Optimal Dosing of Enoxaparin in Overweight and Obese Children

Aim:Current enoxaparin dosing guidelines in children are based on total bodyweight. This is potentially inappropriate in obese children as it may overestimate thedrug clearance. Current evidence suggests that obese children may require lower ini-tial doses of enoxaparin, therefore the aim of this work was to characterise the phar-macokinetics of enoxaparin in obese children and to propose a more appropriatedosing regimen.Methods:Data from 196 unique encounters of 160 children who received enoxa-parin treatment doses were analysed. Enoxaparin concentration was quantified usingthe chromogenic anti factor Xa (anti-Xa) assay. Patients provided a total of 552 anti-Xa samples. Existing published pharmacokinetic (PK) models were fitted and evalu-ated against our dataset using prediction-corrected visual predictive check plots(pcVPCs). A PK model was fitted using a nonlinear mixed-effects modelling approach.The fitted model was used to evaluate the current standard dosing and identify anoptimal dosing regimen for obese children.Results:Published models of enoxaparin pharmacokinetics in children did not capturethe pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one-compartment model with linear elimination best described the pharmacokinetics ofenoxaparin. Allometrically scaled fat-free mass with an estimated exponent of 0.712(CI 0.66-0.76) was the most influential covariate on clearance while linear fat-freemass was selected as the covariate on volume. Simulations from the model showedthat fat-free mass-based dosing could achieve the target anti-Xa activity at steadystate in 77.5% and 78.2% of obese and normal-weight children, respectively, com-pared to 65.2% and 75.5% for standard total body weight-based dosing.Conclusions:A population PK model that describes the time course of anti-Xa activ-ity of enoxaparin was developed in a paediatric population. Based on this model, aunified dosing regimen was proposed that will potentially improve the success rate oftarget attainment in overweight/obese patients without the need for patient bodysize categorisation. Therefore, prospective validation of the proposed approach iswarranted

Ex vivo and In vivo Evaluation of Chitosan Coated Nanostructured Lipid Carriers for Ocular Delivery of Acyclovir

Background: Herpes keratitis is the most common infectious cause of blindness in the developed world. It may be treated by acyclovir (ACV), however this antiviral drug is poorly soluble with low ocular bioavailability requiring high and frequent dosing. Nanostructured lipid carriers (NLCs) were investigated to improve the ocular bioavailability of ACV by enhancing corneal penetration as well as prolonging the exposure of infected cells to the antiviral agent. Methods: Cell uptake studies, ex vivo tolerance and cell uptake efficacy as well as in vivo corneal permeation of the developed lipid based formulations were investigated. NLCs were fabricated by the hot microemulsion technique and coated with 0.5% w/v chitosan. NLCs were capable of increasing the cell uptake of encapsulated fluorescein and ACV as examined by fluorescence microscopy and high performance liquid chromatography (HPLC) respectively. Results: When entrapped in NLCs, the antiviral efficacy of ACV was increased by 3.5 fold after 24 hrs of exposure. The in vivo corneal permeation of the formulation was studied on Albino rabbits with NLCs capable of increasing the corneal bioavailability by 4.5 fold when compared to a commercially available ACV ophthalmic ointment. Conclusion: NLCs enhanced the ocular bioavailability and antiviral properties of ACV through cell internalisation, sustained release, and increased corneal permeation

Reading behaviour project report 2016 : ‘Digital Magpies’ - the academic reading habits of undergraduate students

Engagement with the Library is essential in delivering a successful student experience. A previous Library Impact Project found that students who use the Library more tend to achieve better academic results. However, analytics from library systems indicate declining book borrowing and electronic resource usage. Are students really reading less? Student academic reading patterns have adapted to the increase in digital resources. As a result they may be “reading smarter’’. Feedback indicates they expect to find and use information quickly, synthesising information from a variety of sources. As part of a commitment to improve retention and completion figures, the Library has initiated a Reading Behaviours project at the University of Salford, focused on the reading habits of undergraduate students. It explores what motivates their academic reading; whether reading patterns vary according to purpose or source, academic discipline, status, or age and what this means for our role in helping students to find resources. In light of findings, how should we tailor classroom training, e-learning and collaboration with academics to support the student journey? Several key issues have emerged during this project:1. Synthesizing information for an academic purpose2. Embedding information literacy as a flexible learning habit3. Supporting students as they adapt to new learning context

