INTRODUCTION: Data on age-related differences in rejection rates, infectious episodes, and tacrolimus exposure in pediatric kidney transplant recipients (pKTRs) on a tacrolimus-based immunosuppressive regimen are scarce. METHODS: We performed a large-scale analysis of 802 pKTRs from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry from 40 centers in 14 countries. The inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least 2 years of follow-up. The patient population was divided into 3 age groups (infants and young children aged <6 years, school-aged children 6-12 years, and adolescents aged >12 years) to assess age-related differences in outcome. RESULTS: Median follow-up was 48 months (interquartile range [IQR], 36-72). Within the first 2 years posttransplant, infants, and young children had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P < 0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first-year posttransplant (21.7%) than infants and young children (12.6%, P = 0.007). Infants and young children had significantly lower tacrolimus trough levels, lower tacrolimus concentration-to-dose (C/D) ratios as an approximation for higher tacrolimus clearance, and higher tacrolimus interpatient variability (TacIPV) (all P < 0.01) than adolescents. CONCLUSION: This is the largest study to date in European pKTRs on a tacrolimus-based immunosuppressive regimen, and it shows important age-related differences in rejection rates, infection episodes, as well as tacrolimus exposure and clearance. This data suggests that immunosuppressive therapy in pKTRs should be tailored and personalized according to the age-specific risk profiles of this heterogeneous patient population. The data may serve as a benchmark for future studies with novel immunosuppressive drugs.

• Klíčová slova
• allograft rejection, hospitalization, infection, pediatric kidney transplantation, tacrolimus,
• Publikační typ
• časopisecké články MeSH

Idiopathic infertility is a serious problem, which can be caused and explained by exposure to endocrine disruptors, such as bisphenols. In our study, we studied transactional exposure to bisphenol and its effects on newborn male mice throughout their reproductive life. Newborn male mice were exposed to bisphenol S and bisphenol F through maternal milk from post-natal day 0 to post-natal day 15 at concentrations of 0.1 ng.g/bw/day and 10 ng.g/bw/day, respectively. Although there were minimal differences between the control and experimental groups in testicular tissue quality and spermatozoa quality, we discovered an interesting influence on early embryonic development. Moderate doses of bisphenol negatively affected cleavage of the early embryo and subsequently, the blastocyst rate, as well as the number of blastomeres per blastocyst. In our study, we focused on correlations between particular stages from spermatogenesis to blastocyst development. We followed epigenetic changes such as dimethylation of histone H3 and phosphorylation of histone H2 from germ cells to blastocysts; we discovered the transfer of DNA double-strand breaks through the paternal pronucleus from spermatozoa to blastomeres in the blastocyst. We elucidated the impact of sperm DNA damage on early embryonic development, and our results indicate that idiopathic infertility in adulthood may have causes related to the perinatal period.

• Klíčová slova
• DNA damage, bisphenol, idiopathic infertility, nursing exposure, spermatogenesis,
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVES: Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 µg selexipag (Treatment A) vs. 4 paediatric tablets of 50 µg (Treatment B) in healthy adult male subjects. METHODS: This was an open-label, randomized, two-treatment, two-period, crossover biocomparison study. Bioequivalence criteria were explored and safety variables (vital signs, electrocardiogram, and laboratory parameters) were assessed. RESULTS: The exploratory analysis showed that the 90% confidence intervals of geometric mean ratio (Treatment B/Treatment A) for maximum plasma concentration (C max), area under the plasma concentration-time curve from zero to infinity (AUC0-∞) of ACT-333679, as well as AUC0-∞ of selexipag, were within the bioequivalence interval (0.80, 1.25). In addition, no relevant difference in C max for selexipag between the two treatments can be concluded. Single oral dose administration of 200 µg selexipag as one tablet of 200 µg or four tablets of 50 µg was well tolerated. CONCLUSIONS: Pharmacokinetic characteristics of selexipag and its metabolite ACT-333679 following administration of one adult tablet of 200 µg selexipag and four paediatric tablets of 50 µg selexipag were comparable. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02745860.

• MeSH
• acetamidy škodlivé účinky   krev   farmakokinetika   MeSH
• acetáty škodlivé účinky   farmakokinetika   MeSH
• aplikace orální MeSH
• dospělí MeSH
• klinické křížové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• pyraziny škodlivé účinky   krev   farmakokinetika   MeSH
• terapeutická ekvivalence MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• (4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid MeSH Prohlížeč
• acetamidy MeSH
• acetáty MeSH
• pyraziny MeSH
• selexipag MeSH Prohlížeč