Risk management profile of etoricoxib: an example of personalized medicine

The development of nonsteroidal anti-inflammatory drugs (NSAIDs) selective for cyclooxygenase (COX)-2 (named coxibs) has been driven by the aim of reducing the incidence of serious gastrointestinal (GI) adverse events associated with the administration of traditional (t) NSAIDs – mainly dependent on the inhibition of COX-1 in GI tract and platelets. However, their use has unravelled the important protective role of COX-2 for the cardiovascular (CV) system, mainly through the generation of prostacyclin. In a recent nested-case control study, we found that patients taking NSAIDs (both coxibs and tNSAIDs) had a 35% increase risk of myocardial infarction. The increased incidence of thrombotic events associated with profound inhibition of COX-2-dependent prostacyclin by coxibs and tNSAIDs can be mitigated, even if not obliterated, by a complete suppression of platelet COX-1 activity. However, most tNSAIDs and coxibs are functional COX-2 selective for the platelet (ie, they cause a profound suppression of COX-2 associated with insufficient inhibition of platelet COX-1 to translate into inhibition of platelet function), which explains their shared CV toxicity. The development of genetic and biochemical markers will help to identify the responders to NSAIDs or who are uniquely susceptible at developing thrombotic or GI events by COX inhibition. We will describe possible strategies to reduce the side effects of etoricoxib by using biochemical markers of COX inhibition, such as whole blood COX-2 and the assessment of prostacyclin biosynthesis in vivo

Novel Insights into the Vasoprotective Role of Heme Oxygenase-1

Cardiovascular risk factors contribute to enhanced oxidative stress which leads to endothelial dysfunction. These events trigger platelet activation and their interaction with leukocytes and endothelial cells, thus contributing to the induction of chronic inflammatory processes at the vascular wall and to the development of atherosclerotic lesions and atherothrombosis. In this scenario, endogenous antioxidant pathways are induced to restrain the development of vascular disease. In the present paper, we will discuss the role of heme oxygenase (HO)-1 which is an enzyme of the heme catabolism and cleaves heme to form biliverdin and carbon monoxide (CO). Biliverdin is reduced enzymatically to the potent antioxidant bilirubin. Recent evidence supports the involvement of HO-1 in the antioxidant and antiinflammatory effect of cyclooxygenase(COX)-2-dependent prostacyclin in the vasculature. Moreover, the role of HO-1 in estrogen vasoprotection is emerging. Finally, possible strategies to develop novel therapeutics against cardiovascular disease by targeting the induction of HO-1 will be discussed

Characterization of protein tyrosine phosphatase H1 knockout mice in animal models of local and systemic inflammation

<p>Abstract</p> <p>Background</p> <p>PTPH1 is a protein tyrosine phosphatase expressed in T cells but its effect on immune response is still controversial. PTPH1 dephosphorylates TCRzeta <it>in vitro</it>, inhibiting the downstream inflammatory signaling pathway, however no immunological phenotype has been detected in primary T cells derived from PTPH1-KO mice. The aim of the present study is to characterize PTPH1 phenotype in two <it>in vivo </it>inflammatory models and to give insights in possible PTPH1 functions in cytokine release.</p> <p>Methods</p> <p>We challenged PTPH1-KO mice with two potent immunomodulatory molecules, carrageenan and LPS, in order to determine PTPH1 possible role in inflammatory response <it>in vivo</it>. Cytokine release, inflammatory pain and gene expression were investigated in challenged PTPH1-WT and KO mice.</p> <p>Results</p> <p>The present study shows that carrageenan induces a trend of slightly increased spontaneous pain sensitivity in PTPH1-KO mice compared to WT (wild-type) littermates, but no differences in cytokine release, induced pain perception and cellular infiltration have been detected between the two genotypes in this mouse model. On the other hand, LPS-induced TNFα, MCP-1 and IL10 release was significantly reduced in PTPH1-KO plasma compared to WTs 30 and 60 minutes post challenge. No cytokine release modulation was detectable 180 minutes post LPS challenge.</p> <p>Conclusion</p> <p>In conclusion, the present study points out a slight potential role for PTPH1 in spontaneous pain sensitivity and it indicates that this phosphatase might play a role in the positive regulation of the LPS-induced cytokines release <it>in vivo</it>, in contrast to previous reports indicating PTPH1 as potential negative regulator of immune response.</p

