Analysis of spontaneous adverse events reports of antiepileptic drugs Author: Ivana Šoborová Supervisor: PharmDr. Eva Zimčíková, Ph.D. Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Introduction: Epilepsy is one of the most common neurological diseases, which occurs worldwide. Antiepileptic drugs (AED) suppress the onset of an epileptic seizure. Analysis of spontaneous adverse drug reactions (ADRs) analysis is important data source for generating the potential risks signals in pharmacotherapy. Objective: The aim of this work was to analyse spontaneous reports of ADRs from the Czech Central Database of ADRs of the State Institute for Drug Control (SÚKL) in the period from June 2004 to October 2017. The analyses of potential drug interactions of all medicinal products mentioned in the reports and the assessment of the reported ADRs expectability was the secondary goal. Methods: Retrospective analyses of the spontaneous ADR reports of antiepileptic drugs obtained from the SÚKL in the given period. Anonymized data was processed using the descriptive statistics in MS Excel. For example, the patient characteristics or seriousness and expectability of the ADRs were evaluated. The specific adverse drug reactions were divided according to the system...

Magister Pharmaceuticae - MPharm / Gestational diabetes mellitus (GDM) is a condition that affects pregnant women and is one of the most common complications related to pregnancy. According to the World health organisation (WHO), the usual window for diagnosing GDM is between 24 and 28 weeks of gestation and the primary aim of diagnosing gestational diabetes is to identify women and infants at risk of short- or longer-term adverse outcomes. Recent results from the hyperglycaemia and adverse pregnancy outcome (HAPO) study have suggested that even mild levels of hyperglycaemia can have adverse effects on foetal outcomes but there are uncertainties about the prevalence of these outcomes in GDM diagnosed according to the latest WHO 2013 guideline and/or IADPSG 2010 criteria in diverse populations. GDM prevalence has been studied by different researchers, but the prevalence of adverse foetal outcomes in GDM diagnosed based on the latest WHO 2013 guideline and/or IADPSG 2010 criteria have not yet been explored except for the data published by the HAPO study. Due to the lack of sufficient knowledge on foetal outcomes in GDM, this study was conducted to review the evidence on the prevalence of adverse foetal outcomes in GDM diagnosed according to WHO 2013 guideline and/or the IADPSG 2010 criteria. Different databases including PubMed, Science Direct, Google Scholar and CINAHL as well as bibliographic citations were searched using a well-formulated search strategy to find the relevant observational studies (prospective/retrospective cohort and case-control) using explicit inclusion and exclusion criteria. The following search terms were used, “gestational diabetes”, “pregnancy”, “adverse fetal outcomes” and “adverse foetal outcomes”. The findings of this study were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the obtained data analysed using MetaXL ® version 5.3. This review was registered online on PROSPERO, the International prospective register of systematic reviews (registration number: CRD42020155061). Fifteen studies with 88,831 pregnant women (range: 83-25,543 participants) from 12 countries around the world were identified, with a wide variation in the prevalence of foetal outcomes in GDM using the stipulated criteria. These studies were unevenly distributed geographically as six of them were conducted in Asia, four in Europe, four in North America, one in Australia and none in Africa, Antarctica and South America. A meta-analysis found that the overall prevalence of foetal outcomes ranged from 1% (perinatal mortality) to 11% ( large for gestational age). The finding is limited due to the paucity of data on the prevalence of foetal outcomes in GDM. However, more studies using these criteria in low- and middle- income countries (LMICs) are needed by health care providers, to inform practice and allocate resources for control of GDM and its adverse foetal outcomes in diverse settings and ethnic groups, especially in LMICs.

