Marta Šoltésová Prnová, Lucia Račková, Lucia Kováčiková, Jana Balleková, Jana Viskupičová, Silvia Micháliková, Betul Taşkoparan, Zübeyir Elmazoğlu, Tea Lanišnik Rižner, Cimen Karasu, Sreeparna Banerjee and Milan Štefek
Cemtirestat, 3-mercapto-5H-[1,2,4]-triazino[5,6-b]indole-5-acetic acid was recently designed and patented as a highly selective and efficient aldose reductase inhibitor endowed with antioxidant activity. The aim of the present study was to assess the general toxicity of cemtirestat using in silico predictions, in vitro and in vivo assays. ProTox-II toxicity prediction software gave 17 “Inactive” outputs, a mild hepatotoxicity score (0.52 probability) along with a predicted LD50 of 1000 mg/kg. Five different cell lines were used including the immortalized mouse microglia BV-2, the primary human fibroblasts VH10, the insulinoma pancreatic β-cells INS-1E, the human colon cancer cells HCT116 and the human immortalized epithelial endometrial cell lines HIEEC. In contrast to the clinically used epalrestat, cemtirestat showed remarkably low cytotoxicity in several different cell culture viability tests such as MTT proliferation assay, neutral red uptake, BrdU incorporation, WST-1 proliferation assay and propidium iodide staining followed by flow cytometry. In a yeast spotting assay, the presence of cemtirestat in incubation of Saccaromyces cerevisiae at concentrations as high as 1000 µM did not affect cell growth rate significantly. In the 120-day repeated oral toxicity study in male Wistar rats with daily cemtirestat dose of 6.4 mg/kg, no significant behavioral alterations or toxicological manifestations were observed in clinical and pathological examinations or in hematological parameters. In summary, these results suggest that cemtirestat is a safe drug that can proceed beyond preclinical studies.
Dorin-Gheorghe Triff, Zorica Triff, Mușata-Dacia Bocoș and Eugenia Naghi
International Symposium on Work Ability, Helsinki 2004 (pp. 1-25).
9. Tuomi K, Ilmarinen J, Jahkola A, Katajarinne L, Tulkki A. Work ability index. Helsinki: Institute of Occupational Health; 1994.
10. 36-Item Short Form Survey (SF-36). Avalaible at: https://www.rand.org/health/surveys_tools/mos/36-item-short-form.html (downloaded on 22.07.2019).
11. The SF-36 scoring. Avalaible at: http://www.alswh.org.au/images/content/pdf/InfoData/Data_Dictionary_Supplement/DDSSection2SF36.pdf (downloaded on 22.07.2019).
Early amniotomy is one of the main interventions to enhance the labor progress and prevent dystocia in pregnant women. However, the efficacy of amniotomy has not been approved via labor-related indices and outcomes and has remained a subject for debate and future research. The present study was conducted to evaluate the effect of early amniotomy on labor indices and outcomes in nulliparous women. This randomized clinical trial was performed on 151 singleton pregnant women who were referred to Besat Hospital in Sanandaj, Iran, from March 2016 to March 2018. Participants were randomly divided into an early amniotomy (EA) group and a control group. Duration of the first and second phases of labor, corioamionit, dystocia rate, Apgar score at the first and fifth minutes, prolonged labor and post-partum haemorrhage were evaluated and compared between the two groups. Data were recorded in a checklist and analysed using SPSS Version 23. The p value <0.05 was considered significant. Results showed that labor indices such as duration of the first and second phases, Apgar score one and five minutes after delivery and frequency of prolonged labor, foetal distress and postpartum haemorrhage were significantly improved in patients of the early amniotomy group, compared with the control group (p≤0.05). Early amniotomy significantly decreased the total labor duration without significant increase in the rate of maternal and neonatal complications.
