Before market authorization of new medicines, their efficacy and safety are evaluated using randomized controlled trials. While there is no doubt about the scientific value of randomized trials, they are usually conducted in selected populations with questionable generalizability to routine care.  In the digital data revolution era, with healthcare data growing at an unprecedented rate, drug monitoring in routine care is still highly under-utilized. Although many countries have access to data on prescription drugs at the individual level in ambulatory care, such data are often missing for hospitals. This is a growing problem considering the clear trend towards more new and expensive drugs administered in the hospital setting. The aim of this thesis was therefore to develop methods for extracting data on drug use from a hospital-based electronic health record system and further to build and evaluate models for real-time monitoring of effectiveness and safety of new drugs in routine care using data from electronic health records and regional and national health care registers. Using the developed techniques, we were able to demonstrate drug use and health service utilization for inflammatory bowel disease and to evaluate the comparative effectiveness and safety of antiarrhythmic drugs. With a rapidly evolving drug development, it is important to optimize the evaluation of effectiveness, safety and health economic value of new medicines in routine care. We believe that the models described in this thesis could contribute to fulfil this need.

Objectif: Déterminer si l’efficacité de l’amiodarone pour le maintien du rythme sinusal varie selon la fonction systolique ventriculaire gauche. Contexte: Malgré un profil de sécurité établi en insuffisance cardiaque, nous ignorons si l’efficacité de l’amiodarone et son impact sur différentes issues cardiovasculaires sont modulés par la fonction ventriculaire gauche. Méthode: Nous avons effectué une analyse combinée de 3307 patients (âgés de 68,0±0,9 ans ; 31,1% de femmes) recrutés dans les études AFFIRM et AF-CHF qui ont été randomisés au contrôle du rythme par l’amiodarone (N=1107) ou au contrôle de la fréquence cardiaque (N=2200). Résultats: Chez les patients sous amiodarone, la survie sans fibrillation auriculaire était de 84% et de 45% à 1 et 5 ans respectivement, sans égard à la fraction d’éjection ventriculaire gauche (P=0,8754, ajusté). De façon similaire, la proportion moyenne ajustée de temps en fibrillation auriculaire (15,0±1,8%) n’a pas été influencée par la fraction d’éjection (P=0,6094). Durant le suivi, 1963 patients (59,4%) ont requis au moins une hospitalisation, incluant 1401 (42,6%) patients hospitalisés pour cause cardiovasculaire. Les taux ajustés d’hospitalisation pour toutes causes et pour cause cardiovasculaire étaient similaires entre les patients sous amiodarone et ceux dans le groupe de contrôle de la fréquence dans l’ensemble de la population ainsi que dans les sous-groupes de patients avec et sans dysfonction ventriculaire gauche sévère. De façon similaire, les taux ajustés de mortalité globale et cardiovasculaire étaient similaires entre chez les patients sous amiodarone et ceux traités par le contrôle de la fréquence dans l’ensemble de la population ainsi que dans les sous-groupes de patients avec et sans dysfonction ventriculaire gauche sévère. Conclusions: L’efficacité de l’amiodarone pour le maintien du rythme sinusal n’est pas influencée par la fonction ventriculaire gauche. Le contrôle du rythme avec l’amiodarone s’associe à des taux de mortalité et d’hospitalisation comparables au contrôle de la fréquence à la fois chez les patients avec et sans dysfonction ventriculaire gauche sévère. / Objectives: To determine whether amiodarone’s efficacy in maintaining sinus rhythm varies according to left ventricular systolic function. Background: Despite amiodarone’s established safety profile in heart failure, it is unknown whether its impact on cardiovascular outcomes is modulated by ventricular function. Methods: We conducted a pooled analysis of 3307 patients (age 68.0±0.9 years; 31.1% female) enrolled in AFFIRM and AF-CHF trials who were randomized to rhythm control with amiodarone (N=1107) or rate control (N=2200). Results: In amiodarone-treated patients, freedom from recurrent atrial fibrillation was 84% and 45% at 1 and 5 years, respectively, with no differences according to left ventricular function (adjusted P=0.8754). Similarly, the adjusted mean proportion of time in atrial fibrillation (15.0±1.8%) did not vary according to ventricular function (P=0.6094). During follow-up, 1963 (59.4%) patients required at least one hospitalization, with 1401 (42.6%) patients hospitalized for a cardiovascular reason. Adjusted all-cause and cardiovascular hospitalization rates were similar with amiodarone versus rate control in the overall population and in subgroups of patients with and without severe left ventricular dysfunction. Similarly adjusted all-cause and cardiovascular mortality rates were similar with amiodarone versus rate control, overall and in subgroups of patients with and without severe left ventricular dysfunction. Conclusions: Amiodarone’s efficacy in maintaining sinus rhythm and reducing the burden of atrial fibrillation is similar in patients with and without left ventricular dysfunction. Rhythm control with amiodarone was associated with similar mortality and hospitalisation rates when compared to rate control in patients with and without severe left ventricular dysfunction.

