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Population pharmacokinetic and pharmacodynamic study of efavirenz in HIV–1–infected children treated with first line antiretroviral therapy in South Africa / Viljoen, M.Viljoen, Michelle January 2011 (has links)
Highly active antiretroviral therapy (HAART) has improved the life expectancy of
HIV–1–infected patients dramatically since it was launched in 1996, but there are still
many challenges in the provision of HAART, especially to children in resource limited
countries. Efavirenz (EFV), a non–nucleoside reverse transcriptase inhibitor (NNRTI)
forms part of the recommended national first line antiretroviral treatment regimen for
children older than 3 years and weighing more than 10 kg in South Africa. Limited
pharmacokinetic information on EFV plasma concentrations in sub–Saharan HIV–1–
infected children is available. EFV is primarily metabolised by hepatic CYP2B6
isoenzymes. The CYP2B6 gene is characterised by extensive inter–individual
variability in hepatic expression and activity. The single nucleotide change, 516G>T,
on the CYP2B6 gene has consistently been associated with elevated EFV plasma
levels in different ethnic populations and these are more frequently observed in
populations of African descent. The recommended therapeutic range of EFV plasma
levels is 1–4 ug/ml and the Cmin should be above 1 ug/ml.
In this prospective study (PK/PD.EFV.07) cohort, 60 black children, both genders,
with no prior exposure to antiretroviral therapy and eligible for antiretroviral therapy
(ART) were enrolled and followed up at 1, 3, 6, 12, 18 and 24 months post HAART
initiation. They all attended the outpatient clinic at Harriet Shezi Children’s Clinic,
Chris Hani Baragwanath Hospital, Soweto, South Africa. The required ethics
approval was obtained to conduct this study.
The objectives of this investigation were to: develop and validate a suitable LCMS/
MS method to accurately determine plasma EFV levels from this study
population, determine the prevalence and effect of CYP2B6 516G>T polymorphism
on EFV plasma levels, determine the population pharmacokinetic clearance (CL/F)
value of EFV, identify covariates that influence the clearance of EFV in HIV–1–
infected children, and investigate specific pharmacodynamic effects and therapeutic outcomes of this EFV–based regimen within this paediatric population over the 24
months post–HAART initiation.
The main findings of the measured mid–dose EFV plasma concentrations showed
that sub–therapeutic concentrations (<1 ug/ml) accounted for 18% (116/649), within
therapeutic range (1–4 ug/ml) represented 52.5% (341/649), and concentrations
above the therapeutic range (>4 ug/ml) represented 29.5% (192/649). A significant
number of the samples (47.5%) were outside the accepted therapeutic range during
this 24 month follow–up period. Possible reasons contributing to this include genetic
variation in drug metabolism and non–adherence.
Genotype results on all 60 study participants were: 23% 516 T/T homozygotes, 42%
516 G/G homozygotes and 35% 516 G/T heterozygotes. The 516 T–allelic variant
frequency was relatively high at 41%. This also supports and explains why such a
large number (29.5%) of the mid–dose interval plasma samples were above (>4
ug/ml) the accepted therapeutic range.
Repeated measures ANOVA confirmed that CYP2B6 516 G/G, G/T and T/T
genotypes were consistently predictive of the log EFV concentrations at all times (P
= 0.0001). The total median (IQR) EFV plasma concentrations over the 24 months
post–HAART when pooled, were 6.36 (3.47 - 7.28) for T/T, 2.55 (1.62 - 3.59) for
G/T, and 1.41 (1.02 - 1.74) ug/ml for G/G groups respectively (P<0.00001). Multiple
comparisons by groups revealed that the EFV plasma concentrations between the
T/T and G/G (P=0.000002) and between G/T and G/G (P=0.009) were statistically
significant. However, the differences between the EFV plasma concentrations of the
T/T and G/T groups were not significantly different (P=0.074). This supports
previous results that the presence of the 516 T–allelic variant is responsible for the
higher EFV plasma concentrations within individuals presenting with this single
nucleotide mutation on the CYP2B6 gene.
This EFV–based treatment was well tolerated even at plasma concentrations above
the therapeutic range (>4 ug/ml) and most side effects subsided spontaneously.
89% of the participants were virally suppressed at 24 months post–HAART. The
efficacy of this EFV–based treatment did not affect the three genotype groups
differently and they showed similar improvement in their immunological (CD4–cell count and CD4%) markers and reduction in viral load over the 24 months post–
HAART initiation. We found no association of the CYP2B6 516G>T polymorphism
and side effects reported after 1 month of treatment within this study population.