An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals

<p>Abstract</p> <p>Background</p> <p>MI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction. It is closely related to MDM2 antagonists MI-219 and Nutlin-3 in terms of the expected working mechanisms. The purpose of this study was to evaluate anti-lymphoma activity of MI-319 in WSU-FSCCL, a B-cell follicular lymphoma line. For comparison purpose, MI-319, MI-219 and Nutlin-3 were assessed side by side against FSCCL and three other B-cell hematological tumor cell lines in growth inhibition and gene expression profiling experiments.</p> <p>Results</p> <p>MI-319 was shown to bind to MDM2 protein with an affinity slightly higher than that of MI-219 and Nutlin-3. Nevertheless, cell growth inhibition and gene expression profiling experiments revealed that the three compounds have quite similar potency against the tumor cell lines tested in this study. <it>In vitro</it>, MI-319 exhibited the strongest anti-proliferation activity against FSCCL and four patient cells, which all have wild-type p53. Data obtained from Western blotting, cell cycle and apoptosis analysis experiments indicated that FSCCL exhibited strong cell cycle arrest and significant apoptotic cell death; cells with mutant p53 did not show significant apoptotic cell death with drug concentrations up to 10 μM, but displayed weaker and differential cell cycle responses. In our systemic mouse model for FSCCL, MI-319 was tolerated well by the animals, displayed effectiveness against FSCCL-lymphoma cells in blood, brain and bone marrow, and achieved significant therapeutic impact (p < 0.0001) by conferring the treatment group a > 28% (%ILS, 14.4 days) increase in median survival days.</p> <p>Conclusion</p> <p>Overall, MI-319 probably has an anti-lymphoma potency equal to that of MI-219 and Nutlin-3. It is a potent agent against FSCCL <it>in vitro </it>and <it>in vivo </it>and holds the promises to be developed further for the treatment of follicular lymphoma that retains wild-type p53.</p

Population Pharmacokinetics of Olanzapine in Children

Aims The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. Methods The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. Results Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2–19.2) and 14.1 kg (4.2–111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or \u3c15 kg and fixed doses for children ≥15 kg. Conclusion We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance

Applying refinement to the use of mice and rats in rheumatoid arthritis research

Rheumatoid arthritis (RA) is a painful, chronic disorder and there is currently an unmet need for effective therapies that will benefit a wide range of patients. The research and development process for therapies and treatments currently involves in vivo studies, which have the potential to cause discomfort, pain or distress. This Working Group report focuses on identifying causes of suffering within commonly used mouse and rat ‘models’ of RA, describing practical refinements to help reduce suffering and improve welfare without compromising the scientific objectives. The report also discusses other, relevant topics including identifying and minimising sources of variation within in vivo RA studies, the potential to provide pain relief including analgesia, welfare assessment, humane endpoints, reporting standards and the potential to replace animals in RA research

Effects of Antiepileptic Drugs on GABA Responses and on Reduction of GABA Responses by PTZ and DMCM on Mouse Neurons in Cell Culture

