Understanding the processes that govern pre-systemic drug absorption and elimination is of high importance in pharmaceutical research and development, and clinical pharmacotherapy, as the oral route remains the most frequently used route of drug administration. The emergence of systems pharmacology has enabled the utilisation of in silico physiologically-based pharmacokinetic (PBPK) modelling and simulation (M&S) coupled to in vitro-in vivo extrapolation in order to perform extrapolation and exploratory M&S in special populations and scenarios were concerns regarding alterations in oral drug exposure may arise, such as following gastrointestinal (GI) surgery or metabolic drug-drug interactions (DDIs).Due to the multi-factorial physiological implications of bariatric surgery, resulting in the partial resection of the GI tract, the inability to rationalise and predict trends in oral drug bioavailability (Foral) following surgery present considerable pharmacotherapeutical challenges. PBPK M&S is a highly implemented approach for the prediction of DDIs. Reoccurring issues have emerged with regards to predictions of the magnitude of mechanism-based inhibition (MBI) where overestimations of DDIs have repeatedly been reported for drugs exhibiting high intestinal extraction. The aim of this thesis was to explore the interplay between oral drug absorption and metabolism occurring in the GI tract through the exploration of the impact of bariatric surgery on oral drug exposure and by theoretically examining the nesting and hierarchy of enterocyte and enzyme turnover and its impact on MBIs in the small intestine. This would be carried out by utilising a systems pharmacology PBPK M&S approach under a general model development framework of identification and characterisation of critical intrinsic factors and parameters, model implementation and validation. Developed post bariatric surgery PBPK models allow a framework to theoretically explore physiological mechanisms associated with altered oral drug exposure pre to post surgery, which could be assigned to the interplay between dissolution, absorption and gut-wall metabolism, where dissolution and formulation properties emerged as the perhaps most important parameters in predicting the drug disposition following surgery. Model validation identified missing critical factors that are essential for additional model refinement. Developed post bariatric surgery PBPK models have the potential of aiding clinical pharmacotherapy and decision-making following surgery. A mechanistic PBPK model was developed to describe the hierarchical dependency of enzyme and enterocyte turnover in the small intestine. Predicted enzyme recovery using the nested enzyme-within-enterocyte turnover model may potentially account for reported overpredictions of mechanism-based inhibition. Developed models in this thesis showcase the advantage of PBPK M&S in the extrapolation of oral drug exposure to special population and the potential of a PBPK approach in understanding underlying the underlying mechanism governing Foral and additionally highlight the need for generation of interdisciplinary data to support model development.