The final population pharmacokinetic (PK) estimates for EFV clearance (CL/F) were,
2.46, 4.60, and 7.33 l/h for the T/T, G/T, and G/G respective genotype groups. The
volume of distribution (V/F) estimate was 89.52 l. The importance of interoccasion
variability (IOV) in a PK model for a longitudinal study was again highlighted by this
investigation.
To our knowledge, this is the first study in black South African HIV–1–infected
children with measured sequential EFV plasma concentrations which also
investigated the influence of the CYP2B6 516G>T polymorphism on EFV plasma
concentrations and the population clearance (CL/F) value of EFV in a longitudinal
study over a period of 24 months post–HAART initiation. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2011.
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Population pharmacokinetic and pharmacodynamic study of efavirenz in HIV–1–infected children treated with first line antiretroviral therapy in South Africa / Viljoen, M.Viljoen, Michelle January 2011 (has links)
Highly active antiretroviral therapy (HAART) has improved the life expectancy of
HIV–1–infected patients dramatically since it was launched in 1996, but there are still
many challenges in the provision of HAART, especially to children in resource limited
countries. Efavirenz (EFV), a non–nucleoside reverse transcriptase inhibitor (NNRTI)
forms part of the recommended national first line antiretroviral treatment regimen for
children older than 3 years and weighing more than 10 kg in South Africa. Limited
pharmacokinetic information on EFV plasma concentrations in sub–Saharan HIV–1–
infected children is available. EFV is primarily metabolised by hepatic CYP2B6
isoenzymes. The CYP2B6 gene is characterised by extensive inter–individual
variability in hepatic expression and activity. The single nucleotide change, 516G>T,
on the CYP2B6 gene has consistently been associated with elevated EFV plasma
levels in different ethnic populations and these are more frequently observed in
populations of African descent. The recommended therapeutic range of EFV plasma
levels is 1–4 ug/ml and the Cmin should be above 1 ug/ml.
In this prospective study (PK/PD.EFV.07) cohort, 60 black children, both genders,
with no prior exposure to antiretroviral therapy and eligible for antiretroviral therapy
(ART) were enrolled and followed up at 1, 3, 6, 12, 18 and 24 months post HAART
initiation. They all attended the outpatient clinic at Harriet Shezi Children’s Clinic,
Chris Hani Baragwanath Hospital, Soweto, South Africa. The required ethics
approval was obtained to conduct this study.
The objectives of this investigation were to: develop and validate a suitable LCMS/
MS method to accurately determine plasma EFV levels from this study
population, determine the prevalence and effect of CYP2B6 516G>T polymorphism
on EFV plasma levels, determine the population pharmacokinetic clearance (CL/F)
value of EFV, identify covariates that influence the clearance of EFV in HIV–1–
infected children, and investigate specific pharmacodynamic effects and therapeutic outcomes of this EFV–based regimen within this paediatric population over the 24
months post–HAART initiation.
The main findings of the measured mid–dose EFV plasma concentrations showed
that sub–therapeutic concentrations (<1 ug/ml) accounted for 18% (116/649), within
therapeutic range (1–4 ug/ml) represented 52.5% (341/649), and concentrations
above the therapeutic range (>4 ug/ml) represented 29.5% (192/649). A significant
number of the samples (47.5%) were outside the accepted therapeutic range during
this 24 month follow–up period. Possible reasons contributing to this include genetic
variation in drug metabolism and non–adherence.
Genotype results on all 60 study participants were: 23% 516 T/T homozygotes, 42%
516 G/G homozygotes and 35% 516 G/T heterozygotes. The 516 T–allelic variant
frequency was relatively high at 41%. This also supports and explains why such a
large number (29.5%) of the mid–dose interval plasma samples were above (>4
ug/ml) the accepted therapeutic range.
