Factors Affecting Pharmacokinetic Variability of Docetaxel

In the early 1960s, the US National Cancer Institute started a program aimed at the discovery of new anticancer drugs by releasing protocols for widespread screening of substances and extracts from various origins for antineoplastic activity. Of the more than 100,000 compounds from 35,000 plant species tested between 1960 and 1981, paclitaxel, a complex diterpene isolated from the Pacific Yew tree (Taxus brevifolia), proved one of the most interesting and active agents. Extensive studies on the synthesis of paclitaxel analogues and the development of structure-activity relationships have been carried out over the last few decades, and led in 1986 to the development of docetaxel, a semisynthetic taxane derivative prepared from a noncytotoxic precursor isolated from the European Yew tree (Taxus baccata). Following an extensive clinical evaluation program that started in 1990, docetaxel has currently been recognized as one of the most widely active agents available, and it has been approved in most countries for the treatment of advanced breast cancer and nonsmall cell lung cancer

Interparticle Potential up to Next-to-leading Order for Gravitational, Electrical, and Dilatonic Forces

Long-range forces up to next-to-leading order are computed in the framework of the Einstein-Maxwell-dilaton system by means of a semiclassical approach to gravity. As has been recently shown, this approach is effective if one of the masses under consideration is significantly greater than all the energies involved in the system. Further, we obtain the condition for the equilibrium of charged masses in the system.Comment: 19 pages, 19 figures, RevTeX4.1. Revised version, Title change

National Plans of Action (NPOAs) for reducing seabird bycatch: Developing best practice for assessing and managing fisheries impacts

Fisheries bycatch is one of the biggest threats to seabird populations. Managers need to identify where and when bycatch occurs and ensure effective action. In 1999, the Food and Agriculture Organization of the United Nations released the International Plan of Action for Reducing Incidental Catch of Seabirds in Longline Fisheries (IPOA-s) encouraging states to voluntarily assess potential seabird bycatch problems and implement a National Plan of Action (NPOA) if needed. However, the IPOA-s is ambiguous about the steps and objectives, diminishing its value as a conservation tool

BioAcoustica : a free and open repository and analysis platform for bioacoustics

We describe an online open repository and analysis platform, BioAcoustica (http://bio. acousti.ca), for recordings of wildlife sounds. Recordings can be annotated using a crowdsourced approach, allowing voice introductions and sections with extraneous noise to be removed from analyses. This system is based on the Scratchpads virtual research environment, the BioVeL portal and the Taverna workflow management tool, which allows for analysis of recordings using a grid computing service. At present the analyses include spectrograms, oscillograms and dominant frequency analysis. Further analyses can be integrated to meet the needs of specific researchers or projects. Researchers can upload and annotate their recordings to supplement traditional publication

Inhibition of OATP1B1 by tyrosine kinase inhibitors: In vitro-in vivo correlations

Background:Several tyrosine kinase inhibitors (TKIs) can decrease docetaxel clearance in patients by an unknown mechanism. We hypothesised that these interactions are mediated by the hepatic uptake transporter OATP1B1.Methods:The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent Oatp1b2. Pharmacokinetic studies were performed with Oatp1b2-knockout and OATP1B1-transgenic mice.Results:All docetaxel-interacting TKIs, including sorafenib, were identified as potent inhibitors of OATP1B1 in vitro. Although Oatp1b2 deficiency in vivo was associated with increased docetaxel exposure, single- or multiple-dose sorafenib did not influence docetaxel pharmacokinetics.Conclusion: These findings highlight the importance of identifying proper preclinical models for verifying and predicting TKI-chemotherapy interactions involving transporters

Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents

Background: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patients dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria.Methods:Three BSA bands were defined: BSA1.7 m2, 1.7 m2 BSA1.9 m 2, BSA1.9 m2 and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m 2, respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug.Results:For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between 14% and 22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P=0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs.Conclusion:For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure

Impact of non-menthol flavours in e-cigarettes on perceptions and use: an updated systematic review

