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Study of intestinal transporters and their role in drug absorption
Huličiak, Martin ; Červený, Lukáš (advisor) ; Mladěnka, Přemysl (referee) ; Chládek, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Kralove Training Workplace Department of Pharmacology and Toxicology Doctoral Degree Program Pharmacology and Toxicology Candidate Mgr. Martin Huliciak Supervisor Assoc. Prof. PharmDr. Lukas Cerveny, PhD. Advisor PharmDr. Ivan Vokral, PhD. Title of Doctoral Thesis Study of intestinal transporters and their role in drug absorption Oral drug administration is a widely accepted method due to its convenience and cost- effectiveness, with the small intestine playing a crucial role in drug absorption, thus affecting bioavailability and serving as a potential site for drug-drug interactions (DDIs). Efflux drug transporters such as P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), along with metabolizing enzymes such as cytochrome P450 3A4 (CYP3A4) at the intestinal barrier, significantly contribute to DDIs. Risk factors for DDIs include comorbidities, advanced age, and polypharmacotherapy. People living with HIV requiring antiretroviral therapy (ART) are particularly susceptible to DDIs, especially when co-infected with HCV. Antivirals, commonly used in ART and in the treatment of HCV infection, can interact with efflux transporters and CYP enzymes, affecting drug efficacy and safety. Therefore, this study mainly focuses on the DDIs of...
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Study of the vasodilatory effect of tamarixetin in an ex vivo porcine coronary vessel model
Gaidosová, Barbora ; Pourová, Jana (advisor) ; Smutný, Tomáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Barbora Gaidosová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Study of the vasodilatory effect of tamarixetin in an ex vivo porcine coronary vessel model. Flavonoids, as one of the most common herbal substances, are known for their beneficial effects on the human organism and in particular on the cardiovascular system. The aim of this thesis was to screen ten substances contained in hawthorn for vasodilatory effects, select the most active one, and subsequently verify mechanism(s) of its vasodilatory action. The experiments were conducted on an ex vivo vascular model using the pig coronary artery. In screening, the tested substance was always cumulatively added to the precontracted arterial rings at increasing concentrations while monitoring the vasodilatation. Vasoactive inhibitors or agonists of several vasodilatory pathways were used for verification of possible mechanism(s) of action. The results showed that the most active vasodilatory substance was tamarixetine with an EC50 of 47.8 µmol.l-1 . The detail mode of action has not been discovered however tamarixetine has been shown to influence the voltage dependent calcium channels of L-type on the vascular smooth...
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Vasodilatory effects of 3-hydroxy phenylacetic acid: ex vivo mechanism of action
Štefancová, Monika ; Pourová, Jana (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Monika Štefancová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Vasodilatory effects of 3-hydroxy phenylacetic acid: ex vivo mechanism of action It is known from clinical studies that the intake of polyphenols from food acts as a prevention of cardiovascular diseases. However, the parent compounds themselves often have low bioavailability. The emphasis is therefore on their bioactive metabolites. 3-hydroxy phenylacetic acid (3-HPAA) is among such metabolites. The aim of this study was to verify the mechanism of the vasodilatory effect of 3-HPAA using standardized ex vivo method on an isolated pig coronary artery. The administration of 3-HPAA resulted in relaxation of maximally contracted segments of porcine artery by mechanism partially dependent on the integrity of endothelium. By inhibiting endothelial nitric oxide synthase, the relaxation was significantly impaired. The blockage of SKCa and IKCa channels, muscarinic receptors, cyclooxygenase or L-type calcium channels did not affect relaxation. Thus, 3-HPPA causes dose-dependent vasodilatation of coronary arteries ex vivo at least partially mediated by endothelium with the participation of nitric oxide. Key words:...