Repeated measures ANOVA confirmed that CYP2B6 516 G/G, G/T and T/T
genotypes were consistently predictive of the log EFV concentrations at all times (P
= 0.0001). The total median (IQR) EFV plasma concentrations over the 24 months
post–HAART when pooled, were 6.36 (3.47 - 7.28) for T/T, 2.55 (1.62 - 3.59) for
G/T, and 1.41 (1.02 - 1.74) ug/ml for G/G groups respectively (P<0.00001). Multiple
comparisons by groups revealed that the EFV plasma concentrations between the
T/T and G/G (P=0.000002) and between G/T and G/G (P=0.009) were statistically
significant. However, the differences between the EFV plasma concentrations of the
T/T and G/T groups were not significantly different (P=0.074). This supports
previous results that the presence of the 516 T–allelic variant is responsible for the
higher EFV plasma concentrations within individuals presenting with this single
nucleotide mutation on the CYP2B6 gene.
This EFV–based treatment was well tolerated even at plasma concentrations above
the therapeutic range (>4 ug/ml) and most side effects subsided spontaneously.
89% of the participants were virally suppressed at 24 months post–HAART. The
efficacy of this EFV–based treatment did not affect the three genotype groups
differently and they showed similar improvement in their immunological (CD4–cell count and CD4%) markers and reduction in viral load over the 24 months post–
HAART initiation. We found no association of the CYP2B6 516G>T polymorphism
and side effects reported after 1 month of treatment within this study population.
The final population pharmacokinetic (PK) estimates for EFV clearance (CL/F) were,
2.46, 4.60, and 7.33 l/h for the T/T, G/T, and G/G respective genotype groups. The
volume of distribution (V/F) estimate was 89.52 l. The importance of interoccasion
variability (IOV) in a PK model for a longitudinal study was again highlighted by this
investigation.
To our knowledge, this is the first study in black South African HIV–1–infected
children with measured sequential EFV plasma concentrations which also
investigated the influence of the CYP2B6 516G>T polymorphism on EFV plasma
concentrations and the population clearance (CL/F) value of EFV in a longitudinal
study over a period of 24 months post–HAART initiation. / Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2011.
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Studium interakcí vybraných anthokyanidinů s farnesoidním X receptorem / Interaction of selected anthocyanidins with farnesoid X receptorJeřábková, Jana January 2013 (has links)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Jana Jeřábková Supervisor: Doc. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Interaction of selected anthocyanidins with farnesoid X receptor Human farnesoid X receptor (FXR) is a member of nuclear receptor superfamily that act as ligand-activated transcription factors. FXR binds to specific regulatory DNA regions and induces expression of many target genes. These regulated genes are involved in bile acid metabolism and transport, maintaining blood lipids, liporoteins and glucose homeostasis and also contribute to maintain intestinal bacterial balance, hepatoprotection and liver regeneration. The interest of recent studies is to test the range of FXR ligands for treatment and prevention of many diseases such as cholestais, cholesterol gallstone disease, steato-hepatitis, dyslipidemia, atherosclerosis, type 2 diabetes mellitus, metabolic syndrome, liver cancer and other forms of cancer such as breast cancer. In this experimental diploma thesis we are focused on testing of potencial ligands of human farnesoid X receptor from the group of natural plant pigments anthocyanidins (cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin) using the human hepatoma cell line...
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Polimerazės grandininės reakcijos metodo taikymas farmakogenetiniuose tyrimuose / Use of polymerase chain reaction in pharmacogeneticsTatarūnas, Vacis 03 August 2007 (has links)
Kiekvieno vaisto sukeltas tiek farmakologinis (veiksmingumo), tiek toksikologinis poveikis kiekvienam pacientui yra skirtingas, todėl gana dažnai vaistų skyrimas ir vartojimas tampa labai komplikuotas. Prancūzijoje 3.2% hospitalizacijos atvejų yra sąlygoti vaistų. Tai sudaro 320 milijonų eurų sumą per metus. Genetiniai faktoriai, sąlygojantys vaistų farmakokinetiką ir farmakodinamiką, dalinai paaiškina skirtingą vaistų poveikį žmogui. Tyrimo tikslas: 1. Patikrinti galimybę gausinti serume ir plazmoje esančią DNR nauju būdu ir atlikti genetinius tyrimus. 2. Patvirtinti realaus laiko polimerazės grandininės reakcijos (PGR) metodiką aromatazės genui, panaudojus ląsteles, kurių šio geno raiška yra pakankama. Rezultatai: Patikrinta galimybė gausinti serume ir plazmoje esančią DNR, sekvenavus gautą DNR ir sekas palyginus su esančiomis duomenų bazėje : rezultatai teigiami. Nustatyta, kad, ekstrahuojant druskiniu metodu, gaunama daugiau DNR, bet ji blogesnės kokybės, nei naudojant QIAGEN kolonėles. Patvirtinta realaus laiko PGR metodika aromatazės genui, naudojant krūties vėžio ląsteles. / There is much variability in the manner individuals respond to drugs, such that the management of some drugs is problematic. In France, the incidence of hospital admissions related to adverse drug reactions is estimated to be 3.2 %, at an annual cost of over 300 millions euros. Genetic factors affecting the pharmacokinetics and pharmacodynamics of drugs partly explain interindividual variability in drug response. Aim of experiment: 1. verify, if it is possible to amplify serum and plasma DNA using new method, and make a genetic research. 2. verify real time polymerase chain reaction to aromatase gene. Find cell line, whish have a sufficient expression of this gene. Results : We verified the possibility to amplify serum and plasma DNA using new method. We made the sequencing of DNA extracts and we compared results in data base : results are positives. It`s important, that QIAGEN extracts are cleanner than salt extracts, but there are few of DNA. We confirmed real time PCR method to aromatase gene, using breast cancer cells.