Introduction : Bien que la pratique de l’usage de la warfarine se soit améliorée au cours de la dernière décennie, aucune recommandation claire basée sur le dosage de l’amiodarone n’a été jusqu’à maintenant standardisée, ce qui représente un grand obstacle pour les cliniciens. La warfarine a un index thérapeutique étroit nécessitant un suivi régulier et un ajustement individuel de la posologie, ceci afin de déterminer la dose thérapeutique, tout en prévenant les effets secondaires qui pourraient être fatals dans certains cas. La variabilité interindividuelle de la réponse à la warfarine dépend de plusieurs facteurs, dont l’âge, le sexe, le poids, l’alimentation et l’interaction médicamenteuse, mais ceux-ci n’expliquent que partiellement les différences de sensibilité à la warfarine. Les polymorphismes des gènes CYP2C9 et VKORC1 jouent un rôle important dans la réponse à la warfarine et expliquent jusqu’à 50% de la variabilité des doses. L’utilisation d’antiarythmiques telle l’amiodarone peut accentuer considérablement l’effet de la warfarine et nécessite généralement une diminution de 30 à 50% de la dose de la warfarine. Aucune étude à ce jour n’a tenté de déterminer l’utilité du génotypage des polymorphismes des gènes CYP2C9 et VKORC1 chez les patients sous traitement combiné de warfarine et amiodarone. Objectif : Notre étude a pour objectif tout d’abord de déterminer si des facteurs génétiques influencent la première dose de stabilisation de la warfarine chez les patients en FA après l’introduction de l’amiodarone. Nous allons également tenter de confirmer l’association préalablement rapportée entre les facteurs génétiques et la première dose de stabilisation de warfarine dans notre population à l’étude. Méthodes : Un devis de cohorte rétrospective de patients qui fréquentaient la clinique d'anticoagulothérapie de l’Institut de cardiologie de Montréal entre le 1er janvier 2007 et le 29 février 2008 pour l’ajustement de leur dose selon les mesures d'INR. Au total, 1615 patients ont été recrutés pour participer à cette étude de recherche. Les critères de sélection des patients étaient les patients avec fibrillation auriculaire ou flutter, ayant un ECG documenté avec l'un de ces deux diagnostics et âgé de moins de 67 ans, en raison d’une moindre comorbidité. Les patients souffrant d’insuffisance hépatique chronique ont été écartés de l’étude. Tous les patients devaient signer un consentement éclairé pour leur participation au projet et échantillon de sang a été pri pour les tests génétiques. La collecte des données a été effectuée à partir du dossier médical du patient de l’Institut de cardiologie de Montréal. Un formulaire de collecte de données a été conçu à cet effet et les données ont ensuite été saisies dans une base de données SQL programmée par un informaticien expert dans ce domaine. La validation des données a été effectuée en plusieurs étapes pour minimiser les erreurs. Les analyses statistiques utilisant des tests de régression ont été effectuées pour déterminer l’association des variants génétiques avec la première dose de warfarine. Résultats : Nous avons identifié une association entre les polymorphismes des gènes CYP2C9 et VKORC1 et la dose de la warfarine. Les polymorphismes génétiques expliquent jusqu’à 42% de la variabilité de dose de la warfarine. Nous avons également démontré que certains polymorphismes génétiques expliquent la réduction de la dose de warfarine lorsque l’amiodarone est ajoutée à la warfarine. Conclusion : Les travaux effectués dans le cadre de ce mémoire ont permis de démontrer l’implication des gènes CYP2C9 et VKORC1 dans la réponse au traitement avec la