Adaption of Norway spruce and European beech forests under climate change: from resistance to close-to-nature silviculture

In time of climate change, close-to-nature silviculture is growing in importance as a tool for future forest management. The paper study the tree layer and natural regeneration of monospecific Norway spruce (Picea abies [L.] Karst.), trough mixed spruce-beech to dominant European beech (Fagus sylvatica L.) forests in Jizerské hory Mts., the Czech Republic. In the locality, shelterwood and selection system have been applied since 2000. The research objectives were to evaluate production parameters, structural diversity, species richness, natural regeneration dynamics and radial growth of individual tree species in relation to climatic factors and air pollution. The stand volume on permanent research plots amounted to 441 – 731 m3 ha−1 in initial stage of transformation. Natural regeneration showed high expansion of beech and decrease of spruce compared to mature tree species composition. Radial growth of spruce was in significant negative correlation with SO2 and NOX concentrations compared to no effect on beech increment. Moreover, spruce was more sensitive to significant years with extreme low radial growth. Beech was more stable in radial growth. Spruce was more resistant to air pollution and climatic stress in mixed stands. Low temperature was limiting factor of radial growth together with climate extremes (such as strong frosts and more frequent droughts) and biotic factors (bark beetle, beech scale). Close-to-nature management supporting admixed tree species should lead in future to diversification of stand structure toward higher species, spatial and age structure to mitigate negative effect of climatic change

Ganciclovir Pharmacokinetics and Individualized Dosing Based on Covariate in Lung Transplant Recipients

The aim of this prospective study was to evaluate the pharmacokinetics of ganciclovir in lung transplant recipients, to explore its covariates, and to propose an individualized dosing regimen. Ganciclovir was administered according to the protocol in a standardized intravenous dose of 5 mg/kg twice daily. Serum ganciclovir concentrations were monitored as a trough and at 3 and 5 h after dosing. Individual ganciclovir pharmacokinetic parameters were calculated in a two-compartmental pharmacokinetic model, while regression models were used to explore the covariates. Optimal loading and maintenance doses were calculated for each patient. In lung transplant recipients (n = 40), the median (IQR) ganciclovir total volume of distribution and clearance values were 0.65 (0.52–0.73) L/kg and 0.088 (0.059–0.118) L/h/kg, respectively. We observed medium-to-high inter-individual but negligible intra-individual variability in ganciclovir pharmacokinetics. The volume of distribution of ganciclovir was best predicted by height, while clearance was predicted by glomerular filtration rate. Bodyweight-normalized clearance was significantly higher in patients with cystic fibrosis, while distribution half-life was reduced in this subgroup. On the basis of the observed relationships, practical nomograms for individualized ganciclovir dosing were proposed. The dosing of ganciclovir in patients with cystic fibrosis requires special caution, as their daily maintenance dose should be increased by approximately 50%

Pharmacokinetic Variability in Pre-Clinical Studies: Sample Study with Abiraterone in Rats and Implications for Short-Term Comparative Pharmacokinetic Study Designs

One of the major concerns for all in vivo experiments is intra- and inter-subject variability, which can be a great source of inaccuracy. The aim of this study is, therefore, to estimate the ability of parallel vs. cross-over design studies in order to describe the relative pharmacokinetic performance of the studied drug formulations. We analyzed the data from a drug development program that examined the performance of innovative abiraterone acetate formulations against the identical reference product in three stages. In stages 1–3, groups A–F were dosed with the reference product once in a parallel manner. Stage 4 was performed to evaluate the intra-individual variability (IIV) by repeated administration of the reference product to the same animals. Although the geometric mean (90% CI) values of abiraterone AUClast in groups A–F were similar to the IIV group (24.36 (23.79–41.00) vs. 26.29 (20.56–47.00) mg/mL·min·g), the results generated in the isolated parallel groups provided imprecise estimates of the true AUClast values ranging from 9.62 to 44.62 mg/mL·min·g due to chance. Notably, in 4 out of 15 possible pair comparisons between the parallel groups, the confidence intervals did not include 100%, which is the true ratio for all comparisons tested after identical formulation administration to all groups. A cross-over design can significantly improve the methodology in short-term comparative pre-clinical pharmacokinetic studies, and can provide more precise and accurate results in comparison to more traditional pre-clinical study designs

Table1_Ivacaftor pharmacokinetics and lymphatic transport after enteral administration in rats.DOCX

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration.Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport.Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively.Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.</p