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Detekce polymorfismu v genu MDR1 u ovčáckých a honáckých psůStaroveská, Marieta January 2016 (has links)
This thesis is focused on polymorphism of MDR1 gene and related drug resistance. Resistance is caused by deletion of four nucleotids, that resulting in a frame shift and synthesis of nonfunctional transport of P-glycoprotein. The text describes a polymorphism of MDR1 (ABCB1) gene, which results in reduced resistance to drugs belonging to the group of macrocyclic lactones. It also describes inheritance of this phenomenon and it deals with the detection of mutation using PCR (polymerase chain reaction) and by fragmentation analyses. A review of literature study is a form of research solely from scientific publications. 128 dogs were included into the own analysis. The results confirmed that Collies had the highest presence of deletions (29,73 %) with a high number of carriers in the study population of dogs (54,05 %). The percentage of affected individuals in the breed of Australian Shepherd and Sheltie was significantly lower (7,32 % and 6 %), but the percentage of carriers were also high in both Australian Shepherds (34,14 %) and the breed Sheltie (48 %).
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Farmakogenetika v revmatologii. / Pharmacogenetics in rheumatoid arthritisKobrlová, Martina January 2017 (has links)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Martina Kobrlová Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of diploma thesis: Pharmacogenetics in rheumatoid arthritis Based on scientific progress in the research of human genome and the discovery of polymorphisms, which are involved in the interindividual differences in human population, there is also a growing interest in pharmacogenetics. It is a field combining pharmacology and genetics with the aim of identifying specific features that could explain the different responses of patients to treatment by clinically used drugs. Applying this knowledge could contribute to a simpler choice of medication for a particular patient and it could reduce the risk of side effects or poor response. In this diploma thesis I dealt with the latest scientific knowledge on pharmacogenetics in rheumatology, in particular the rheumatoid arthritis. From available studies, reviews, and meta-analyzes that have been published, I summarized current data on the relationship between polymorphisms and disease modifying drugs (DMARDs) used for the treatment of this disease. The largest amount of data was found on the most commonly used methotrexate. Further, the work examines the leflunomide and other...
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Farmakogenetika v revmatologii - role miRNA / Pharmacogenetics in rheumatology - role of miRNAsVicherková, Petra January 2017 (has links)
Charles University, Faculty of Pharmacy in Hradec Králové Department of pharmacology and toxicology Candidate: Bc. Petra Vicherková Supervisor: prof. PharmDr. Petr Pávek, Ph.D. Title of master thesis: Pharmacogenetics in rheumatology - role of miRNA Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that causes progressive joint damage and can result in to life-long depreciation of life. The influence on the onset and course of the disease is not only genetic, but due to the heterogeneous character of the disease, it is also strongly influenced by lifestyle. This disease, based on the malfunction of our immune system in RA, is still incurable. The treatment of RA uses conventional synthetic drugs as well as biological treatment. To diagnose the effect of anti-rheumatic therapy, monitoring and evaluating the response to treatment is necessary. Important indicators of RA activity, functional status, quality of life, and structural progression of the disease are important. In clinical practice, we use DAS 28 composite system according to recommendation of ČRS. Recent discoveries in the area of diagnostics raise the question of whether some miRNAs could be appropriate biomarkers of RA progression. In my diploma thesis, I summarize available knowledge in this field, obtained from...
