WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma.

CIC-DUX4 rearrangements define an aggressive and chemotherapy-insensitive subset of undifferentiated sarcomas. The CIC-DUX4 fusion drives oncogenesis through direct transcriptional upregulation of cell cycle and DNA replication genes. Notably, CIC-DUX4-mediated CCNE1 upregulation compromises the G1/S transition to confer a dependence on the G2/M cell cycle checkpoint. Through an integrative transcriptional and kinase activity screen using patient-derived specimens, we now show that CIC-DUX4 sarcomas depend on the G2/M checkpoint regulator WEE1 as part of an adaptive survival mechanism. Specifically, CIC-DUX4 sarcomas depended on WEE1 activity to limit DNA damage and unscheduled mitotic entry. Consequently, genetic or pharmacologic WEE1 inhibition in vitro and in vivo led to rapid DNA damage-associated apoptotic induction of patient-derived CIC-DUX4 sarcomas. Thus, we identified WEE1 as a vulnerability targetable by therapeutic intervention in CIC-DUX4 sarcomas.

Risk perception of NSAIDs in South Dakota in comparison with Slovakia and Greece.

AIM: Adverse effects (ADRs) of non-steroidal anti-inflammatory drugs (NSAIDs) represent a public health problem. To decrease the negative effect on the population, an improvement of risk awareness is crucial. We aimed to evaluate the risk perception and the use of NSAIDs in South Dakota in comparison with Slovakia and Greece. METHOD: A structured questionnaire evaluating NSAID use in 185 patients in a hospital in South Dakota. RESULTS: 95.7 % of respondents reported the use of analgesics. On 1-10 visual analogue scale, perceived risk of NSAIDs was 4.27±2.46, similar to Greece (4.36±2.41, p=0.360), but significantly higher than in Slovakia (3.8±1.9, p=0.038). Only 12.4 % were familiar with gastrointestinal ADRs and only 1.1 % were aware of cardiovascular risk. Although 57.8 % were informed about ADRs by their doctor or pharmacist, only 33.0 % were informed spontaneously, without actively asking. Providers in South Dakota were informing patients spontaneously more often than in Slovakia (15.9 %, p≤0.001) and on par with Greece (36.3 %, p=0.631). CONCLUSIONS: Public awareness about NSAID risk is dangerously low. Only a third of providers are informing patients about possible risks spontaneously (Tab. 6, Ref. 15) Keywords: non-steroidal anti-inflammatory drugs, risk perception, adverse effects, cardiovascular risk, gastrointestinal risk.

Drug usage analysis in pregnant women.

BACKGROUND: Drug usage in pregnant women is associated with a problem of possible negative influence on prenatal development. It is always necessary to judge the need for drug administration during pregnancy. OBJECTIVE: The aim of presented study was to analyse data about pregnant women hospitalized in the postpartum period. METHODS: The study was designed as a retrospective observational study including 300 women hospitalized at the 2nd Department of Gynaecology and Obstetrics, University Hospital, Bratislava. Data were obtained through questionnaires in form of an interview. RESULTS: The average age of women was 30.79 ± 4.40 years. Risk pregnancy occured in 20.59 % of women. Chronic disorders before pregnancy required regular pharmacotherapy in 29.24 %. Drug usage analysis: I. trimester, 31 % used at least one drug, 52 % nutritional supplements, 63.3 % drug and/or nutritional supplement; II. trimester, 23 % used at least one drug, 45 % nutritional supplements, 58.3 % drug and/or nutritional supplement; III. trimester, 32 % used at least one drug, 67 % nutritional supplements, 75.3 % drug and/or nutritional supplement. CONCLUSION: Drug usage during pregnancy requires great precaution at choosing pharmacotherapy. The benefit of pharmacotherapy should always outweight the potential risk of administered drug (Tab. 3, Fig. 3, Ref. 37).