warfarine et l’amiodarone. Les résultats obtenus permettent d’établir un profil personnalisé pour réduire les risques de toxicité, en permettant un dosage plus précis de la warfarine pour assurer un meilleur suivi des patients. Dans le futur, d’autres polymorphismes génétiques dans ces gènes pourraient être évalués pour optimiser davantage la personnalisation du traitement. / Background: Although the practice of the use of warfarin has improved during the last decade, no clear recommendation based on the determination of Amiodarone has been standardized until now, which is a major obstacle for clinicians. Warfarin has a narrow therapeutic index requiring regular monitoring and an individual dose ajustement, to this determines the therapeutic dose, while avoiding the side effects that could be fatal in some cases. The interindividual variability to the Warfarin depends on several factoring age, sex, weight, food and drug interactions but they only partially explain the differences in sensitivity to Warfarin. The polymorphisms of the genes CYP2C9 and VKORC1 play an important role in the response to the Warfarine and explain 50% of the variability of doses.The use of antiarrhythmic Amiodarone can greatly enhancethe effect of Warfain and generally requires a reduction of 30-50% of the dose of Warfarin. No study to date has attempted to determine the utility of genotyping polymorphisms of CYP2C9 and VKORC1 in patients on combination therapy of Warfarin and Amiodarone. Objectives: Our study aims to first determine if genetic factors influence the first dose stabilization of Warfarin in patients with AF after the introduction of Amiodarone. We will also attempt to confirm the previously reported between genetic association and the first dose of Warfarin stabilization in our study population. Methods: A retrospective cohort of all patients who frequent the clinic Warfarin of Montreal Heart Institute between 01/01/2007 and 02/30/2008 for the adjustment of their INR. The total of 1615 patients were recruited. The criteria for selection were patients with atrial fibrillation or flutter, with ECG documented with one of these tow diagnostic and younger than 67 years because of reduced morbidity. Patients with chronic liver disease were excluded from the study. All patients had to sign an informed consent for their participation in the project to which they contributed 15 ml of blood for genetic testing. Data collection was conducted from the patient's medical record of the Montreal Heart Institute. A data collection form was designed for this purpose and the data were then entered into a SQL database programmed by a computer expert in this field. Data validation was performed in several steps to minimize errors. Statistical analysis using regression tests were conducted to determine the association of genetic variants with the first dose of Warfarin. Results: We identified an association between polymorphisms of the genes CYP2C9 and VKORC1 and warfarin dose. Genetic polymorphisms to explain 42% of the variability in dose of Warfarin. We also demonstrated that genetic polymorphisms explain the reduction in the dose of Warfarin when Amiodarone is added to Warfarin. Conclusion: Our Work in the context of this thesis have shown the involvement of CYP2C9 and VKORC1 genes in response to treatment with Warfarin and Amiodarone. The results are used to create a personalized profile to reduce the risk of toxicity, enabling a more accurate dosing of warfarin for better monitoring of patients. In the future, other genetic polymorphisms in these genes could be evaluated to optimize the value of personalised therapy.

