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Interactions of antiretrovirals with drug efflux transporters and their role in the transplacental pharmacokinetics
Ptáčková, Zuzana ; Štaud, František (advisor) ; Trejtnar, František (referee) ; Ulčová-Gallová, Zdeňka (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Zuzana Ptáčková Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultant: PharmDr. Lukáš Červený, Ph.D. Title of doctoral thesis: Interactions of antiretrovirals with drug efflux transporters and their role in the transplacental pharmacokinetics The combination antiretroviral therapy that should be administered during the whole pregnancy is the backbone of prevention of mother-to-child transmission of HIV infection. One of the prophylactic mechanisms of such treatment is the presence of antiretrovirals in the fetal circulation. However this can be associated with the potentially harmful effects of drugs on the developing fetus. To select optimal therapy while minimizing risks it is inevitable to have detailed knowledge of all the factors affecting transplacental transport of drugs. The aim of this study was to detect whether drug efflux transporters are able to protect fetus against xenobiotics can affect the transplacental pharmacokinetics of the selected antiretroviral drugs. Employing variety of in vitro, in vivo, in situ and ex vivo methods we determined the role of the drug efflux transporters in the distribution of drugs between mother and fetus. We suggested that...
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Interactions of antiretrovirals with drug efflux transporters and their role in the transplacental pharmacokinetics
Ptáčková, Zuzana ; Štaud, František (advisor) ; Trejtnar, František (referee) ; Ulčová-Gallová, Zdeňka (referee)
Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Zuzana Ptáčková Supervisor: prof. PharmDr. František Štaud, Ph.D. Consultant: PharmDr. Lukáš Červený, Ph.D. Title of doctoral thesis: Interactions of antiretrovirals with drug efflux transporters and their role in the transplacental pharmacokinetics The combination antiretroviral therapy that should be administered during the whole pregnancy is the backbone of prevention of mother-to-child transmission of HIV infection. One of the prophylactic mechanisms of such treatment is the presence of antiretrovirals in the fetal circulation. However this can be associated with the potentially harmful effects of drugs on the developing fetus. To select optimal therapy while minimizing risks it is inevitable to have detailed knowledge of all the factors affecting transplacental transport of drugs. The aim of this study was to detect whether drug efflux transporters are able to protect fetus against xenobiotics can affect the transplacental pharmacokinetics of the selected antiretroviral drugs. Employing variety of in vitro, in vivo, in situ and ex vivo methods we determined the role of the drug efflux transporters in the distribution of drugs between mother and fetus. We suggested that...
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The woman at immunological risk and her infant
Mocková, Alice ; Ulčová-Gallová, Zdeňka (advisor) ; Madar, Jindřich (referee) ; Šedivá, Anna (referee)
Women in childbearing age are often affected by autoimmune diseases (AD) associated with the presence of antiphospholipid antibodies (aPL) that may influence further develop-ment of their children. The primary objective of our prospective study was to determine the presence of the following aPL: anti β2 glycoprotein I (anti-β2GPI), anticardiolipin (aCL), antiphosphatidylserine, antiphosphatidylinositol, antihospha- tidylethanolamine, antiphosphatidylglycerol, antiphosphatidic acid, antiannexin V in mothers with defined AD and their children after birth, at 6 and 12 months of life, and to compare the incidence of aPL with a control group. A secondary objective of the study was a 2-year follow-up of children born to aPL negative and aPL positive mothers with AD in order to detect the possible impact of maternal AD on the health of the offspring. In children, we analysed anthropometric data, blood cell count, cerebral and abdominal ultrasound examination, transient evoked otoacoustic emission test (TEOAE), electrocardiograph (ECG), the presence and kinetics of aPL. At the age of 2 years the Bayley Scales of Infant Development (BSID-II) were used for children's assessment of motor, language and cognitive development. 31 mothers from the total examined 82 aPL positive women with AD delivered 34 neonates...
