320 research outputs found
Irinotecan pharmacokinetics-pharmacodynamics: the clinical relevance of prolonged exposure to SN-38
We have shown previously that the terminal disposition half-life of SN-38, the active metabolite of irinotecan, is much longer than earlier thought. Currently, it is not known whether this prolonged exposure has any relevance toward SN-38-induced toxicity. Here, we found that SN-38 concentrations present in human plasma for up to 3 weeks after a single irinotecan infusion induce significant cytotoxicity in vitro. Using pharmacokinetic data from 26 patients, with sampling up to 500 h, relationships were evaluated between systemic exposure (AUC) to SN-38 and the per cent decrease in absolute neutrophil count (ANC) at nadir, or by taking the entire time course of ANC into account (AOC). The time course of SN-38 concentrations (AUC500 h) was significantly related to this AOC (P<0.001). Based on these findings, a new limited-sampling model was developed for SN-38 AUC500 h using only two timed samples: AUC500 h=(6.588×C2.5 h)+(146.4×C49.5 h)+15.53, where C2.5 h and C49.5 h are plasma concentrations at 2.5 and 49.5 h after start of infusion, respectively. The use of this limited-sampling model may open up historic databases to retrospectively obtain information about SN-38-induced toxicity in patients treated with irinotecan
Oscillatory surface rheotaxis of swimming E. coli bacteria
Bacterial contamination of biological conducts, catheters or water resources
is a major threat to public health and can be amplified by the ability of
bacteria to swim upstream. The mechanisms of this rheotaxis, the reorientation
with respect to flow gradients, often in complex and confined environments, are
still poorly understood. Here, we follow individual E. coli bacteria swimming
at surfaces under shear flow with two complementary experimental assays, based
on 3D Lagrangian tracking and fluorescent flagellar labelling and we develop a
theoretical model for their rheotactic motion. Three transitions are identified
with increasing shear rate: Above a first critical shear rate, bacteria shift
to swimming upstream. After a second threshold, we report the discovery of an
oscillatory rheotaxis. Beyond a third transition, we further observe
coexistence of rheotaxis along the positive and negative vorticity directions.
A full theoretical analysis explains these regimes and predicts the
corresponding critical shear rates. The predicted transitions as well as the
oscillation dynamics are in good agreement with experimental observations. Our
results shed new light on bacterial transport and reveal new strategies for
contamination prevention.Comment: 12 pages, 5 figure
Investigating online psychological treatment for adolescents with a visible difference in the Dutch YP Face IT study: protocol of a randomised controlled trial
Imatinib, sunitinib and pazopanib:From flat-fixed dosing towards a pharmacokinetically guided personalized dose
Tyrosine kinase inhibitors (TKIs) are anti-cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure-treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib
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Transforming bonds: ritualising post-mortem relationships in the Netherlands
People continue relationships with their dead in a variety of ways. Since the 1990s, the idea of ‘continuing bonds’ has provided a framework for exploring and understanding post-mortem relationships. However, the dynamics of the bonds between the living and the dead have received little attention. By looking at the intersection of things, practices and spaces, this paper demonstrates that expressions of continuing bonds do not always point to continuity, and indeed can signify discontinuity. It explores the ‘transforming bonds’ between the recently bereaved and their deceased in the Netherlands, illustrating how post-mortem relationships change and how such changes affect the social location of the deceased and the bereaved. By attending to the ritual dynamics of separation, transition and integration, two aspects of the social and material relationships between the living and the dead are highlighted. First, attention is given to the ways wherein the bereaved relocate their deceased through material objects within and outside of their homes, enabling them to renegotiate the absence–presence of the deceased. Second, the paper illustrates that personalised incorporation practices are inevitably linked to negotiations and contestations in the social sphere, and the norms and values of the social environment
Impact of concomitant administration of gastric acid-suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials
Purpose: Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid-suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects.Experimental Design: The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients.Results: Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11-1.99; P = 0.01]. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31-2.49; P < 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51-1.34; P = 0.43 for PFS and HR, 0.84; 95% CI, 0.48-1.48; P = 0.54 for OS).Conclusions: Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy
Tyrosine Kinase Inhibitors and Proton Pump Inhibitors:An Evaluation of Treatment Options
Tyrosine kinase inhibitors (TKIs) have rapidly become an established factor in oncology, and have been shown to be effective in a wide variety of solid and hematologic malignancies. Use of the oral administration route of TKIs offers flexibility and is convenient for the patient; however, despite these advantages, the oral route of administration also causes a highly relevant new problem. Acid-inhibitory drugs, such as proton pump inhibitors (PPIs), increase the intragastric pH, which may subsequently decrease TKI solubility, bioavailability, and treatment efficacy. Clear and practical advice on how to manage PPI use during TKI therapy is currently not available in the literature. Since PPIs are extensively used during TKI therapy, prescribers are presented with a big dilemma as to whether or not to continue the combined treatment, resulting in patients possibly being deprived of optimal therapy. When all pharmacological characteristics and data of either TKIs and PPIs are considered, practical and safe advice on how to manage this drug combination can be given
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