Eduard Ujházy, Mojmír Mach, Jana Navarová, Ingrid Brucknerová and Michal Dubovický
Safety assessment of the pyridoindole derivative SMe1EC2: developmental neurotoxicity study in rats
The present study deals with effect of prenatal and neonatal administration of the synthetic pyridoindole derivative SMe1EC2 (2-ethoxycarbonyl-8-methoxy-2,3,4,4a, 5,9b-hexahydro-1H-pyrido-[4,3b] indolinium chloride) on postnatal and neurobehavioral development of the rat offspring. The substance tested was administered to pregnant rats orally in the doses 5, 50 and 250 mg/kg from day 15 of gestation to day 10 post partum (PP). From the day 4 PP, the postnatal development and neurobehavioral characteritics of offspring were evaluated. The following variables were observed: body weight, pinna detachment, incisor eruption, ear opening, eye opening, testes descent and vaginal opening, righting reflex, negative geotaxia, startle reflex, dynamic air righting and exploratory behavior in a new environment. No maternal death, abortion or dead fetuses occurred either in the control or SMe1EC2 groups. Dynamic righting reflex was delayed one day in the groups of animals treated via their mothers with 5 and 50 mg/kg SMe1EC2. The delay in the development of this reflex was only transient. On day 20 PP, all pups tested had a positive score of the reflex. Administration of SMe1EC2 did not reveal any significant changes in other variables of somatic growth and maturation, reflex and neuromotor development and exploratory behavior, either of young or adult animals of both genders, assessed by analysis of variance.
The aim of the present study was to evaluate local irritant effects to rabbit skin following a single application of test samples of non-sterile polyamide non-absorbable surgical sutures POLYMED ®. The polar and nonpolar extracts were prepared by using saline solution and olive oil, respectively, after sinking the materials tested (2.0 g) in 10 ml of the corresponding liquid. Incubation was carried out at the temperature of 37°C for 72 h. The saline solution and pure olive oil, which had no contact with the materials tested, were used as negative control samples and were incubated under the same conditions as above. Assessments of the extracts from each material were conducted on 2 albino rabbits of the New Zealand breed. On the back of each animal, 5 intracutaneous injections of the extract tested and 5 injections of the control solution, each of 0.2 ml, were carried out. The degree of irritation was scored at 4, 24, 48, 72 hours after injection and no skin changes were found. The intracutaneous irritation index (III) was calculated and yielded 0.0. Hence it was concluded that under the experimental conditions the extracts of the material tested, i.e. non-sterile polyamide non-absorbable surgical sutures POLYMED ®, were ‘non-irritant’ to the skin of rabbits when compared with the respective control groups. The experimental procedure was conducted according to ISO10993-10.
Ruzena Sotnikova, Viera Nosalova and Jana Navarova
Reactive oxygen species has been implicated to contribute significantly to tissue injury associated with ulcerative colitis. Thus compounds with antioxidant properties could be potential therapeutic agents in this disease. Flavonoid compounds are known to possess antioxidative and antiinflammatory properties. Two derivatives of the flavonoid quercetin (Q), chloronaphthoquinone quercetin (CNC) and monochloropivaloyl quercetin (MCP), showed improved antioxidant properties and moreover, they efficiently inhibited aldose reductase activity in vitro. The aim of the work was to test the potential efficacy of quercetin and these synthetic derivatives in vivo in prevention of intestinal inflammation during ulcerative colitis in rats. Colitis was induced by intracolonic administration of acetic acid (4% solution). The control group received the same volume of saline. The vehicle dimethyl sulfoxide (DMSO) and the drugs Q, CNC or MCP were administered orally two hours and then one hour before the acetic acid or saline instillation. After 48 hours, the animals were sacrificed and the colon was weighed, measured and scored for visible damage. Acetic acid triggered an intense inflammatory response of the colon, characterised by haemorrhage, ulceration and bowel wall thickening. From the drugs tested, only CNC (2 × 50 mg/kg) effectively depressed inflammatory damage of the colon. The mechanism of this beneficial effect remains to be elucidated.
