CuAAC-Based Synthesis, Copper-Catalyzed Aldehyde-Forming Hydrolytic Fission and Antiproliferative Evaluation of Novel Ferrocenoylamino-Substituted Triazole-Tethered Quinine-Chalcone Hybrids.

A series of novel triazole-tethered ferrocenoylamino-substituted cinchona-chalcone hybrids along with two representative benzoylamino-substituted reference compounds were prepared by three methods of CuAAC chemistry. In line with the limited success or complete failure of attempted conversions with low catalyst loadings, by means of DFT modeling studies, we demonstrated that a substantial part of the Cu(I) ions can be chelated and thus trapped in the aroylamino-substituted cinchona fragment and all of the accessible coordinating sites of the chalcone residues. Accordingly, increased amounts of catalysts were used to achieve acceptable yields; however, the cycloadditions with para-azidochalcones were accompanied by partial or complete aldehyde-forming hydrolytic fission of the enone C=C bond in a substituent-, solvent- and copper load-dependent manner. The experienced hydrolytic stability of the hybrids obtained by cycloadditions with ortho-azidochalcones was interpreted in terms of relative energetics, DFT reactivity indices and MO analysis of simplified models of two isomer copper-enone complexes. The novel hybrids were evaluated on HeLa, MDA-MB-231 and A2780 cell lines and showed substantial activity at low-to-submicromolar concentrations. An organometallic model carrying 3,4,5-trimethoxyphenyl residue in the enone part with a para-disubstituted benzene ring in the central skeletal region was identified as the most potent antiproliferative lead, characterized by submicromolar IC50 values measured on the three investigated cells. The biological assays also disclosed that this ferrocenoylamino-containing lead compound displays a ca. two- to five-fold more substantial antiproliferative effect than its benzoylamino-substituted counterpart.

A Comprehensive Assessment of Apigenin as an Antiproliferative, Proapoptotic, Antiangiogenic and Immunomodulatory Phytocompound.

Apigenin (4',5,7-trihydroxyflavone) (Api) is an important component of the human diet, being distributed in a wide number of fruits, vegetables and herbs with the most important sources being represented by chamomile, celery, celeriac and parsley. This study was designed for a comprehensive evaluation of Api as an antiproliferative, proapoptotic, antiangiogenic and immunomodulatory phytocompound. In the set experimental conditions, Api presents antiproliferative activity against the A375 human melanoma cell line, a G2/M arrest of the cell cycle and cytotoxic events as revealed by the lactate dehydrogenase release. Caspase 3 activity was inversely proportional to the Api tested doses, namely 30 µM and 60 µM. Phenomena of early apoptosis, late apoptosis and necrosis following incubation with Api were detected by Annexin V-PI double staining. The flavone interfered with the mitochondrial respiration by modulating both glycolytic and mitochondrial pathways for ATP production. The metabolic activity of human dendritic cells (DCs) under LPS-activation was clearly attenuated by stimulation with high concentrations of Api. Il-6 and IL-10 secretion was almost completely blocked while TNF alpha secretion was reduced by about 60%. Api elicited antiangiogenic properties in a dose-dependent manner. Both concentrations of Api influenced tumour cell growth and migration, inducing a limited tumour area inside the application ring, associated with a low number of capillaries.

Phytochemical Characterization and Evaluation of the Antimicrobial, Antiproliferative and Pro-Apoptotic Potential of Ephedra alata Decne. Hydroalcoholic Extract against the MCF-7 Breast Cancer Cell Line.

Ephedra alata Decne. belongs to the Ephedraceae family. It is a species of Ephedra that grows mostly in the desert. Today, the main importance of Ephedra species in the medical field is due to the presence of the alkaloids derived from phenyl-alanine, which act on the sympathetic nervous system as a sympathomimetic. The aim of this study was to conduct a phytochemical characterization of the hydroalcoholic extract of the aerial part of Ephedra alata Decne., which is indigenous to Tunis, that involves the total phenolic content, individual phenolic content, and antioxidant activity as well as a biological screening for the evaluation of the antimicrobial, antifungal, antiproliferative, pro-apoptotic, and cytotoxic potential against the MCF-7 breast cancer cell line. The results show that the hydroalcoholic extract contains polyphenolic phytocompounds (156.226 ± 0.5 mgGAE/g extract) and elicits antioxidant activity (7453.18 ± 2.5 µmol Trolox/g extract). The extract acted as a bacteriostatic agent against all tested bacterial strains, but was bactericidal only against the Gram-positive cocci and Candida spp. In the set experimental parameters, the extract presents antiproliferative, pro-apoptotic, and cytotoxic potential against the MCF-7 human breast cancer cell line.