INTRODUÇÃO: A amiodarona pode causar tireotoxicose, principalmente em áreas geográficas onde a ingestão de iodo é insuficiente. Dois tipos distintos de tireotoxicose associada à amiodarona (TAA) podem ser encontrados: A) o tipo 1 - a doença é secundária à sobrecarga de iodo (fenômeno Jod-Basedow), geralmente encontrada em indivíduos com doença tireóidea preexistente, B) o tipo 2 - quando a tireotoxicose deve-se a uma tireoidite destrutiva, com ruptura folicular e liberação do conteúdo folicular. A distinção entre os dois tipos é fundamental para a conduta terapêutica. Este estudo transversal, realizado no Instituto de Radiologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo entre janeiro de 2004 a março de 2006, objetivou: A) Demonstrar a utilidade da densidade de pixéis coloridos (DPC), parâmetro objetivo obtido por meio de programa de computador, na distinção entre os dois tipos de TAA. B) Determinar os melhores critérios objetivos de distinção entre os dois tipos de TAA por meio da ultra-sonografia dúplex-Doppler colorido da tireóide. C) Conhecer o grau de concordância intra-observadores e interobservadores dos padrões subjetivos de vascularização do parênquima tireóideo. MÉTODOS: Foram examinadas 158 glândulas tireóideas por meio de dúplex-Doppler colorido. Após passagem pelos critérios de seleção, 137 indivíduos foram divididos em quatro grupos: Grupo N (n = 84), grupo A (n = 30), grupo I (n = 14) e grupo II (n = 9), compostos por indivíduos normais, eutireóideos em uso de amiodarona, pacientes com tireotoxicose tipos 1 e 2, respectivamente. Todos os indivíduos foram submetidos ao estudo dúplex-Doppler colorido da tireóide e testes laboratoriais. Os pacientes em tireotoxicose também realizaram captação de iodo radioativo em 24 horas. RESULTADOS: No grupo I, tanto a densidade de pixéis coloridos (DPC = 17,22 ± 20,81%) quanto as velocidades de pico sistólico nas artérias tireóideas superiores (VSTS = 38,54 ± 18,62 cm/s) e inferiores (VSTI = 35,35 ± 18,08 cm/s) foram maiores do que nos demais grupos (p < 0,05). As análises de concordância do padrão subjetivo de vascularização do parênquima tireóideo mostraram coeficientes kappa ponderado (kw) variando de 0,78 a 0,79 para intra-observadores e de 0,83 a 0,86 para interobservadores. CONCLUSÕES: A) A DPC tem, isoladamente, boa capacidade para distinguir os dois tipos de TAA. B) Os melhores critérios objetivos na distinção entre TAA tipos 1 e 2 são a DPC e as velocidades de pico sistólico nas artérias tireóideas. C) As análises subjetivas dos padrões de vascularização apresentam boa concordância tanto intra-observadores quanto interobservadores. / INTRODUCTION: Amiodarone can cause thyrotoxicosis, mainly in geographic insufficient iodine intake areas. Two different types of amiodarone-associated thyrotoxicosis can be found: A) type 1 - it occurs in patients with preexistent thyroid disease, such as goiter or autonomous nodule, and the iodine load associated with amiodarone triggers increased synthesis of thyroid hormones (Jod-Basedow fenomenon), B) type 2 - a destructive thyroiditis is found, characterized by follicular rupture and release of its content. In order to treat appropriately, the differentiation between the two types is crucial. This transversal study, carried through at the Institute of Radiology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo from January 2004 to March 2006, aimed to: A) demonstrate the utility of the color pixel density (CPD), a semiquantitative parameter gotten by means of computer program, in the differentiation between the two types of AAT, B) verify the best objective criteria of distinction between the two types of AAT through the duplex-Doppler sonography of the thyroid, C) investigate the agreement intra and interobservers of the subjective classification of the thyroid vascularization. METHODS: thyroid glands of 158 subjects were examined by means of duplex-Doppler sonography. After all the selection criteria, 137 individuals were selected into four groups; group N (n = 84), group A (n = 30), group I (n = 14) and II (n = 9), compounded of normal individuals, euthyroids in use of amiodarone, and patients with thyrotoxicosis types 1 and 2, respectively. All the individuals were submitted to perform the duplex-Doppler sonography of the thyroid and laboratorial tests. Also, the patients with thyrotoxicosis had also carried through 24 hour radioactive iodine uptake. RESULTS: In the group I, not only the color pixel density (CPD = 17.22 ± 20.81%) but also the values of systolic peak velocity in the superior and the inferior thyroid arteries (SPVS = 38.54 ± 18.62 cm/s and SPVI = 35.35 ± 18.08 cm/s) were greater than in the other groups (p < 0.05). The subjective agreement analysis of the vascularization patterns showed kappa weighted (kw) coefficients varying between 0.78 and 0.79 for intra-observer, and 0.83 and 0.86 for interobserver analyses. CONCLUSIONS: A) CPD is separately able to distinguish the two types of AAT. B) The best objective criteria in the distinction between AAT types 1 and 2 are the color pixel density CPD and the peak systolic velocity in the thyroid arteries. C) The subjective analyses of the vascularization pattern show good and very good intraobserver and interobserver agreements.

