The stress stability of olanzapine: studies of interactions with excipients in solid state pharmaceutical formulations

Stress stability testing represents an important part of the drug development process. It is used as an important tool for the identification of degradation products and degradation pathways, as well as for the assessment of changes in physical form of drug molecules. The impact of excipients on the stability of olanzapine confirms that levels of impurities and degradants are limiting parameters and are therefore used for stability evaluation. The major degradation product of olanzapine was identified as 2-methyl-5,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepine-4-one (III). The structure of III was determined by using LC-MS, IR and NMR. Compatibility and stress stability results demonstrated that tablet formulations of olanzapine are sensitive to temperature and moisture. In samples protected from moisture, the increase in concentration of III was shown to be highly temperature dependent and the degradation followed zero-order kinetics. In addition, studies of olanzapine with excipients and in formulated tablets revealed polymorphic phase changes in some samples, influenced by a combination of stress temperature and humidity conditions. Polymorphic transitions were monitored using x-ray powder diffraction (XRPD) analysis and exhibited no correlation between the phase change (appearance of a new polymorph) and the degradation process.     

A Lack of GD3 Synthase Leads to Impaired Renal Expression of Connexins and Pannexin1 in St8sia1 Knockout Mice

The aim of this study was to determine the effects of altered ganglioside composition on the expression of Cx37, Cx40, Cx43, Cx45, and Panx1 in different kidney regions of St8sia1 gene knockout mice (St8sia1 KO) lacking the GD3 synthase enzyme. Experiments were performed in twelve male 6-month-old mice: four wild-type (C57BL/6-type, WT) and eight St8sia1 KO mice. After euthanasia, kidney tissue was harvested, embedded in paraffin wax, and processed for immunohistochemistry. The expression of connexins and Panx1 was determined in different regions of the kidney: cortex (CTX.), outer stripe of outer medulla (O.S.), inner stripe of outer medulla (IN.S.), and inner medulla (IN.MED.). We determined significantly lower expression of Cx37, Cx40, Cx45, and Panx1 in different parts of the kidneys of St8sia1 KO mice compared with WT. The most consistent decrease was found in the O.S. where all markers (Cx 37, 40, 45 and Panx1) were disrupted in St8si1 KO mice. In the CTX. region, we observed decrease in the expression of Cx37, Cx45, and Panx1, while reduced expression of Cx37 and Panx1 was more specific to IN.S. The results of the present study suggest that deficiency of GD3 synthase in St8sia1 KO mice leads to disruption of renal Cx expression, which is probably related to alteration of ganglioside composition.     

Modified Fluoroquinolones as Antimicrobial Compounds Targeting Chlamydia trachomatis

Chlamydia trachomatis causes the most common sexually transmitted bacterial infection and trachoma, an eye infection. Untreated infections can lead to sequelae, such as infertility and ectopic pregnancy in women and blindness. We previously enhanced the antichlamydial activity of the fluoroquinolone ciprofloxacin by grafting a metal chelating moiety onto it. In the present study, we pursued this pharmacomodulation and obtained nanomolar active molecules (EC₅₀) against this pathogen. This gain in activity prompted us to evaluate the antibacterial activity of this family of molecules against other pathogenic bacteria, such as Neisseria gonorrhoeae and bacteria from the ESKAPE group. The results show that the novel molecules have selectively improved activity against C. trachomatis and demonstrate how the antichlamydial effect of fluoroquinolones can be enhanced.     

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.     

The Influence of Glow and Afterglow Cold Plasma Treatment on Biochemistry,Morphology, and Physiology of Wheat Seeds

Cold plasma (CP) technology is a technique used to change chemical and morphological characteristics of the surface of various materials. It is a newly emerging technology in agriculture used for seed treatment with the potential of improving seed germination and yield of crops. Wheat seeds were treated with glow (direct) or afterglow (indirect) low-pressure radio-frequency oxygen plasma. Chemical characteristics of the seed surface were evaluated by XPS and FTIR analysis, changes in the morphology of the seed pericarp were analysed by SEM and AFM, and physiological characteristics of the seedlings were determined by germination tests, growth studies, and the evaluation of α-amylase activity. Changes in seed wettability were also studied, mainly in correlation with functionalization of the seed surface and oxidation of lipid molecules. Only prolonged direct CP treatment resulted in altered morphology of the seed pericarp and increased its roughness. The degree of functionalization is more evident in direct compared to indirect CP treatment. CP treatment slowed the germination of seedlings, decreased the activity of α-amylase in seeds after imbibition, and affected the root system of seedlings.     