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Frekvence výskytu vybraných bodových polymorfismů CYP2C8 a MDR1 v české populaci a jejich vliv na působení amiodaronu / Frequency of occurrence of selected single nucleotide polymorphisms of CYP2C8 and MDR1 in the Czech population and their influence on the effect of amiodaronePechandová, Kristina January 2013 (has links)
Frequency of occurrence of selected single nucleotide polymorphisms of CYP2C8 and MDR1 in the Czech population and their influence on the effect of amiodarone Introduction: Variability in drug response is sometimes conditioned by genetic differences in the metabolism and the transport of drugs. Interindividual differences are often caused by polymorphisms affecting biotransformation activity of enzymes and expression of transporters. In the thesis we paid attention to the cytochrome P450 CYP2C8 and MDR1. First, we described the frequency of occurrence of selected variant alleles CYP2C8 * 2, CYP2C8 * 3 (2 substitution in exon 3 and 8, CYP2C8 and CYP2C8 * 3G416A * 3A1196G), CYP2C8 * 4, CYP2C8 P404A in the healthy Czech population and MDR1 variant alleles in these exons: 26 C3435T, 21 G2677A/T, 12 C1236T a 17 T-76A. Subsequently, we studied the influence of these polymorphisms on effects of amiodarone in the selected group of patients. Methods: We determined genotypes MDR1 a CYP2C8 by PCR-RFLP by using restriction enzymes and specific primers. We determined the frequency of MDR1 genotypes in 189 healthy volunteers and CYP2C8 in 161 healthy subjects. Further we included into the study 63 patients treated with amiodarone for longer than two months. Their treatment was assessed from medical records and...
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Cytochrom P450 oxidoreduktáza: Strukturálně funkční studie. Molekulární patologie Antley - Bixlerova syndromu. / Cytochrome P450 oxidoreductase: Structurally functional study. Molecular pathology of Antley-Bixler syndrome.Tomková, Mária January 2015 (has links)
NADPH-P450 oxidoreductase (POR) is a membrane bound flavoprotein that donates electrons to a wide spectrum of heme-containing proteins, among which are several steroidogenic and many xenobiotics-metabolizing enzymes. Given the important role of POR protein in drug metabolism and pharmacogenomics, there is a particular need to understand the contributions of POR genetic variants to these processes. Mutations in POR gene cause a disorder called POR deficiency, which manifests with a wide phenotypic spectrum ranging from disordered steroidogenesis to skeletal malformation, namely, Antley-Bixler syndrome (ABS). The aim of the present work was to investigate the POR gene in patients suspected to have POR deficiency syndrome from Czech Republic and to perform genotyping in Czech and Jewish control populations. We analyzed 644 alleles in unrelated individuals from the general Czech population and 1128 alleles in Jewish population, where 330 alleles were of Askhenazi and 798 of Sephardic Jews. We have also studied the impact of selected new genetic variants on POR activity and identified fourteen amino acid variations, two of which we have studied in detail to establish their influence on POR activity. Using the available human POR three-dimensional structure, we then modelled the newly identified variants...
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Cytochrom P450 oxidoreduktáza: Strukturálně funkční studie. Molekulární patologie Antley - Bixlerova syndromu. / Cytochrome P450 oxidoreductase: Structurally functional study. Molecular pathology of Antley-Bixler syndrome.Tomková, Mária January 2015 (has links)
NADPH-P450 oxidoreductase (POR) is a membrane bound flavoprotein that donates electrons to a wide spectrum of heme-containing proteins, among which are several steroidogenic and many xenobiotics-metabolizing enzymes. Given the important role of POR protein in drug metabolism and pharmacogenomics, there is a particular need to understand the contributions of POR genetic variants to these processes. Mutations in POR gene cause a disorder called POR deficiency, which manifests with a wide phenotypic spectrum ranging from disordered steroidogenesis to skeletal malformation, namely, Antley-Bixler syndrome (ABS). The aim of the present work was to investigate the POR gene in patients suspected to have POR deficiency syndrome from Czech Republic and to perform genotyping in Czech and Jewish control populations. We analyzed 644 alleles in unrelated individuals from the general Czech population and 1128 alleles in Jewish population, where 330 alleles were of Askhenazi and 798 of Sephardic Jews. We have also studied the impact of selected new genetic variants on POR activity and identified fourteen amino acid variations, two of which we have studied in detail to establish their influence on POR activity. Using the available human POR three-dimensional structure, we then modelled the newly identified variants...
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