INTRODUÇÃO: A amiodarona pode causar tireotoxicose, principalmente em áreas geográficas onde a ingestão de iodo é insuficiente. Dois tipos distintos de tireotoxicose associada à amiodarona (TAA) podem ser encontrados: A) o tipo 1 - a doença é secundária à sobrecarga de iodo (fenômeno Jod-Basedow), geralmente encontrada em indivíduos com doença tireóidea preexistente, B) o tipo 2 - quando a tireotoxicose deve-se a uma tireoidite destrutiva, com ruptura folicular e liberação do conteúdo folicular. A distinção entre os dois tipos é fundamental para a conduta terapêutica. Este estudo transversal, realizado no Instituto de Radiologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo entre janeiro de 2004 a março de 2006, objetivou: A) Demonstrar a utilidade da densidade de pixéis coloridos (DPC), parâmetro objetivo obtido por meio de programa de computador, na distinção entre os dois tipos de TAA. B) Determinar os melhores critérios objetivos de distinção entre os dois tipos de TAA por meio da ultra-sonografia dúplex-Doppler colorido da tireóide. C) Conhecer o grau de concordância intra-observadores e interobservadores dos padrões subjetivos de vascularização do parênquima tireóideo. MÉTODOS: Foram examinadas 158 glândulas tireóideas por meio de dúplex-Doppler colorido. Após passagem pelos critérios de seleção, 137 indivíduos foram divididos em quatro grupos: Grupo N (n = 84), grupo A (n = 30), grupo I (n = 14) e grupo II (n = 9), compostos por indivíduos normais, eutireóideos em uso de amiodarona, pacientes com tireotoxicose tipos 1 e 2, respectivamente. Todos os indivíduos foram submetidos ao estudo dúplex-Doppler colorido da tireóide e testes laboratoriais. Os pacientes em tireotoxicose também realizaram captação de iodo radioativo em 24 horas. RESULTADOS: No grupo I, tanto a densidade de pixéis coloridos (DPC = 17,22 ± 20,81%) quanto as velocidades de pico sistólico nas artérias tireóideas superiores (VSTS = 38,54 ± 18,62 cm/s) e inferiores (VSTI = 35,35 ± 18,08 cm/s) foram maiores do que nos demais grupos (p < 0,05). As análises de concordância do padrão subjetivo de vascularização do parênquima tireóideo mostraram coeficientes kappa ponderado (kw) variando de 0,78 a 0,79 para intra-observadores e de 0,83 a 0,86 para interobservadores. CONCLUSÕES: A) A DPC tem, isoladamente, boa capacidade para distinguir os dois tipos de TAA. B) Os melhores critérios objetivos na distinção entre TAA tipos 1 e 2 são a DPC e as velocidades de pico sistólico nas artérias tireóideas. C) As análises subjetivas dos padrões de vascularização apresentam boa concordância tanto intra-observadores quanto interobservadores. / INTRODUCTION: Amiodarone can cause thyrotoxicosis, mainly in geographic insufficient iodine intake areas. Two different types of amiodarone-associated thyrotoxicosis can be found: A) type 1 - it occurs in patients with preexistent thyroid disease, such as goiter or autonomous nodule, and the iodine load associated with amiodarone triggers increased synthesis of thyroid hormones (Jod-Basedow fenomenon), B) type 2 - a destructive thyroiditis is found, characterized by follicular rupture and release of its content. In order to treat appropriately, the differentiation between the two types is crucial. This transversal study, carried through at the Institute of Radiology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo from January 2004 to March 2006, aimed to: A) demonstrate the utility of the color pixel density (CPD), a semiquantitative parameter gotten by means of computer program, in the differentiation between the two types of AAT, B) verify the best objective criteria of distinction between the two types of AAT through the duplex-Doppler sonography of the thyroid, C) investigate the agreement intra and interobservers of the subjective classification of the thyroid vascularization. METHODS: thyroid glands of 158 subjects were examined by means of duplex-Doppler sonography. After all the selection criteria, 137 individuals were selected into four groups; group N (n = 84), group A (n = 30), group I (n = 14) and II (n = 9), compounded of normal individuals, euthyroids in use of amiodarone, and patients with thyrotoxicosis types 1 and 2, respectively. All the individuals were submitted to perform the duplex-Doppler sonography of the thyroid and laboratorial tests. Also, the patients with thyrotoxicosis had also carried through 24 hour radioactive iodine uptake. RESULTS: In the group I, not only the color pixel density (CPD = 17.22 ± 20.81%) but also the values of systolic peak velocity in the superior and the inferior thyroid arteries (SPVS = 38.54 ± 18.62 cm/s and SPVI = 35.35 ± 18.08 cm/s) were greater than in the other groups (p < 0.05). The subjective agreement analysis of the vascularization patterns showed kappa weighted (kw) coefficients varying between 0.78 and 0.79 for intra-observer, and 0.83 and 0.86 for interobserver analyses. CONCLUSIONS: A) CPD is separately able to distinguish the two types of AAT. B) The best objective criteria in the distinction between AAT types 1 and 2 are the color pixel density CPD and the peak systolic velocity in the thyroid arteries. C) The subjective analyses of the vascularization pattern show good and very good intraobserver and interobserver agreements.