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Inhibins in reproduction
Babčová, Katarína ; Ulčová-Gallová, Zdeňka (advisor) ; Kužel, David (referee) ; Crha, Igor (referee)
Inhibin A and B participate to regulation of gametogenesis. We investigated their applicability as a marker of gametogenesis of men fertility disorders. We monitored the levels of inhibins during the treatment. We interested in their paracrine activity, relationship in sera, follicular fluid and seminal plasma depending on cause of fertility failure. We studied the levels of inhibin B in serum and seminal plasma from 355 men treated for fertility failure, in the context of their andrological and immunological findings (quality of spermiogrammes and acrosome area). We monitored concentration of levels of inhibin A and B in serum and follicular fluids depending on cause of fertility failure, on course and treatment outcome. We took blood samples in the time of the oocytes collection, of the embryotransfer and early pregnancy. The follicular fluids were obtained during the oocytes collection. The levels of both of inhibins were measured by ELISA in all medium (serum, follicular fluid, seminal plasma). We confirm, that inhibin B is useful marker of spermatogenesis in men, but is necessary to examine patient in complex with determination of immunology profile or quality of acrosome. Seminal plasma is, in some indicated cases, more suitable diagnostics material. Similarly inhibin B in women seems to be...
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The study of fluids and secretions from reproductive tracts of pig (Sus scrofa f. domestica) and cattle (Bos primigenius f. taurus)
Dráb, Tomáš ; Liberda, Jiří (advisor) ; Jonáková, Věra (referee) ; Ulčová-Gallová, Zdeňka (referee)
Interactions between proteins and saccharide moieties play an indispensable role in mammalian reproduction as they stand behind of such processes as maturation and mutual recognition of gametes and sperm oviductal reservoir formation. In my dissertation thesis I focused on activities of glycosidases from bovine and porcine follicular fluids and their changes connected with follicle development. Activities of five glycosidases were detected in tertiary and preovulatory follicles in both species. The most active enzymes were α-L-fucosidase in cow and α-D-mannosidase in sow and both enzymes also demonstrated the most pronounced increase in their activities during follicle maturation. Interestingly, both α-L-fucose in cow and α-D-mannose in sow were described as saccharides responsible for the formation of the sperm oviductal reservoir and we offered a hypothetical mechanism of synchronisation between sperm release from their reservoir with the time of ovulation based on a surge of activities of corresponding follicular glycosidases through the oviduct. Subsequently, it was demonstrated that β-D-galactosidase and α-D-mannosidase affect sperm-zona pellucida binding in pig, as they both decrease interaction between sperm receptors for zona pellucida and zona pellucida. This may explain the observation...
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Levels of umbilical cord blood pathogen pattern receptors and proinflammatory molecules - the relation to histological chorioamnionitis
Mitášová, Eva ; Andrýs, Ctirad (advisor) ; Procházka, Martin (referee) ; Ulčová-Gallová, Zdeňka (referee)
The umbilical cord blood (UCB) represents the earliest haematological sample of the fetus/neonate without invasive intervention or any risk for mother and her child during sampling. From the UCB we are able to determine a lot of information about the clinical status of newborn. The fetal response to preterm birth with IAI is characterised by increased levels of proinflammatory cytokines in the UCB. Our aim was therefore to investigate the association of IAI and immunological parameters interleukin IL-6, IL-8, matrix metalloproteinase 8 (MMP-8), pentraxin 3 (PTX3), soluble form of Toll-like receptor 2 (sTLR2) and soluble form of scavenger receptor CD163 (sCD163). The strengths of our study include quantification of sTLR2, sCD163, PTX3 and MMP-8 in UCB and their relationship to IAI that has never been examined. There was a significant increase in inflammatory markers IL-6 and sCD163 in UCB in infants exposed to preterm premature rupture of membranes (PPROM) and to histological chorioamnionitis (HCA) compared to those without intraamniotic inflammation (IAI). There was significant differences in IL-6, IL-8, MMP-8 and sCD163 levels in those with and without funisitis in women with PPROM. However, no significant differences were observed between levels of sTLR2 and PTX3 in UCB in subjects with and...
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The significance of thrombophilic and immunologic factors in human reproduction
Šubrt, Ivan ; Ulčová-Gallová, Zdeňka (advisor) ; Kužel, David (referee) ; Šantavý, Jiří (referee)
The aim of presented study was to compare frequencies of eight antiphospholipid antibodies (aPL) in serum and assorted genetic thrombophilic factors and their mutual relation in patients with recurrent pregnancy loss (RPL) and controls. Enzyme-linked immunosorbent assay was used for detection of aPL against phosphatidyl-L-serine, phosphatidylethanolamine, phosphatidylinositol, phosphatidyl- DL-glycerol, phosphatidic acid, annexin V, cardiolipin, and beta2-GPI. Thrombophilic mutations factor V Leiden (F5 G1691A), F II G20210A, and MTHFR C677T and A1298C variants were determined using a melting curve analysis of the PCR amplification product detected by the fluorescence resonance energy transfer (FRET). PAI1 (-675)4G/5G, PROZ intron F G79A, PROZ A(-13)G and PROZ R255H variants were determined using standard PCR-RFLP method. Genotypes distribution and allelic frequencies were calculated. Correlation between aPL and thrombophilic factors was tested by chi-square and Fisher exact test. Our results showed significantly increased prevalence of aPL against phosphatidylinositol (17 - 19.6 % dependent on number of spontaneous miscarriages) and against phosphatidyl-L-serine (18-25 %). aPL in IgG prevailed. In 96 % of studied group we found at least one risk factor (either aPL positivity or thrombophilic factor). Both...