Risk perception of NSAIDs in hospitalized patients in Greece.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used analgesics worldwide in different syndromes. There is a relevant evidence about NSAIDs various adverse effects (AEs) on gastrointestinal, cardiovascular, renal, pulmonary, nervous systems. Many of these problems are preventable with respects to appropriate patient´s risk perception. OBJECTIVES: The main goal of our study was to examine drug risk perception with relation to participation factors as comorbidities in patients. METHODS: A structured questionnaire was delivered to 124 patients hospitalized at Department of Internal Medicine in a selected General Hospital in Greece. Data were evaluated using a descriptive statistics. RESULTS: Low awareness of NSAID risk was recorded, with 45.16 % of respondents unaware of any particular AEs. Lack of this knowledge appears to be attributed to low communication of physicians and pharmacists with patients about possible risk from comorbidity, over half of respondents (55.8 %) had history of hypertension, and 25.9 % were diabetics, which would increase the risk of NSAID therapy. CONCLUSION: Our study revealed a restricted knowledge about risk of NSAIDs in the studied population and showed some important data related to the presence of comorbidity in patients, which could potentiate the risk of cardiovascular AEs (Fig. 5, Ref. 22).

A commentary on a decrease in consumption of selective COX-2 inhibitors (coxibs) Comparison between Slovakia and Nordic countries.

PURPOSE: The aim of our work was to analyze utilization patterns in Slovakia and Nordic countries and to determine coxib risk perception among medical professionals. METHODS: The consumption of coxibs in Slovakia during 1999-2009 was analyzed. Data were obtained from the State Institute for Drug Control in SR. Obtained results were compared to data based on annual health statistics in Denmark, Finland and Norway. General Practitioners were asked on a perceived risk. RESULTS: We observed an increase of consumption in first years, followed with a marked decrease after year 2004. Slovak consumption was very small. Coxibs represented in Slovakia only a small part of totally prescribed non-steroidal anti-inflammatory drugs. They constituted only 1.44 % in the year 2003, whereas in Norway 41.2 %. 14 % of respondents (n=570) marked coxibs to be the safest analgesic drug. CONCLUSION: Published data show that consumption of coxibs (rofecoxib was linked with serious thrombotic cardiovascular adverse effect) fall down markedly. Consumption data from 1999 until 2009 from Slovakia and three Nordic countries showed significant differences (p<0.001). During the observed period, the utilization of coxibs in Slovakia was very small - a possible explanation is new drug, higher prize, doctor's habits (Tab. 2, Fig. 1, Ref. 11).

Comments to regional problems of analgesic risk perception.

OBJECTIVES: The aim of our study was to analyse analgesic risk perception and then to compare analgesic drug choice among general practitioners. METHOD: The structured questionnaire was used and completed during continuous medical education lectures. Series of targeted open or close questions and visual analog scale (VAS) to determine drug risk perception were used. Slovak general practitioners attending continuous medical education lectures during 2004-2005 were invited to participate in the study. Group 1 consisted of respodents from Bratislava (capital city of Slovakia, n = 245) and group 2 consisted of general practitioners from 3 other cities (middle and eastern Slovakia, n = 325). Data were compared to reported adverse drug reactions. RESULTS: Quarter of doctors 25.3% (n = 62), (25.2% (n = 82) respectively), considered non-steroidal anti-inflammatory drugs to be the safest group of analgesics. Gastrointestinal damage in general was perceived as most common adverse drug reaction. 72.41% (75.94% respectively) of respondents considered analgesics as exactly or probably danger. Perceived drug risk labeled on VAS was 4.23 (SD 1.52), (3.22 (SD 2.19) respectively) (p < 0.05). Total number of reported adverse drug reactions in years 1998-2002 was 3249, 412 were related to analgesic use. Specific organotoxic adverse drug reactions (nephrotoxicity, etc.) were reported rarely. CONCLUSION: The actual perception of analgesic risk in Slovakia seems to be generally inadequate. We found only a low support of spontaneous adverse drug reactions reporting to the national monitoring system (Tab. 1, Fig. 2, Ref. 11).

A comparison of the opinion of general practitioners and their patients on compliance with pharmacotherapy.