Lipid Peroxidation and Depressed Mood in Community-Dwelling Older Men and Women

It has been hypothesized that cellular damage caused by oxidative stress is associated with late-life depression but\ud epidemiological evidence is limited. In the present study we evaluated the association between urinary 8-iso-prostaglandin\ud F2a (8-iso-PGF2a), a biomarker of lipid peroxidation, and depressed mood in a large sample of community-dwelling older\ud adults. Participants were selected from the Health, Aging and Body Composition study, a community-based longitudinal\ud study of older persons (aged 70–79 years). The present analyses was based on a subsample of 1027 men and 948 women\ud free of mobility disability. Urinary concentration of 8-iso-PGF2a was measured by radioimmunoassay methods and adjusted\ud for urinary creatinine. Depressed mood was defined as a score greater than 5 on the 15-item Geriatric Depression Scale and/\ud or use of antidepressant medications. Depressed mood was present in 3.0% of men and 5.5% of women. Depressed men\ud presented higher urinary concentrations of 8-iso-PGF2a than non-depressed men even after adjustment for multiple\ud sociodemographic, lifestyle and health factors (p=0.03, Cohen’s d = 0.30). This association was not present in women\ud (depressed status-by-sex interaction p = 0.04). Our study showed that oxidative damage may be linked to depression in\ud older men from a large sample of the general population. Further studies are needed to explore whether the modulation of\ud oxidative stress may break down the link between late-life depression and its deleterious health consequences

Knockout mice reveal a role for protein tyrosine phosphatase H1 in cognition

<p>Abstract</p> <p>Background</p> <p>The present study has investigated the protein tyrosine phosphatase H1 (PTPH1) expression pattern in mouse brain and its impact on CNS functions.</p> <p>Methods</p> <p>We have previously described a PTPH1-KO mouse, generated by replacing the PTP catalytic and the PDZ domain with a LacZ neomycin cassette. PTPH1 expression pattern was evaluated by LacZ staining in the brain and PTPH1-KO and WT mice (n = 10 per gender per genotype) were also behaviorally tested for CNS functions.</p> <p>Results</p> <p>In CNS, PTPH1 is expressed during development and in adulthood and mainly localized in hippocampus, thalamus, cortex and cerebellum neurons. The behavioral tests performed on the PTPH1-KO mice showed an impact on working memory in male mice and an impaired learning performance at rotarod in females.</p> <p>Conclusion</p> <p>These results demonstrate for the first time a neuronal expression of PTPH1 and its functionality at the level of cognition.</p

Aroma Profile of Montepulciano d'Abruzzo Wine Fermented by Single and Co-culture Starters of Autochthonous Saccharomyces and Non-saccharomyces Yeasts

Montepulciano d'Abruzzo is a native grape variety of Vitis vinifera L., grown in central Italy and used for production of high quality red wines. Limited studies have been carried out to improve its enological characteristics through the use of indigenous strains of Saccharomyces cerevisiae. The main objective of the present work was to test two indigenous strains of S. cerevisiae (SRS1, RT73), a strain of Starmerella bacillaris (STS12), one of Hanseniaspora uvarum (STS45) and a co-culture of S. cerevisiae (SRS1) and S. bacillaris (STS12), in an experimental cellar to evaluate their role in the sensory characteristic of Montepulciano d'Abruzzo wine. A S. cerevisiae commercial strain was used. Fermentations were conducted under routine Montepulciano d'Abruzzo wine production, in which the main variables were the yeast strains used for fermentation. Basic winemaking parameters, some key chemical analysis and aroma compounds were considered. S. cerevisiae strain dynamics during fermentation were determined by molecular methods. The musts inoculated with the co-culture were characterized by a faster fermentation start and a higher content of glycerol after 3 days of fermentation, as well as the musts added with strains S. bacillaris (STS12) and H. uvarum (STS45). At the end of fermentation the parameters studied were quite similar in all the wines. Total biogenic amines (BA) content of all the wines was low. Ethanolamine was the predominant BA, with a concentration ranging from 21 to 24 mg/l. Wines were characterized by esters and alcohols. In particular, 2-phenylethanol, 3-methylbut-1-yl methanoate, and ethyl ethanoate were the major aroma volatile compounds in all wines. Statistical analysis highlighted the different role played by aroma compounds in the differentiation of wines, even if it was impossible to select a single class of compounds as the most important for a specific yeast. The present study represents a further step toward the use of tailored autochthonous strains to impart the specific characteristics of a given wine which are an expression of a specific terroir