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Clinical and genetic predictors of drug dependency in inflammatory bowel disease
Ďuricová, Dana ; Lukáš, Milan (advisor) ; Keil, Radan (referee) ; Špičák, Julius (referee)
IN ENGLISH Drug dependency in inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), is a specific disease phenotype which determines disease prognosis and hence may be used as a prognostic marker for treatment management. Drug dependency in IBD has been well described in corticosteroid treatment and recently also in infliximab (IFX) therapy. The aims of this thesis were: 1) to assess the occurrence of IFX dependency in paediatric and adult patients with CD; further to search for clinical and genetic predictors of IFX outcome and to evaluate the impact of IFX dependency on surgical rate; 2) to assess in CD patients the outcome of the first course of 5-ASA monotherapy with emphasis on 5-ASA dependency and to define clinical predictors of 5-ASA treatment outcome. We found that 66% of children and 29% of adults with CD became IFX dependent. The high frequency in paediatrics is in agreement with previously published studies, while the finding in adult patients indicates a lower rate of IFX dependency in the only study to date. Perianal disease and no bowel surgery prior to IFX start were predicative of IFX dependency in paediatric patients. In adult cohort, 2 genetic variants LTA c.207 A>G and CASP9 c.93 C>T were associated with IFX outcome, whereas no relevant clinical...
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název v anglickém jazyce není uveden
Koubíková, Petra ; Lukáš, Milan (advisor) ; Zbořil, Vladimír (referee) ; Konečný, Michal (referee)
Background: Thioguanine derivatives, azathioprine (AZA) and 6-mercaptopurine (6-MP), have been used for many years in the treatment of inflammatory bowel disease (IBD). They represent major drugs in therapy of steroid-dependent and chronic active IBD. In 20-35% of the patients administration of AZA or 6-MP does not lead to improvement of the disease. Another limitation is the occurrence of adverse events of the therapy which can be observed in 10-15% of the patients. The metabolism of AZA/6-MP is influenced by thiopurine methyl transferase (TPMT). Since there is a significant variability in the activity of TPMP, there is an idea that monitoring the enzyme activity or the genotyping can significantly minimize the toxicity. Several studies have analysed correlation between the levels of AZA/6-MP and the efficacy or toxicity. The cut-off level corresponds to 230-250 pmol/8x108 RBC. High concentrations are linked with a risk of myelotoxicity. The occurrence of hepatotoxicity is dependent on the concentration of 6-methylmercaptopurine (6-MMP) in the erythrocytes. 6-thioguanine (6-TG) has been studied as an alternative therapy in patients with inflammatory bowel disease, who are resistant or intolerant to AZA/6-MP.The administration of 6-TG is effective in approximately 60% of patients. However, 6-TG...
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Carcinogenesis of colorectal cancer and cancer associated with inflammatory bowel diseases: theoretical basis and its implications for clinical practice
Bortlík, Martin ; Lukáš, Milan (advisor) ; Zavoral, Miroslav (referee) ; Dítě, Petr (referee)
Colorectal cancer originates as a consequence of accumulating genetic changes and sequential conversion from normal epithelium through dysplastic, intraepithelial neoplasia. It is called an adenoma in subjects with sporadic cancer and dysplasia in those with ulcerative colitis. An inactivation of the APC gene in former and p53 gene in the later group was found to be an initial genetic event in most cases. However, in case of sporadic adenoma, some data indicate the possibility that mutation of only one APC allele occurs early at the stage of adenoma, while the loss of the second allele may occur later, at the time of adenoma to carcinoma progression. Epigenetic changes, namely hypermethylation of the gene promoter, play an important role during carcinogenesis of both sporadic and UC related types of neoplasia. Recent epidemiologic studies suggest the relative risk for UC associated colorectal cancer varies between 2-3. Besides risk factors already recognized, i.e. disease extension and duration, and coincidental primary sclerosing cholangitis, the severity of inflammation and presence of structural changes in the bowel substantially affect the risk for neoplastic conversion. Using the current technique, most dysplastic lesions in IBD patients are nowadays detectable endoscopically. Also, their endoscopic...
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Genetic variability of drug metabolizing enzymes
Slanař, Ondřej ; Perlík, František (advisor) ; Průša, Richard (referee) ; Lukáš, Milan (referee)
Drug metabolism is one of the key processes allowing to eliminate the administered dose. High interindividual variability of the activity of drug metabolizing enzymes is caused by many genetic and epigenetic factors. This variation can result in substantial differences in clinical response to the drug, ranging from failure of the therapy to appearance of toxic side effects or frequent onset of drug-drug interactions. The aim of the thesis was to evaluate the influence of genetically determined variability in drug metabolizing enzymes activity on the drug pharmacokinetics, pharmacodynemics and to asses whether either phenotyping or genotyping can be effectively applied under the naturalistic conditions of routine clinical practice, for e.g. as a prediction tool during to asses individual risk of development and progress of a disease or to forecast the drug response. The thesis mainly summarizes previously published articles on the topic. We have studied genetically determined variability of tramadol pharmacokinetics as well as drug-induced miosis in healthy volunteers with known CYP2D6 status. The lowest blood concentrations of principal active metabolite O-demethyltramadol accompanied by the highest levels of the parent compound at all sampling intervals up to 12 hours post-dose were found in the...
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