OBJECTIVES: The aim of the study was to identify and confront the opinions of both patients and general practitioners on their relationship. METHODS: Our questionnaire was designed according to the target of our study--to analyse the communication between the GP and the patient as well as the adherence to the treatment procedures--in the group of 100 GPs and 500 patients. RESULTS: The response rate was 95% in GPs and 86.6% in patients. Totally, 88% of patients and 52% of GPs were convinced that the compliance with the treatment and the trust to the GP are related. CONCLUSIONS: Non-compliance is a frequent reason for the patient's unsatisfying response to the therapy. A professional approach to this problem is an essential precondition of an increased quality of health care and an increased patient's satisfaction without requirements of health care system for additional financial resources (Tab. 1, Fig. 1, Ref. 12).

5 most consumpted opioid analgesics in Slovakia in the year 2006--comparison to five other countries (Finland, Norway, Denmark, Spain, Australia).

INTRODUCTION: Opioid analgesics are drugs of choice in the treatment of moderate and severe malignant or noncancer pain. Consumption data helps us to evaluate the status of country's public health. METHODS: We analysed the consumption of opioid analgesics from ATC class N02A in Slovakia in the year 2006 and compared it with five other countries -- Finland, Norway, Denmark, Spain and Australia. We then calculated drugs that accounted for 90% of the total volume of DDDs in the year 2006. RESULTS: Slovakia showed a dominance of tramadol consumption that constituted three quarters of the total group consumption. Tramadol is the commonest consumed opioid analgesic in all observed countries (in Norway it constituted only 35% of total group consumption, whereas in Slovakia it was 72%). DISCUSSION: Opioid consumption in Slovakia is increasing, but comparison with the Nordic countries, Spain and Australia showed a significantly lower consumption. Exception is tramadol with the highest consumption in Slovakia. CONCLUSION: Observed trends in consumption indicate a well known accent of the Nordic countries on treatment of pain. Opiod consumption in Slovakia continues to stay low (Tab. 1, Fig. 1, Ref. 10). Full Text (Free, PDF) www.bmj.sk.

Modified problem-based learning in pharmacology.

OBJECTIVE: The aim of this study was to determine differences between PBL as compared to modified PBL with special focus on acquiring EBM principles. METHODS: Two groups consisted of total 152 students (139 respectively). The use of EBM principles means integrating individual expertise with the best available external clinical evidence by using available data sources and national guidelines. CONCLUSION: Our findings suggest that modified PBL with extended EBM approach could be superior to "classical" PBL (Fig. 3, Ref. 29). Full Text (Free, PDF) www.bmj.sk.

Comparison of NSAID consumption in Slovakia, Finland and Norway.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) belong to most frequently used drugs worldwide. NSAIDs belong to the family of drugs that represent the biggest drug risk as to the number of adverse drug reactions (ADRs), as well as to the number of deregistered drugs. METHODS: We analysed the whole consumption of NSAIDs from ATC class M01 in Slovakia during 1996-2007. RESULTS: Most frequently used NSAIDs in Slovakia were ibuprofen and diclofenac. There was a marked increasing trend in piroxicam, meloxicam, ibuprofen and especially nimesulide medicines. CONCLUSION: Prescription habits of doctors in Slovakia reflect the drug risk only partially, nevertheless the total consumption of dangerous medicines is decreasing and substances with safer profile remain being more used. In the prescribing process the patients' risk factors together with the differences in drug characteristics should be considered. Nevertheless some of these drugs are OTC, and their consumption is strongly influenced by pharmacists and advertisement (Tab. 2, Fig. 1, Ref. 18). Full Text (Free, PDF) www.bmj.sk.

Biochemical evaluation of the antiplatelet effect of aspirin in patients at different levels of cardiovascular risk.

BACKGROUND: The phenomenon called aspirin resistance is being intensively discussed. METHODS: To evaluate the biochemical aspirin response, the method of urinary 11-dehydro TXB2 levels measurement was used. Quantitative detection of TXB2 in urine was determined by competitive enzyme immunoassay, using human Thromboxane B2 ELISA-kit. We investigated the urine samples from 69 patients. RESULTS: The mean urinary levels of 11-dehydro TXB2 were significantly lower in patients in the primary and secondary types of aspirin prevention comparing with the control group of patients not taking aspirin. The difference in thromboxane concentrations between the two groups of patients taking aspirin did not reach statistical significance. Our results did not show significant differences in the biochemically measured aspirin response when comparing diabetics with non-diabetics. Similarly, the observed tendency to higher thromboxane levels in women did not show to be significantly different from men. CONCLUSION: Our pilot study did not show any significant differences among patients at different cardiovascular risk. Since there is currently no standard laboratory method to detect aspirin non-responders available, the term aspirin resistance remains controversial and requires further research. Every effort should be done to improve patients' compliance and to prevent clinically relevant interactions of aspirin with ibuprofen. The elimination of these two factors as was the case in our study may provide better efficacy of the antithrombotic prevention by aspirin (Fig. 2, Tab. 4, Ref. 19). Full Text (Free, PDF) www.bmj.sk.