No description available.

Objectif: Déterminer si l’efficacité de l’amiodarone pour le maintien du rythme sinusal varie selon la fonction systolique ventriculaire gauche. Contexte: Malgré un profil de sécurité établi en insuffisance cardiaque, nous ignorons si l’efficacité de l’amiodarone et son impact sur différentes issues cardiovasculaires sont modulés par la fonction ventriculaire gauche. Méthode: Nous avons effectué une analyse combinée de 3307 patients (âgés de 68,0±0,9 ans ; 31,1% de femmes) recrutés dans les études AFFIRM et AF-CHF qui ont été randomisés au contrôle du rythme par l’amiodarone (N=1107) ou au contrôle de la fréquence cardiaque (N=2200). Résultats: Chez les patients sous amiodarone, la survie sans fibrillation auriculaire était de 84% et de 45% à 1 et 5 ans respectivement, sans égard à la fraction d’éjection ventriculaire gauche (P=0,8754, ajusté). De façon similaire, la proportion moyenne ajustée de temps en fibrillation auriculaire (15,0±1,8%) n’a pas été influencée par la fraction d’éjection (P=0,6094). Durant le suivi, 1963 patients (59,4%) ont requis au moins une hospitalisation, incluant 1401 (42,6%) patients hospitalisés pour cause cardiovasculaire. Les taux ajustés d’hospitalisation pour toutes causes et pour cause cardiovasculaire étaient similaires entre les patients sous amiodarone et ceux dans le groupe de contrôle de la fréquence dans l’ensemble de la population ainsi que dans les sous-groupes de patients avec et sans dysfonction ventriculaire gauche sévère. De façon similaire, les taux ajustés de mortalité globale et cardiovasculaire étaient similaires entre chez les patients sous amiodarone et ceux traités par le contrôle de la fréquence dans l’ensemble de la population ainsi que dans les sous-groupes de patients avec et sans dysfonction ventriculaire gauche sévère. Conclusions: L’efficacité de l’amiodarone pour le maintien du rythme sinusal n’est pas influencée par la fonction ventriculaire gauche. Le contrôle du rythme avec l’amiodarone s’associe à des taux de mortalité et d’hospitalisation comparables au contrôle de la fréquence à la fois chez les patients avec et sans dysfonction ventriculaire gauche sévère. / Objectives: To determine whether amiodarone’s efficacy in maintaining sinus rhythm varies according to left ventricular systolic function. Background: Despite amiodarone’s established safety profile in heart failure, it is unknown whether its impact on cardiovascular outcomes is modulated by ventricular function. Methods: We conducted a pooled analysis of 3307 patients (age 68.0±0.9 years; 31.1% female) enrolled in AFFIRM and AF-CHF trials who were randomized to rhythm control with amiodarone (N=1107) or rate control (N=2200). Results: In amiodarone-treated patients, freedom from recurrent atrial fibrillation was 84% and 45% at 1 and 5 years, respectively, with no differences according to left ventricular function (adjusted P=0.8754). Similarly, the adjusted mean proportion of time in atrial fibrillation (15.0±1.8%) did not vary according to ventricular function (P=0.6094). During follow-up, 1963 (59.4%) patients required at least one hospitalization, with 1401 (42.6%) patients hospitalized for a cardiovascular reason. Adjusted all-cause and cardiovascular hospitalization rates were similar with amiodarone versus rate control in the overall population and in subgroups of patients with and without severe left ventricular dysfunction. Similarly adjusted all-cause and cardiovascular mortality rates were similar with amiodarone versus rate control, overall and in subgroups of patients with and without severe left ventricular dysfunction. Conclusions: Amiodarone’s efficacy in maintaining sinus rhythm and reducing the burden of atrial fibrillation is similar in patients with and without left ventricular dysfunction. Rhythm control with amiodarone was associated with similar mortality and hospitalisation rates when compared to rate control in patients with and without severe left ventricular dysfunction.

