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Open access

Ana Testen, Miha Plevnik, Bogdan Štefane and Irena Kralj Cigić

Abstract

Development of safe and effective drugs requires complete impurity evaluation and, therefore, knowledge about the formation and elimination of impurities is necessary. During impurity profiling of a key intermediate during synthesis of candesartan cilexetil (1-(((cyclohexyloxy)carbonyl) oxy)ethyl 1-((2’-(2H-tetrazol-5-yl)-[1,1’-biphenyl]-4-yl) methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate, TCV-116), a novel compound, which had not been reported previously, was observed. Structural elucidation of impurity was achieved by liquid chromatography hyphenated to different high resolution mass analyzers. Based on exact mass measurements and fragmentation pattern, a chloro alkyl carbonate ester analogue of the intermediate was identified. Structure of the impurity was confirmed by mass spectro-metric and NMR analyses of the target substance. Identified impurity could represent a hazard if it is transferred to the final API stage and its presence should be kept below allowed limits. Further investigation could reveal whether bis(1-chloroethyl) carbonate is a precursor to impurity formation. Therefore, synthesis should be regulated so as to minimize impurity production. Analysis of the final product indicated that the amount of impurity did not exceed 50 mg L−1, which represents the detection limit, determined according to the signal/noise ratio.

Open access

Linda Bāra, Jeļena Eglīte, Pēteris Ošs, Vinita Cauce, Vilnis Lietuvietis, Ludmila Vīksna, Elvīra Hagina and Angelika Krūmiņa

Abstract

Undeniably, sepsis is still a profoundly damaging and life-threatening condition for many individuals. With multiple changes in sepsis patients it is difficult to precisely classify an individual’s response in sepsis as proinflammatory or immunosuppressed. The aim of this study was to investigate genetically determined predisposition to developed sepsis by analysis of distribution of human leukocyte antigen (HLA) class II genes. Samples from patients with sepsis were collected at Pauls Stradiņš Clinical University Hospital, Latvia, in an intensive care unit between October 2016 and May 2017. The study group included 62 patients with sepsis, who were genotyped for HLA-DR; DQ using real time polymerase chain reaction – sequence specific primer (RT PCR-SSP). As a control group, data of 100 individuals were taken from the genetic bank of RSU Joint Laboratory of Clinical Immunology and Immunogenetics. The summarised results showed that the frequency of alleles DRB1*04:01 (OR = 5.54; 95% CI = 1.88–16.29); DRB1*07:01 (OR = 19.03; 95% CI = 2/37–152.82); DQA1*05:01 (OR = 14.17; 95% CI = 5.67–35.4); and DQB1*02:01 (OR = 50.00; 95% CI = 2.90–861.81) were significantly increased in patients with sepsis compared to the control group patients. The frequency of DRB1*16:01 (OR = 0.17, 95% CI = 0.04–0.59); DRB1*17:01 (OR = 0.04; 95% CI = 0.00–0.69); DQA1*01:01 (OR = 0.04; 95% CI = 0.00–0.31); DQA1*01:02 (OR = 0.03; 95% CI = 0.00–0.23); DQB1*02:02 (OR = 0.12; 95% CI = 0.03–0.42) alleles was lower in sepsis patients than in control subjects. The most frequent HLA-DRB1/DQA1/DQB1 haplotypes that was significantly increased in patients with sepsis were: DRB1*01:01/DQA1*05:01/DQB1*03:01 (OR = 12.6; 95% CI = 1.51–105.0; p < 0.003). Sepsis patients with pneumonia and alleles and DRB1 04:01; 07:01, DQB1 02:01 had the highest mortality rate. Undoubtedly, our preliminary data showed that development of sepsis can be associated with alleles and haplotypes of HLA class II genes. For more precise conclusion the research should be continued to include a larger patient group.

Open access

Eduardo José Barbosa and Humberto Gomes Ferraz

Abstract

The aim of this work was to evaluate gellan gum as binder in pellet formulations, with theophylline as the model drug, in comparison with polyvinylpyrrolidone (PVP). A full 32 factorial design was realized, with binder and diluent factors at three levels each. Pellets were produced by the extrusion/spheronization technique, and dried in a fluid-ized bed. Physical tests and dissolution tests were conducted. The results showed that the binder factor was not significant for pellet size and granulometry distribution. Rather, trends of a different response of gellan gum were identified, in comparison with PVP, in aspect ratio and dissolution tests: more round pellets were obtained in formulations with gellan gum, and more variable dissolution resulted when this polysaccharide was present. Therefore, if the usage of this compound in immediate release pellet formulations is verified, this justifies the interest in the development of sustained release systems using gellan gum.

Open access

Giray Bozkaya, Nuriye Uzuncan, Sibel Bilgili and Ozlem Demirezen

Summary

Background: Hemoglobin A1c, (HbA1c) which is the major constituent of glycated hemoglobin, has been used in the follow-up of retrospective glycemia for years and in the diagnosis of diabetes mellitus nowadays. Since the analytical performance of HbA1c should be high likewise all laboratory tests, various quality control measures are used. Sigma metrics is one of these measures and it is the combination of bias, precision and total allowable error that ensures a general evaluation of analytical quality. The aim of our study was to evaluate the analytical performance of Bio-Rad’s Variant Turbo II HbA1c analyzer according to sigma metrics.