Should medical students learn to develop a personal formulary? An international, multicentre, randomised controlled study.

OBJECTIVE: This study was performed to determine whether students who are trained in developing a personal formulary become more competent in rational prescribing than students who have only learned to use existing formularies. METHODS: This was a multicentre, randomised, controlled study conducted in eight universities in India, Indonesia, the Netherlands, the Russian Federation, Slovakia, South Africa, Spain and Yemen. Five hundred and eighty-three medical students were randomised into three groups: the personal formulary group (PF; 94), the existing formulary group (EF; 98) and the control group (C; 191). The PF group was taught how to develop and use a personal formulary, whereas e the EF group was taught how to review and use an existing formulary. The C group received no additional training and participated only in the tests. Student's prescribing skills were measured by scoring their treatment plans for written patient cases. RESULTS: The mean PF group score increased by 23% compared with 19% for the EF group (p < 0.05) and 6% for controls (p < 0.05). The positive effect of PF training was only significant in universities that had a mainly classic curriculum. CONCLUSION: Training in development and use of a personal formulary was particularly effective in universities with a classic curriculum and with traditional pharmacology teaching. In universities with a general problem-based curriculum, pharmacotherapy teaching can be based on either existing or personal formularies.

Current opinions on the role of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the main cases of mortality and morbidity of population worlwide. In spite of enormous efforts there are not pharmacological agents evidently influencing natural course of disease available. Besides looking for new drugs influencing the long term outcome of patients with COPD, there is also running the process of reevaluation of the role of several already established drug groups. METHODS: Through the use of recent knowledge and results from large-scale clinical studies as well as metaanalyses we give a view on action of inhaled corticosteroids in the pathophysiological mechanisms of COPD and complex summary of their role in the therapeutic management of the disease. CONCLUSION: Contrary to systemic corticosteroids, agreement regarding usage of inhaled corticosteroids necessary by acute exacerbations of disease has not been reached yet. Recent meta-analyses of the long-term clinical studies have clearly demonstrated that inhaled corticosteroids could pose with ability of slowing down the progressive deterioration of lung functions and lead to the prolongation of life in broad population of patients with COPD. Benefit of treatment insists in decrease of frequency and severity of exacerbations, mildering symptoms, improving overall health state as well as exercise tolerance in patients with COPD. Clinical relevant is also reduction of the number of hospitalizations and mortality related to progression of COPD (Tab. 2, Ref 45) Full Text (Free, PDF) www.bmj.sk.

Perception of drug risk in the database of Drug Information Centre in Bratislava.

OBJECTIVE: The aim of the presented study was to analyse the types and quantity of inquiries received at Drug Information Centre in Bratislava during the period from May 1997 to May 2006. The study analyses also the profile of the users of the latter centre with focus on the perception of drug risk, adverse drug reactions, and drug interactions. BACKGROUND: The Drug Information Centre (Druginfo) was established in Slovak Republic as part of the Department of Pharmacology in May 1997. In 2002 Druginfo became a member of International Register of Drug Information Services of the Society of Hospital Pharmacists of Australia. Druginfo provides voluntary free of charge drug information for healthcare professionals. METHODS: Statistical processing of all inquiries received at Druginfo during a 10-year period focused on the aspect of drug risk perception. RESULTS: 867 inquiries were received in total. The most frequent inquiries came from hospital teaching clinics in Bratislava. Questions concerning pregnancy/lactation (25 %), adverse drug reactions (16 %), basic information about drugs (14 %) and interactions (13 %) were asked most frequently. CONCLUSION: The types of inquiries and inquirers using the service are generally similar to those recorded at many others Druginfos within Europe and USA. The number of questions is lower than in other centres. Druginfo in Bratislava has a very important role in providing independent drug information (Tab. 1, Fig. 8, Ref. 9). Full Text (Free, PDF) www.bmj.sk.