Background: Root Cause Analysis (RCA) is a method of investigating adverse events (AEs). The purpose of RCA is to improve quality of care and patient safety through a retrospective, structured investigative process of an incident, resulting in recommendations to prevent the recurrence of medical errors. Aim: The aim of the study was to develop and validate a prototype questionnaire to establish whether the RCA model and processes employed at the research setting were perceived by the users to be acceptable, thorough and credible in terms of internationally established criteria. Methods: This is a validation study comprising four phases to meet the study objectives: 1) the development of a prototype questionnaire guided by a literature review; 2) assessing the validity of the content of the questionnaire by and numerical evaluation of the face validity thereof; 3) assessing the qualitative face validity cognitive interviews; and 4) reliability by test-retest. Results: Content validity assessment in Phase 2 resulted in removal of 1/36 (2.77%) question items and amendment of 7/36 (19.44%), resulting in 35 for the revised questionnaire. Analysis of data from the cognitive interviews resulted in amendment of 20/35 (57.14%) question items but no removal. Reliability of the final questionnaire achieved the predetermined ≥0.7 level of agreement. Conclusion: The questionnaire achieved a high content validity index and face validity was enhanced by cognitive interviews by providing qualitative data. The inter-rater coefficient indicated a high level of reliability. The tool was designed for a local private healthcare sector and this may limit its use.

Introduction Tennessee (TN) ranked 16th among US states for the number of HIV diagnoses in 2015. By TN grand division region (East, Middle, and West), the highest rate of persons living with HIV/AIDS (PLWH) were in the Middle and West. Barriers to HIV testing are still very much unknown in research studies. Further, understanding how Adverse Childhood Experience (ACEs) play a role in HIV testing and specifically in marginalized groups is not fully understood. The present study sought to understand the relationship between ACEs, living in poverty, and testing for HIV among adults in Tennessee. Methods Behavioral Risk Factor Surveillance System data for 2016 and 2017 were obtained from the Tennessee Department of Health. Sociodemographic factors, diagnosis of depression, binge drinking behaviors, HIV risk behaviors (one or more of these in the past year: injection drug use, anal sex, sex without a condom, paid sex, four or more sexual partners), grand division, poverty level, and ACEs were analyzed to determine if an association exists with having been tested for HIV in the past year (yes or no). ACEs were categorized into 0, one to three, or four or more, all having occurred before the age of 18. Frequencies, percents, chi-square, and independent T-tests were completed. Sex stratified simple and multiple logistic regression models were conducted to determine the strength of association with having been tested for HIV (N=1,506 males; N=1,433 females). Results Males who reported HIV risk behaviors were 46% less likely to be tested for HIV (aOR: 0.54, 95% CI: 0.53-0.55) whereas females with HIV risk behaviors were 61% less likely to test for HIV (aOR: 0.39, 95% CI: 0.39-0.40) compared to those without HIV risk behaviors. Males with 4 or more ACEs were 38% more likely to be tested for HIV compared to males with 0 ACEs (aOR: 1.38, 95% CI 1.36-1.39), whereas females with 4 or more ACEs were two times more likely to be tested for HIV (aOR: 2.09, 95% CI: 2.07-2.11) compared to females with 0 ACEs. Males making <$25,000 annually were only 5% more likely to be tested for HIV (aOR: 1.05, 95% CI: 1.04-1.06), whereas women making the same income were 30% less likely to be tested for HIV (aOR: 0.70, 05% CI: 0.69-0.71) compared to incomes greater than $25,000. Males in West TN were 12% less likely to be tested for HIV compared to males in East TN (aOR: 0.88, 95% CI: 0.87-0.89). Similarly, females in West TN were 15% less likely to be tested for HIV compared to females in East TN (aOR: 0.85, 95% CI: 0.84-0.86). Conclusion Education and awareness may be too focused on adults with more ACEs rather than ensuring individuals with HIV risk behaviors, living in poverty, or residing in West TN, understand their risk and have access to HIV testing. Regions of TN, specifically West TN compared to East TN, may require additional resources to ensure the general population understands their risk for HIV; however further research is warranted through longitudinal studies.

