Influence of genetic factors on drug treatment efficacy and safety in cardiovascular diseases

Farmakoterapia może być w wielu przypadkach nieskuteczna lub spowodować niebezpieczne dla życia działania niepożądane. Jednym z powodów może być osobnicza wrażliwość pacjenta na podany lek, związana z jego genotypem. W artykule opisano istotne klinicznie polimorfizmy genów kodujących: enzymy metabolizujące leki (CYP2C9, CYP2D6, CYP3A), białka transportujące leki przez błony biologiczne (glikoproteina-P) oraz receptory farmakologiczne leków, ze szczególnym uwzględnieniem leków stosowanych w chorobach sercowo-naczyniowych. Polimorfizmy te są spowodowane zamianą pojedynczych nukleotydów, rzadko delecją lub insercją nukleotydów. Mogą one być przyczyną braku efektów terapeutycznych lub groźnych dla życia działań niepożądanych.Drug treatment is in many cases ineffective. Besides patients who do not respond to the treatment, adverse drug reactions as a consequence of the treatment are a major clinical problem. This review presents clinical implications and molecular mechanisms of genetic polymorphisms of drug metabolizing enzymes (CYP2C9, CYP2D6, CYP3A), drug transporters (P-glycoprotein) and drug receptors, which play a significant role in intersubject variability. Polymorphisms in the genes can affect an individual’s risk of having an adverse drug reaction, or can alter the efficacy of drug treatment in that individual

Taxonomic individuality of Leonurus cardiaca and Leonurus quinquelobatus in view of morphological and molecular studies

The main goal of this study was to determine the number and taxonomic rank of taxa belonging to the complex Leonurus cardiaca agg. in Poland. Based on statistical analysis of selected features, two morphological forms of this plant were distinguished. In order to determine their genetic polymorphism and the relationships between them, the nuclear, mitochondrial and chloroplast genomes were analysed with the use of RAPD and PCR–RFLP markers. 39 RAPD primers produced a total of 234 nuclear DNA fragments, of which 128 were polymorphic and distributed almost equally between two forms. It was found that 87 % of the compared pairs of RAPD profiles differ from each other. Five chloroplast and two mitochondrial primer pairs were used to amplify non-coding regions of organelle genomes. Restriction analysis revealed uniformity of mtDNA and occurrence of two cpDNA haplotypes, corresponding to naked and hairy forms of L. cardiaca agg. The obtained results justifies the recognition of these forms as separate species L. cardiaca s. s. L. and L. quinquelobatus Gilib., respectively. The distribution of both species in Poland is given in the paper

Farmakologiczne podstawy immunoterapii

Współczesna farmakologia dysponuje coraz większymi możliwościami stosowania nowoczesnych postaci leków (przygotowywanych zgodnie ze złożonymi procedurami biotechnologicznymi), dostosowując formy i technikę ich podawania do przebiegu złożonych procesów etiopatologicznych określonych stanów klinicznych. Immunofarmakologia opiera się na klasycznych lekach immunomodulacyjnych, a zwłaszcza immunosupresyjnych - glikokortykosteroidach, cyklosporynie A, takrolimusie, sirolimusie, metotreksacie, mykofenolacie mofetilu, i cytostatykach typu azatiopryna, mitoksantron. Coraz częściej sięga się także do leków biologicznych. W artykule przedstawiono najważniejsze pojęcia dotyczące tej szybko rozwijającej się grupy leków o działaniu immunomodulacyjnym, możliwości ich zastosowania, a także niebezpieczeństwa wczesnych i odległych działań niepożądanych. Polski Przegląd Neurologiczny 2009; 5 (4): 194-20

Malus ×oxysepala (M. domestica Borkh. × M. sylvestris Mill.) – a new spontaneous apple hybrid

A study of the three Malus species (M. domestica, M. sylvestris, and a hybrid species, M. domestica × M. sylvestris, which was named M. ×oxysepala) was carried out based on the morphological and micromorphological features and molecular investigation. Observations performed for 47 quantitative traits showed that this hybrid species exhibits intermediate values between M. domestica and M. sylvestris, or are similar to traits of one of the parents. Sepals proved to be the best diagnostic feature because they were acuminate and much longer than sepals in M. domestica and M. sylvestris. Seed testa cells are distinct, rimmed with straight anticlinal walls and strongly bulged periclinal walls. Simultaneous genetic analyses based on PCR RAPD reactions fully confirmed earlier morphological observations. Genetic profiles of the hybrid obtained with the use of 30 primers, next to species-specific amplification products, contain common products with each of the parents. However, both the profile analysis and the dendrogram constructed on its basis showed that the hybrid is genetically closer to M. sylvestris

Polimorfizm genu oksydoreduktazy cytochromu P450 a farmakokinetyka pantoprazolu u zdrowych ochotników