Endothelaemia--a marker of vascular damage.

OBJECTIVES: The aim of the study was to determine the amount of circulating endothelial cells (CECs) in patients with an advanced cardiovascular (CV) disease, compare the values with a control group and finally to ascertain if there are statistically significant differences within the studied patient groups. BACKGROUND: Endothelaemia has been intensively studied as a marker of vascular injury. Clinical studies have demonstrated an increased endothelaemia in patients at high CV risk but also in certain non-cardiovascular disorders. Its possible usage in the diagnostics of the acute coronary syndrome and for CV risk assessment needs further investigations. METHODS: Thirty six hospitalized patients were studied. Quantitative measurement of endothelaemia was performed by the method developed by J. Hladovec. It is based on ECs counting in Bürker's chamber after their isolation with platelets and the removal of the latter by an addition of adenosine-diphosphate. RESULTS: The mean baseline endothelaemia was significantly higher in patients with increased cardiovascular risk when compared with the control group (1.38 +/- 0.899): ACS (4.9 +/- 1.59, p < 0.05) and PAOD (3.74 +/- 0.61, p < 0.05). When comparing the mean endothelaemia values in patients with PAOD before (2.67 +/- 0.86) and after (3.88 +/- 0.77) surgery, a significant increase of endothelaemia was observed (p < 0.05). CONCLUSION: Our pilot study, though limited by a relatively small number of patients, proved a significant increase of endothelaemia in patients at high CV risk, which is consistent with other available data. The introduction of newer specific methods based on immunomagnetic principles may provide a wider use of endothelaemia measurement in clinical settings (Fig. 3, Ref. 17). Full Text (Free, PDF) www.bmj.sk.

[Gastroduodenal complications associated with non-steroidal anti-inflammatory drugs in Slovak Republic: results of one-year prospective study]. / Podiel gastroduodenálnych komplikácií vo vzt'ahu k liecbe nesteroidovými antiflogistikami v Slovenskei republike: rocná prospektívna stúdia.

The aim of the one-year prospective study was to estimate the prevalence of non-steroidal anti-inflammatory drugs using in patients with symptomatic gastroduodenal ulcers, the upper gastrointestinal bleeding and perforation (PUB--perforation, ulcer, bleeding). Among of 326 patients with PUB, prevalence of non-steroidal anti-inflammatory drugs using was 60%. In the group of 194 patients with non-steroidal antiinflammatory drugs induced PUB, 49% patients took aspirin, 38% non-aspirin non-steroidal anti-inflammatory drugs and 13% their combination. Low dosing aspirin (daily dosis < or =200 mg) was associated with PUB in 21% of patients. Age higher than 60 years and women had statisticaly signiticant higher prevalence of non-steroidal anti-inflammatory drugs induced PUB.

Perception of potentially inappropriate medication in elderly patients by Slovak physicians.

PURPOSE: The aim of the present study was to determine the risk perception of potentially inappropriate drug treatment of elderly patients by Slovak physicians. In Slovakia, a list of such drugs is not available. METHODS: The study sample consisted of 600 patients aged > or =65 years hospitalized at the Department of Internal Medicine in a Slovak general hospital between 1 December 2003 and 31 March 2005. The use of potentially inappropriate drugs at the time of hospital admission and discharge was compared. Potentially inappropriate drug use was defined by Beers 2003 criteria. In addition, 206 physicians were asked to mark the drugs that they considered potentially inappropriate for elderly patients out of a list provided in a questionnaire analysis. RESULTS: Out of 600 patients 20.2% and 20% were treated with at least one potentially inappropriate drug at the time of hospital admission and discharge, respectively. Hospitalization had no significant influence on the number of potentially inappropriate medicines used. The most frequently prescribed potentially inappropriate drugs were digoxin >0.125 mg/day and ticlopidine. Out of 206 responding physicians only 4.9% considered ticlopidine as potentially inappropriate for elderly patient. On the other hand, more than 20% of respondents were aware of the potential inappropriateness of amitriptyline, diazepam and chlordiazepoxide. Mentioned drugs were observed in less than 2% of study population (n = 600). CONCLUSIONS: The results of the questionnaire analysis in physicians as well as the prevalence of potentially inappropriate medication demonstrate that Slovak clinicians are aware of the risk of certain treatments in elderly patients.

