Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl

Conclusion Both voriconazole and fluconazole delay the elimination of fentanyl significantly. Caution should be exercised, especially in patients who are given voriconazole or fluconazole during long-lasting fentanyl treatment, because insidiously elevated fentanyl concentration may lead to respiratory depression

Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2-4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose-adjusted geometric mean area under the concentration-time curve from zero to infinity (AUC(0-infinity)) of ibrutinib 10.0-fold (90% confidence interval (CI) 7.2-13.9; P <0.001) and peak plasma concentration (C-max) 8.8-fold (90% CI 6.3-12.1; P <0.001). During itraconazole, the intersubject variation for the AUC(0-infinity) (55%) and C-max (53%) was around half of that during placebo (104%; 99%). In conclusion, itraconazole markedly increases ibrutinib bioavailability and decreases its interindividual variability, offering a possibility to improved dosing accuracy and cost savings.Peer reviewe

Strategies in conveying information about unshared events using aided communication

Describing events may be challenging for any child, but children who use communication aids may face unique linguistic, pragmatic, and strategic challenges in conveying information with the communication means they have available. This study explores strategies used by young, aided communicators when describing the content of a video unknown to their communication partners. The participants of the study were 48 aided communicators (aged 5;3-15;2) from nine countries and seven language groups and their communication partners (parents, professionals, and peers) who used natural speech. Descriptive and statistical analyses were utilized to investigate the relationships between individual characteristics, linguistic and non-linguistic factors, linguistic strategies, and performance in conveying the content of the video event. Analyses of the 48 videotaped interactions revealed the use of a variety of linguistic elements and multimodal strategies, demonstrating both creativity and challenges. Success in relaying messages was significantly related to age, mode of communication, and individual profiles, such as everyday communication functioning and comprehension of grammar. Measures of receptive vocabulary and non-verbal reasoning were not significantly related to communicative success. The use of shared context and negotiation of meaning of potentially ambiguous utterances demonstrate the shared responsibility of disambiguation and meaning construction in interactions involving aided and naturally speaking communicators.Peer reviewe

The role of comptetitors for Chrysomela lapponica, a north Eurasian willow pest, in pioneering a new host plant

The Palaearctic leaf beetle Chrysomela lapponica usually feeds upon willows in the northern region of its occurrence. However, in Central Europe, some populations are known that have specialised on birch. In this study, we investigated the significance of other herbivores occurring together on the same host plants as possible exploitative competitors of C. lapponica. Two populations were studied: a population from Finland specialised on the willow Salix borealis, and a population from the Czech Republic, specialised on the birch Betula pubescens. Abundances of folivorous and suctivorous insects on both host plants were recorded at both population sites. The willow leaf beetle Phratora vitellinae was the most abundant herbivorous insect at both study sites on willow. A field study was conducted to examine the effects of P. vitellinae on the performance of C. lapponica. The presence of P. vitellinae larvae on the same twig upon which C. lapponica larvae were feeding did not affect increase of body weight in C. lapponica larvae. Thus, the high resource availability of both willows and birches suggest that interspecific competition is unlikely to be a selection factor driving the evolution of host shift in C. lapponica

Constructing narratives to describe video events using aided communication

Narratives are a pervasive form of discourse and a rich source for exploring a range of language and cognitive skills. The limited research base to date suggests that narratives generated using aided communication may be structurally simple, and that features of cohesion and reference may be lacking. This study reports on the analysis of narratives generated in interactions involving aided communication in response to short, silent, video vignettes depicting events with unintended or unexpected consequences. Two measures were applied to the data: the Narrative Scoring Scheme and the Narrative Analysis Profile. A total of 15 participants who used aided communication interacted with three different communication partners (peers, parents, professionals) relaying narratives about three video events. Their narratives were evaluated with reference to narratives of 15 peers with typical development in response to the same short videos and to the narratives that were interpreted by their communication partners. Overall, the narratives generated using aided communication were shorter and less complete than those of the speaking peers, but they incorporated many similar elements. Topic maintenance and inclusion of scene-setting elements were consistent strengths. Communication partners offered rich interpretations of aided narratives. Relative to the aided narratives, these interpreted narratives were typically structurally more complete and cohesive and many incorporated more elaborated semantic content. The data reinforce the robust value of narratives in interaction and their potential for showcasing language and communication achievements in aided communication.Peer reviewe