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Vasodilatory effects of 4-methyl catechol: ex vivo mechanism of action
Kuzdřalová, Kateřina ; Pourová, Jana (advisor) ; Smutná, Lucie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Kateřina Kuzdřalová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: The mechanism of vasodilation effect of 4-methylcatechol ex vivo Keywords: rat, aorta, flavonoids, 4-methylcatechol, vascular smooth muscle, vasodilation Flavonoids belong to the group of polyphenolic bioactive substances found abundantly in plants, fruits and vegetables. Thanks to their pharmacological and biochemical effects, they play a crucial role for human health, especially in the prevention of numerous diseases - metabolic syndrome, osteoporosis, atherosclerosis and also diseases of a cardiovascular system. The aim of the diploma thesis was to determine the mechanism of the vasorelaxant effect of one of the most important metabolites of flavonoids - 4-methylcatechol. For the research we used a standardized ex vivo method on isolated Wistar rat aortic rings. We were able to confirm the vasodilatory effects of 4-methylcatechol. We also confirmed the fact that the flavonoid metabolite directly affects a vascular smooth muscle. Furthermore, we found that the tested compound potentiates the vasodilatory activity of sodium nitroprusside and forskolin, and that vasodilation depends on the activity of...
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Vasodilatory effects of 3-hydroxy phenylacetic acid: ex vivo mechanism of action
Štefancová, Monika ; Pourová, Jana (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Monika Štefancová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Vasodilatory effects of 3-hydroxy phenylacetic acid: ex vivo mechanism of action It is known from clinical studies that the intake of polyphenols from food acts as a prevention of cardiovascular diseases. However, the parent compounds themselves often have low bioavailability. The emphasis is therefore on their bioactive metabolites. 3-hydroxy phenylacetic acid (3-HPAA) is among such metabolites. The aim of this study was to verify the mechanism of the vasodilatory effect of 3-HPAA using standardized ex vivo method on an isolated pig coronary artery. The administration of 3-HPAA resulted in relaxation of maximally contracted segments of porcine artery by mechanism partially dependent on the integrity of endothelium. By inhibiting endothelial nitric oxide synthase, the relaxation was significantly impaired. The blockage of SKCa and IKCa channels, muscarinic receptors, cyclooxygenase or L-type calcium channels did not affect relaxation. Thus, 3-HPPA causes dose-dependent vasodilatation of coronary arteries ex vivo at least partially mediated by endothelium with the participation of nitric oxide. Key words:...
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Vasodilatory effects of 4-methyl catechol: ex vivo mechanism of action
Kuzdřalová, Kateřina ; Pourová, Jana (advisor) ; Smutná, Lucie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Kateřina Kuzdřalová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: The mechanism of vasodilation effect of 4-methylcatechol ex vivo Keywords: rat, aorta, flavonoids, 4-methylcatechol, vascular smooth muscle, vasodilation Flavonoids belong to the group of polyphenolic bioactive substances found abundantly in plants, fruits and vegetables. Thanks to their pharmacological and biochemical effects, they play a crucial role for human health, especially in the prevention of numerous diseases - metabolic syndrome, osteoporosis, atherosclerosis and also diseases of a cardiovascular system. The aim of the diploma thesis was to determine the mechanism of the vasorelaxant effect of one of the most important metabolites of flavonoids - 4-methylcatechol. For the research we used a standardized ex vivo method on isolated Wistar rat aortic rings. We were able to confirm the vasodilatory effects of 4-methylcatechol. We also confirmed the fact that the flavonoid metabolite directly affects a vascular smooth muscle. Furthermore, we found that the tested compound potentiates the vasodilatory activity of sodium nitroprusside and forskolin, and that vasodilation depends on the activity of...
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Vasodilatory effects of catechol derivatives ex vivo
Šmídová, Kristýna ; Pourová, Jana (advisor) ; Carazo Fernández, Alejandro (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Kristýna Šmídová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Vasodilatory effects of catechol derivatives ex vivo Polyphenols, including flavonoids, are a broad group of natural substances with significant effects on human health, including the prevention of cardiovascular diseases. Their metabolites can also be active, with clinical effects which may even exceed those of the parent compounds. The aim of this diploma thesis was to verify vasodilatory effects of one flavonoid metabolite type, a series of catechol derivatives and elucidate the mechanism of action of the most potent substance. The established ex vivo method of isolated aortic rings of Wistar rats with isotonic registration of tissue contraction and dilation (software S.P.E.L. Advanced Kymograph Software) was used. In the experiments with the rat aorta precontracted by norepinephrin, 3-methoxycatechol was the most effective vasodilator (EC50 = 7,6 µmol.l-1). In the mechanistic study, we found out that its effect is endothelium-independent, and that 3-methoxycatechol enhances the vasodilatory effect of sodium nitropruside. However, the specific mechanism responsible for vasodilation was not identified and...
