The purpose of this study was to identify clinical and demographic predictors of seizure recurrence in medically-treated patients with epilepsy. Innovus Invision™ Data Mart insurance claims from January 1, 2007 to September 30, 2010 were retrospectively analyzed. Patients aged 18-64 years with a primary or secondary diagnosis of epilepsy and >1 prescription claim for an antiepileptic drug (AED) pre-index were included. The primary outcome was incidence of seizures defined as an occurrence of an emergency room visit, ambulance service use or hospitalization with a primary or secondary diagnosis of epilepsy during the 1-year follow-up period. Predictor variables included antiepileptic drug (AED) adherence (Proportion of Days Covered ≥ 80 %), general comorbidity (Charlson’s Comorbidity Index ≥ 1), any mental health comorbidity, evidence of a prior seizure, type of epilepsy diagnosis (intractable versus non-intractable), presence of AED-interacting medications and any bioequivalent AED switch. The covariates included age, gender and geographic region of residence. The overall incidence of post-index seizures in the 1-year follow-up period for all four monotherapy cohorts combined was 5.3 % (n=166/3140), but was higher for the Keppra®/levetiracetam cohort (7.9%; n=88/1114) compared to the other cohorts [Lamictal®/lamotrigine (3.9%; n=45/1143), Trileptal®/oxcarbazepine (4.0%; n=18/456) and Topamax®/topiramate (3.5%; n=15/427)]. The combined cohort analysis demonstrated that pre-index seizures (odds ratio [OR] = 4.28; 95% CI, 2.81-6.53), any mental health comorbidity ([OR] = 3.41; 95% CI, 2.10-5.54), Charlson comorbidity Index ≥1 ([OR] = 2.88; 95% CI, 1.96-4.24) and monotherapy with Keppra®/levetiracetam ([OR] = 1.54; 95% CI, 1.03-2.31) were significant predictors of seizure recurrence. Among covariates, only geographic region was a significant predictor, with patients residing in the Northeast U.S. having higher odds of post-index seizure ([OR] = 1.92; 95% CI, 1.19-3.10), while controlling for clinical, medication and demographic characteristics. A bioequivalent AED switch, type of epilepsy diagnosis, AED adherence and the presence of interacting medications were not significant predictors of seizure recurrence in the combined cohort (p>0.05). Results indicate that epilepsy patients with comorbid conditions (both mental and somatic diseases), as well as patients who may have initially been unstable (with previous seizure occurrences) were more likely to experience seizures during the follow-up period. / text

Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Biological and medicinal sciences Candidate Karolína Arnošová Consultant doc.MUDr. Josef Herink DrSc. Title of thesis Adverse effects of epilepsy medication in children The aim of this thesis was to determine the most commonly used antiepileptics in children, its adverse effects and to compare these results with the adult epileptology. In the theoretical part there are etiopathogenesis, pathophysiology, clinical manifestation, types of the seizures and epileptic syndromes described. The specifics of epilepsy treatment in children, not only pharmacotherapy, but also non-pharmacological treatment options, were documented as well. In the study there was exact half of patients treated with monotherapy and the other half with combined therapy which is not in line with the original hypothesis that assumed a predominance of monotherapy. The most commonly used antiepileptics in children were valproate (62,5 %), lamotrigine (25 %), topiramate and levetiracetame (both in 18,75 %). The hypothesis assuming a higher incidence of adverse effects in combination therapy has been confirmed. The most common adverse effects in children were the effects on total daily activity, occuring in 83,33 %, even with the mildest score on average....

