Dual action of dipyridothiazine and quinobenzothiazine derivatives : anticancer and cholinesterase-inhibiting activity

The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with $IC_{50}$ values from 0.78 to 19.32 $\mu$M, while their $IC_{50}$ values against eqBuChE ranged from 0.46 to 10.38 $\mu$M. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an $IC_{50}$ value of 0.46 $\mu$M. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives

A retrospective study of hospitalized pneumonia in two Polish counties (2006–2008)

WSTĘP: Dane dotyczące etiologii zapaleń płuc w Polsce są skąpe, a wyszczepialność szczepionką pneumokokową wśród osób w najmłodszej i najstarszej grupie wiekowej — nieznaczna. Celem prezentowanego badania była ocena leczonego szpitalnie zapalenia płuc we wszystkich grupach wiekowych w dwóch powiatach Polski.MATERIAŁ I METODY: W badaniu wykorzystano dane zawarte w elektronicznych szpitalnych bazach danych, dotyczące mieszkańców powiatów, hospitalizowanych w Szpitalach Powiatowych w Chrzanowie i Inowrocławiu w latach 2006–2008, z rozpoznaniem zapalenia płuc. Uzyskane wyniki: częstość hospitalizacji na 1000 osób, współczynnik śmiertelności w trakcie pobytu w szpitalu na 100 osób, mediana długości hospializacji, zgrupowano według roku przyjęcia, płci i wieku.WYNIKI: W Szpitalu Powiatowym w Chrzanowie stwierdzono 1444, a w Inowrocławiu 2956 przypadków hospitalizacji z niezależnymi epizodami zapalenia płuc. Częstość hospitalizacji wyniosła 3,76 (95% przedział ufności [CI]: 3,57;3,96) i 5,99 (95% CI: 5,77; 6,21) na 1000, odpowiednio dla powiatów chrzanowskiego i inowrocławskiego. W całej badanej grupie najwyższą częstość hospitalizacji obserwowano w grupie 0–4 lat (30,77 [95% CI: 29,06; 32,55]) oraz ≥ 75 lat (25,39 [95% CI: 24,01; 26,83]). Współczynnik śmiertelności w szpitalu w obu badanych ośrodkach wzrastał wraz z wiekiem. Mediana długości pobytu w szpitalu wyniosła 8 dni.WNIOSKI: Liczba hospitalizacji z powodu zapalenia płuc była znacząca, szczególnie w najmłodszej i najstarszej grupie wiekowej. Przyszłe działania opieki zdrowotnej skierowane do tych grup wiekowych mogą wpłynąć na zapadalność na zapalenie płuc oraz poprawić wyniki leczenia.INTRODUCTION: In Poland, multi-cause pneumonia is not well characterized, and there is limited pneumococcal vaccination in the youngest and oldest age groups. The goal of this study was to assess hospitalized pneumonia across all age groups in two Polish counties.MATERIAL AND METHODS: Using electronic administrative databases, cases were identified as county residents hospitalized at Chrzanów and Inowrocław County Hospitals from 2006–2008, assigned a diagnosis of pneumonia. Calculations by admission year, sex, and age category were: hospitalization rates per 1000 persons; in-hospital mortality rates per 100 persons; and median length of stay (LOS).RESULTS: There were 1444 and 2956 hospitalizations for new episodes of pneumonia with rates of 3.76 (95% confidence interval [CI] 3.57–3.96) and 5.99 (95% CI 5.77–6.21) per 1000 persons in Chrzanów and Inowrocław counties, respectively. In combined data, the highest hospitalization rate was among patients aged 0–4 years (30.77; 95% CI 29.06–32.55) followed by those aged ≥ 75 years (25.39; 95% CI 24.01–26.83). In-hospital mortality rates increased with age at both sites. The median LOS was 8 days.CONCLUSIONS: Pneumonia hospitalizations were substantial, especially for the youngest and oldest age groups. Future public health interventions aimed at these age groups might improve disease outlook