Restraining of calcium contamination in near‐net shape alumina ceramics during slip casting

The traditional method for shaping ceramics is by slip casting on gypsum molds; however, its application for near‐net shaping of ceramic components is limited due to contamination by calcium ions. The focus of this study is the modification of the mold to limit Ca²⁺ contamination and to maintain favorable sucking properties. Cement was added to a standard gypsum mold to suppress its erosion, and a decrease in the sucking rate was observed due to its reduced macroporosity. The highest values of green densities were obtained at gypsum/cement weight ratios of 90/10 and 70/30. The microstructure analysis showed that alumina blocks prepared from the molds containing higher quantities of cement (30 or 50 wt%) were resistant to abnormal grain growth caused by Ca²⁺ contamination from the gypsum. The gypsum/cement mixtures for making molds for slip casting significantly limit mold erosion due to a lower sucking rate and abnormal grain growth of the slip cast samples because of the decreased diffusivity of Ca²⁺ ions. Therefore, the present modification of the mold renders the slip casting method more suitable for the near‐net shaping of ceramics.     

A comparison between hexaaluminates and perovskites for catalytic combustion applications

Hexaaluminates and perovskites are two promising candidates for use in catalytic combustion applications. In the present study two hexaaluminates, LaMnAl₁₁O₁₉ and LaCoAl₁₁O₁₉, were compared with two perovskites, LaMnO₃ and LaCoO₃, with respect to their thermal stability and catalytic activity for combustion of methane and gasified biomass. The results showed that the hexaaluminates retained a much higher surface area even after calcination at 1200 °C compared to the perovskites. LaMnAl₁₁O₁₉ showed the highest catalytic activity of all catalysts. LaCoAl₁₁O₁₉ generally showed low activity. Of the two perovskites, LaCoO₃ was the most active, and the initial test run the activity for biomass combustion were close to that one of LaMnAl₁₁O₁₉ even though its surface area was only one tenth of the hexaaluminate's. However, it was severely deactivated in the second test run. Similar deactivation but less severe was also found for the other catalyst.     

System Reconstruction in the Field-Specific Methodology of Economic Subjects

The proposal is focused on reconsideration and total reconstruction of recent economic education on the basis of different teaching styles, real competence-based learning, education for entrepreneurship and other trends in life-long education. These qualities are closely and mainly linked to target competencies which are the results of education and are reconditioned by these qualities. A modernized taxonomy of teaching methods and styles and instructions for their application in a diverse form will be proposed. The project applicants believe that the conceptual changes should be addressed by basic research as an innovation of methodological support in the form of teaching aids stratification. Teachers of economic subjects must be able to create their own teaching aids independently. They should be field methodology innovators, too. The new proposed taxonomy should be reflected in the training of teachers so that they avail of the new paradigm. This article is provided as one of the outputs of the research project of the Faculty of Finance and Accounting, which is realized in the framework of institutional support University of Economics IP 100040.     

The constitutive values of Swedish schooling: a challenge to the inner life of schools

Schooling has always been a tool for transferring values to future generations. Despite social changes such as globalisation, information technology and the retreat of national capital, schools are still institutions where a civic identity is promoted. In a multicultural society, the challenge is to advocate constitutive values without excluding citizens. The Swedish curriculum identifies educational goods by emphasizing constitutive values such as democracy, solidarity and equality in accordance with ethics linked to Western Christian humanism. In addition, these values have to be interpreted and concretised in local contexts. This article examines these aspects of curriculum and the national question. It has three sections. It discusses constitutive values in Swedish schooling; it links deliberation to the localisation and concretisation of these national values, and it reflects on the implementation of these values in a Swedish school. Overall, the article focuses on possibilities for deliberative practice in a multicultural school.     

Impairment of Hypoxia-Induced CA IX by Beta-Blocker Propranolol—Impact on Progression and Metastatic Potential of Colorectal Cancer Cells

The coexistence of cancer and other concomitant diseases is very frequent and has substantial implications for treatment decisions and outcomes. Beta-blockers, agents that block the beta-adrenergic receptors, have been related also to cancers. In the model of multicellular spheroids formed by colorectal cancer cells we described a crosstalk between beta-blockade by propranolol and tumour microenvironment. Non-selective beta-blocker propranolol decreased ability of tumour cells to adapt to hypoxia by reducing levels of HIF1α and carbonic anhydrase IX in 3D spheroids. We indicated a double action of propranolol in the tumour microenvironment by inhibiting the stability of HIF1α, thus mediating decrease of CA IX expression and, at the same time, by its possible effect on CA IX activity by decreasing the activity of protein kinase A (PKA). Moreover, the inhibition of β-adrenoreceptors by propranolol enhanced apoptosis, decreased number of mitochondria and lowered the amount of proteins involved in oxidative phosphorylation (V-ATP5A, IV-COX2, III-UQCRC2, II-SDHB, I-NDUFB8). Propranolol reduced metastatic potential, viability and proliferation of colorectal cancer cells cultivated in multicellular spheroids. To choose the right treatment strategy, it is extremely important to know how the treatment of concomitant diseases affects the superior microenvironment that is directly related to the efficiency of anti-cancer therapy