The mechanisms of action of antiepileptic drugs effective against generalized absence seizures (antiabsence AEDs) remain uncertain. Antiabsence AEDs are generally effective against seizures induced in experimental animals by pentylenÉtÉtrazol (PTZ) and methyl-6,7-dimethoxy-4-ethyl-Β-carboline-3-carboxylate (DMCM), drugs which reduce GABAergic inhibition. Thus, antiabsence AEDs have been suggested to enhance GABAergic inhibition. We studied the effects of several AEDs on GABA responses recorded from mouse spinal cord neurons grown in primary dissociated cell culture. Four antiabsence AEDs were included: ethosuximide (ESM), dimethadione (DMO), sodium valproate (VPA), and diazepam (DZP). Two experimental AEDs, CGS 9896 and ZK 91296, with anticonvulsant action against PTZ- or DMCM-induced seizures were also included. Possible effects of the antiabsence and experimental AEDS on PTZ- and DMCM-induced inhibition of GABA responses were also evaluated. PTZ and DMCM revers-ibly reduced GABA responses in a concentration-dependent manner. PTZ complÉtÉly inhibited GABA responses at 10 mM (IC 50 of 1.1 mM), whereas DMCM-induced inhibition of GABA responses reached a plateau level of 39% of control values at 1 p.M (IC 50 of 33 nM). ESM (1,200 ΜM), DMO (6 mM), VPA (200 u.M), CGS 9896 (2 ΜM), and ZK 98% (2 Μ M ) did not alter GABA responses. DZP enhanced GABA responses in a concentration-dependent manner. The inhibition of GABA responses produced by PTZ 1 mM was unaltered by ESM (600 Μ M ), DMO (6 mM), CGS 9896 (1 Μ M), or ZK 9896 (1 ΜM)- Coapplication of VPA (200 ΜM) and PTZ (1 mM) slightly enhanced the PTZ effect. DZP (> 10 nM), however, reversed the PTZ-induced reduction of GABA responses. The DMCM (250 nM) inhibition of GABA-responses was unaltered by ESM (600 Μ.M), DMO (2 mM), or VPA (200 ΜM). CGS 9896 (2 Μ M ) and ZK 91296 (2 ΜM), however, antagonized the DMCM effect. DZP (> 10 nM) significantly reversed the DMCM-induced inhibition of GABA responses. The lack of effect of VPA, ESM, and DMO on postsynaptic GABA responses suggests that direct enhancement of postsynaptic GABA action is not a common mechanism of action of antiabsence AEDs. The AEDs DZP, CGS 98%, and ZK 912% all reversed DMCM, but not PTZ, reduction of GABA responses, suggesting that these AEDs blocked DMCM seizures by acting at benzodiazepine receptors. However, since only DZP enhanced GABA responses, it is unclear how CGS 98% and ZK 912% blocked PTZ seizures. Key Words: Anticonvulsants–GABA–Neuron culture–Cell culture–Spinal cord neurons–Convulsants. RESUMEN Los mecanismos de accidn de las medicaciones antiepilÉpticas eficaces contra los ataques generalizados de ausencia (AEDs antiausencia) permanecen inciertos. Los AEDs antiausencia son, generalmente, eficaces contra ataques experimentales inducidos por el pentilentetrazol (PTZ) y el metil-6,7-dimetoxy-4-etil-Pcarbolina-3-carboxilato (DMCM) en animates, medicaciones que reducen la inhibiciÓn GABAÉrgica. Hemos estudiado los efectos de varios AEDs sobre respuestas-GABA registradas en las neuronas de la mÉdula espinal de ratones que habian crecido en cultivos de cÉlulas primarieas disociadas. Cuatro AEDs antiausencia fueron incluidos: etoxusimida (ESM), dimetadiona (DMO), valproato sÓdico (VPA) y diazepan (DZP). TambtÉn se incluyeron dos AEDs experimentales, CGS 9896 y ZK 912%, con acciÓn anticonvulsiva contra los ataques inducidos por PTZ o DMCM. TambiÓn se valoraron los posibles efectos de los AEDs antiausencia y experimentales sobre el PTZ y la inhibiciÓn de las respuestas-GABA inducidas por el DMCM. El PTZ y el DMCM redujeron las respuestas-GABA de modo reversible y dependiendo de sus concentraciones. El PTZ inhibiÓ cmpleta-mente las respuestas-GABA a 10 mM (IC 50 de 1.1 mM) mientras que la inhibitiÓn de las respuestas GABA inducida por el DMCM alcanzÓ un nivel estable del 39% de los valores control con 1 Μ. M (IC 50 de 33 mM). La ESM (1200 Μ.M), la DMO (6 mM), el VPA (200 Μ M ), el CGS 98% (2 Μ M) y el ZK 98% (2 Μ M) no alteraron las respuestas-GABA. El DZP aumentÓ las respuestas GABA de una manera concentraciÓn-dependiente. La inhibition de las respuestas-GABA producidas por el PTZ (1 mM), no se altero con las ESM (600 Μ M), la DMO (6 mM), el CGS 98% (1 Μ M) o el ZK 98% (1 Μ .M). La co-aplicacion de VPA (200 Μ M) y el PTZ (1 mM) aument6 ligeramente los efectos del PTZ. Sin embargo el DZP (10 nM) revirtiÓ significativamente la inhibition de las respuestas GABA inducidas por el DMCM. La falta de efectos de CPA, ESM y DMO sobre las respuestas GABA post-sinÁpticas sugiere que el incremento de la acciÓn GABA post-sinÁptica no es un mecanismo comÚn de actuatiÓn de las AEDs antiausencia. Todas las AEDs DZP, CGS 98% y ZK 912% revirtieron la reduction de las respuestas GABA producidas por el DMCM pero no las inducidas por el PTZ lo que sugiere que estos AEDs bloquean los ataques DMCM actuando sobre los receptores de la benzodiazepina. Sin embargo, puesto que el incremento de las respuestas GABA sÓlÓ se produce por el DZP, permanece todavia sin aclarar el por quÉ el CGS 98% y el ZK 912% bloquean los ataques producidos por el PTZ. ZUSAMMENFASSUNG Der Wirkmechansimus von Antiepileptika gegen generalisierte Absencen ist unklar. Antiabsencemittel sind generell wirkungs-voll gegen PTZ- und Methyl-6,7-Dimethoxy-4-Äthyl-P-Carbolin-Β-Carboxylat (DMCM) induzierte tierexperimentelle AnfÄlle, also von Medikamenten, die die GABA-erge Inhibition reduzieren. Es wurde vermutet, daß Antiabsencemittel die GABA-erge Inhibition verstÄrken. Wir untersuchten die Wirkung von verschiedenen Antiepileptika auf GABA-Antworten in spinalen MÄuseneuronen, die in Zellkulturen gew-achsen waren. Es wurden 4 Absencemittel untersucht: Ethosux-imid (ESM), Dimethadion (DMD), Sodium Valproat (VPA) und Diazepam (DZP). ZusÄtzlich wurden 2 experimentelle Antiepileptika, CGS 98% und ZK 912%, die gegen PTZ0 oder DMCM-induzierte AnfÄlle wirkungsvoll sind, eingeschlossen. Mogliche Wirkungen der Antiabsence- und experimentellen Antiepileptika auf PTZ- und DMCM-induzierte Hemmung der GABA-Antworten wurden ebenfalls ausgewertet. PTZ und DMCM zeigten eine konzentrationsabhÄngige reversible Reduktion der GABA-Antworten. PTZ zeigte eine komplette Hemmung der GABA-Antworten bei 10 mM (IC 50 1,1 mM), DMCM-Hemmung der GABA-Antworten zeigte ein Plateau von 39% der Kontroll-werte bei 1 uJtf (ICJO von 33 mAfl. ESM (1200 uJtf), DMD (6 mM), VPA (200 Μ M), CGS 98% (2 Μ M) und ZK 98% (2 Μ M) anderten nicht die GABA-Antworten. DZP verstarkte die GABA-Antworten konzentrationsabhangig. Die durch PTZ (1 mM) hervorgerufene Hemmung der GABA-Antworten war bei ESM (600 Μ M), DMD (6 mM), CGS 98% (1 mAO und ZK 3836 (1 mM) unverÄndert. ZusÄtliche Anwendung von VPA (200 mM) und PTZ (1 mM) verstÄrkten geringfÜgig den PTZ-Effekt. DZP (10 nM) kehrte die durch PTZ hervorgerufene Reduktion der GABA-Antworten um. Die durch DMCM (250 nM) hervorgerufene Hemmung der GABA-Antworten war durch ESM (600 Μ .M), DMD (2 mM) und VPA (200 Μ M ) unbeeinflusst. CGS 98% (2 Μ M) und ZK 912% (2 Μ M ) antagonisierten die DMCM-Wirkung. DZP (>10 nM) kehrte die durch DMCM-induzierte Hemmung der GABA-Antworten um. Das Fehlen einer Wirkung von VPA. ESM und DMD auf die postsynaptischen GABA-Antworten legen nahe, daß eine direkte VerstÄrkung der postsynaptischen GABA-Aktion kein gemeinsamer Mechanis-mus der Antiabsencemittel darstellt. Die Antiepileptika DZP, CGS 98% und ZK 912% kehrten die DMCM-Wirkung auf die GABA-Antworten um, jedoch nicht die von PTZ, was vermuten lapt, daß diese Antiepileptika die DMCM-AnfÄlle Über die Wirkung an den Benzodiazipin-Rezeptoren verhinderte. Da jedoch nur DZP GABA-Antworten verstarkte, ist unklar, in welcher Weise CGS 98% und ZK 912% die PTZ-AnfaUe ver-hinderten.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65188/1/j.1528-1157.1989.tb05275.x.pd

‘There is a Time to be Born and a Time to Die’ (Ecclesiastes 3:2a): Jewish Perspectives on Euthanasia

Reviewing the publications of prominent American rabbis who have (extensively) published on Jewish biomedical ethics, this article highlights Orthodox, Conservative and Reform opinions on a most pressing contemporary bioethical issue: euthanasia. Reviewing their opinions against the background of the halachic character of Jewish (biomedical) ethics, this article shows how from one traditional Jewish textual source diverse, even contradictory, opinions emerge through different interpretations. In this way, in the Jewish debate on euthanasia the specific methodology of Jewish (bio)ethical reasoning comes forward as well as a diversity of opinion within Judaism and its branches