Frequency of occurrence of selected single nucleotide polymorphisms of CYP2C8 and MDR1 in the Czech population and their influence on the effect of amiodarone Introduction: Variability in drug response is sometimes conditioned by genetic differences in the metabolism and the transport of drugs. Interindividual differences are often caused by polymorphisms affecting biotransformation activity of enzymes and expression of transporters. In the thesis we paid attention to the cytochrome P450 CYP2C8 and MDR1. First, we described the frequency of occurrence of selected variant alleles CYP2C8 * 2, CYP2C8 * 3 (2 substitution in exon 3 and 8, CYP2C8 and CYP2C8 * 3G416A * 3A1196G), CYP2C8 * 4, CYP2C8 P404A in the healthy Czech population and MDR1 variant alleles in these exons: 26 C3435T, 21 G2677A/T, 12 C1236T a 17 T-76A. Subsequently, we studied the influence of these polymorphisms on effects of amiodarone in the selected group of patients. Methods: We determined genotypes MDR1 a CYP2C8 by PCR-RFLP by using restriction enzymes and specific primers. We determined the frequency of MDR1 genotypes in 189 healthy volunteers and CYP2C8 in 161 healthy subjects. Further we included into the study 63 patients treated with amiodarone for longer than two months. Their treatment was assessed from medical records and...

No description available.

It is a major clinical problem that survival rates after out-of-hospital cardiac arrest have not markedly improved during the last decades, despite extensive research and the introduction of new interventions. However, recent studies have demonstrated promising treatments such as targeted temperature management (TTM) and methylene blue (MB). In our first study, we investigated the effect of MB administered during experi-mental cardiopulmonary resuscitation (CPR) in the setting of postponed hypother-mia in piglets. We set out to study if MB could compensate for a delay to establish targeted TTM. The study demonstrated that MB more than compensated for 30 min delay in induction of TTM. The effect of MB added to that of TTM. The second study examined the effects of TTM and S-PBN on the endothelin system and nitric oxide synthases (NOS) after prolonged CA in a porcine CPR mod-el. The study was designed to understand the cardioprotective mechanism of S-PBN and TTM by their influence on the endothelin system and NOS regulation. We veri-fied for the first time, that these two cardioprotective postresuscitative interventions activate endothelin-1 and its receptors concomitantly with eNOS and nNOS in the myocardium. We concluded that nitric oxide and endothelin pathways are implicated in the postresuscitative cardioprotective effects of TTM. The third study compared survival and hemodynamic effects of low-dose amio-darone and vasopressin to vasopressin in a porcine hypovolemic CA model. The study was designed to evaluate whether resuscitation with amiodarone and vasopressin compared to vasopressin alone would have an impact on resuscitation success, survival, and hemodynamic parameters after hemorrhagic CA. We found that combined resuscitation with amiodarone and vasopressin after hemorrhagic circulatory arrest resulted in greater 3-hour survival, better preserved hemodynamic parameters and smaller myocardial injury compared to resuscitation with vasopressin only. In our fourth study we planned to compare hemodynamic parameters between the treatment group (milrinone, esmolol and vasopressin; MEV) and control group (vasopressin only) during resuscitation from prolonged cardiac arrest in piglets. The study was designed to demonstrate if MEV treatment improved hemodynamics or cardiac damage compared to controls. We demonstrated that MEV treatment reduced cardiac injury compared with vasopressin alone.