Botanical Therapeutics: Phytochemical Screening and Biological Assessment of Chamomile, Parsley and Celery Extracts against A375 Human Melanoma and Dendritic Cells.

Chamomile, parsley, and celery represent major botanical sources of apigenin, a well-known flavone with chemopreventive properties. The aim of this study was to assess the phytochemical composition, antioxidant, and anti-inflammatory potential of methanol extracts obtained from chamomile, parsley, and celery collected from Romania, as well as the biological activity against A375 human melanoma and human dendritic cells. Results have shown that all three extracts are rich in polyphenolic compounds and flavonoids, and they generate a radical scavenger capacity, iron chelation potential, as well as lipoxygenase inhibition capacity. Chamomile and celery extracts present weak antiproliferative and pro-apoptotic properties in the set experimental conditions, while parsley extract draws out significant pro-apoptotic potential against A375 human melanoma cells. Parsley and chamomile extracts affected the fibroblast-like morphology of the screened tumor cell line. On the other hand, chamomile and celery extracts abrogated the expansion of LPS-activated dendritic cells, while the metabolic activity was attenuated by stimulation with celery extract; chamomile and parsley extracts had no effect upon this parameter. Chamomile and parsley extracts incubation with naive dendritic cells did not trigger cytokine secretion (TNF-alpha, IL-6, IL-10), but celery extract stimulation significantly reduced the anti-inflammatory, cytokine IL-10.

Medication use and risk of falls among nursing home residents: a retrospective cohort study.

Background Geriatric falls are leading causes of hospital trauma admissions and injury-related deaths. Medication use is a crucial element among extrinsic risk factors for falls. To reduce fall risk and the prevalence of adverse drug reactions, potentially inappropriate medication (PIM) lists are widely used. Objective Our aim was to investigate the possible predictors of geriatric falls annualized over a 5-year-long period, as well as to evaluate the medication use of nursing home residents. Setting Nursing home residents were recruited from the same institution between 2010 and 2015 in Szeged, Hungary. Method A retrospective epidemiological study was performed. Patient data were analysed for the first 12 months of residency. Chi-squared test and Fisher's-test were applied to compare the categorical variables, Student's t test to compare the continuous variables between groups. Binary logistic regression analysis was carried out to determine the association of falls with other variables found significant in univariate analysis. Microsoft Excel, IBM SPSS Statistics (version 23) and R (3.2.2) programs were used for data analysis. Main outcome measure Falls affected by age, gender, number of chronic medications, polypharmacy, PIM meds. Results A total of 197 nursing home residents were included, 150 (76.2%) women and 47 (23.8%) men, 55 fallers (annual fall prevalence rate was 27.9%) and 142 non-fallers. Gender was not a predisposing factor for falls (prevalence in males: 23.4 vs 29.3% in females, p > 0.05). Fallers were older (mean years ± SD; 84.0 ± 7.0) than non-fallers (80.1 ± 9.3, p < 0.01). The age ≥80 years was a significant risk factor for falls (p < 0.001). The number of chronic medications was higher in male fallers (12.4 ± 4.0) than in non-fallers (6.9 ± 4.2, p < 0.001). Polypharmacy (taking four or more chronic medications) was a significant risk factor of falls (p < 0.01). Those PIMs carrying fall risk were taken by 70.9% of fallers and 75.3% of non-fallers (p > 0.05). Taking pantoprazole, vinpocetine or trimetazidine was a significant risk factor for falls. Conclusion Older age, polypharmacy and the independent use of pantoprazole, vinpocetine, and trimetazidine were found to be major risk factors for falls. Further real-life epidemiological studies are necessary to confirm the role of particular active agents, and to help professionals prescribe, evaluate and review geriatric medication use.

[Antibiotic use in the Hungarian hospitals in the last two decades (1996-2015)]. / Hazai kórházi antibiotikum-alkalmazás az elmúlt két évtizedben (1996­2015).

