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Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy
Číhalová, Daniela ; Štaud, František (advisor) ; Kollár, Peter (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Daniela Číhalová Supervisor: Prof. PharmDr. František Štaud, PhD. Consultant: PharmDr. Martina Čečková, PhD. Title of doctoral thesis: Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy Cyclin-dependent kinases play an important role in cell cycle regulation and their enhanced activity can lead to the development of various malignancies. Therefore, these kinases have become a rational target for inhibition in cancer therapy and many compounds from the group of cyclin-dependent kinase inhibitors (CDKIs) are being evaluated in clinical trials. ABC efflux transporters are expressed in physiological tissues, where they influence the absorption, distribution and elimination of their substrates including drugs and determine their pharmacokinetic properties. On the other hand, overexpression of ABC transporters in cancer cells can contribute to the development of multidrug resistance (MDR) against structurally and functionally diverse compounds. Three members of the ABC transporter family play the most prominent role in the development of MDR: ABCB1 (P-glycoprotein), ABCG2 (breast cancer...
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Development of HPLC method for assesment of stability of amorphous compounds
Číhalová, Daniela ; Solich, Petr (advisor) ; Sklenářová, Hana (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Analytical Chemistry Candidate: Daniela Číhalová Supervisor: Prof. RNDr. Petr Solich, CSc., Prof. Seppo Auriola, MSc. Marko Lehtonen Title of diploma thesis: Development of HPLC method for assessment of stability of amorphous compounds Solid materials can be found in many diverse forms which are distinguishable by different properties. In my thesis, I focus on amorphous solids, their properties, significance, occurrence and, most of all, characterization. The most widely used methods are introduced and described, focusing on their practical use in characterizing polymorphic and amorphous compounds. During the preparation of an amorphous solid, rapid heating and cooling down occurs and therefore degradation can be expected. To prove thermal stability, an HPLC method has been developed and validated for the determination of concentration decrease of an active pharmaceutical ingredient in amorphous state of 8 compounds. The compounds (benzocaine, chlorpropamide, clotrimazole, furosemide, piroxicam, salicylic acid, thiosalicylic acid, and tolbutamide) were determined separately. The method was carried out on a reversed-phase column (1.8µm, 50 × 4.6 mm) maintained at 40řC. The mobile phase was acetonitrile-water containing...
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Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy
Číhalová, Daniela ; Štaud, František (advisor) ; Kollár, Peter (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Daniela Číhalová Supervisor: Prof. PharmDr. František Štaud, PhD. Consultant: PharmDr. Martina Čečková, PhD. Title of doctoral thesis: Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy Cyclin-dependent kinases play an important role in cell cycle regulation and their enhanced activity can lead to the development of various malignancies. Therefore, these kinases have become a rational target for inhibition in cancer therapy and many compounds from the group of cyclin-dependent kinase inhibitors (CDKIs) are being evaluated in clinical trials. ABC efflux transporters are expressed in physiological tissues, where they influence the absorption, distribution and elimination of their substrates including drugs and determine their pharmacokinetic properties. On the other hand, overexpression of ABC transporters in cancer cells can contribute to the development of multidrug resistance (MDR) against structurally and functionally diverse compounds. Three members of the ABC transporter family play the most prominent role in the development of MDR: ABCB1 (P-glycoprotein), ABCG2 (breast cancer...
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Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy
Číhalová, Daniela ; Štaud, František (advisor) ; Kollár, Peter (referee) ; Mičuda, Stanislav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Daniela Číhalová Supervisor: Prof. PharmDr. František Štaud, PhD. Consultant: PharmDr. Martina Čečková, PhD. Title of doctoral thesis: Interactions of cyclin-dependent kinase inhibitors with ABC efflux transporters in vitro: impact on multidrug resistance in cancer therapy Cyclin-dependent kinases play an important role in cell cycle regulation and their enhanced activity can lead to the development of various malignancies. Therefore, these kinases have become a rational target for inhibition in cancer therapy and many compounds from the group of cyclin-dependent kinase inhibitors (CDKIs) are being evaluated in clinical trials. ABC efflux transporters are expressed in physiological tissues, where they influence the absorption, distribution and elimination of their substrates including drugs and determine their pharmacokinetic properties. On the other hand, overexpression of ABC transporters in cancer cells can contribute to the development of multidrug resistance (MDR) against structurally and functionally diverse compounds. Three members of the ABC transporter family play the most prominent role in the development of MDR: ABCB1 (P-glycoprotein), ABCG2 (breast cancer...
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Development of HPLC method for assesment of stability of amorphous compounds
Číhalová, Daniela ; Solich, Petr (advisor) ; Sklenářová, Hana (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Analytical Chemistry Candidate: Daniela Číhalová Supervisor: Prof. RNDr. Petr Solich, CSc., Prof. Seppo Auriola, MSc. Marko Lehtonen Title of diploma thesis: Development of HPLC method for assessment of stability of amorphous compounds Solid materials can be found in many diverse forms which are distinguishable by different properties. In my thesis, I focus on amorphous solids, their properties, significance, occurrence and, most of all, characterization. The most widely used methods are introduced and described, focusing on their practical use in characterizing polymorphic and amorphous compounds. During the preparation of an amorphous solid, rapid heating and cooling down occurs and therefore degradation can be expected. To prove thermal stability, an HPLC method has been developed and validated for the determination of concentration decrease of an active pharmaceutical ingredient in amorphous state of 8 compounds. The compounds (benzocaine, chlorpropamide, clotrimazole, furosemide, piroxicam, salicylic acid, thiosalicylic acid, and tolbutamide) were determined separately. The method was carried out on a reversed-phase column (1.8µm, 50 × 4.6 mm) maintained at 40řC. The mobile phase was acetonitrile-water containing...
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