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Interaction of cidofovir and brincidofovir with human skin in vitro
Vencovská, Lenka ; Vávrová, Kateřina (advisor) ; Kováčik, Andrej (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of organic and bioorganic chemistry Lenka Vencovská Supervisor: prof. PharmDr. Kateřina Vávrová, Ph.D. Title of diploma thesis: Interaction of cidofovir and brincidofovir with human skin in vitro Brincidofovir (BCDV) is a broad spectrum antiviral drug used for the treatment of various viral infections. This prodrug is after targeting the site converted to cidofovir (CDV), whose topical activity has been studied. The application of drugs into or through the skin has a number of advantages over conventional routes of administration. The disadvantage of this type of administration is the inability of drugs to penetrate through the skin in sufficient quantities. To improve skin permeation, we use substances calles transdermal permeation enhancers. 6-dimethylaminohexanoic acid dodecyl ester (DDAK) was used for this study. In my thesis, I have studied the penetration of BCDV into isolated human skin, the effect of the addition of transdermal permeation enhancer on this permeation and the changes that the drug may exert on the skin barrier. The changes in the skin barrier have been studied by infrared spectroscopy, electrical impedance and water loss through the skin. The results of the study show that the amount of drug...
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Effect of darunavir and atazanavir on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Hradecká, Tereza ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Student: Tereza Hradecká Department of Pharmacology & Toxicology Supervisor: PharmDr. Vokřál Ivan, Ph.D. Oral administration of drugs is currently the most common and most convenient method of drug administration. Most drugs administered in this way are subsequently absorbed in the intestine and enter the systemic circulation. The absorption of drugs in the intestine can be influenced by a number of factors. Factors influencing drug absorption include, for example, efflux transporters or biotransformation enzymes. Currently, the most studied intestinal transporter is P-glycoprotein (P-gg), which is able to transport various substances back into the lumen of the intestine. Another factor affecting the absorption of drugs is intestinal metabolism, which in the first phase often takes place through enzymes from the cytochrome P450 family, while most drugs are metabolized through CYP3A4, which is also widely represented in the intestine. The activity of efflux transporters and biotransformation enzymes can be reduced (inhibition) or, conversely, increased (induction) by some drugs. This can subsequently lead to a whole range of drug interactions. The possible pharmacokinetic consequences of enzyme or transporter induction depend on the specific...
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Effect of darunavir and atazanavir on ABCB1 and CYP3A4 expression in human precision-cut intestinal slices
Hradecká, Tereza ; Vokřál, Ivan (advisor) ; Červený, Lukáš (referee)
Charles University Faculty of Pharmacy in Hradec Králové Student: Tereza Hradecká Department of Pharmacology & Toxicology Supervisor: PharmDr. Vokřál Ivan, Ph.D. Oral administration of drugs is currently the most common and most convenient method of drug administration. Most drugs administered in this way are subsequently absorbed in the intestine and enter the systemic circulation. The absorption of drugs in the intestine can be influenced by a number of factors. Factors influencing drug absorption include, for example, efflux transporters or biotransformation enzymes. Currently, the most studied intestinal transporter is P-glycoprotein (P-gg), which is able to transport various substances back into the lumen of the intestine. Another factor affecting the absorption of drugs is intestinal metabolism, which in the first phase often takes place through enzymes from the cytochrome P450 family, while most drugs are metabolized through CYP3A4, which is also widely represented in the intestine. The activity of efflux transporters and biotransformation enzymes can be reduced (inhibition) or, conversely, increased (induction) by some drugs. This can subsequently lead to a whole range of drug interactions. The possible pharmacokinetic consequences of enzyme or transporter induction depend on the specific...
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In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters
Halodová, Veronika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Halodová Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters Tenofovir (TFV) is the first-line agent in the treatment of hepatitis B virus (HBV) infection for patients aged over 12 years and one of the first-line choices for the combination antiretroviral therapy (cART) of infections caused by human immunodeficiency virus (HIV). Two commercially available prodrugs have been developed for oral administration of TFV, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). These prodrugs increase TFV membrane permeability and oral bioavailability. One of the factors that can affect the bioavailability of orally administrated drugs is active transport mediated by efflux transporters, mainly by P-glycoprotein (ABCB1, P-gp) and Breast cancer resistance protein (ABCG2, BCRP). It has been already proved that TDF and TAF are substrates of both of these transporters. The goal of this diploma thesis was to use in vitro and ex vivo models of intestinal barrier to assess the impact of the efflux transporters on TDF and TAF transport in the intestine and on their...
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Synthesis of novel types of acyclic nucleoside phosphonates and preparation of prodrugs and drug delivery systems
Kalčic, Filip ; Janeba, Zlatko (advisor) ; Míšek, Jiří (referee) ; Krečmerová, Marcela (referee)
First part of this thesis was focused on the previously overlooked field of C1'-branched acyclic nucleoside phosphonates (ANPs). Five diverse synthetic approaches were developed/optimized affording key 6-chloropurine intermediates bearing N9 -phosphonomethoxyethyl (PME) branched at C1' position in 2-4 steps. It was demonstrated that these intermediates can be further vastly diversified into ANPs bearing both natural and unnatural nucleobases. Single enantiomers as well as racemates of final C1'-branched ANPs (overall 48 final compounds) were prepared and selected compounds were evaluated with respect to their biological properties. The aforementioned ANPs showed no antiviral potency against studied viruses and only weak to moderate cytostatic activity. Adenine C1'-branched ANPs proved to be the most potent currently known inhibitors of Trypanosoma brucei adenine phosphoribosyl transferase (TbrAPRT), an enzyme involved in purine salvage pathway (PSP) of T. brucei. Further biological evaluation of prepared compounds is in progress. Second part of this thesis was focused on development of novel prodrug moieties with higher selectivity index (i.e. toxicity/potency ratio - SI) based on so-called ProTide prodrugs where phenol (present in ProTides) was replaced by tyrosine derivatives. Tenofovir was...
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Fungal secondary metabollites with antiviral activity
Besedová, Alena ; Čmoková, Adéla (advisor) ; Kolařík, Miroslav (referee)
The past year 2020 has clearly shown how quickly some viral infections can reach pandemic proportions. Thus, there is still a need to discover new substances with antiviral activity. Such substances (eg. asteltoxin E, cytosporaquinone B) have been discovered in the past in several groups of fungi, however, their potential as a source of virostatic chemotherapeutics has not been much explored. The possible use of fungi as a source of substances with antiviral activity is also indicated by the use of some species (eg. Ganoderma linghzi, Lentinula edoles) in the alleviation or prevention of viral diseases in traditional medicine. In most cases, however, it was not possible to find substances responsible for this effect. Therefore, in my bachelor's thesis I will first analyse kinds of fungi traditionally used as treatment of viral infections in traditional medicine. I will also summarize the most important fungal substances for which antiviral activity has been demonstrated. The bachelor's thesis will provide a comprehensive overview of currently known secondary metabolites of fungi and their virostatic effects. The information summarized in the work may point to possible candidates in the fight against viral infections.
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Impact of plant alkaloids on viral infection
Šnejdarová, Aneta ; Horníková, Lenka (advisor) ; Váňová, Jana (referee)
Plant products have been used to treat various diseases since ancient times thanks to the many active substances they contain. One such group of substances are alkaloids. Alkaloids are biologically active substances which, in addition to antimicrobial, anti-inflammatory, antioxidant and many other properties, also possess antiviral properties. As a result, they can help treat viral infections, which are still a major medical problem today. Alkaloids affect all steps of virus replication, both viral components but especially cellular processes, without which a successful progress of viral cycle is not possible. In connection with the treatment of viral infections, the tropane, troponol, purine and isoquinoline alkaloids have been best investigated, which are also the subject of this work. The tropane alkaloid atropine acts mainly on enveloped viruses due to its ability to change the properties of biological membranes. Purine alkaloid caffeine, thanks to its ability to inhibit the cellular enzyme phosphodiestrase, causes an increase in intracellular cAMP levels and it has an impact on viral replication. Its antioxidant and immunomodulatory properties are also beneficial for the treatment. The anti-inflammatory effects of the tropane alkaloid colchicine stem from its ability to inhibit the dynamics of...