Introdução: A derivação gástrica em Y-de-Roux (DGYR) é um dos procedimentos bariátricos mais realizados em todo o mundo. Apesar de sua alta eficácia, significativa proporção de pacientes recupera parte do peso perdido. Várias terapias endoscópicas foram introduzidas como alternativas para tratar o reganho de peso, mas a maioria dos artigos publicados tem amostra relativamente pequena, com dados pouco claros e de curto prazo. Objetivo: Avaliar sistematicamente a eficácia das terapias endoscópicas para reganho de peso pós-DGYR. Métodos: Foram realizadas buscas nas bases MEDLINE, EMBASE, Scopus, Web of Science, Cochrane, OVID, CINAHL/EBSCo, LILACS/Bireme e literatura cinzenta. Os desfechos primários avaliados foram perda absoluta de peso (PAP), perda de excesso de peso (PEP) e perda total de peso corporal (PPTP). Resultados: Trinta e dois estudos foram incluídos na análise qualitativa. Vinte e seis trabalhos envolvendo 1148 pacientes descreveram sutura endoscópica de espessura total (SET) e PAP, PEP e PPTP em 3 meses foram 8,5±2,9kg, 21,6±9,3% e 7,3±2,6%, respectivamente. Aos 6 meses, foram de 8,6±3,5kg, 23,7±12,3% e 8,0±3,9%. Aos 12 meses, 7,63±4,3kg, 16,9±11,1% e 6,6±5,0%. A análise de subgrupos mostrou melhores resultados no subgrupo submetido à coagulação com plasma de argônio (APC) prévio à SET (p < 0,0001). A metanálise incluindo 15 desses estudos mostrou resultados concordantes e confirmou a superioridade estatística da SET+APC em comparação à SET isolada. Três estudos descreveram sutura de espessura superficial (SEP) com PAP média de 3,0±3,8kg, 4,4±0,07kg e 3,7±7,4 kg em 3, 6 e 12 meses, respectivamente. No seguimento de curto, médio e longo prazo, a SET proporcionou resultados superiores em relação à SEP (p < 0,05). Dois artigos descreveram APC isolada com PAP média de 15,4±2,0 kg e 15,4±9,1kg em 3 e 6 meses. Nenhum estudo relatando escleroterapia satisfez os critérios de elegibilidade. Conclusões: A sutura de espessura total é efetiva no tratamento do reganho de peso pós-DGYR. A realização de APC antes da sutura parece resultar em maior perda de peso. Estudos comparativos são necessários para confirmar nossos resultados. A sutura de espessura total relaciona-se com melhores resultados em comparação à sutura de espessura superficial. Poucos estudos avaliam adequadamente a eficácia de outras técnicas endoscópicas / Introduction: Roux-en-Y Gastric Bypass (RYGB) is the most commonly performed bariatric procedure. Despite its high efficacy, some patients regain part of their lost weight. Several endoscopic therapies have been introduced as alternatives to treat weight regain but most of the articles are relatively small with unclear long-term data. Aim: To systematically assess the efficacy of endoscopic therapies for weight regain after RYGB. Methods: We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane, OVID, CINAHL/EBSCo, LILACS/Bireme and gray literature. Primary outcomes were absolute weight loss (AWL), excess weight loss (EWL) and total body weight loss (TBWL). Results: Thirty-two studies were included in qualitative analysis. Twenty-six articles enrolling 1148 patients described fullthickness (FT) endoscopic suturing and pooled AWL, EWL and TBWL at 3 months were 8.5±2.9kgs, 21.6±9.3% and 7.3±2.6%, respectively. At 6 months, they were 8.6±3.5kg, 23.7±12.3% and 8.0±3.9%. At 12 months, they were 7.63±4.3kg, 16.9±11.1% and 6.6±5.0%. Subgroup analysis showed that all outcomes were significantly higher in the group with FT suturing combined with argon plasma coagulation (APC) (p < 0.0001). Meta-analysis including 15 FT studies showed greater results and confirmed the significant superiority of FT-APC compared to FT alone. Three studies described superficial-thickness suturing with pooled AWL of 3.0±3.8kg, 4.4±0.07kg and 3.7±7.4kg at 3, 6 and 12 months, respectively. At short, mid and long-term follow-up, FT suturing provided better outcomes compared to ST (p < 0.05). Two articles described APC alone with mean AWL of 15.4±2.0kg and 15.4±9.1kg at 3 and 6 months. No study describing sclerotherapy fulfilled eligibility criteria. Conclusions: Full-thickness suturing is effective at treating weight regain after RYGB. Performing APC prior to suturing seems to result in greater weight loss. Head-to-head studies are needed to confirm our results. Full-thickness suturing lead to greater outcomes compared to superficial thickness suturing. Few studies adequately assess effectiveness of other endoscopic techniques

1) INTRODUCTION: Obesity is a global problem and its the prevalence is constantly rising. Overweight and obesity are key risk factors for many diseases. Obese patients are a greater economic burden for the state, they often rely on the help of others. The goal of obesity treatment is to reduce weight and then keep it within the recommended range. In an obese patient, it is not always just about the actual weight loss, but also about treating the associated diseases caused by obesity. Bariatric surgery allows patients to lose weight in a relatively short period of time and has a very positive effect on associated diseases. 2) OBJECTIVE: The aim of this diploma thesis was to evaluate the physical and mental condition before and after gastric bypass and to determine whether this surgery has a positive or negative effect on the physical and mental condition of the patient. The objective was further divided into sub-goals and hypotheses. 3) METHODOLOGY: The research was carried out using a quantitative method. This is an observational study, in which the mental and physical condition and advancement of patients who were about to undergo bariatric surgery - gastric bypass - were monitored for 6 months. Mental status was monitored using four standardized questionnaires: MAF, HADS, iADL, SF-36 in four time...

INTRODUCTION TO THE ISSUE: Obesity together with possible occurrence of many difficulties carries with it negative effect on physical and mental health. Many patients with severe obesity (class 3) cannot do physical activities or usual daily activities. These patients suffer from feelings of inferiority, decreased self-esteem and other mental issues. It could be classified as a vicious cycle for patients, but the bariatric surgery offers a way out. A gastric bypass is one of the bariatric procedures which is very helpful to reduce the weight of the patients who belongs into class 3 obesity. OBJECTIVES, METHODOLOGY: The main goal of this study was to find out if applying the gastric bypass to patients has positive or negative effect for their obesity level, quality of life, physical and mental state. The research sample was consisted of patients who were about to undergo gastric bypass. The patient's weight, BMI and body fat ratio were monitored to obtain data related to the assessment of the severity of obesity. The quality of life was evaluated using the SF-36 questionnaire (Short form 36). The standardized MAF (Multidimensional Assessment of Fatigue Scale) was used to review of patient's fatigue. The mental state of patients was subjectively assessed using the standardized HADS scale (Hospital...

