Abstract Background Orodispersible tablet (ODT) is a different tablet formulation that disperse upon contact with the moist mucosal surfaces of the oral cavity and quickly release its components before swallowing; thus drug dissolution and absorption, as well as onset of clinical effect, can be obtained conveniently easily and quickly. Recently, Ticagrelor 90 mg ODT has become available and bioequivalence studies on healthy volunteers documented its effectiveness with consequent approval by the European Medicine Agency. It is unknown whether Ticagrelor ODT might be an effective route of drug administration in high-risk acute coronary syndrome (ACS) patients. Purpose The aim of the present study is to evaluate the superiority in platelet inhibition with 180 mg Ticagrelor loading dose (LD) administered as ODT as compared with standard (coated table) Ticagrelor formulation, among 130 ACS patients undergoing PCI. Methods Patients presenting within STEMI or very high-risk NSTEMI referred for immediate (<2 hours) angiography were randomly assigned to receive ODT or standard ticagrelor LD. Platelet reactivity was assessed by Platelet Reactivity Units (PRU) VerifyNow 1, 2, 4 and 6 hours after ticagrelor LD. The primary study endpoint was residual platelet reactivity 1 hour after Ticagrelor LD. Safety endpoints were major bleedings and other in-hospital ticagrelor administration-related adverse events across the two different regimens of Ticagrelor administration. Potential morphine-ticagrelor interaction was assessed by stratified randomization according to morphine use. An interim analysis was planned after the enrollment of 50% (n=65 patients) of the entire study population. The study was supported by an unrestricted grant from AstraZeneca. Results At the interim analysis, the 2 study group were well matched according to all the baseline characteristics (such as age, sex, diabetes mellitus, chronic renal failure, STEMI at presentation, Killip class, multivessel disease, number of stents implanted, and morphine use). Main pharmacodynamic data are depicted in Figure 1. One hour after LD, PRU (97±99 vs 115±92; p=0.40) was numerically lower, but not statistically different, in the ODT group as compared to standard ticagrelor group. The percentage of platelet inhibition was 55±44% vs 42±44% (p=0.21) in the 2 groups. No significant difference was observed between patients receiving ODT or standard ticagrelor LD regarding in-hospital adverse events or drug side-effects. The study enrollment is ongoing, and final results will be presented at the Congress. Conclusions ODT administration might represent the most convenient way of treating lying supine ACS patients in the ambulance, emergency room or on the cath lab. Moreover, in patients with difficulties in swallowing ODT represent an easy way of ticagrelor administration. Figure 1 Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): AstraZeneca S.P.A.
Objective Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-γ receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. Rosiglitazone (Avandia) is a PPAR-γ agonist (the most potent PPAR-γ agonist of the thiazolidinedione antidiabetics). In the present study, we investigated the effects of rosiglitazone on the development of nonseptic shock caused by zymosan in mice. Design Experimental study. Setting University laboratory. Subjects Male CD mice. Interventions We investigated the effects of rosiglitazone (3 mg/kg) on the development of nonseptic shock caused by zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) in mice. Measurements and Main Results Organ failure and systemic inflammation in rats were assessed 18 hrs after administration of zymosan and/or rosiglitazone and monitored for 12 days (for loss of body weight and mortality rate). Treatment of mice with rosiglitazone (3 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. Rosiglitazone also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity and malondialdehyde concentrations caused by zymosan in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, and poly(adenosine diphosphate-ribose) revealed positive staining in lung and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine, inducible nitric oxide synthase, and poly(adenosine diphosphate-ribose) was markedly reduced in tissue sections obtained from zymosan-treated mice that received rosiglitazone. To elucidate whether the protective effects of rosiglitazone are related to activation of the PPAR-γ receptor, we also investigated the effect of a PPAR-γ antagonist, GW 9662, on the protective effects of rosiglitazone. GW 9662 (1 mg/kg administered intraperitoneally 30 mins before treatment with rosiglitazone) significantly antagonized the effect of the PPAR-γ agonist and thus abolished the protective effect. Conclusions This study provides evidence, for the first time, that rosiglitazone attenuates the degree of zymosan-induced nonseptic shock in mice.
One of the main problems of seafood marketing is the ease with which fish and shellfish undergo deterioration after death. (1)H NMR spectroscopy and microbiological analysis were applied to get in depth insight into the effects of cold storage (4 °C and 0 °C) on the spoilage of the mussel Mytilus galloprovincialis. This data article provides information on the average distribution of the microbial loads in mussels׳ specimens and on the acquisition, processing, and multivariate analysis of the (1)H NMR spectra from the hydrosoluble phase of stored mussels. This data article is referred to the research article entitled "Metabolomics analysis of shucked mussels' freshness" (Aru et al., 2016) [1].
This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D-PGJ2 reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ2, however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ2, but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.
Twenty-three Lactobacillus strains of dairy origin were evaluated for some functional properties relevant to their use as probiotics. A preliminary subtractive screening based on the abilities to inhibit the growth of microbial pathogens and hydrolyze conjugated bile salts was applied, and six strains were selected for further characterization including survival under gastrointestinal environmental conditions, adhesion to gut epithelial tissue, enzymatic activity, and some safety properties. All selected strains maintained elevated cell numbers under conditions simulating passage through the human gastrointestinal tract, well comparable to the values obtained for the probiotic strain Lactobacillus rhamnosus GG, and were able to adhere to Caco-2 cells to various extents (from 3 to 20%). All strains exhibited high aminopeptidase, and absent or very low proteolytic and strong β -galactosidase activities; none was found to be haemolytic or to produce biogenic amines and all were susceptible to tetracycline, chloramphenicol, erythromycin, ampicillin, and amoxicillin/clavulanic acid. Our results indicate that the Lactobacillus strains analyzed could be considered appropriate probiotic candidates, due to resistance to GIT simulated conditions, antimicrobial activity, adhesion to Caco-2 cell-line, and absence of undesirable properties. They could be used as adjunct cultures for contributing to the quality and health related functional properties of dairy products.
Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM‐1) in the colon. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15‐deoxy‐Δ 12,14 ‐PGJ 2 (15d‐ PGJ 2 ) functions as an early anti‐inflammatory signal. The aim of the present paper is to investigate the effects of 15d‐PGJ 2 in rats subjected to experimental colitis. Colitis was induced in rats by intra‐colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d‐PGJ 2 was administered daily as intraperitoneal injection (20 or 40 μg kg −1 ). On day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. 15d‐PGJ 2 significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d‐PGJ 2 also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde (MDA) and (iv) of the pro‐inflammatory cytokines tumour necrosis factor‐alpha (TNF‐α) and interleukin‐1β (IL‐1β). Furthermore, 15d‐PGJ 2 reduced the increase in immunohistochemical staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and (iii) poly (ADP‐ribose) polymerase (PARP), as well as (iv) the increased expression of ICAM‐1 caused by DNBS in the colon. Electrophoresis mobility shift assay (EMSA) of inflamed colon revealed that 15d‐ PGJ 2 also caused a substantial reduction of the activation of nuclear factor‐kappaB (NF‐κB). Furthermore, 15d‐PGJ 2 stimulates the activation of heat shock protein 72 ( hsp72 ) in the inflamed colon, as assessed by Western blot analysis. In conclusion, 15d‐PGJ 2 reduces the development of experimental colitis. British Journal of Pharmacology (2003) 138 , 678–688. doi: 10.1038/sj.bjp.0705077
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