Genetycznie uwarunkowana aktywność enzymów metabolizujących leki może mieć znaczenie dla bezpieczeństwa i skuteczności leczenia. We wcześniejszych badaniach wykazano, że na aktywność enzymatyczną CYP2C19 może wpływać nie tylko polimorfizm genu kodującego ten cytochrom, lecz także zawartość reduktazy cytochromu P450 (POR) w mikrosomach ludzkich hepatocytów. Ludzki gen POR wykazuje dużą zmienność, a allel POR*28 jest związany ze zwiększoną aktywnością reduktazy, co w konsekwencji może prowadzić do zwiększonej aktywności układu CYP P450, w tym enzymu CYP2C19. Celem badania było określenie związku pomiędzy polimorfizmem genu POR a parametrami farmakokinetycznymi pantoprazolu, substratu CYP2C19 w grupie zdrowych ochotników. W analizie uwzględniono także warianty genu CYP2C19. U 30 osób, u których wykonano badanie pod kątem występowania jednonukleotydowych polimorfizmów: rs4244285 (681G>A, CYP2C19*2), rs12248560 (-806C>T, CYP2C19*17) oraz rs1057868 (31696C>T, POR*28). Stężenia pantoprazolu w osoczu zmierzono metodą wysokosprawnej chromatografii cieczowej w ciągu 8 godz. od przyjęcia pojedynczej doustnej dawki leku (40 mg). Nie stwierdzono istotnych różnic w stężeniu pantoprazolu pomiędzy osobami o różnych genotypach POR (*1/*1, *1/*28 i *28/*28). Analiza wieloczynnikowa wykazała, że genotyp CYP2C19 istotnie wpływał na wartość wszystkich analizowanych parametrów farmakokinetycznych (p < 0.05), podczas gdy genotyp POR nie był istotnie związany z żadnym z nich. Wyniki badania wskazują, że polimorfizm genu POR nie wpływa istotnie na farmakokinetykę pantoprazolu.It has recently been demonstrated that CYP2C19 activity may be influenced not only by CYP2C19 polymorphism, but also cytochrome P450 oxidoreductase (POR) protein abundance in human liver microsomes. The human POR gene is highly polymorphic and a common POR*28 allele is associated with increased POR activity, which may result in increased CYP P450 activity (including CYP2C19). The aim of the current study was to evaluate the association between POR and CYP2C19 polymorphisms and CYP2C19 substrate pharmacokinetics, i.e. pantoprazole, in Polish Caucasian healthy volunteers. The study enrolled 30 subjects, genotyped for rs4244285 (681G>A, CYP2C19*2), rs12248560 (-806C>T, CYP2C19*17) and rs1057868 (31696C>T, POR*28). Pantoprazole concentration in plasma was determined by validated highperformance liquid-chromatography method 1 h, 2 h, 3 h, 4 h, 6 h and 8 h after a single oral 40 mg dose of the drug. No significant differences in the drug concentrations between POR*1/*1, POR*1/*28 and POR*28/*28 carriers were observed. Multivariate analysis revealed that the CYP2C19 genotype significantly influenced all the investigated pharmacokinetic parameters (p < 0.05), while the POR genotype was not associated with any of the parameters. The results of the current study suggest that POR polymorphism does not significantly influence pantoprazole pharmacokinetics

Abscisic Acid Insensitive 4 transcription factor is an important player in the response of Arabidopsis thaliana to two-spotted spider mite (Tetranychus urticae) feeding.

Plants growing in constantly changeable environmental conditions are compelled to evolve regulatory mechanisms to cope with biotic and abiotic stresses. Effective defence to invaders is largely connected with phytohormone regulation, resulting in the production of numerous defensive proteins and specialized metabolites. In our work, we elucidated the role of the Abscisic Acid Insensitive 4 (ABI4) transcription factor in the plant response to the two-spotted spider mite (TSSM). This polyphagous mite is one of the most destructive herbivores, which sucks mesophyll cells of numerous crop and wild plants. Compared to the wild-type (Col-0) Arabidopsis thaliana plants, the abi4 mutant demonstrated increased susceptibility to TSSM, reflected as enhanced female fecundity and greater frequency of mite leaf damage after trypan blue staining. Because ABI4 is regarded as an important player in the plastid-to-nucleus retrograde signalling process, we investigated the plastid envelope membrane dynamics using stroma-associated fluorescent marker. Our results indicated a clear increase in the number of stroma-filled tubular structures deriving from the plastid membrane (stromules) in the close proximity of the site of mite leaf damage, highlighting the importance of chloroplast-derived signals in the response to TSSM feeding activity

The Magic of Sound and Colour. Multimodality in Eleanor Farjeon’s Martin Pippin Books and their translations into Polish

Eleanor Farjeon belonged to the most popular British authors writing for children in the first decades of the 20th century. However, very few of her stories have occurred in translation. There exist no translations of her major work, Martin Pippin in the Apple Orchard, and its sequel, Marin Pippin in the Daisy Field,into German, French, Spanish, Russian, or the Scandinavian languages. One of the reasons may be that in Eleanor Farjeon’s work, sound effects play a central role. Hertexts are multimodal in many aspects, but rhyme, wordplays, and linguistic jokes pose the utmost challenge to translators. However, theMartin Pippin books have beentranslated into Polish, by Hanna Januszewska. The article investigates the linguistic exponents of multimodality in Farjeon’s books and their equivalents in the Polish version. The theoretical framework is the translationshift approach [Vinay and Darbelnet1958/1995] and its later extensions. The conclusion is that Hanna Januszewska’s translation is an almost perfect example of functional equivalence