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Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts
Gala, Viktor ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Viktor Gala Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts The nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC) is now the mainstay of combination antiretroviral therapy (cART) for HIV in pregnant women. The introduction of cART, along with several other measures, has reduced mother-to-fetus transmission of HIV to less than 1% in recent years. The placenta is a key organ for the health of both the fetus and the mother. Imbalances in placental development can result in adaptive changes and fetal programming errors. cART recommended in pregnancy is known for its good safety profile, but some epidemiological studies suggest a higher risk of reduced fetal weight, preterm birth, etc. The placenta is a rapidly growing organ dependent on the supply of building materials that resembles tumor growth in certain aspects. Nucleosides are promoters of tumor proliferation and are involved in the development of immunotolerance. The placenta is complexly equipped for nucleoside synthesis, uptake,...
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Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts
Gala, Viktor ; Červený, Lukáš (advisor) ; Čečková, Martina (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Viktor Gala Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: Effect of abacavir on the expression of nucleoside transporters, adenosine receptors, and enzymes involved in adenosine synthesis and biodegradation in trophoblasts The nucleoside reverse transcriptase inhibitor (NRTI) abacavir (ABC) is now the mainstay of combination antiretroviral therapy (cART) for HIV in pregnant women. The introduction of cART, along with several other measures, has reduced mother-to-fetus transmission of HIV to less than 1% in recent years. The placenta is a key organ for the health of both the fetus and the mother. Imbalances in placental development can result in adaptive changes and fetal programming errors. cART recommended in pregnancy is known for its good safety profile, but some epidemiological studies suggest a higher risk of reduced fetal weight, preterm birth, etc. The placenta is a rapidly growing organ dependent on the supply of building materials that resembles tumor growth in certain aspects. Nucleosides are promoters of tumor proliferation and are involved in the development of immunotolerance. The placenta is complexly equipped for nucleoside synthesis, uptake,...
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Study of degradation behavior of abacavir using a diamond film electrode
Pražáková, Lucie ; Kubíčková, Anna (advisor) ; Kozlík, Petr (referee)
In this work the electrochemical degradation behavior of the drug abacavir is studied with the use of boron-doped diamond electrode. Oxidative degradation of the active substance abacavir, used to treat patients with HIV disease, was studied in a batch of three-electrode and two-electrode settings. In this work, the characteristics of five working boron-doped diamond electrodes, differing in a boron/carbon doping ratio of 500 ppm, 1000 ppm, 2000 ppm, 4000 ppm and 8000 ppm, were studied. The degradation in the three-electrode arrangement took place under potenciostatic electrolysis at potentials from 0,6 V to 2,0 V. The degradation in the two-electrode arrangement took place under conditions of potenciostatic electrolysis at higher potentials from 2,0 to 4,5 V. Optimal degradation, to the required values up to 25 %, was achieved at a potential of 3,5 V for an oxidation time of 10 minutes on a boron-doped diamond electrode with a boron/carbon doping ratio of 500 ppm and 1000 ppm. Separation and determination of abacavir and its degradation products were performed by ultra-high performance liquid chromatography with a mass detector. The degradation of abacavir produced two known degradation products, DP1 with relative retention times of 0,40 and DP2 with relative retention times of 0,45. The...
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In vitro and ex vivo study of drug-drug interactions of antiretrovirals on intestinal ATP-binding drug transporters
Jahodová, Michaela ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Bc. Michaela Jahodová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: In vitro and ex vivo study of drug-drug interactions of antiretrovirals on intestinal ATP-binding drug transporters The absorption of orally administered drugs takes place especially in the intestine, where it can affect by the activity of drug's ABC transporters located on the apical membrane of the intestinal epithelium. Study of drug interactions in intestinal ABC transporters is essential to ensure effective and safe pharmacotherapy. Testing of bi- directional transport on Caco-2 cells is generally the preferred method for in vitro evaluation of substrates and inhibitors of ABC transporters. Drawbacks of the Caco-2 model increase the need and necessity to introduce new models. A great potential is the involvement of ex vivo methodologies in the human or rat intestine. The aim of the work was to introduce an in vitro methodology using the Caco-2 cell monolayer and the ex vivo methodology of precision-cut rat intestinal slices. By the bi-directional transport method, we analyzed drug interactions of the model substrate P-gp and BCRP Rhodamine 123 (RHD123) and clinically-used tenofovir...
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Oxidative degradation study of abacavir
Šušová, Nikola ; Kubíčková, Anna (advisor) ; Sobotníková, Jana (referee)
The aim of this study is forced oxidative degradation of active pharmaceutical ingredient abacavir, used to treat HIV-infected patients. A fast and sensitive method for the determination of abacavir and its degradation products by ultra-high performance liquid chromatography has been developed and validated, that made it possible to evaluate the oxidation stability of abacavir and Ziagen tablets. Suitable chromatographic separation was achieved using a Kinetex C18 column and gradient elution with a mobile phase consisting of acetonitrile and ammonium acetate (c = 20 mmol dm−3 , pH = 7.0). The total run time was 11 minutes. The determination of abacavir and its degradation products was performed by a photodiode array detector at λ = 254 nm. The optimized method for the determination of abacavir and its degradation products was applied to study the oxidation of abacavir by both traditional and electrochemical approaches. The forced degradation study in solution revealed abacavir instability in the presence of 3% hydrogen peroxide and during electrochemical oxidation. The study found that excipients in the tablet suppress the degradation of abacavir by approximately 10 %. Abacavir is oxidized by 15 % by hydrogen peroxide after 24 hours at 25 řC, after 1.5 hours at 50 řC and after 5 minutes at...
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The use of electrochemical oxidation in abacavir degradation studies
Pražáková, Lucie ; Kubíčková, Anna (advisor) ; Kozlík, Petr (referee)
The focus of this bachelor's thesis is the electrochemical degradation of abacavir. Abacavir is the active pharmaceutical ingredient of the medicine for human immunodeficiency virus (HIV). It was developed an electrochemical method for the oxidation of abacavir, including its excipients found in Ziagen tablets given to patients. Abacavir at a concentration of 0,15 mg·cm-3 was oxidized electrochemically at a constant potential (1,15V) on a specially assembled three-electrode apparatus. Subsequently, the quantity and type of the resulting products were analysed by a previously optimized chromatography method. The oxidation was relatively fast. After 7 minutes about 20 % of abacavir was oxidized. Two oxidation products were formed and their structures were confirmed by mass spectrometry.
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In vitro and ex vivo study of drug-drug interactions of antiretrovirals on intestinal ATP-binding drug transporters
Jahodová, Michaela ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Bc. Michaela Jahodová Supervisor: PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: In vitro and ex vivo study of drug-drug interactions of antiretrovirals on intestinal ATP-binding drug transporters The absorption of orally administered drugs takes place especially in the intestine, where it can affect by the activity of drug's ABC transporters located on the apical membrane of the intestinal epithelium. Study of drug interactions in intestinal ABC transporters is essential to ensure effective and safe pharmacotherapy. Testing of bi- directional transport on Caco-2 cells is generally the preferred method for in vitro evaluation of substrates and inhibitors of ABC transporters. Drawbacks of the Caco-2 model increase the need and necessity to introduce new models. A great potential is the involvement of ex vivo methodologies in the human or rat intestine. The aim of the work was to introduce an in vitro methodology using the Caco-2 cell monolayer and the ex vivo methodology of precision-cut rat intestinal slices. By the bi-directional transport method, we analyzed drug interactions of the model substrate P-gp and BCRP Rhodamine 123 (RHD123) and clinically-used tenofovir...
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