Prospective, population-based surveillance of the burden of Streptococcus pneumoniae in community-acquired pneumonia in older adults, Chrzanów County, Poland, 2010 to 2012

INTRODUCTION: Community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae is a substantial cause of morbidity and mortality among older adults. This study estimated incidences of CAP, chest x-ray−confirmed CAP (CXR+CAP), S pneumonia- positive CAP, S pneumonia-positive CXR+CAP, and S. pneumoniae serotype distribution among 46,000 at-risk adults aged ≥ 50 years residing in Chrzanów County, Poland. MATERIAL AND METHODS: From January 2010 to January 2012, all facilities providing ambulatory and inpatient care enrolled all consenting resident patients with suspicion of CAP. Chest x-rays, urine, blood, and sputum samples were analyzed. Annualized incidence rates were determined. Presence of S pneumonia-positive CAP and/or S. pneumoniae serotype distribution was determined using the urine antigen detection assay (capable of detecting the serotypes in the 13-valent pneumococcal conjugate vaccine [PCV13]), BinaxNOW®, and/or microbiology cultures. RESULTS: Among 5055 enrolled patients, 1195 (23.7%) were diagnosed with CAP and 1166 (23.4%) had CXR+CAP. S. pneumoniae was detected in 144 (12.1%) and 131 (11.2%) patients from the CAP and CXR+CAP cohorts, respectively. Annualized incidence rates of CAP, CXR+CAP, S pneumonia-positive CAP, and S. pneumonia-positive CXR+CAP were 12.8, 12.5, 1.6, and 1.4 per 1000 residents, respectively. Among CXR+CAP patients, 39.7% were aged 50 to 64 years and 60.3% were aged ≥ 65 years. Incidence rates generally increased with age. The most common serotypes in S. pneumoniae-positive CXR+CAP patients were 3 (n = 15), 23F (n = 10), 18C (n = 9), and 9V (n = 6). CONCLUSIONS: CAP due to PCV13 serotypes is a source of morbidity among adults >50 years and may be reduced by greater access to pneumococcal vaccines.INTRODUCTION: Community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae is a substantial cause of morbidity and mortality among older adults. This study estimated incidences of CAP, chest x-ray−confirmed CAP (CXR+CAP), S pneumonia- positive CAP, S pneumonia-positive CXR+CAP, and S. pneumoniae serotype distribution among 46,000 at-risk adults aged ≥ 50 years residing in Chrzanów County, Poland. MATERIAL AND METHODS: From January 2010 to January 2012, all facilities providing ambulatory and inpatient care enrolled all consenting resident patients with suspicion of CAP. Chest x-rays, urine, blood, and sputum samples were analyzed. Annualized incidence rates were determined. Presence of S pneumonia-positive CAP and/or S. pneumoniae serotype distribution was determined using the urine antigen detection assay (capable of detecting the serotypes in the 13-valent pneumococcal conjugate vaccine [PCV13]), BinaxNOW®, and/or microbiology cultures. RESULTS: Among 5055 enrolled patients, 1195 (23.7%) were diagnosed with CAP and 1166 (23.4%) had CXR+CAP. S. pneumoniae was detected in 144 (12.1%) and 131 (11.2%) patients from the CAP and CXR+CAP cohorts, respectively. Annualized incidence rates of CAP, CXR+CAP, S pneumonia-positive CAP, and S. pneumonia-positive CXR+CAP were 12.8, 12.5, 1.6, and 1.4 per 1000 residents, respectively. Among CXR+CAP patients, 39.7% were aged 50 to 64 years and 60.3% were aged ≥ 65 years. Incidence rates generally increased with age. The most common serotypes in S. pneumoniae-positive CXR+CAP patients were 3 (n = 15), 23F (n = 10), 18C (n = 9), and 9V (n = 6). CONCLUSIONS: CAP due to PCV13 serotypes is a source of morbidity among adults >50 years and may be reduced by greater access to pneumococcal vaccines