Valproic acid (Depakote) is an antiepileptic drug approved for the treatment of bipolar disorder, migraine prophylaxis, and seizure disorders. While the exact mechanism is still unknown, thrombocytopenia, defined as platelet counts < 150,000/uL, has been reported secondary to Depakote treatment. The frequency of Depakote-induced thrombocytopenia varies greatly, with reported rates ranging from 5 to 54%. This adverse effect is dose-dependent and possible risk factors include lower baseline platelet counts, female gender, and high VPA serum concentrations.Our team came across two patient cases where thrombocytopenia during Depakote therapy was observed. Patient information was gathered through electronic medical records. The first patient was a 65-year-old male who was started on 500 mg Depakote ER three tablets at night for bipolar affective disorder. After several months on this dose, the patient’s platelets decreased to 59 X 103per microliter. One month after the drug was discontinued, the platelets recovered to 160 X 103per microliter. The second patient was a 57-year-old woman who had two occurrences of thrombocytopenia while on Depakote. The patient was started on Depakote for a seizure disorder. She was later admitted for symptomatic bradycardia, hypotension, and concern for thrombocytopenia. Her Depakote dose was decreased from 500 mg three times a day to twice a day. Approximately 5 weeks later, she presented to the emergency room for decreased arousal and hypotension. She was again found to have thrombocytopenia with a platelet count of 28 X 103per microliter with a Depakote level of 101 mcg/mL. The team discovered she had been receiving Depakote 500 mg three times a day following discharge from her last admission, not the reduced dose prescribed. On day four of admission, her platelets had not improved and the Depakote dose was decreased further to 250 mg twice daily. After Depakote was discontinued her platelets gradually improved and returned to normal after four days, the eighth day of admission. Utilizing the Naranjo adverse drug reaction probability scale, the first patient case had a probable reliability that this adverse reaction was due to Depakote, while the second patient case had a definite reliability.These cases illustrate the potential for thrombocytopenia secondary to Valproic acid use. Although this adverse event isn’t well understood, these cases add to the evidence that it can occur. Recognition of this reaction is important and clinicians should monitor hematologic labs, including platelets, for patients receiving Valproic acid.

Research has found that adverse childhood experiences (ACEs) are associated with changes in both parenting stress and cortisol. Resilience-building interventions may be able to help diminish the effects of ACEs, thus impacting parenting stress and cortisol reactivity. This study aims to examine how two resilience-building interventions (emotion-based and behavior-based) will impact parenting stress and cortisol reactivity in mothers with ACEs. This project is in the preliminary stages of data collection; as such, this honors thesis will review the relevant literature, describe current methodology and proposed analyses, and discuss possible implications and future directions. Participants (goal N=100) undergo a pre-assessment where parenting stress and cortisol reactivity are measured. Participants are then randomly assigned to receive an emotion-based curriculum (goal n= 50) or behavior-based curriculum (goal n=50) for 8 weeks. After completing their curriculum, participants’ parenting stress and cortisol reactivity will be reassessed. Participants from both resilience-building interventions are hypothesized to have a reduction in parenting stress and cortisol reactivity, but participants who received the emotion-based curriculum are predicted to have greater reductions. Additionally, it is hypothesized that changes in parenting stress will be correlated with changes in cortisol reactivity, so participants with greater reductions in parenting stress are anticipated to have greater reductions in cortisol reactivity.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Tereza Klapková Supervisor: Assoc. Prof. PharmDr. František Trejtnar, CSc. Title of diploma thesis: Recent knowledge on drug effect on male fertility Among the various types of side effects presented in clinically used drugs, negative effects on male reproductive functions can be find. This issue seems to be important and current especially due to the general trend of the decrease in fertility in men and the increasing drug use in younger age groups. The aim of this diploma thesis was to create an overview summarizing current expert knowledge on the effect of drugs on male fertility. For this purpose, we selected relevant publications in the PubMed database, perform their analysis and create the text ofthe thesis. The review focuses mainly on groups of drugs that are often clinically used and discussed in relation to male fertility, such as drugs acting on the cardiovascular system, antimicrobial drugs, drugs used in pain therapy, antidepressants, antiepileptics, antipsychotics, immunosuppressants and some other drugs. In addition to standard drugs, the review also includes several important natural substances, which are used as adjunctive therapy of various diseases or are important from a...

