The application of selected quality tools in analysing the reasons for discrepancies in wet refractory mortar manufacture

The basic objective of this paper is to present the possibilities of applying selected quality tools in analysing the reasons for discrepancies as exemplified by the process of manufacturing wet refractory mortars. Using various methods and tools, the authors looked for the root causes of a quality rejects occurrence. The following selected methods and tools were used: analysis of variance - ANOVA, the individual moving range (I-MR) chart, SIPOC process mapping, analysis of regression, identification of potential root causes of a problem - 7M, Gauge Repeatability and Reproducibility (GRR). The paper shows how it is possible to search for the causes of quality rejects by means of deliberately selected tools and methods and to successfully decrease the number of discrepancies after introduction of the appropriate corrective actions. The authors indicate how it is possible to analyse the processes of manufacturing wet refractory mortars and what can be done in the situation when a faulty measuring system (returning seriously erroneous results) is the reason for a lack of or lower detectability of wet mortar flaws as it has affected the accuracy of feeding of all components of the recipe, as well as the consistency, moisture content, and hardness/softness of mortar. The collected analysis results allowed the authors to conclude that there were seven probable root causes influencing the hardening of mortar and the loss of its primary functions. This paper could be useful for those wet refractory mortars manufacturers who find it difficult to build their knowledge about product properties based on available publications sources

Aryl-1,3,5-triazine ligands of histamine H4H_{4} receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide

Objective and design Histamine $H_{4}$ receptor ($H_{4}R$) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of $H_{4}R$ with particular reference to their anti-inflammatory and analgesic activity. Materials and subjects We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test. Treatments In the in vivo tests, animals were pre-treated with the increasing doses of investigated compounds (12.5, 25 and 50 mg/kg) and reference compounds: JNJ7777120 (25 mg/kg), indomethacin (10 mg/kg). Macrophages were pre-treated with two concentrations of tested compounds 100 and 10 $\mu$M. Methods We examined anti-inflammatory and analgesic effects of the new $H_{4}R$ antagonists in the in vivo models of inflammation induced by carrageenan or zymosan. We assessed the level of cAMP and release of cytokines, ROS and NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Moreover, we assessed the affinity of the investigated compounds for histamine $H_{1}$ receptor in functional studies. Results Both investigated compounds reduced paw edema, mechanical and thermal hyperalgesia in the carrageenaninduced acute inflammation. Moreover, administration of the investigated compounds resulted in decreased granulocyte influx and attenuated nociceptive reaction in the zymosan-induced peritonitis model. In the same model of inflammation, the investigated compounds reduced vascular permeability; however, this effect was observed only after the highest applied dose. Furthermore, the test compounds had no impact on cell viability in the experiments on RAW 264.7 macrophages. In these cells, stimulated with LPS, the test compounds decreased reactive oxygen species (ROS) production. They increased the cellular concentration of cAMP and attenuated the production of inflammatory cytokines such as $TNF\alpha$ and $IL-1\beta$. All results were comparable to those obtained for the reference compound JNJ7777120 with the exception of the impact on NO production. Nevertheless, this effect was similar to that obtained for the other reference compound rolipram, which is a phosphodiesterase 4 (PDE 4) inhibitor. Further experiments revealed that both of the investigated compounds possessed relatively low affinity for histamine H$_{1}$ receptor and do not inhibit the activity of the PDE 4B1 enzyme. In addition, all the effects of the investigated compounds in in vivo experiments were observed at doses that did not cause neurologic deficits in rotarod test and did not reduce spontaneous locomotor activity. Conclusions Our results demonstrate the anti-inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily $H_{4}R$-dependent

Lipid profile disorders in diabetes mellitus type 2 coexisting with hypertension, CAD and obesity

