10 research outputs found
Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients
No full textSequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (C(max,ss)) and area under the curve (AUC(tau,ss)) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUC(tau,ss), C(max,ss), and trough (C(min,ss)) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C(max,ss) occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUC(tau,ss) at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUC(tau,ss), C(max,ss), and C(min,ss) were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments
Absolute oral bioavailability and disposition of deferasirox in healthy human subjects.
No full textDeferasirox is a novel iron chelator formulated as tablets for dispersion (suspension) for once-a-day oral administration. The current study evaluated the absolute bioavailability of a single 375-mg oral dose of deferasirox administered in the form of tablets compared with a 130-mg intravenous infusion of deferasirox. Since this was a first-in-man study using the deferasirox intravenous (IV) formulation, the safety and tolerability of the IV formulation was evaluated in a pilot phase with a lower dose (65 mg) in 3 subjects prior to the main phase. The main study phase consisted of 17 healthy male volunteers. Plasma concentrations of deferasirox were measured following each treatment, and pharmacokinetic parameters including absolute oral bioavailability were determined. Absolute oral bioavailability of the deferasirox tablets was 70% (90% confidence interval, 62%-80%). Deferasirox was characterized as having a low plasma clearance of 3.53 (+/- 0.87) L/h. A small volume of distribution of deferasirox at steady state (V(ss)) of 14.37 (+/-2.69 L) was determined, indicating a low tissue distribution
Deferasirox does not induce QT/QTc-prolongation in healthy subjects.
No full textThe International Conference on Harmonization (ICH) E14 guidance recommends that almost all drugs should undergo careful clinical testing in a thorough QT/QTc study. Deferasirox (Exjade, ICL670) is a once-daily oral iron chelator, developed for the treatment of blood transfusion-related iron overload
Effets odorants Du côté de chez Swann
No full textInternational audienceThis article argues for a multisensory approach to architectural and urban experience, with a particular focus on olfaction as a spatially situated sense. Moving beyond vision-centered definitions of architecture, it considers smell as a key component of lived spatial experience and atmosphere. Drawing on concepts from sensory studies and environmental psychology, the author mobilizes the notion of effects—originally developed in sound studies—to analyze ordinary olfactory experiences in the built environment.Based on a grounded theory methodology, the research draws on more than 150 short olfactory narratives collected through semi-structured interviews. These accounts were analyzed in relation to interdisciplinary knowledge on smell perception, leading to the construction of a repertoire of forty-five “olfactory effects.” These effects describe recurrent olfactory–spatial situations (scenosmies) and are organized into two main families: dynamic effects (related to movement, spatial distribution, and temporal processes) and semantic effects (related to meaning, identification, and interpretation of odors). Examples include attraction and repulsion, diffusion and invasion, halos and olfactory zoning, the “Madeleine effect” (olfactory reminiscence), iconic and generic odors, accords, and olfactory synecdoche.Beyond its analytical value for architecture and urban design, the article explores the transdisciplinary potential of this repertoire by applying it to literary analysis. A systematic reading of Du côté de chez Swann by Marcel Proust identifies twenty-two passages in which odors and places interact, forming literary scensomies. The analysis shows that, contrary to the dominant focus on memory and reminiscence associated with the famous madeleine episode, Proust’s text primarily emphasizes the spatial and dynamic modalities of odor diffusion—such as localization, irruption, and invasion. Dynamic spatial effects largely prevail over semantic ones.The article concludes by proposing the concept of spatio-olfactory thinking as a tool for both architectural design and literary analysis. In architecture, understanding how odors contribute to spatial identity, familiarity, and sensory transitions may support a rebalancing of sensory priorities beyond vision. In literature, analyzing olfactory effects rather than symbolic meanings alone opens new perspectives on how sensory atmospheres and spatial experiences are constructed through smell
Absence of an effect of a single-dose deferasirox on the steady-state pharmacokinetics of digoxin.
No full textDeferasirox (Exjade, ICL670) is a potent iron chelator, recently approved as first-line therapy for the treatment of blood-transfusion-related iron overload. Iron deposition in the heart may lead to cardiac dysfunction in patients with iron overload. Thus, the combination of cardiac glycosides and deferasirox is likely to be used in clinical practice
Randomized calcineurin inhibitor cross over study to measure the pharmacokinetics of co-administered enteric-coated mycophenolate sodium.
No full textEnteric-coated mycophenolate sodium (EC-MPS) (myfortic) is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying the release of MPA until the small intestine. A randomized, calcineurin inhibitor crossover, steady-state pharmacokinetic study in stable renal transplant patients receiving EC-MPS demonstrated increased MPA exposure of 19% higher, MPA C(max,ss) 19% lower and MPA C(min,ss) approximately twofold higher with tacrolimus, than cyclosporine microemulsion. No study drug-related adverse events were recorded, but mean blood glucose concentration was higher in patients receiving tacrolimus (p = 0.031). The dose changes in relation to MPA exposure in patients is dependent on the clinical situation and may not always be warranted. These observations should be taken into consideration when switching from one calcineurin inhibitor to another, but the final dosage should be based on both this pharmacokinetic data and the clinical situation
If Human Brain Organoids Are the Answer to Understanding Dementia, What Are the Questions?
