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Interactions of antiretroviral drugs with membrane transporters
Martinec, Ondřej ; Červený, Lukáš (advisor) ; Boušová, Iva (referee) ; Chládek, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Ondřej Martinec Supervisor: Assoc. Prof. PharmDr. Lukáš Červený, Ph.D. Title of doctoral thesis: Interactions of antiretroviral drugs with membrane transporters Oral delivery is the most common, convenient, and economical form of drug administration. Absorption of orally administered drugs occurs mainly in the intestine. Intestinal absorption can be reduced by the activity of efflux drug ABC transporters, mainly p-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), located in the apical membrane of the intestinal epithelium. HIV-infected patients are dependent on lifelong pharmacotherapy, which includes a combination of three or more antiretroviral drugs. Hepatitis C (HCV) is a common co-infection of HIV. In addition, the HIV-positive population is aging, which is associated with burden of other comorbidities. This results in an indication of polypharmacy and thus an increased risk of drug-drug interactions. Many antiretroviral drugs used are substrates, inhibitors and /or inducers of ABCB1, so they might quantitatively affect the intestinal absorption of co-administered drugs (ABCB1 substrates), thereby affecting the efficacy/safety of treatment. As part of this...
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Development of novel Constitutive androstane receptor (CAR) ligands
Dušek, Jan ; Pávek, Petr (advisor) ; Hudeček, Jiří (referee) ; Chládek, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Jan Dušek Supervisor Prof. PharmDr. Petr Pávek, Ph.D. Title of Doctoral Thesis Development of novel Constitutive androstane receptor (CAR) ligands Constitutive androstane receptor is nowadays known as the established nuclear receptor that regulates the expression of several key cytochrome P450 enzymes, predominantly CYP3A4 and CYP2B6. Recently it has been shown that CAR has also essential role in the regulation of endogenous metabolism of glucose, lipids, cholesterole or bile acids. Simultaneously, this receptor is considered to have proliferative effect on human hepatocytes and protective effects against toxic and dietary damage of liver parenchyme. Given the possible therapeutic utilization of CAR, its therapeutic options are being intensively studied. Unfortunately, currently known ligands of human or mouse CAR are either poorly selective or indirect. The aim of my doctoral thesis was to find new ligands of mouse and human CAR, that would enable more detailed study of the receptor.
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Interactions of antiretrovirals with drug transporters; role in pharmacokinetics
Řezníček, Josef ; Štaud, František (advisor) ; Chládek, Jaroslav (referee) ; Trejtnar, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Josef Řezníček Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultant: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of antiretrovirals with drug transporters; role in pharmacokinetics Current pharmacotherapy of HIV positive patients consists of co-administration of three or more antiretrovirals from different pharmacotherapeutic groups, so called combination antiretroviral therapy (cART). Using this approach, a significant reduction in viral load, delayed viral resistance progression and prolonged efficacy of therapy is achieved. However, the use of cART often bears the risk of drug-drug interactions, which may result in subtherapeutic or supratherapeutic concentrations of drugs in organism with subsequent failure of therapy, or manifestation of toxic effects. Drug transporters expressed in many tissues of human body are widely responsible for occurrence of drug-drug interactions. Therefore, detailed knowledge on antiretrovirals pharmacokinetics and their interactions with drug transporters is important to ensure safe and effective therapy of HIV infection. The aim of this thesis was to study interactions of drugs used in combination antiretroviral...
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Kinetically guided therapy with gentamicin in neonates with sepsis during the first week of life
Pokorná, Pavla ; Chládek, Jaroslav (advisor) ; Perlík, František (referee) ; Patočková, Jitka (referee)
Gentamicin (Ge) belongs to the group of aminoglycoside antibiotics frequently used in the treatment of neonates with sepsis in combination with betalactams. The first part of the disertation investigates a kinetically guided therapy with gentamicin (Ge) and the impact of covariates on pharmacokinetics/pharmacodynamics (PK/PD) while the second part describes the tolerability of treatment. This open-label, prospective study included preterm and term neonates (n=108) who experienced critically illness during the first week of life and were treated with Ge and admitted to the neonatal intensive care unit. The primary goal of the study was to perform a pharmacokinetic study after the first dose of Ge. The influence of covariates on PK was analyzed (body weight, gestational age-GA, fluid retention, persistent ductus arteriosus-PDA, postnatal age, therapeutic hypothermia-HT) as well as the success rate in the achivement of target therapeutic concentrations in the first week of pharmacotherapy. Fitting of the parameters of two-compartment model to the four plasma concentrations of Ge (CplGe) concentations after the first dose was used to estimate individual PK of Ge: distribution volume (Vd1) and clearance (CL1). Neonates were stratified into four groups according to GA and the presence of a PDA (S1-PDA=18,...