Abstract The aim of this thesis was to explore the associations between the use of nervous system medications and suicidal ideation and behaviour in various different diagnostic groups in a large population-based cohort. Information on prescribed antipsychotic, antidepressant, benzodiazepine and antiepileptic medications within the Northern Finland Birth Cohort 1966 was collected from the register of the Social Insurance Institution of Finland and from a postal questionnaire sent to all cohort members in 1997. The presence of suicidal ideation and depression and anxiety symptoms was assessed via the Hopkins Symptom Checklist-25 questionnaire in 1997. Data on suicides were collected from the cause-of-death statistics and on suicide attempts from the Finnish Care Register for Health Care in a 15-year follow up. The use of antipsychotic, antidepressant, or benzodiazepine medication was associated with increased suicidal ideation, suicide attempts, and suicides. Antiepileptic medication was not associated with increased suicidality. The polypharmacy of nervous system medications was associated with increased suicidality. All nervous system medications were associated with increased severity of depression and anxiety symptoms. When depression and anxiety symptoms were taken into account, most of the associations between medication and suicidal ideation were statistically non-significant. Regarding specific groups, among those who did not have psychosis, high doses of antipsychotic medication correlated particularly with increased suicidal ideation even when other symptoms of depression and anxiety were taken into account. Among those with insomnia, the use of antidepressant medication associated with increased suicidal ideation also when other symptoms were taken into account. Although nervous system medication is associated with increased suicidal ideation, the association with other symptoms is also strong, and therefore it could not be stated that medication associates specifically with suicidal ideation. However, certain groups, i.e., non-psychotic subjects with high doses of antipsychotic medication, or subjects with insomnia and using antidepressant medication, should be closely monitored as they could be more vulnerable to suicidal ideation. / Tiivistelmä Tämän väitöstutkimuksen tarkoituksena oli tutkia hermostoon vaikuttavien lääkkeiden, lähinnä psykoosilääkkeiden, masennuslääkkeiden, bentsodiatsepiinien sekä epilepsialääkkeiden, yhteyttä itsetuhoisiin ajatuksiin, itsemurhayrityksiin ja itsemurhiin. Aihetta tutkittiin eri diagnoosiluokissa suuressa väestöaineistossa, Pohjois-Suomen vuoden 1966 syntymäkohortissa. Tieto tutkimushenkilöiden lääkkeenkäytöstä vuodelta 1997 kerättiin Kelan lääkeostorekisteristä sekä postikyselyn avulla. Itsetuhoisten ajatusten ja muiden masennus- ja ahdistusoireiden vakavuutta mitattiin Hopkins Symptom Checklist-25 -kyselyn avulla vuonna 1997. Tieto itsemurhista kerättiin 15 vuoden seurannassa kuolinsyyrekisteristä ja tieto itsemurhayrityksistä hoitoilmoitusrekisteristä. Psykoosilääkkeiden, masennuslääkkeiden ja bentsodiatsepiinien käyttö oli yhteydessä lisääntyneisiin itsetuhoisiin ajatuksiin, itsemurhayrityksiin ja itsemurhiin. Epilepsialääkkeet eivät liittyneet itsetuhoisuuteen. Usean hermostoon vaikuttavan lääkkeen yhtäaikainen käyttö oli yhteydessä lisääntyneeseen itsetuhoisuuteen. Kaikki hermostoon vaikuttavat lääkkeet liittyivät lisääntyneisiin masennus- ja ahdistusoireisiin. Kun lääkityksen yhteys masennus- ja ahdistusoireisiin otettiin huomioon, lääkkeet eivät olleet erityisesti yhteydessä itsetuhoisiin ajatuksiin. Diagnostisten ryhmien välillä ei ollut eroa hermostoon vaikuttavien lääkkeiden ja itsemurhayritysten tai itsemurhien välisessä yhteydessä. Henkilöillä, joilla ei ole psykoosia, suuremmat psykoosilääkeannokset olivat yhteydessä itsetuhoisten ajatusten vakavuuteen kun muiden masennus- ja ahdistusoireiden vakavuus otettiin huomioon. Unettomuudesta kärsivillä henkilöillä masennuslääkkeen käyttö oli liittyi lisääntyneisiin itsetuhoisiin ajatuksiin kun muut oireet huomioitiin. Hermostoon vaikuttavat lääkkeet ovat yhteydessä lisääntyneisiin itsetuhoisiin ajatuksiin, mutta ne ovat myös vahvasti yhteydessä muihin masennus- ja ahdistusoireisiin. Tietyt henkilöt voivat kuitenkin olla erityisen herkkiä nimenomaan itsetuhoisille ajatuksille, ja heitä tulisi seurata erityisen tiiviisti. Tällaisia ovat henkilöt, joilla ei ole psykoosia, mutta jotka käyttävät suuria psykoosilääkeannoksia, sekä vakavasta unettomuudesta kärsivät henkilöt, jotka käyttävät masennuslääkettä.

Jakub Žalud PhDr. Alena Javůrková Ph.D. adverse effects of antiepileptics, their classification and expression from the patient's subjective assumption was that the patient's experience of the adverse effects of antiepileptic drugs will significant overall (p˂0.05; R2 = 0.20). ts was not statistically significant (p˃0.05; R2 = 0.21). (p˃0.05; R2 = 0.16).