Frantisek Drafi, Katarina Bauerova, Viera Kuncirova, Silvester Ponist, Danica Mihalova, Tatiana Fedorova, Juraj Harmatha and Radomir Nosal
Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. A certain correlation was observed between oxidative stress, arthritis and the immune system. Reactive oxygen species produced in the course of cellular oxidative phosphorylation and by activated phagocytic cells during oxidative burst, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein, lipids, nucleic acids, and matrix components. Patients with rheumatoid arthritis have an altered antioxidant defense capacity barrier. In the present study the effect of substances with antioxidative properties, i.e. pinosylvin and carnosine, was determined in monotherapy for the treatment of adjuvant arthritis (AA). Moreover carnosine was evaluated in combination therapy with methotrexate. Rats with AA were administered first pinosylvin (30 mg/kg body mass daily per os), second carnosine (150 mg/kg body mass daily per os) in monotherapy for a period of 28 days. Further, rats with AA were administered methotrexate (0.3 mg/kg body mass 2-times weekly per os), and a combination of methotrexate+carnosine, with the carnosine dose being the same as in the previous experiment. Parameters, i.e. changes in hind paw volume and arthritic score were determined in rats as indicators of destructive arthritis-associated clinical changes. Plasmatic levels of TBARS and lag time of Fe2+- induced lipid peroxidation (tau-FeLP) in plasma and brain were specified as markers of oxidation. Plasmatic level of CRP and activity of γ-glutamyltransferase (GGT) in spleen and joint were used as inflammation markers. In comparison to pinosylvin, administration of carnosine monotherapy led to a significant decrease in the majority of the parameters studied. In the combination treatment with methotrexate+carnosine most parameters monitored were improved more remarkably than by methotrexate alone. Carnosine can increase the disease-modifying effect of methotrexate treatment in rat AA.
Agata Michalak, Katarzyna Laskowska, Piotr Radwan, Beata Kasztelan-Szczerbinska, Marek Cybulski and Halina Cichoz-Lach
Various laboratory parameters are commonly used to assess the efficacy of biological treatment (BT). The aim of our study was to assess the correlation between platelet (PLT) indices: (mean platelet volume (MPV), plateletcrit (PCT), platelet distribution width (PDW)), C-reactive protein (CRP) and endoscopic picture in the course of infliximab induction regimen in ulcerative colitis (UC) patients. The study enrolled 46 patients with UC – 32 men and 16 women. They were administered infliximab (standard induction therapy). Laboratory tests (CRP and PLT indices) and colonoscopy were performed in all patients during the induction regimen – at 0, 2, and 6 weeks and in follow-up six weeks after the completion of induction therapy. The study revealed a statistically significant decrease in CRP and PLT, and an increase in MPV, together with improvement of endoscopic picture (p <0.001) (MAYO score, MAYO endoscopic subscore) in all patients. PCT and PDW values remained in normal ranges before BT and after the finish of the induction regimen. PCT correlated positively with CRP before the introduction of BT (p = 0.018). In addition, positive correlations between PCT and PLT count were noticed before infliximab induction regimen and in follow-up after the finished of therapy (p <0.001). Additionally, a negative correlation between PLT count and MPV prior to the first dose of infliximab was observed (p=0.032). Our data suggest that PLT indices could be useful biomarkers for determining active UC and for assessing the efficacy of BT. From what we know, this is the first survey devoted to PLT parameters in Polish patients with UC.
Marina Ruxandra Oțelea, Anca Streinu-Cercel, Daniela Manolache, Andreea Mutu, Lavinia Călugăreanu, Dana Mateș and Oana Săndulescu
, O’Brien CS, Ng KT, Rajaratnam SM. Validation of a questionnaire to screen for shift work disorder. Sleep.2012;35:1693–1703.
19. European Society of Cradiology.Score risk charts. https://www.escardio.org/Education/Practice-Tools/CVD-prevention-toolbox/SCORE-Risk-Charts,pdf dowloaded 10.02.2019.
20. Prineas R, Crow R, Blackburn H. The Minnesota Code Manual of Electrocardiographic Findings. 2nd edition, London: Springer-Verlag; 2010.
21. Sagie A, Larson MG, Goldberg RJ, Bengtson JR, Levy D. An improved method for adjusting the QT interval for
Islam M. Sadiqul, Saimon Mohiful Kabir, Zannatul Ferdous, Khan Mst. Mansura and Rahman Md. Khalilur
. Ecotoxicology 16 : 385–391.
Fenech M, Chang WP, Kirsch-Volders HMN, Bonassi S, Zeiger E. (2003). HUMAN project: detailed description of the scoring criteria for the cytokinesis block micronucleus assay using isolated human lymphocyte cultures. Mut Res 534 : 65–75.
Finney DJ. (1971). Probit analysis, Cambridge University, Press, London, UK (3 rd Edn.).
Folch J, Lees M, Sloane Stanley GH. (1957). A simple method for the isolation and purification of total lipides from animal tissues. J Biochem Chem 226 (1): 497–509.
Gerhardt P, Murray RGE, Wood