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Factors Affecting Metabolism of Anthelmintics
Forstová, Veronika ; Skálová, Lenka (advisor) ; Machala, Miroslav (referee) ; Chládek, Jaroslav (referee)
Nowadays, anthelmintic therapy is the main method in the fight with parasitic worms. Anthelmintics, as well as other xenobiotics, undergo structural changes by effect of biotransformation enzymes, when lipophilic substances are transformed to polar substances more easily eliminable from the organism. Generally, biological effects of metabolites and parent compound are different. Activity of biotransformation enzymes is thus the fundamental factor influencing velocity of detoxification and elimination of the compound from the body and duration of drug effect as well. Modulation of biotransformation enzymes' activities can lead to changes in pharmacokinetic parameters of drug itself as well as other xenobiotics and thus to the risk of decrease in desired effect and/or increase in adverse effects with corresponding impact on the quality of drug therapy. In addition, possible risk of drug residues' presence in animal products has to be considered in farm animals. Biotransformation of xenobiotics is affected by many physiological as well as pathological factors. These factors can be divided into inter-individual (species, gender, genetic polymorphism) and intra-individual (age, diet, medication, disease, etc.). All these factors cause wide variability in occurrence and activity of biotransformation...
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Interactions of antiretroviral drugs with membrane transporters
Martinec, Ondřej ; Červený, Lukáš (advisor) ; Boušová, Iva (referee) ; Chládek, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Ondřej Martinec Supervisor: Assoc. Prof. PharmDr. Lukáš Červený, Ph.D. Title of doctoral thesis: Interactions of antiretroviral drugs with membrane transporters Oral delivery is the most common, convenient, and economical form of drug administration. Absorption of orally administered drugs occurs mainly in the intestine. Intestinal absorption can be reduced by the activity of efflux drug ABC transporters, mainly p-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), located in the apical membrane of the intestinal epithelium. HIV-infected patients are dependent on lifelong pharmacotherapy, which includes a combination of three or more antiretroviral drugs. Hepatitis C (HCV) is a common co-infection of HIV. In addition, the HIV-positive population is aging, which is associated with burden of other comorbidities. This results in an indication of polypharmacy and thus an increased risk of drug-drug interactions. Many antiretroviral drugs used are substrates, inhibitors and /or inducers of ABCB1, so they might quantitatively affect the intestinal absorption of co-administered drugs (ABCB1 substrates), thereby affecting the efficacy/safety of treatment. As part of this...
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Development of novel Constitutive androstane receptor (CAR) ligands
Dušek, Jan ; Pávek, Petr (advisor) ; Hudeček, Jiří (referee) ; Chládek, Jaroslav (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Jan Dušek Supervisor Prof. PharmDr. Petr Pávek, Ph.D. Title of Doctoral Thesis Development of novel Constitutive androstane receptor (CAR) ligands Constitutive androstane receptor is nowadays known as the established nuclear receptor that regulates the expression of several key cytochrome P450 enzymes, predominantly CYP3A4 and CYP2B6. Recently it has been shown that CAR has also essential role in the regulation of endogenous metabolism of glucose, lipids, cholesterole or bile acids. Simultaneously, this receptor is considered to have proliferative effect on human hepatocytes and protective effects against toxic and dietary damage of liver parenchyme. Given the possible therapeutic utilization of CAR, its therapeutic options are being intensively studied. Unfortunately, currently known ligands of human or mouse CAR are either poorly selective or indirect. The aim of my doctoral thesis was to find new ligands of mouse and human CAR, that would enable more detailed study of the receptor.
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Interactions of antiretrovirals with drug transporters; role in pharmacokinetics
Řezníček, Josef ; Štaud, František (advisor) ; Chládek, Jaroslav (referee) ; Trejtnar, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Josef Řezníček Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultant: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of antiretrovirals with drug transporters; role in pharmacokinetics Current pharmacotherapy of HIV positive patients consists of co-administration of three or more antiretrovirals from different pharmacotherapeutic groups, so called combination antiretroviral therapy (cART). Using this approach, a significant reduction in viral load, delayed viral resistance progression and prolonged efficacy of therapy is achieved. However, the use of cART often bears the risk of drug-drug interactions, which may result in subtherapeutic or supratherapeutic concentrations of drugs in organism with subsequent failure of therapy, or manifestation of toxic effects. Drug transporters expressed in many tissues of human body are widely responsible for occurrence of drug-drug interactions. Therefore, detailed knowledge on antiretrovirals pharmacokinetics and their interactions with drug transporters is important to ensure safe and effective therapy of HIV infection. The aim of this thesis was to study interactions of drugs used in combination antiretroviral...
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Interactions of antiretrovirals with drug transporters; role in pharmacokinetics
Řezníček, Josef ; Štaud, František (advisor) ; Chládek, Jaroslav (referee) ; Trejtnar, František (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Josef Řezníček Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultant: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of antiretrovirals with drug transporters; role in pharmacokinetics Current pharmacotherapy of HIV positive patients consists of co-administration of three or more antiretrovirals from different pharmacotherapeutic groups, so called combination antiretroviral therapy (cART). Using this approach, a significant reduction in viral load, delayed viral resistance progression and prolonged efficacy of therapy is achieved. However, the use of cART often bears the risk of drug-drug interactions, which may result in subtherapeutic or supratherapeutic concentrations of drugs in organism with subsequent failure of therapy, or manifestation of toxic effects. Drug transporters expressed in many tissues of human body are widely responsible for occurrence of drug-drug interactions. Therefore, detailed knowledge on antiretrovirals pharmacokinetics and their interactions with drug transporters is important to ensure safe and effective therapy of HIV infection. The aim of this thesis was to study interactions of drugs used in combination antiretroviral...
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