Effect of pentoxifylline on endothelaemia and hypothalamic-pituitary-adrenocortical axis activation in female rats under stress exposure.

Endothelial dysfunction may belong to negative consequences of stress exposure accompanied by activation of several stress systems including the hypothalamic-pituitary-adrenocortical (HPA) axis. The present experiments were aimed at testing the hypotheses that i) immobilization (IMO) stress results in sustained increase in endothelaemia for 24 h and that ii) pentoxifylline, a drug with endothelium protective properties, attenuates the rise in endothelaemia and HPA axis activation in female rats as shown previously in males. Circulating endothelial cells increased immediately after the IMO for 2 h, returned back to control levels at 12 h and increased again at 24 h. Stress-induced rise in adrenocorticotropic hormone (ACTH) and corticosterone levels was particularly high immediately after the IMO. Pretreatment with pentoxifylline (20 mg/kg subcutaneously for 7 days) attenuated the rise in endothelaemia and adrenal corticosterone measured at 24 h following IMO. Plasma levels of ACTH and proopiomelanocortin gene expression in the anterior pituitary were not affected by pentoxifylline treatment. The present results indicate that IMO stress in female rats induces a biphasic rise in endothelaemia early at the time of stress exposure and than 24 h thereafter. Based on these data and our previous study we can conclude that intensive stress has a negative influence on endothelial cells in both sexes and no gender differences seem to be present in the protective action of pentoxifylline.

[Consultation activity of two Slovak centres for pharmacotherapy during pregnancy and lactation]. / Konzultacná cinnost' dvoch slovenských centier pri farmakoterapii v gravidite a laktácii.

BACKGROUND: In our paper we present analysis based on number and structure of consultations concerning drug used in pregnancy and lactation in the Drug Information Centre in Bratislava and at the Department of Clinical Pharmacology in Nitra during period 2000 to 2003. METHODS AND RESULTS: In both centres the questions related to pregnancy and lactation represented the significant part of total sum of the requested information. Vast majority of consulted drugs belonged to C category concerning FDA pregnancy drug risk classification. In these drugs animal studies have revealed a risk, but studies in pregnant women were not available and thus the drugs had limited applicability from view point of safety. Decisions of consultants regarding drug use were based on the availability of information sources. A serious problem is the evaluation of retrospective drug risks in cases of drugs administered before pregnancy was confirmed. CONCLUSIONS: The evaluation of drug risk in fertile age, especially in early pregnancy, long-term drug administration during pregnancy and lactation becomes indispensable within professional field of clinical pharmacy and pharmacology in developing local teratogen surveillance system.

Experience with problem oriented teaching in pharmacology.

Pharmacology is one of the core subjects for further graduation in both preclinical and clinical area. Medical education is being performed either in the "classical" way (lecture based learning--LBL) or in a more advanced form, such as problem based learning (PBL). According to the Medline database, the interest in PBL is still increasing. At our department, the PBL has been introduced using the knowledge obtained at the the Mac Master University and University of Groningen. PBL in pharmacology requires well-qualified staff with clinical experience. A common character of PBL is the use of selected clinical cases as models and starting points to study certain topics with a student centred approach. In an interview we made on a sample of 88 students of our medical faculty in the last study year, 65.5% of them found the amount of information concerning pharmacotherapy not sufficient for their future clinical practice and 83.3% did not feel able to use the knowledge obtained. More than 90% of students did not see enough opportunities for pharmacotherapy training during clinical subject courses. These results are in support of our orientation of teaching towards the PBL. This type of teaching forces students to be active, trains their skills in communication and selection of knowledge, which is believed to enhance the long-term knowledge retention. By using the hybrid PBL-LBL model at our department we respect the principal proposal of medical education and attempt to improve skills in decision making in training of future medical doctors. (Tab. 3, Fig. 2, Ref. 13.)