Background: Long term negative physical and mental health problems occur from the lack of appropriate interventions targeting the adult population who experienced adverse childhood experiences (ACEs) and partake in risky alcohol consumption behaviors. Objective: This study aimed to identify the risk for alcohol consumption behaviors, specifically binge drinking (BD) and any drinking (AD), among adults with a history of adverse childhood experiences (ACEs). Methods: Behavioral Risk Factor Surveillance System (BRFSS) 2011–2012 data were used. Descriptive statistics were completed followed by simple and multiple logistic regression to determine the strength of association between ACEs and alcohol consumption, controlling for sociodemographic factors. Results: The final adjusted sample size was 69,793. Adults who experienced household abuse were 30% more likely to BD (Odds Ratio (OR): 1.30, 95% Confidence Interval (CI): 1.20–1.41) and 21% more likely for AD (OR: 1.21, 95% CI: 1.14–1.28) in the past month. Males were over two times more likely to BD (OR: 2.12, 95% CI: 1.96–2.29) and 60% more likely for AD (OR: 1.60, 95% CI: 1.51–1.69) in the past month compared to females. Individuals who completed some college were at higher risk of BD (OR: 1.51, 95% CI: 1.26–1.82), whereas those who graduated college were nearly two and a half times more likely to report AD in the past month (OR: 2.27, 95% CI: 1.99–2.59) compared to individuals with less than high school education. Conclusion: Adults who experienced household abuse, are male, or possess at least some college education are at increased risk for BD and AD.

Aluminium is an element of increasing clinical importance. It not only has uses as a medicinal substance but also in recent years it has been shown to be the cause of considerable toxicity, particularly in the setting of chronic renal failure. Diseases that have been shown to be associated with aluminium, or in which it has been implicated, include dialysis dementia, renal osteodystrophy and Alzheimer's disease. This thesis has studied aspects of the interaction between aluminium and the kidney. The work has addressed two major issues. Firstly, a study is described where Malvin's stop-flow technique was used to determine any excretory/absorptive tubular site for Al in the pig kidney. Al was found to be excreted in the distal nephron of the pig kidney. Secondly, the toxic effects of Al in vitro on the DNA of pig kidney cell line LLC-PKl were investigated, in an attempt to elucidate some of the mechanisms of toxic action. DNA synthesis was measured using ³H-TdR incorporation. Over increases of both time (9-72 h) and Al concentration (0.01-8.0 mM), ³H-TdR incorporation was diminished. Effects were evident at concentrations as low as 0.05 mM Al. The production of DNA strand breaks was assessed by the increase in size of cell nucleoids (ie DNA in supercoiled form). Nucleoid size was analyzed in a Epics 753 Fluorescence Activated Cell Sorter interfaced with an MDADSII data acquisition and analysis system. After 90 min incubation with Al (over the concentration range 0.001-32 mM), an increase in nucleoid size was noted at concentrations above 0.05 mM. The data demonstrate that Al exerts an effect on kidney cells in vitro which is expressed as diminished DNA synthesis and production of DNA strand breaks. These effects on DNA may have important long-term implications on various disease states associated with Al toxicity.

This dissertation consists of three essays on dynamic contracts. Chapter One studies a dynamic principal-agent model in which the agent continuously works on a project which may yield a success. The principal cannot observe the success, but she observes imperfect signals over time after the agent stops working. The principal is more patient than the agent and both are risk neutral. In the optimal contract where the agent observes the success, the agent is induced to exert full effort until success and report it truthfully. The optimal payment scheme features a combination of wage and deferred bonus. When the agent does not observe the success, the optimal contract features a stochastic deadline and a deferred bonus payment. Chapter Two studies a discrete time principal-agent model where the agent's effort and ability are both private information. The wage is exogenously fixed and the principal designs a firing policy to incentivize the agent to work. In each period, the agent works on a project with binary outcomes. The high type has a higher probability of getting a good outcome than the low type conditional on high effort. The outcome in each period is publicly observed. In the optimal contract, the principal hires the high type for sure and hires the low type with some probability. Conditional on being hired, the high type faces a higher standard of performance. Chapter Three studies a dynamic model of delegated decision making with adverse selection and imperfect monitoring. In each period, a principal may delegate to a biased agent who has better information. The quality of the agent's information depends on his ability. In the optimal mechanism where the agent's ability is publicly observable, the principal delegates to the agent at the beginning of their relationship and the agent behaves in the principal's interest. Depending on the history, the principal either commits to delegating forever or stops delegating eventually. When the agent's ability is private information, the optimal mechanism features pooling at the top. The principal offers the same mechanism to the agent if his ability is known to be above a cutoff.