A new analytical methodology was developed in order to investigate the presence of five psychoactive drugs (anxiolytic and antiepileptics), namely, bromazepam, carbamazepine, clonazepam, diazepam, and lorazepam in the effluent of the University Hospital of Santa Maria (HUSM) of the Federal University of Santa Maria (UFSM), since these compounds are widely used in the treatment of anxiety and epilepsy. Samples were collected from two points to check the concentration of the compounds: Point A (Emergency) and point B (General Effluent - which covers the Central Library and HUSM). The method of clean-up/pre-concentration by solid phase extraction (SPE) was used to assess the occurrence of anxiolytic and antiepileptic drugs in the effluent of HUSM. Three methods were developed and validated to determine these compounds: i) high performance liquid chromatography with ultraviolet detection (HPLCUV), ii) high performance liquid chromatography with detection by mass spectrometry (LC-MS), and iii) liquid chromatography-ion trap-tandem mass spectrometry with electrospray ionization (LCMS/ MS_Qtrap). Among the methods evaluated, LC-MS/MS_Qtrap with electrospray in positive mode yielded better results. The detection limit (LOD, S/N ≥3) for lorazepam and bromazepam was 4.90±0.95 ng L-1 and for carbamazepine, clonazepam and diazepam, 6.10±1.50 ng L-1. The limit of quantification (LOQ, S/N ≥10) was 30.00±1.10 ng L-1 bromazepam , clonazepam and lorazepam; 50.00±1.81 ng L-1, carbamazepine; and 40.00±0.98 ng L-1 diazepam. The linear range of the assay (LC-MS/MS_Qtrap) was 30-1500 ng L-1 for bromazepam; 50-2500 ng L-1, carbamazepine; 30-2500 ng L-1, clonazepam; 40-2500 ng L-1, diazepam; and 30 - 2000 ng L-1, lorazepam. The correlation coefficient (R2>0.997) for all compounds. The effectiveness of the methodology was verified by recovery with the fortification of three concentration levels in triplicate samples of hospital effluent. The average recovery rates observed were: 93.9±2.1% for bromazepam; 92.6±4.2%, carbamazepine; 93.9%±3.0 clonazepam; 91.8%±6.0 for diazepam; and 93.8%±4.3 for lorazepam. The mean concentrations of psychiatric drugs detected in the effluent of the Emergency and General Effluent were respectively: 195.0±6.4 ng L-1 and 137.1±7.0 ng L-1 for bromazepam; 589.6±6.1 ng L-1, and 460.7±9.3 ng L-1, carbamazepine; 645.0±0.3 ng L-1 and 571.0± 9.9ng L-1, diazepam; 95.7±6.7 ng L-1 and 42.4±4.2 ng L-1 lorazepam; and 134.3 ± 9.8 ng L-1 and 56.9 ± 9.9 ng L-1 clonazepam. The identification of metabolites in the hospital effluent was made through (LCMS/ MS_Qtrap). The metabolites identified were: 3-hydroxybromazepam (bromazepam), 7- aminoclonazepam (clonazepam), carbamazepine 10,11-epoxide, 10-dihydroxy-10,11- dihydrocarbamazepine, iminoquinone, 2-hydroxy-carbamazepine and acridone (carbamazepine), and nordiazepam, oxazepam and temazepam (diazepam), and their fragmentation pathways were proposed. Was performed a preliminary risk assessment of anxiolytic and antiepileptic drugs with the aid of literature data and found that the carbamazepine and diazepam compounds showed the highest risk (0.85 and 0.90, respectively) among the compounds analyzed. According to the results we can say that they present medium risk requiring more attention in terms of toxicity. However, no literature data were found on the Predicted No Effect Concentration (PNEC) for bromazepam, lorazepam, clonazepam, not allowing the calculation of risk quotient (RQ) for these compounds.Therefore, we observed the occurrence of anxiolytic and antiepileptic drugs in the effluent of HUSM at concentrations in the order of ng L-1. The analytical method for LC-MS/MS_Qtrap developed for the determination of psychoactive drugs (bromazepam, carbamazepine, clonazepam, diazepam and lorazepam) in hospital effluent proved to be sensitive and selective, eliminating laborious sample handling and requiring chromatographic run of just 15 minutes. The occurrence of these drugs and environmental risks associated demonstrate the need for more efficient treatment for the hospital effluent. / Uma nova metodologia analítica foi desenvolvida com a finalidade de investigar a presença