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<p>Background: The objective of this thesis was to examine the role of psychosocial factors in weight loss success after bariatric surgery. It was proposed that a higher pre-operative body mass index (BMI), greater weight, depression, low self-esteem, and a childhood history of sexual abuse (CSA) would predict poor outcomes one year after Roux-en-y gastric bypass as evidenced by a BMI > 35 kg/m²and a lower percent total weight loss (%TWL). Methods: We administered a battery of psychological screening tools, including the Beck Depression Inventory-II, the Rosenberg Self-Esteem Scale and a self-report measure assessing CSA, to 262 patients seeking bariatric surgery at St. Joseph's Healthcare Hamilton. Patients completed the questionnaires prior to surgery and again one year post-surgery. Results: On average patients (n = 79) achieved good weight loss outcomes (BMI = 32.8 kg/m²) at one-year follow-up. Through multiple regression analysis we found that pre-operative BMI accounted for a significant proportion of variance in postoperative BMI [<em>R²</em> = .60, <em>F</em>(1, 77) = 114.4, <em>p</em> < .001]. Weight before surgery, however, did not predict %TWL after surgery. None of the psychosocial variables significantly predicted post-operative BMI or weight loss. These results are preliminary and are limited by the fact that participants did not present with clinically significant symptomatology and those with active psychopathology were excluded as suitable surgical candidates. Conclusion: These findings indicate that pre-operative BMI is a significant predictor of BMI one year after bariatric surgery, suggesting that more attention should be directed toward managing pre-operative BMI for heavier patients.</p> / Master of Science (MSc)

Introduction: Obesity is frequently associated with its hepatic manifestation, the nonalcoholic fatty liver disease (NAFLD). The most effective treatment for morbid obesity is bariatric surgery (BS) also improving NAFLD and liver function. In patients where NAFLD has already progressed to liver cirrhosis, BS can be considered a high-risk procedure. Hence, consideration of the procedure and the most appropriate timing is crucial. Material and Methods: Obese patients suffering from NAFLD who underwent BS from two German University Medical Centers were retrospectively analyzed. Results: Twenty-seven patients underwent BS. Most common procedures were laparoscopic Roux-en-Y-gastric (RYGB) and laparoscopic sleeve gastrectomy (SG). All patients suffered from liver cirrhosis Child A. A preoperative transjugular portosystemic shunt (TIPS) was established in three patients and failed in another patient. Postoperative complications consisted of wound healing disorders (n = 2), anastomotic bleeding (n = 1), and leak from the staple line (n = 1). This patient suffered from intraoperatively detected macroscopic liver cirrhosis. Excess weight loss was 73% and 85% after 1 and 2 years, respectively. Two patients suffered from postoperative aggravation of their liver function, resulting in a higher Child–Pugh score, while three could be removed from the waiting list for a liver transplantation. Conclusion: BS leads to weight loss, both after SG and RYGB, and potential improvement of liver function in liver cirrhosis. These patients need to be considered with care when evaluated for BS. Preoperative TIPS implantation may reduce the perioperative risk in selected patients.

Obesity has grown to epidemic proportions, and in lack of efficient life-style and medical treatments, the bariatric surgeries are performed in rising numbers. The most common surgery is the Gastric Bypass (GBP) surgery, with the Biliopancreatic diversion with duodenal switch (DS) as an option for the most extreme cases with a BMI&gt;50 kg/m2. In paper I 20 GBP-patients were examined during the first post-operative year regarding the natriuretic peptide, NT-ProBNP, which is secreted from the cardiac ventricles. Levels of NT-ProBNP quickly increased during the first post-surgery week, and later established itself on a higher level than pre-surgery. In paper II we report of 5 patient-cases after GBP-surgery with severe problems with postprandial hypoglycaemia that were successfully treated with GLP-1-analogs. The effect of treatment could be observed both symptomatically and in some cases using continuous glucose measuring systems (CGMS). In paper III three groups of subjects; 15 post-GBP patients, 15 post-DS, and 15 obese controls were examined for three days using CGMS during everyday life. The post-GBP group had high glucose variability as measured by MAGE and CONGA, whereas the post-DS group had low variability. Both post-operative groups exhibited significant time in hypoglycaemia, about 40 and 80 minutes per day &lt;3.3mmol/l and 20 and 40 minutes &lt; 2.8mmol/l, respectively, longer time for DS-group. Remarkably, only about 20% of these hypoglycaemic episodes were accompanied with symptoms. In Paper IV the hypoglycaemia counter regulatory system was investigated; 12 patients were examined before and after GBP-surgery with a stepped hypoglycaemic hyperinsulinemic clamp. The results show a downregulation of symptoms, counter regulatory hormones (glucagon, cortisol, epinephrine, norepinephrine, growth hormone), incretin hormones (GLP-1 and GIP), and sympathetic nervous response. In conclusion patients post bariatric surgery exhibit a downregulated counter regulatory response to hypoglycaemia, accompanied by frequent asymptomatic hypoglycaemic episodes in everyday life. Patients suffering from severe hypoglycaemic episodes can often be treated successfully with GLP-1-analogues.