Comparative Hepatic and Intestinal Efflux Transport of Statins

Previous studies have shown that lipid-lowering statins are transported by various ATP-binding cassette (ABC) transporters. However, because of varying methods, it is difficult to compare the transport profiles of statins. Therefore, we investigated the transport of 10 statins or statin metabolites by six ABC transporters using human embryonic kidney cell-derived membrane vesicles. The transporter protein expression levels in the vesicles were quantified with liquid chromatography-tandem mass spectrometry and used to scale the measured clearances to tissue levels. In our study, apically expressed breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) transported atorvastatin, fluvastatin, pitavastatin, and rosuvastatin. Multidrug resistance-associated protein 3 (MRP3) transported atorvastatin, fluvastatin, pitavastatin, and, to a smaller extent, pravastatin. MRP4 transported fluvastatin and rosuvastatin. The scaled clearances suggest that BCRP contributes to 87%-91% and 84% of the total active efflux of rosuvastatin in the small intestine and the liver, respectively. For atorvastatin, the corresponding values for P-gp-mediated efflux were 43%-79% and 66%, respectively. MRP3, on the other hand, may contribute to 23%-26% and 25%-37% of total active efflux of atorvastatin, fluvastatin, and pitavastatin in jejunal enterocytes and liver hepatocytes, respectively. These data indicate that BCRP may play an important role in limiting the intestinal absorption and facilitating the biliary excretion of rosuvastatin and that P-gp may restrict the intestinal absorption and mediate the biliary excretion of atorvastatin. Moreover, the basolateral MRP3 may enhance the intestinal absorption and sinusoidal hepatic efflux of several statins. Taken together, the data show that statins differ considerably in their efflux transport profiles. SIGNIFICANCE STATEMENT This study characterized and compared the transport of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid and four atorvastatin metabolites by six ABC transporters (BCRP, MRP2, MRP3, MRP4, MRP8, P-gp). Based on in vitro findings and protein abundance data, the study concludes that BCRP, MRP3, and P-gp have a major impact in the efflux of various statins. Together with in vitro metabolism, uptake transport, and clinical data, our findings are applicable for use in comparative systems pharmacology modeling of statins.Peer reviewe

Stereospecific modulation of GABA(A) receptor function by urocanic acid isomers

A deamination product of histidine, urocanic acid, accumulates in the skin of mammals as trans-urocanic acid. Ultraviolet (UV) irradition converts it to the cis-isomer that is an important mediator in UV-induced immunosuppression. We have recently shown that urocanic acid interferes with the agonist binding to GABAA receptors. We now report that the effects of urocanic acid on binding of a convulsant ligand (t-butylbicyclo[35S]phosphorothionate) to GABAA receptors in brain membrane homogenates are dependent on pH of the incubation medium, the agonistic actions being enhanced at the normal pH of the skin (5.5). Using Xenopus laevis oocytes expressing recombinant rat alpha1beta1gamma2S GABAA receptors, the low pH potentiated the direct agonistic action of trans-urocanic acid under two-electrode voltage-clamp, whereas cis-urocanic acid retained its low efficacy both at pH 5.5 and 7.4. The results thus indicate clear differences between urocanic acid isomers in functional activity at one putative receptor site of immunosuppression, the GABAA receptor, the presence of which in the skin remains to be demonstrated.</p

A Mechanistic, Model-Based Approach to Safety Assessment in Clinical Development

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