Methods: Sigma levels were calculated using the data obtained from two levels of internal and 12 external quality control materials (Bio-Rad) of Variant II Turbo HbA1c analyzer according to s= (TEa% - Bias%) / CV% formula.

Results: The mean sigma levels for low and high quality control materials were found to be 3.0 and 4.1, respectively.

Conclusions: The annual mean analytical performance of Variant II Turbo HbA1c analyzer was found to be acceptable according to sigma metrics. In order to be sure of the difference in HbA1c results indicating the success or failure in treatment but not arise from analytical variation, it is thought that more stringent quality control measures should be applied to reach higher sigma levels.

Open access

Gaia Piazzi, Lorenzo Campo, Simone Gabellani, Fabio Castelli, Edoardo Cremonese, Umberto Morra di Cella, Hervé Stevenin and Sara Maria Ratto

Abstract

The knowledge of snowpack dynamics is of critical importance to several real-time applications especially in mountain basins, such as agricultural production, water resource management, flood prevention, hydropower generation. Since simulations are affected by model biases and forcing data uncertainty, an increasing interest focuses on the assimilation of snow-related observations with the purpose of enhancing predictions on snowpack state. The study aims at investigating the effectiveness of snow multivariable data assimilation (DA) at an Alpine site. The system consists of a snow energy-balance model strengthened by a multivariable DA system. An Ensemble Kalman Filter (EnKF) scheme allows assimilating ground-based and remotely sensed snow observations in order to improve the model simulations. This research aims to investigate and discuss: (1) the limitations and constraints in implementing a multivariate EnKF scheme in the framework of snow modelling, and (2) its performance in consistently updating the snowpack state. The performance of the multivariable DA is shown for the study case of Torgnon station (Aosta Valley, Italy) in the period June 2012 - December 2013. The results of several experiments are discussed with the aim of analyzing system sensitivity to the DA frequency, the ensemble size, and the impact of assimilating different observations.

Open access

Affidah Sabran, Endang Kumolosasi and Ibrahim Jantan

Abstract

Recent studies suggest that annexin A1 (ANXA1) promotes apoptosis in cancerous cells. This study aims to investigate the effects of ANXA1 on apoptosis and cell cycle arrest in K562, Jurkat and U937 cells and peripheral blood mononu-clear cells (PBMC). Cells were treated with ANXA1 and cyclophosphamide prior to flow cytometry analysis for apoptosis and cell cycle arrest induction. At 2.5µM, ANXA1 induced significant apoptosis in K562 (p ≤ 0.001) and U937 (p ≤ 0.05) cells, with EC 50 values of 3.6 and 3.8 µM, respectively. In Jurkat cells, induction was not significant (EC 50, 17.0 µM). No significant apoptosis induction was observed in PBMC. ANXA1 caused cycle arrest in the G0/G1 phase in K562 and U937 cells with p ≤ 0.001 for both, and (p ≤ 0.01) for Jurkat cells. ANXA1 induced apoptosis and cycle arrest in the G0/G1 phase in K562 and U937 cells, causing only cell cycle arrest in Jurkat cells.

Open access

Anatolijs Požarskis and Aivars Lejnieks

Abstract

Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with age and featured by typical symptoms and reduced blood testosterone level. Among males aged over 30 years, the incidence of androgen deficiency is 7 to 30%. The aim of this study was to investigate the incidence of hypogonadism in patients aged over 40 years with an underlying condition and/or a comorbidity, such as arterial hypertension, Chronic obstructive pulmonary disease (COPD), metabolic syndrome, Type 2 of diabetes mellitus, dyslipidaemia, adiposity in various General practice (GP) and physician-sexologists’ offices in Latvia, and to determine the influence of chronic diseases on the development of hypogonadism. Males aged 39 years who turned to family doctors at nine GP were offered to fill in Aging Male Study (AMS) questionnaires used for the diagnostics of late-onset hypogonadism. Males aged 40 years who visited the office of the physician sexologist Anatolijs Požarskis were offered to fill in the same questionnaires. After compiling the data from AMS questionnaires, a group of males exhibiting signs of LOH were isolated (in total 1222 persons). In these patients, we determined blood testosterone and sex-hormone binding globulin (SHBG) levels. Chronic diseases were found in these men in data evaluation of patient medical records, and after performing physical and laboratory examinations. Late-onset hypogonadism was laboratory-diagnosed in 79% of patients with signs of late-onset hypogonadism in accordance with the AMS questionnaires and with concomitant diseases and in 4.7% of patients with signs of late-onset hypogonadism in accordance with the AMS questionnaires and without the aforementioned concomitant diseases. Persons with arterial hypertension, dyslipidaemia, adiposity, metabolic syndrome, COPD and Type 2 of diabetes mellitus had higher chance of developing hypogonadism (p < 0.001). Arterial hypertension, dyslipidaemia, adiposity, metabolic syndrome, COPD statistically significantly (p < 0.001) decreased the level of total testosterone by 0.47, 1.18, 0.36, 0.67, and 0.18 ng/ml, respectively, and decreased the level of free testosterone by 2.52, 2.71, 1,69, 6.77, and 4.58 pg/ml, respectively. Type 2 diabetes mellitus had no statistically significant effect on the level of total and free testosterone (p = 0.95, p = 0.10). The most significant decrease in the level of testosterone was observed in cases of dyslipidemia, COPD and metabolic syndrome. General physicians should pay special attention to patients with this disease, as these patients belong to a group with a high risk of development of expressed LOH syndrome.