WSTĘP. Obecnie cukrzycę uważa się za chorobę cywilizacyjną. Jednym z najważniejszych powikłań cukrzycy jest wczesny rozwój choroby niedokrwiennej serca (CAD, coronary artery disease). Początek i przebieg izolowanej CAD znacząco różni się w porównaniu z CAD u chorych leczonych dodatkowo z powodu cukrzycy. Inną chorobą związaną z cukrzycą jest nadciśnienie tętnicze. W insulinoniezależnej cukrzycy, nadciśnienie tętnicze wiąże się z otyłością centralną, insulinoopornością, wysokim stężeniem insuliny we krwi i zaburzeniami lipidowymi. Wszystkie te objawy tworzą obraz zespołu metabolicznego. MATERIAŁ I METODY. Badaniem objęto 113 osób: 46 mężczyzn i 67 kobiet w wieku 61 ± 35 lat leczonych z powodu cukrzycy typu 2 z współistniejącą chorobą niedokrwienną serca, nadciśnieniem tętniczym oraz otyłością. Analizowano wybrane parametry metaboliczne w odniesieniu do płci, wieku i współistnienia nadciśnienia tętniczego, CAD oraz wskaźnika masy ciała (BMI, body mass index). WYNIKI. W badanej grupie chorych znamiennie częściej CAD występowała u kobiet, natomiast nadciśnienie tętnicze w obu grupach występowało jednakowo często. W grupie kobiet częściej niż u mężczyzn CAD współistniała z cukrzycą typu 2. Wyższe wartości BMI częściej odnotowano u kobiet niż u mężczyzn. W grupie mężczyzn chorujących na CAD wartości BMI były wyższe w porównaniu z mężczyznami, u których choroba ta nie wystąpiła. U kobiet wartości BMI były porównywalne, niezależne od CAD. W grupie kobiet stwierdzono wyższe niż u mężczyzn stężenia cholesterolu frakcji HDL i frakcji LDL. WNIOSKI. Wiek to najistotniejszy czynnik ryzyka CAD. Podwyższone stężenie glukozy na czczo wpływa na zmniejszenie stężenia cholesterolu frakcji HDL u kobiet, a u mężczyzn na zwiększenie stężenia cholesterolu frakcji LDL. Większe ryzyko wystąpienia nadciśnienia tętniczego u chorych na cukrzycę typu 2 zależny od hipercholesterolemii.INTRODUCTION. Diabetes is one of the most common metabolic diseases. One of the most relevant complication of diabetes is early development of coronary artery disease (CAD). The onset and the progress of CAD is different in patients with and without diabetes. Another illness connected with diabetes is hypertension. In insulin- non depended diabetes, hypertension is connected with central obesity, insulin resistance, high level of insulin in blood and lipid disorders. All those symptoms together are called metabolic syndrome. MATERIAL AND METHODS. In 113 patients, 46 male and 67 female, correlations between individual metabolic disorders in diabetes type 2 (lipid disorders: total cholesterol, LDL-cholesterol, HDL-cholesterol; triglyceride; fasting glucose) were analysed. RESULTS. Research concerns connections between metabolic disorders and CAD, hypertension and obesity, illnesses which are closely connected with diabetes (depending on age and sex). CONCLUSIONS. Age is the most important risk factor of CAD in patients with diabetes type 2. It was observed, that increased level of fasting glucose and high value of BMI have significant influence on a reduction of HDL-cholesterol level, which is independent risk factor of CAD development. Hypercholesterolaemic patients with diabetes type 2 are at the risk of increased hypertension

Computer-Aided Studies for Novel Arylhydantoin 1,3,5-Triazine Derivatives as 5-HT6 Serotonin Receptor Ligands with Antidepressive-Like, Anxiolytic and Antiobesity Action In Vivo

This study focuses on the design, synthesis, biological evaluation, and computer-aided structure-activity relationship (SAR) analysis for a novel group of aromatic triazine-methylpiperazines, with an hydantoin spacer between 1,3,5-traizine and the aromatic fragment. New compounds were synthesized and their affinities for serotonin 5-HT6, 5-HT1A, 5-HT2A, 5-HT7, and dopamine D2 receptors were evaluated. The induced-fit docking (IFD) procedure was performed to explore the 5-HT6 receptor conformation space employing two lead structures. It resulted in a consistent binding mode with the activity data. For the most active compounds found in each modification line, anti-obesity and anti-depressive-like activity in vivo, as well as “druglikeness” in vitro, were examined. Two 2-naphthyl compounds (18 and 26) were identified as the most active 5-HT6R agents within each lead modification line, respectively. The 5-(2-naphthyl)hydantoin derivative 26, the most active one in the series (5-HT6R: Ki = 87 nM), displayed also significant selectivity towards competitive G-protein coupled receptors (6–197-fold). Docking studies indicated that the hydantoin ring is stabilized by hydrogen bonding, but due to its different orientation, the hydrogen bonds form with S5.44 and N6.55 or Q6.58 for 18 and 26, respectively. Compound 26 exerted anxiolytic-like and antidepressant-like activities. Importantly, it demonstrated anti-obesity properties in animals fed palatable feed, and did not show toxic effects in vitro

Low-basicity 5-HT7 receptor agonists synthesized using the van Leusen multicomponent protocol

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5- iodo-1H-indole (AGH-107, 1o, Ki 5-HT7=6nM, EC50=19nM, 176-fold selectivity over 5-HT1AR) and 1e (5-methoxy analogue, Ki 5-HT7=30nM, EC50=60nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (Cmax=2723 ng/g) were found for 1o after i.p. (5mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5mg/kg. Docking to 5-HT7R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT1AR selectivity