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Vasodilatory effects of catechol derivatives ex vivo
Šmídová, Kristýna ; Pourová, Jana (advisor) ; Carazo Fernández, Alejandro (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Kristýna Šmídová Supervisor: doc. PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Vasodilatory effects of catechol derivatives ex vivo Polyphenols, including flavonoids, are a broad group of natural substances with significant effects on human health, including the prevention of cardiovascular diseases. Their metabolites can also be active, with clinical effects which may even exceed those of the parent compounds. The aim of this diploma thesis was to verify vasodilatory effects of one flavonoid metabolite type, a series of catechol derivatives and elucidate the mechanism of action of the most potent substance. The established ex vivo method of isolated aortic rings of Wistar rats with isotonic registration of tissue contraction and dilation (software S.P.E.L. Advanced Kymograph Software) was used. In the experiments with the rat aorta precontracted by norepinephrin, 3-methoxycatechol was the most effective vasodilator (EC50 = 7,6 µmol.l-1). In the mechanistic study, we found out that its effect is endothelium-independent, and that 3-methoxycatechol enhances the vasodilatory effect of sodium nitropruside. However, the specific mechanism responsible for vasodilation was not identified and...
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The in vitro effects of selected fenolic substances on isolated rat vessels
Rajtmajerová, Iveta ; Pourová, Jana (advisor) ; Hrdina, Radomír (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Iveta Rajtmajerová Supervisor: PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: The in vitro effects of selected fenolic substances on isolated rat vessels Silymarin flavonolignans are endowed with various aspects. Recently their hepatoprotective effect has been discussed widely as well as their positive influence on the cardiovascular system. This diploma thesis is concerned with the vasodilatory effects of silybin-A, silybin-B, silybin-A + B and isosilybin-A on rat aorta. The aim of this study was to test the vasodilatory effect of selected substances. The dependence of aortic relaxation on the increasing concentration of tested substances was measured. Isolated Wistar breed rat aorta was used. DRC curves were created and EC50 values were assessed from the obtained values of vessel tension. The results were evaluated subsequently. The vasodilator potential of silybin-A and isosilybin-A is comparable; hence the position of the substituents may be irrelevant in having any impact on relaxation of the vessels. Different vasodilatory effects of silybin-A and silybin-B have been observed thus, the relaxation could be stereoselective. The testing of the equimolar mixture of silybin-A and...
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Vasodilatory effects of bisphenol AF ex vivo
Kuchařová, Nela ; Pourová, Jana (advisor) ; Vopršalová, Marie (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Nela Kuchařová Supervisor: PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Vasodilatory effects of bisphenol AF ex vivo Bisphenols are organic compounds used in the manufacture of plastics, resins, varnishes and lot of other products. However, their effects on human body are associated with a number of adverse effect that need to be investigated in more detail. The aim of this diploma thesis was to determine whether bisphenol AF has vasodilating effects ex vivo and to verify the mechanism of the relaxing effect. The experiments were performed on an isolated thoracic aorta of a Wistar rat. Bisphenol AF was added cumulatively to the precontracted aorta at increasing concentrations and we monitored whether vasodilation was induced. In testing the mechanism of action, we used inhibitors of the mechanisms tested during the experiment. The obtained results were evaluated using the GraphPad Prism program. The results show that bisphenol AF has a dose-dependent ex vivo vasodilatory effect (EC50 = 57.16 μmol/l). The mechanism of this effect is the blockage of voltagegated calcium channels on the vascular smooth muscle cell. The participation of other tested mechanisms has not been confirmed. Key...
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