Open access

Londiwe Simphiwe Mbatha, Fiona Chepkoech Maiyo and Moganavelli Singh

Abstract

Use of exogenous small interfering RNA (siRNA) has shown potential in gene silencing. The need for target-specific siRNA delivery vehicles is crucial to successful gene silencing. This study is aimed at developing and evaluating the safety and efficiency of siRNA delivery using unmodified and folic acid (FA) modified poly(amidoamine) generation 5 (PAMAM G5D) functionalized gold nanoparticles (Au:G5D/Au:G5D:FA) in vitro. All formulations were physico--chemically characterized and nanocomplexes were evaluated using the band shift, dye displacement, nuclease protection, MTT cell viability, and luciferase reporter gene assays. Nanocomplexes bound and protected siRNA against degrading RNases, and were well tolerated by the cells. The Au:G5D:FA nanocomplexes elicited excellent gene silencing in folate receptor expressing HeLa-Tat-Luc cells, decreasing significantly in the presence of excess FA ligand, indicating nanocomplex uptake by the mechanism of receptor mediation. These results highlight the synergistic role played by Au and the dendrimer in enhancement of transgene silencing.

Open access

Aldis Strēlnieks, Alberts Bērziņš, Māra Karakone, Irina Pupkeviča, Kristīne Jubele, Maija Vikmane, Sandis Sakne, Oskars Kalējs and Aivars Lejnieks

Abstract

Patients with atrial fibrillation are faced with an increased risk of thromboembolic events, myocardial infarction, chronic heart failure and death. For some patients with atrial fibrillation, direct current cardioversion (DCCV) is a strategy that can be used to reacquire sinus rhythm. Our aim was to analyse the most commonly used medications after an electrical cardioversion, the reasons for not using them, the effects of pharmacotherapy on recurrence rates, and compare results with data from studies in 2014. The prospective study includes patients with electrocardiographically confirmed atrial fibrillation who underwent direct current cardioversion, hospitalised at Pauls Stradiņš Clinical University Hospital (Rīga, Latvia). The average age was 64.6 years. 50% of the patients were female. During the six-month study period, 14.3% patients were using amiodarone, 8.3% patients were on etacizine, 7.1% received propafenone, and 57.1% used beta blockers in monotherapy or in combination. Warfarin was used in 28.0% patients, direct oral anticoagulants (DOAC’s) in 29.9%, 21,4% of patients received aspirin and 16.7% did not use any antithrombotic therapy. Comparing the recurrence rate in patients using different antiarrhythmic drugs, amiodarone showed a statistically significant superiority compared to etacizine and propafenone (p = 0.02). The obtained data showed that over four years, the use of anticoagulants increased by 11.6%.

Open access

Saima Sattar, Mobasher Ahmad, Hamid Saeed, Zikria Saleem, Zeeshan Danish and Muhammad Akhlaq

Abstract

Despite growing prevalence of ovarian cancer (OC) in Pakistan, no literature evidence exists regarding its clinic-pathological characteristics, survival and compliance of patients with recurrent ovarian cancer on various chemo-protocols. An observational study was conducted by enrolling 251 recurrent OC patients on 7 different chemo-protocols, from a specialized cancer care hospital, Lahore, Pakistan, using convenient judgmental sampling. The study was conducted for a period of 6 months. Most of the patients were between 18 and 70 years of age, with IIIC FIGO stage and papillary serous histological grade. As per RECIST, improved partial response (PR) (63.3 %) and complete response (CR) (52.1 %) was observed in the CP (carboplatin + paclitaxel) arm, substantiated by improved median progression free survival (PFS) and overall survival (OS) in CP and CD (carboplatin + docetaxel) arms, respectively, yet with no significant differences in survival curves, PFS (p = 0.12) and OS (p = 0.22). Interestingly, the highest and the lowest patient non-compliance were observed in CG (carboplatin + gemcitabine) (81.6 %) and paclitaxel (4.5 %) arms, resp. As per the hazard model for survival, topotecan showed significant association with the therapy related events/deaths compared to other protocols. These data suggest that CP regimen exhibited improved clinical efficacy and decreased toxicity related non-compliance in recurrent ovarian cancer patients of Lahore.