to block or perhaps reverse tissue fibrosis. LINKED ARTICLESThis article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2012.166.issue-2 Abbreviations CF, cardiac fibroblast; ECM, extracellular matrix; Epac, Exchange protein activated by cyclic AMP; 8-Me-cAMP, 8-CPT-2′-O-Me-cAMP; N6-cAMP, N6-Benzoyl-cAMP; NSAIDs, non-steroidal anti-inflammatory drugs; a-SMA, a-smooth muscle actin Introduction to tissue fibrosis and cAMP signalling Tissue fibrosisTissue fibrosis (scarring) results from the excess deposition of extracellular matrix (ECM) and occurs as part of normal physiology (e.g. aging) and following injury, in particular, with recurrent or persistent stimulation of the inflammatory process. Tissue fibrosis often alters tissue function. For example, cardiac fibrosis contributes to diastolic dysfunction and a decrease in cardiac output that accompany advanced age (Lakatta, 2003;Chen and Frangogiannis, 2010). Inflammation that follows tissue injury produces a series of acute and late-phase responses. In its acute phase, inflammation is characterized by several cardinal features [calor, rubor, dolor and tumour (heat, redness, pain and swelling)], which can be treated by pharmacological agents, in particular nonsteroidal anti-inflammatory drugs (NSAIDs), whose major action is inhibition of COXs and thus the synthesis of prostaglandins.Much less is known regarding the mechanisms that mediate the late phase of inflammation during which resolution of the tissue infiltration of acute inflammatory cells occurs, but tissue fibrosis can be initiated. Recent efforts have helped identify mechanisms of the resolution of inflammation (Serhan, 2010;Maskrey et al., 2011;Wynn, 2011;Yates et al., 2011). Glucocorticoids, the principal class of drugs used to treat this phase of the inflammatory process, block protein synthesis, thereby decreasing the accumulation of collagens and other ECM proteins. However, the use of glucocorticoids is associated with numerous side effects. Pirfenidone is ...

Memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease with a good safety profile, is increasingly being studied in a variety of non-dementia psychiatric disorders. We aimed to critically review relevant literature on the use of the drug in such disorders. We performed a PubMed search of the effects of memantine in animal models of psychiatric disorders and its effects in human studies of specific psychiatric disorders. The bulk of the data relates to the effects of memantine in major depressive disorder and schizophrenia, although more recent studies have provided data on the use of the drug in bipolar disorder as an add-on. Despite interesting preclinical data, results in major depression are not encouraging. Animal studies investigating the possible usefulness of memantine in schizophrenia are controversial; however, interesting findings were obtained in open studies of schizophrenia, but negative placebo-controlled, double-blind studies cast doubt on their validity. The effects of memantine in anxiety disorders have been poorly investigated, but data indicate that the use of the drug in obsessive-compulsive disorder and post-traumatic stress disorder holds promise, while findings relating to generalized anxiety disorder are rather disappointing. Results in eating disorders, catatonia, impulse control disorders (pathological gambling), substance and alcohol abuse/dependence, and attention-deficit hyperactivity disorder are inconclusive. In most psychiatric non-Alzheimer's disease conditions, the clinical data fail to support the usefulness of memantine as monotherapy or add-on treatment However, recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant bipolar disorder.

The aim of our study was to assess the arrhythmic profile in patients with primary pulmonary hypertension (PPH) and its correlation with autonomic features, echocardiographic indexes and pulmonary function. We studied 9 subjects with a mean age of 42 +/- 11 years. All underwent echocardiography, 24-hour Holter monitoring, and cardiopulmonary exercise testing. Left ventricle ejection fraction was normal (65 +/- 6%). The right ventricle end diastolic volume was increased (108 +/- 32 ml/m2) with a slight reduction of ejection fraction (49 +/- 5%). Right ventricle systolic pressure was increased (91 +/- 25 mmHg). Heart rate variability analysis showed evidence of a reduced standard deviation of all NN intervals (SDNN) compared with the control group (102.8 +/- 32 versus 156.1 +/- 32, p < 0.005). Patients with significant ventricular arrhythmias had a lower SDNN, and lower baseline and effort PO2 (SDNN: 87.0 +/- 15 versus 115.4 +/- 38; baseline PO2: 63.2 +/- 12% versus 78.8 +/- 7%; effort PO2: 50.7 +/- 13% versus 68.7 +/- 19%). The patients with SDNN lower than 90 ms were characterized by a higher right ventricle systolic pressure (115.0 +/- 22.9 mmHg versus 79.2 +/- 17.8 mmHg, p = 0.035). The patients who experienced syncope had higher SDNN (131.7 +/- 36 versus 88.4 +/- 20, p < 0.05), higher effort PO2 (77.5 +/- 14 mmHg versus 52.3 +/- 14 mmHg, p < 0.03). The patients with PPH evidenced an increased sympathetic activity. Premature ventricular beats were more frequent in those subjects with higher adrenergic drive and lower oxygen saturation. Patients with episodes of syncope seem to have a relatively higher vagal activity, and effective mechanisms of adjustment in blood oxygenation during effort.

The aim of the present study was to analyse the pharmacokinetic behaviour of amikacin in intensive care unit (ICU) patients using a mixed-effect model and sparse data collected during routine clinical care. The patient population comprised 158 medical ICU patients divided into two groups: one for computing the population model (n = 120) and the other for validation (n = 38). A 1-compartment model was used and the following covariates were tested for their influence on clearance (CL) and volume of distribution (Vd): age, gender, weight, parenteral nutrition, creatinine clearance, duration of therapy and clinical diagnosis. The nonlinear mixed-effect model (NONMEM) was used to assess the population pharmacokinetic model of amikacin in this patient population. In this study, the final population model accounting for amikacin pharmacokinetics in ICU patients was: CL = 0.93 CL(CR) (1 + 0.22 Trauma), Vd = 0.39 TBW (1 + 0.24 Sepsis), where CL(CR) and TBW corresponded to the patients' creatinine clearance and total bodyweight, respectively. The 'Trauma' and 'Sepsis' variables referred to the clinical diagnosis of the patients. This model was subsequently used to predict amikacin serum levels obtained in the validation population by a priori and Bayesian methods. The predictive performance was adequate for clinical purposes, pointing to the feasibility of our population model to provide reference values for a priori prediction as well as the Bayesian approach for individualisation of amikacin therapy in ICU patients.

Our results clearly indicate VKORC1 as the gene with the largest contribution to MWWD. Analyzing only one tag SNP of VKORC1 gene (1173C>T), it is possible to foresee 20% of the total variability. Our results may contribute to give useful indications for clinicians especially in the initiation of therapy so as to avoid the risk of adverse events.

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Total body weight, daily dose of valproate and concomitant therapy with PB are factors that significantly influence VPA kinetic disposition and they should be considered in programming dosage regimens for this antiepileptic drug in the pediatric population. The validation of the model supports its acceptability for clinical purposes.

Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care.