Objectives Given the exponential increase in the use of e-cigarettes among younger age groups and in the growth in research on e-cigarette flavours, we conducted a systematic review examining the impact of non-menthol flavoured e-cigarettes on e-cigarette perceptions and use among youth and adults. Design PubMed, Embase, PyscINFO and CINAHL were systematically searched for studies published and indexed through March 2018. Eligibility criteria Quantitative observational and experimental studies that assessed the effect of non-menthol flavours in e-cigarettes on perceptions and use behaviours were included. Specific outcome measures assessed are appeal, reasons for use, risk perceptions, susceptibility, intention to try, initiation, preference, current use, quit intentions and cessation. Data extraction and synthesis Three authors independently extracted data related to the impact of flavours in tobacco products. Data from a previous review were then combined with those from the updated review for final analysis. Results were then grouped and analysed by outcome measure. Results The review included 51 articles for synthesis, including 17 published up to 2016 and an additional 34 published between 2016 and 2018. Results indicate that non-menthol flavours in e-cigarettes decrease harm perceptions (five studies) and increase willingness to try and initiation of e-cigarettes (six studies). Among adults, e-cigarette flavours increase product appeal (seven studies) and are a primary reason many adults use the product (five studies). The role of flavoured e-cigarettes on smoking cessation remains unclear (six studies). Conclusion This review provides summary data on the role of non-menthol flavours in e-cigarette perceptions and use. Consistent evidence shows that flavours attract both youth and adults to use e-cigarettes. Given the clear findings that such flavours increase product appeal, willingness to try and initiation among youth, banning non-menthol flavours in e-cigarettes may reduce youth e-cigarette use. Longitudinal research is needed to examine any role flavours may play in quit behaviours among adults

Effects of small surface tension in Hele-Shaw multifinger dynamics: an analytical and numerical study

We study the singular effects of vanishingly small surface tension on the dynamics of finger competition in the Saffman-Taylor problem, using the asymptotic techniques described in [S. Tanveer, Phil. Trans. R. Soc. Lond. A 343, 155 (1993)]and [M. Siegel, and S. Tanveer, Phys. Rev. Lett. 76, 419 (1996)] as well as direct numerical computation, following the numerical scheme of [T. Hou, J. Lowengrub, and M. Shelley,J. Comp. Phys. 114, 312 (1994)]. We demonstrate the dramatic effects of small surface tension on the late time evolution of two-finger configurations with respect to exact (non-singular) zero surface tension solutions. The effect is present even when the relevant zero surface tension solution has asymptotic behavior consistent with selection theory.Such singular effects therefore cannot be traced back to steady state selection theory, and imply a drastic global change in the structure of phase-space flow. They can be interpreted in the framework of a recently introduced dynamical solvability scenario according to which surface tension unfolds the structually unstable flow, restoring the hyperbolicity of multifinger fixed points.Comment: 16 pages, 15 figures, submitted to Phys. Rev

The impact of deep-sea fisheries and implementation of the UNGA Resolutions 61/105 and 64/72. Report of an international scientific workshop

The scientific workshop to review fisheries management, held in Lisbon in May 2011, brought together 22 scientists and fisheries experts from around the world to consider the United Nations General Assembly (UNGA) resolutions on high seas bottom fisheries: what progress has been made and what the outstanding issues are. This report summarises the workshop conclusions, identifying examples of good practice and making recommendations in areas where it was agreed that the current management measures fall short of their target

Disposition of docosahexaenoic acid-paclitaxel, a novel taxane, in blood: in vitro and clinical pharmacokinetic studies

PURPOSE: Docosahexaenoic acid-paclitaxel is as an inert prodrug composed of the natural fatty acid DHA covalently linked to the C2'-position of paclitaxel (M. O. Bradley et al., Clin. Cancer Res., 7: 3229-3238, 2001). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of DHA-paclitaxel. EXPERIMENTAL DESIGN: The blood distribution of DHA-paclitaxel was studied in vitro using equilibrium dialysis and in 23 cancer patients receiving the drug as a 2-h i.v. infusion (dose, 200-1100 mg/m(2)). RESULTS: In vitro, DHA-paclitaxel was found to bind extensively to human plasma (99.6 +/- 0.057%). The binding was concentration independent (P = 0.63), indicating a nonspecific, nonsaturable process. The fraction of unbound paclitaxel increased from 0.052 +/- 0.0018 to 0.055 +/- 0.0036 (relative increase, 6.25%; P = 0.011) with an increase in DHA-paclitaxel concentration (0-1000 microg/ml), suggesting weakly competitive drug displacement from protein-binding sites. The mean (+/- SD) area under the curve of unbound paclitaxel increased nonlinearly with dose from 0.089 +/- 0.029 microg.h/ml (at 660 mg/m(2)) to 0.624 +/- 0.216 microg.h/ml (at 1100 mg/m(2)), and was associated with the dose-limiting neutropenia in a maximum-effect model (R(2) = 0.624). A comparative analysis indicates that exposure to Cremophor EL and unbound paclitaxel after DHA-paclitaxel (at 1100 mg/m(2)) is similar to that achieved with paclitaxel on clinically relevant dose schedules. CONCLUSIONS: Extensive binding to plasma proteins may explain, in part, the unique pharmacokinetic profile of DHA-paclitaxel described previously with a small volume of distribution ( approximately 4 liters) and slow systemic clearance ( approximately 0.11 liters/h)