No full textBecause our beliefs regarding our individuality, autonomy, and personhood are intimately bound up with our brains, there is a public fascination with cerebral organoids, the "mini-brain," the "brain in a dish". At the same time, the ethical issues around organoids are only now being explored. What are the prospects of using human cerebral organoids to better understand, treat, or prevent dementia? Will human organoids represent an improvement on the current, less-than-satisfactory, animal models? When considering these questions, two major issues arise. One is the general challenge associated with using any stem cell-generated preparation for in vitro modelling (challenges amplified when using organoids compared with simpler cell culture systems). The other relates to complexities associated with
defining and understanding what we mean by the term "dementia." We discuss 10 puzzles, issues, and stumbling blocks
to watch for in the quest to model "dementia in a dish."The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Australian Dementia Stem Cell Consortium has
received generous start-up travel grants from the Australian
NHMRC National Institute for Dementia Research. Authors have been supported by Dementia Australia Research
Foundation, Yulgilbar Alzheimer’s Research Program, DHB
Foundation (AP), Brain Foundation (DH, AP), the C.F. Leung
Memorial Trust (AP), the University of Melbourne (AP) and
Operational Infrastructure Support from the Victorian
Government (DH, AP), Monash University (AG), JO and JR
Wicking Trust (Equity Trustees) (ALC and AEK), University
of Sydney (MV), and generous gifts from the Sinclair, Smith
and Jolly families (MV). AEK is supported by a National Health
and Medical Research Council (NHMRC) of Australia Boosting
Dementia Research Leadership Fellowship (APP1136913). AG
is supported by a NHMRC-ARC Dementia Research
Development Fellowship (GNT1097461). AP is supported by
an ARC Future Fellowship (FT140100047) and a NHMRC
Senior Research Fellowship (1154389). LO is supported by a
NHMRC of Australia Boosting Dementia Research Leadership
Fellowship (APP1135720). MV is supported by a NHMRC
Career Development Fellowship (APP1112813). VG is supported by Australian Research Council’s Discovery Early
Career Researcher Award (DE180100775)
Effect of food, type of food, and time of food intake on deferasirox bioavailability: recommendations for an optimal deferasirox administration regimen.
No full textDeferasirox (ICL670) is representative of a new class of tridentate iron chelators, formulated as tablets for dispersion. Deferasirox has exhibited high potency and a clinically manageable safety profile in preclinical models and in an extensive clinical program. The effect of food and time of food intake on the pharmacokinetics of deferasirox was investigated in healthy volunteers and patients with transfusional hemosiderosis. The bioequivalence of a single oral dose of deferasirox (20 mg/kg) was assessed following administration either before a high-fat or standard breakfast or concurrent with a standard breakfast in comparison with fasted conditions in healthy volunteers. The bioavailability of deferasirox was determined following a single oral dose (20 mg/kg) under fed and fasted conditions in patients. These data show that the type of food, caloric content, and fat content of the meal influence the bioavailability of deferasirox when consumed concomitantly. In contrast, this is not the case when deferasirox is administered at least 30 minutes before a meal. In conclusion, it is recommended that deferasirox be administered at least 30 minutes prior to meals. When this is not feasible, deferasirox should be administered consistently at the same time before meals to limit the sources of variability that affect absorption
If Human Brain Organoids Are the Answer to Understanding Dementia, What Are the Questions?
No full text© The Author(s) 2020. Because our beliefs regarding our individuality, autonomy, and personhood are intimately bound up with our brains, there is a public fascination with cerebral organoids, the “mini-brain,” the “brain in a dish”. At the same time, the ethical issues around organoids are only now being explored. What are the prospects of using human cerebral organoids to better understand, treat, or prevent dementia? Will human organoids represent an improvement on the current, less-than-satisfactory, animal models? When considering these questions, two major issues arise. One is the general challenge associated with using any stem cell–generated preparation for in vitro modelling (challenges amplified when using organoids compared with simpler cell culture systems). The other relates to complexities associated with defining and understanding what we mean by the term “dementia.” We discuss 10 puzzles, issues, and stumbling blocks to watch for in the quest to model “dementia in a dish.
Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients
No full textSequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic®) and mycophenolate mofetil (MMF, CellCept®) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080mg bid or MMF 1500mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (Cmax,ss) and area under the curve (AUCτ,ss) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUCτ,ss, Cmax,ss, and trough (Cmin,ss) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C max,ss occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUCτ,ss at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUCτ,ss, Cmax,ss, and Cmin,ss were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments. © 2007 Blackwell Munksgaard