INTRODUCTION: Growing bacterial resistance threatens public health, which can be tempered by prudent antibiotic use. AIM: To quantify systemic antibacterial use in Hungarian hospitals. METHOD: Consumption data were analysed using the Anatomical-Therapeutic-Chemical - Defined Daily Dose (ATC/DDD) methodology. Data were standardized for patient turnover and also for population to enable international benchmarking. RESULTS: Hospital antibiotic use was quite constant (22.4 ± 1.5 DDD/100 patient-days), but its composition changed substantially. The use of parenteral products rose gradually (in 1996 26.4% and in 2015 41.6%). The pattern of use was homogenised due to the headway of co-amoxiclav use. A substantial increase of fluoroquinolone (2.3 vs. 4.2 DDD/100 patient-days) and third generation cephalosporin (1.0 vs. 2.9 DDD/100 patient-days) use was detected. In parallel the use of narrow spectra penicillins diminished. CONCLUSION: Hungarian hospital antibiotic use is low. The causes and the justification of this low use together with the internationally outstanding use of certain antibacterials should be addressed in future studies. Orv. Hetil., 2016, 157(46), 1839-1846.

Treatment of Community-Acquired Pneumonia in Adults: Analysis of the National Dispensing Database.

Crude national ambulatory antibiotic dispensing data (2007-2011) of adult patients (aged between 20 and below 65 years) with CAP were obtained and expressed as DDD per 1000 inhabitants and per day (DID). European quality indicators of antibiotic prescribing were calculated and adherence rate to the national CAP guideline was assessed. Antibiotic use for CAP in adults ranged between 0.27 and 0.30 DID in various years. The most frequently used antibacterials were levofloxacin, co-amoxiclav and clarithromycin. Antibiotic use in CAP was compliant with the European recommendations in 6.4% in 2007, which decreased to 4.9% by 2011, in contrast to the optimal compliant range of 80-100%. The consumption of fluoroquinolones mounted up to ~40% in both genders, which exceeded the recommended range (0-5%) substantially. National guideline also favoured the use of macrolides in the empiric therapy of CAP in otherwise healthy adults; hence, guideline-concordant antibiotic use ranged between 24.0-32.3%. Agents that were contra-indicated in the empiric therapy of CAP were also used in 6.5-9.0% in various years. These data reflect some worrisome figures and trends in the outpatient antibiotic treatment of adults with CAP. Clarified and updated national guidelines focusing on outpatients and incentives/regulations to increase guideline concordance are warranted.

Gender inequalities in the treatment of osteoporosis.

INTRODUCTION: Our aim was to perform both gender- and age-specific analysis regarding the utilisation of anti-osteoporotic drugs in Hungary, between 2007 and 2011, and to compare our results with other European countries. METHODS: The database of the Hungarian National Health Insurance Fund was screened for anti-osteoporotic medications, covering 100% of the Hungarian population (10 million people). ICD coding system (International Classification of Diseases) and WHO ATC/DDD methodology were used for medication screening and analysis. RESULTS: In Hungary, the total bisphosphonate use was 6.66 DDD/TID (Defined Daily Dose/1000 inhabitants/day) in 2007, and 6.22 DDD/TID in 2011; the rate of bisphosphonate combinations slightly increased from 1.60 to 2.81 DDD/TID. The total vitamin D use almost doubled (13.73 DDD/TID in 2011), while the calcium supplementation tripled (4.47 DDD/TID in 2011), and so did the strontium ranelate utilisation (0.70 DDD/TID in 2011) within the investigated time period. Denosumab consumption was marginal. Male patients were disproportionately, 10-20 times undertreated in all age groups, and treatment choice was restricted among men. Several differences were seen in our results compared to those in Baltic countries, Finland and in Norway. CONCLUSIONS: Men were significantly undertreated in all age groups, compared to women. The 10 to 20-fold difference calls attention to this unrecognised problem.

[Drug-related problems in the elderly]. / Az idoskori gyógyszeralkalmazás problémái.

The aging population in developed countries is a growing problem nowadays. The burden on healthcare is particularly high, since the prevalence of the diseases, especially chronic diseases increases with age. Prevalence of polypharmacy is common among elderly patients. While comorbidities require usage of several active agents with evidence based indication, polypharmacy increases the likelihood of interactions and adverse drug reactions, reduces patient compliance, affects quality of life and puts a significant financial burden on the patient and society. In order to reduce drug-related problems among the elderly, different lists of potentially inappropriate drugs and doses were created. One of the earliest known lists is the "Beers criteria". The use of listed drugs is risky and not recommended for elderly patients. Following foreign examples, a list was compiled and adapted to the Hungarian drug spectrum based on the main concerns and alternative therapeutic suggestions.