de cinco fármacos psicoativos (ansiolíticos e antiepilépticos): bromazepam, carbamazepina, clonazepam, diazepam e lorazepam no efluente do Hospital Universitário de Santa Maria (HUSM) da Universidade Federal de Santa Maria (UFSM), visto que estes compostos são amplamente utilizados no tratamento da ansiedade e da epilepsia. As amostras foram coletadas de dois pontos para a verificação da concentração dos compostos: o Ponto A (efluente do PAHUSM) e o ponto B (efluente geral que abrange o HUSM e a Biblioteca Central). Utilizou-se um método de clean-up/pré-concentração por extração em fase sólida, para avaliar a ocorrência de ansiolíticos e antiepilépticos no efluente do HUSM. Deste modo, três métodos para determinar estes compostos foram desenvolvidos e validados: i) cromatografia líquida de alta eficiência com detecção por ultravioleta (HPLC-UV), ii) cromatografia líquida de alta eficiência com detecção por espectrometria de massa (LC-MS) e iii) cromatografia líquida acoplada a espectrometria de massa com ionização por eletronebulização e armadilha de íons (LC-MS/MS_Qtrap). Dentre os métodos avaliados, o LC-MS/MS_Qtrap com eletronebulização no modo positivo obteve melhores resultados. O limite de detecção (LOD, S/N ≥3) para bromazepam e lorazepam foi 4,90±0,95 ng L-1 e, para carbamazepina, clonazepam e diazepam, 6,10±1,50 ng L-1. O limite de quantificação (LOQ, S/N ≥10) foi de 30,00±1,10 ng L-1, para bromazepam, clonazepam e lorazepam; carbamazepina, 50,00±1,81 ng L-1 e, diazepam, 40,00±0,98 ng L-1. A faixa linear do método (LC-MS/MS_Qtrap) para bromazepam foi de 30-1500 ng L-1, para carbamazepina 50-2500 ng L-1; clonazepam de 30-2500 ng L-1, diazepam 40-2500 ng L-1 e para lorazepam foi de 30-2000 ng L-1. O coeficiente de correlação (R2 >0,997) para todos os compostos. A eficiência da metodologia foi verificada através da recuperação com a fortificação em três níveis de concentração em triplicata de amostras de efluente hospitalar. As taxas de recuperação média constatadas foram: para bromazepam 93,9%±2,1; carbamazepina 92,6%±4,2; clonazepam 93,9%±3,0; diazepam 91,8%±6,0 e lorazepam foi de 93,8%±4,3. As concentrações médias das drogas psiquiátricas detectadas no efluente do PA-HUSM e efluente geral foram respectivamente: bromazepam, 195,0±6,4 ng L-1 e 137,1±7,0 ng L-1; carbamazepina, 589,6±6,1 ng L-1 e 460,7±9,3 ng L-1, diazepam, 645,0±0,3 ng L-1 e 571,0±9,9 ng L-1, lorazepam, 95,7±6,7 ng L-1 e 42,4±4,2 ng L-1 e clonazepam, 134,3±9,8 ng L-1 e 56,9±9,9 ng L-1. A identificação dos metabólitos no efluente hospitalar foi realizada através de LC-MS/MS_Qtrap. Os metabólitos identificados foram: 3-hidroxi-bromazepam (bromazepam), 7-amino-clonazepam (clonazepam), carbamazepina 10,11-epóxido, 10-dihidroxi-10,11-dihidrocarbamazepina, iminoquinona, 2-hidroxi-carbamazepina e acridona (carbamazepina), nordiazepam, oxazepam e temazepam (diazepam) e, seus caminhos de fragmentação foram propostos. Foi realizada uma avaliação de risco preliminar de ansiolíticos e antiepilépticos com o auxílio de dados da literatura e foi verificado que os compostos carbamazepina e diazepam apresentaram maior risco com Quociente de Risco teórico (0,85 e 0,90, respectivamente) entre os compostos analisados. De acordo com os resultados obtidos pode-se dizer que apresentam risco médio, requerendo maior atenção em termos de toxicidade. Entretanto, dados na literatura não foram encontrados sobre a Concentração Prevista que Não Causa Efeito (PNEC) para bromazepam, clonazepam e lorazepam, impossibilitando o cálculo do quociente de risco (QR) para estes compostos. Portanto, foi evidenciada a ocorrência de ansiolíticos e antiepilépticos no efluente do HUSM em concentrações na ordem de ng L-1. O método analítico por LC-MS/MS_Qtrap desenvolvido para a determinação das drogas psicoativas (bromazepam, carbamazepina, clonazepam, diazepam e lorazepam) no efluente hospitalar provou ser sensível, seletivo, dispensando manipulação laboriosa da amostra e exigindo corrida cromatográfica de apenas 15 minutos. A ocorrência destes fármacos e os riscos ambientais associados demonstram a necessidade de sistema mais eficiente de tratamento para o efluente hospitalar.