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In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters
Halodová, Veronika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Veronika Halodová Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: In vitro and ex vivo study of drug-drug interactions of antivirals on intestinal membrane transporters Tenofovir (TFV) is the first-line agent in the treatment of hepatitis B virus (HBV) infection for patients aged over 12 years and one of the first-line choices for the combination antiretroviral therapy (cART) of infections caused by human immunodeficiency virus (HIV). Two commercially available prodrugs have been developed for oral administration of TFV, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF). These prodrugs increase TFV membrane permeability and oral bioavailability. One of the factors that can affect the bioavailability of orally administrated drugs is active transport mediated by efflux transporters, mainly by P-glycoprotein (ABCB1, P-gp) and Breast cancer resistance protein (ABCG2, BCRP). It has been already proved that TDF and TAF are substrates of both of these transporters. The goal of this diploma thesis was to use in vitro and ex vivo models of intestinal barrier to assess the impact of the efflux transporters on TDF and TAF transport in the intestine and on their...
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In vitro study of drug-drug interactions of HIV protease inhibitor darunavir on efflux ABC transporters
Bezděková, Dominika ; Červený, Lukáš (advisor) ; Vokřál, Ivan (referee)
Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Dominika Bezděková Supervisor: doc. PharmDr. Lukáš Červený, Ph.D. Title of diploma thesis: IN VITRO STUDY OF DRUG-DRUG INTERACTIONS OF HIV PROTEASE INHIBITOR DARUNAVIR ON EFFLUX ABC TRANSPORTERS Abstract: Darunavir is a drug used in the therapy of HIV belonging to the group of protease inhibitors. These protease inhibitors are used as a part of the combination antiretroviral therapy. For the increase of bioavailability, darunavir is always used in combination with ritonavir or cobicistat. As the CYP3A4 and ABCB1 (P-glycoprotein) transporter substrate, darunavir is a drug with a high potential to drug interactions. Considering the amount of adverse effects that can be caused by darunavir, it is necessary to know these drug interactions for the safety of therapy. Inhibition of the intestinal ABCB1 by the co-administrated drugs could also lead to the increased bioavailability of darunavir and to reduction of frequency of administration leading to a cheaper therapy. This thesis studies the drug-drug interactions of darunavir with in vitro methods using two cell lines - MDCKII and Caco-2 cells. The results from the transport of darunavir across the MDCKII cell monolayer indicates that darunavir is a ABCB1...
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Retrocyclins
Soukup, Jakub ; Španielová, Hana (advisor) ; Beranová, Jana (referee)
Defensins are peptides with antimicrobial, antifungal and antiviral activity. Defensins are likely to occur in all vertebrate species. There are three subfamilies of defensins - α, β and θ-defensins. The α-defensins exists only in mammals and θ-defensins were described only in macaques and baboons but their genes occur in genomes of all old world monkeys except Homininae subfamily. In humans no θ-defensins are produces due to premature stop codon in their coding sequence. However, they were produced synthetically in vitro and named retrocyclins. Retrocyclins not only maintain antimicrobial activity - but also exhibit unusual antiviral activity. Retrocyclins successfully protect cells from HIV, HSV, influenza and dengue fever virus infections with no detectable cytotoxicity to host cells. Retrocyclin RC- 101 is close to the clinical testing as microbicide to prevent heterosexual transmission of HIV-1.
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