Burden of varicella in Central and Eastern Europe : findings from a systematic literature review

Funding Information: The authors take full responsibility for the scope, direction, and content of the manuscript, and have approved the submitted manuscript. Medical writing assistance was provided by Eleanor Finn of PAREXEL International and was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The authors wish to thank the following for contributions in development of the manuscript: Barbara J. Kuter, PhD, MPH, Global Vaccines Medical Affairs, and Tracey J. Weiss, Center for Observational and Real-World Evidence (CORE), Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Information: The study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Information: J. Wysocki received travel grants to attend international scientific conferences and fees for lectures from Pfizer and payment from a grant sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. I. Ivaskeviciene has received a USA travel grant to attend international scientific meeting, from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth. M. Pokorn has received a research grant from Pfizer and payment for lectures from Pfizer, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and GSK. L. Jancoriene has received travel grants to attend international scientific conferences and fees for lectures from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, AbbVie and Pfizer and payment for a clinical study sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. J. Pluta and L.J. Wolfson are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholders of Merck & Co., Inc., Kenilworth, NJ, USA. Publisher Copyright: © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.Introduction: Vaccination against varicella rapidly reduces disease incidence, resulting in reductions in both individual burden and societal costs. Despite these benefits, there is no standardization of varicella immunization policies in Europe, including countries in Central and Eastern Europe (CEE). Areas covered: This systematic literature review identified publications on the epidemiology of varicella, its associated health and economic burden, and vaccination strategies within the CEE region, defined as Albania, Bosnia-Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, Slovakia, and Slovenia. Twenty-six studies were identified from a search of PubMed, Embase®, and MEDLINE® biomedical literature databases, supplemented by gray literature and country-specific/global websites. Expert commentary: Limited information exists in published studies on the burden of varicella in CEE. The wide variability in incidence rates between countries is likely explained by a lack of consistency in reporting systems. Funded universal varicella vaccination (UVV) in CEE is currently available only in Latvia as a one-dose schedule, but Hungary together with Latvia are introducing a two-dose strategy in 2019. For countries that do not provide UVV, introduction of vaccination is predicted to provide substantial reductions in cases and rates of associated complications, with important economic benefits.publishersversionPeer reviewe

Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma

Długotrwałe odpowiedzi na leczenie brentuksymabem vedotin u chorych na chłoniaka Hodgkina

Progress in Hodgkin lymphoma (HL) treatment has been achieved due to introduction of new diagnostic methods, disease staging, and new therapy implementations. In spite of it, some patients are challenging in diagnostic and therapeutic process. The topic will provide a brief review of 2 young patients with HL who failed to achieve remission following few therapeutic treatment lines. Both of them response has been achieved when brentuximab vedotin was used. Many patients requires up to date new diagnostic methods implementation. Their interpretation is possible only in the context of clinical data.Postępy w leczeniu chłoniaka Hodgkina (HL) dokonały się dzięki wprowadzeniu nowych metod diagnostycznych, udoskonalenia klasyfikacji, stratyfikacji leczenia oraz wprowadzeniu nowych leków. Mimo tego niektórzy pacjenci sprawiają trudności diagnostyczne i lecznicze. Wielu chorych na HL wymaga wszechstronnej diagnostyki z zastosowaniem najnowszych metod diagnostycznych, które wymagają interpretacji w kontekście danych klinicznych. Celem pracy jest przedstawienie procesu diagnostyki i leczenia 2 młodych chorych na HL, pierwotnie opornych na kilka linii leczenia, po których nie udało się uzyskać remisji choroby. U obu chorych uzyskano odpowiedź po zastosowaniu leczenia brentuksymabem vedotin

The Effect of the Addition of Ozonated and Non-Ozonated Fruits of the Saskatoon Berry (<i>Amelanchier alnifolia</i> Nutt.) on the Quality and Pro-Healthy Profile of Craft Wheat Beers