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Observation of human sperm cell immunogenic properties
Cibulka, Jan ; Ulčová-Gallová, Zdeňka (advisor) ; Fingerová, Helena (referee) ; Madar, Jindřich (referee) ; Šíma, Petr (referee)
The issue of human infertility is becoming increasingly pressing, especially in so- called industrially developed countries. Formally, we can share the infertility attributes between the male and the female partner (as a male and female infertility factor), but the problem finally affects the whole parental couple. Perhaps, due to the complexity of the female reproductive tract, it is estimated that over 40% of the reproductive failure is hidden in one or more of its parts. The "strong point" of the male factor is derived from the pathological sperm count. For the remaining 15 to 20% of causes, whether morphological or functional, cannot be to find either clearly or not at all. We talk about the otherwise unexplained infertility, that can be caused in up to 30% immunologically. Due to broad concept of immunology of reproduction, we have chosen literally as a probe into this issue in all respects unique spermatic cell that represents not only a carrier of genetic information, but also a set of antigenic structures. This cell seems to be perfect for this task, because of its availability to most basic laboratory techniques. We will try to familiarize ourselves with some of the obstacles that may prematurely end its mission, especially with the antibodies against its antigenic structures (ASA -...
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Immunologic Characteristics of Cord Blood in Children with Increased Risk of Allergy Development Preventive Use of Probiotics
Hrdý, Jiří ; Prokešová, Ludmila (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Ulčová-Gallová, Zdeňka (referee)
Allergy is one of the most common diseases. Identification of early prognostic markers pointing to an increased risk of allergy development is therefore of increasing importance. Cord blood represents an easily attainable clinical material for searching for prognostic markers signalizing future allergy development. Proportions of Th1 cytokines, Th2 cytokines and regulatory cytokines were tested in cord blood of children of allergic mothers (children in relatively high risk of allergy development) in comparison with cord blood of children of healthy mothers (low risk children). Also the activities of lymphocytes, dendritic cells (DC) and regulatory cells (Tregs) were compared in children of healthy and allergic mothers. The generally increased activity of both in vitro stimulated and non-stimulated mononuclear cord blood leukocytes was proved in children of allergic mothers in comparison with low risk children. The increased activity of DC of high risk children was detectable only after polyclonal stimulation. Significantly less pronounced functional properties of cord blood Tregs were found in children of allergic mothers when compared with children of healthy mothers. The increased reactivity of lymphocytes and DC together with the decreased activity of Tregs can support an easier...
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Proteomics of biological fluids
Jarkovská, Karla ; Kovářová, Hana (advisor) ; Petrák, Jiří (referee) ; Ulčová-Gallová, Zdeňka (referee)
Reproductive diseases, mainly those resulting in the infertility affect the chances of human being to reproduce. On the contrary, the heart disease, cancer and degenerative diseases currently account for majority of deaths in the world. Usually, these lifestyle diseases need longer lifespan to become the cause of death. The proteins secreted by cells carry important information about the cell's well-being, as well as about the condition of the tissues formed by these cells. Once secreted, these proteins may also be transferred throughout the body by means of body fluids, many of which are easily accessible for further 'in-depth' studies. Cellular and secreted proteins are often a focus of studies using proteomic means and the revelation of protein alterations can lead us to new ideas about the molecular mechanisms of diseases as well as possible identification of proteins that may be used as new targets for pharmaceutical intervention or molecules that could be used for diagnostic or prognostic purposes. Taking into consideration the above aspects, this research was undertaken to find proteins that could: (a) characterise the human follicular fluid as microenvironment of the maturing oocyte, to increase understanding of reproductive processes to improve the techniques of assisted repro- duction;...
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