Cardiovascular effects of conventional sulfonylureas and glimepiride

Sulfonylureas have, in the past, been reported to have adverse cardiovascular effects. Glimepiride is a new sulfonylurea. In spite of stimulating less insulin secretion, it has, depending on the species, equal or higher blood glucose decreasing activity and according to preliminary studies less cardiovascular activity than glibenclamide. Further studies were performed to confirm the lower cardiovascular activity of glimepiride. The IC50 for inhibition of rilmakalim-activated KATP channel currents in isolated ventricular myocytes was 31.6 nM for glimepiride and 6.8 nM for glibenclamide. In endotoxin shock-rats at a dose of 1 x 2 mg/kg i.v., glibenclamide induced a significantly higher blood pressure increase than glimepiride. At two i.v. doses of 20 mg/kg 4 min apart, in normal rats, glibenclamide produced signs of ischemia in the ECG in nearly all animals, glimepiride almost none, in diabetic rats, glibenclamide produced in all animals a lethal cardiogenic shock preceeded by serious ECG changes, glimepiride only in one fifth of the animals. In open-chest dogs, on intracoronary infusion of equieffective blood glucose-lowering doses, glibenclamide, gliclazide and glimepiride all reduced coronary blood flow, increased coronary resistance, depressed the mechanical activity of the heart, enhanced myocardial O2-extraction, reduced the serum potassium level and induced a moderate endocardial ST-segment elevation, but glimepiride to a significantly less extent than glibenclamide and gliclazide. The presented data confirm that glimepiride at equivalent blood glucose decreasing doses has less cardiovascular activity than conventional sulfonylureas.     

Role of mixing parameters in the preparation of poly(ethylene vinyl acetate) nanocomposites by melt blending

Polymer/layered‐silicate nanocomposites have gathered momentum as cost‐effective and versatile materials since the middle of the 20th century. Many publications discuss the chemistry of organomodification and properties of nanocomposites, but relatively few deal with the significance of processing conditions. This article takes into account three mixing parameters and discusses the contribution of each toward nanocomposite formation. Organomodified natural sodium‐type bentonite clay was used in this study. The nanocomposites formed were characterized by X‐ray diffraction and mechanical property tests. Response surface regression was used to optimize the tensile modulus. The analysis shows that nanocomposite formation is promoted by a diffusion mechanism and that the interactions of parameters are as important as individual parameters. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 2652–2658, 2006     

Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model

The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.     

THE “UCKRON-1” TEST PROBLEM FOR REACTION ENGINEERING MODELING

Testing kinetic models against a “true” and detailed kinetic expression was the aim of the Workshop on Kinetic Model Development at the Denver AIChE Meeting in August, 1983. For this purpose an artificial reaction mechanism was created, based on the known thermodynamics of the methanol synthesis as a framework. The kinetic rate laws, that were derived from this mechanism, were made thermodynamically consistent by achieving agreement between equilibrium constants calculated at various temperatures from the given, real original thermodynamic relationship and those calculated from the detailed reversible kinetic expressions.

Using the artificial kinetics as the "true" one, CSTR experiments were simulated. The results of a statistically designed set of experiments were published after 5% random error was added to the data. Participation was invited for all interested to correlate the data, develop kinetic models and to calculate the performance of the specified reactor.

The results of 19 submitted entries are summarized with the conclusion that the models had more differences than were expected, but their predictive values were not as different as was anticipated, if the extreme high production rates due to thermal runaways are not considered. This in turn points out the necessity to check models experimentally, in pilot plant, not only for predicted optimum, but also for calculated runaway conditions. Models which did not capture the true character of this reaction failed to predict the onset of runaway reactions.     

Nonlinear Interval Parameter Programming Combined with Cooperative Games: a Tool for Addressing Uncertainty in Water Allocation Using Water Diplomacy Framework

Water Resources Management - This paper shows the utility of a new interval cooperative game theory as an effective water diplomacy tool to resolve competing and conflicting needs of water users...     

Experimental electrocoagulation of dog esophageal and duodenal mucosa

The per review system for the assessment of research proposals is widely respected by working scientists. Nevertheless two problems associated with the operation of this system by the US National Institutes of Health are identified. First the scientist has no control over which committee will review an application and it may be considered by a quite inappropriate group. Second analysis of the committee composition suggests that in some of the groups several members are not active scientists and therefore not the "peers" of the applicant.     

Empirical validation of object-oriented metrics on open source software for fault prediction

Open source software systems are becoming increasingly important these days. Many companies are investing in open source projects and lots of them are also using such software in their own work. But, because open source software is often developed with a different management style than the industrial ones, the quality and reliability of the code needs to be studied. Hence, the characteristics of the source code of these projects need to be measured to obtain more information about it. This paper describes how we calculated the object-oriented metrics given by Chidamber and Kemerer to illustrate how fault-proneness detection of the source code of the open source Web and e-mail suite called Mozilla can be carried out. We checked the values obtained against the number of bugs found in its bug database - called Bugzilla - using regression and machine learning methods to validate the usefulness of these metrics for fault-proneness prediction. We also compared the metrics of several versions of Mozilla to see how the predicted fault-proneness of the software system changed during its development cycle.     

Development of High-Efficiency,Magnetically Separable Palladium-Decorated Manganese-Ferrite Catalyst for Nitrobenzene Hydrogenation

Aniline (AN) is one of the most important compounds in the chemical industry and is prepared by the catalytic hydrogenation of nitrobenzene (NB). The development of novel, multifunctional catalysts which are easily recoverable from the reaction mixture is, therefore, of paramount importance. Compared to conventional filtration, magnetic separation is favored because it is cheaper and more facile. For satisfying these requirements, we developed manganese ferrite (MnFe₂O₄)–supported, magnetically separable palladium catalysts with high catalytic activity in the hydrogenation of nitrobenzene to aniline. In addition to high NB conversion and AN yield, remarkable aniline selectivity (above 96 n/n%) was achieved. Surprisingly, the magnetic support alone also shows moderate catalytic activity even without noble metals, and thus, up to 94 n/n% nitrobenzene conversion, along with 47 n/n% aniline yield, are attainable. After adding palladium nanoparticles to the support, the combined catalytic activity of the two nanomaterials yielded a fast, efficient, and highly selective catalyst. During the test of the Pd/MnFe₂O₄ catalyst in NB hydrogenation, no by-products were detected, and consequently, above 96 n/n% aniline yield and 96 n/n% selectivity were achieved. The activity of the Pd/MnFe₂O₄ catalyst was not particularly sensitive to the hydrogenation temperature, and reuse tests indicate its applicability in at least four cycles without regeneration. The remarkable catalytic activity and other favorable properties can make our catalyst potentially applicable to both NB hydrogenation and other similar or slightly different reactions.     

Digitoxin Affects Metabolism,ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype

Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1–100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.