Research into the suitability of domestic raw materials, including, for example, new wheat cultivars and fruit additives for the production of flavoured beers, is increasingly being undertaken by minibreweries and craft breweries. The fruits of the Saskatoon berry are an important source of bioactive compounds, mainly polyphenols, but also macro- and microelements. The fruits of two Canadian cultivars of this species, ‘Honeywood’ and ‘Thiessen’, were used in this study. Physicochemical analysis showed that wheat beers with the addition of non-ozonated fruit were characterised by a higher ethanol content by 7.73% on average. On the other hand, enrichment of the beer product with fruit pulp obtained from the cv. ‘Thiessen’ had a positive effect on the degree of real attenuation and the polyphenol profile. Sensory evaluation of the beer product showed that wheat beers with the addition of ‘Honeywood’ fruit were characterised by the most balanced taste and aroma. On the basis of the conducted research, it can be concluded that fruits of both cvs. ‘Honeywood’ and ‘Thiessen’ can be used in the production of wheat beers, but the fermentation process has to be modified in order to obtain a higher yield of the fruit beer product

Physicochemical characterization and dissolution studies of solid dispersions of clotrimazole with chitosan

The aim of the present study was to increase the solubility of clotrimazole. Among the methods to increase the solubility selected solid dispersions of the drug with the polymer. Chitosan was used as the polymer. Clotrimazole was incorporated into the chitosan type 652 with molar masse chitosan Mη = 429 kDa. Solid dispersions were prepared by using different ratios of clotrimazole and chitosan (1:9, 3:7, 5:5, 7:3, 9:1). Formulations were tested dissolution rate of the drug. The highest dissolution of clotrimazole, amounting to 47.95%, was observed after 60 minutes from solid dispersion prepared by grinding method and 42.84% from physical mixtures with drug-polymer weight ratio 1:9 in the presence chitosan. The solubility of the drug improved more than 37-fold. XRPD analysis indicates the presence of the clotrimazole in crystalline form in the solid dispersion obtained by kneading method

The direct and indirect costs of breast cancer in Poland : estimates for 2017 - 2019

Background: In Poland, breast cancer (BC) is the most frequently diagnosed cancer in women and the second most common cause of death after lung cancer. This disease has important economic implications for patients, public payers, and the whole Polish economy. This study aimed to estimate the total National Health Fund (NHF) expenditures on the diagnosis and treatment of patients with breast cancer. In addition, the costs of productivity losses were also calculated. Methods: Cost estimation was prepared using a top-down approach. Direct cost calculations were based on data reported by NHF for patients with the diagnosis of breast cancer. Medical care costs included the following components: screening program, oncological package, surgical treatment, hospitalization, drug program, chemotherapy, radiotherapy, and outpatient care. Indirect costs in the form of absenteeism costs were calculated based on data from Statistics Poland (gross domestic product, number of employees) and the Social Insurance Institution database (the number of sick leave days). Results: Total expenditures for BC including direct costs and indirect costs amounted to EUR 305,371, EUR 332,998, and EUR 344,649, respectively in 2017, 2018, and 2019. Total healthcare costs in 2019 were EUR 4114 lower than in 2018, which resulted from the reduction in expenditure on the drug program (decrease of EUR 13,527), despite the observed increase in all remaining resources. From direct costs, the highest expense was spent on the drug program (nearly 50% of total direct costs), but this expense dropped significantly in 2019. For the remaining parameters, the costs increased year by year, of which the most expensive were surgical treatment (15%), radiotherapy (12%), and the screening program (10%). BC generated over EUR 120 thousand of social costs in 2019 and compared to 2017, there was an increase in productivity loss by 26%. Conclusions: Our results from 2017–2019 demonstrated that total expenditure for BC in Poland increased from year to year. Breast cancer generated almost EUR 345 thousand expenses in 2019, which translates into a significant burden on the public payer’s budget and the society in Poland