Reduction of Steady-State Valproate Levels by Other Antiepileptic Drugs

Steady-state plasma valproate (VPA) levels were analyzed in 37 children after 6 weeks of VPA therapy. Twenty-six patients were receiving other antiepileptic drugs in addition to VPA (experimental group). Eleven patients who received VPA alone served as controls. The mean VPA dose was not statistically different for the two groups (experimental group, 35.4 mg/kg/ day, 11.6 SD; control group, 31.1 mg/kg/day, SD 6.6) The mean plasma VPA level was significantly lower for the experimental group (63.0 Μg/m1, SD 21.8) than for the control (99.3 Μg/m1), SD 23.3) ( p < 0.01). VPA levelrdose ratio (LDR) was also reduced in the experimental group (1.92, SD 0.75) as compared to controls (3.26, SD 0.65) ( p < 0.01). Within the experimental group the VPA levels and VPA LDR were significantly reduced in patients receiving either phenytoin or phenobarbital. The data suggest that other antiepileptic drugs significantly alter the steady-state level to dose relationship for VPA. RÉSUMÉ Le taux plasmatique À l'Équilibre du valproate de sodium (VPA) a ÉtÉÉtudiÉ chez 37 enfants aprÈs 6 semaines de thÉrapeutique. Vingt six patients reÇoivent d'autres mÉdicaments antiÉpileptiques associÉs au VPA (groupe expÉrimental) alors que 11 sujets tÉmoins ne reÇoivent que le VPA seul. La posologie moyenne du VPA n'est pas significativement diffÉrente entre les deux groupes (35,4 mg/kg/jour ± 11,6 centre 31,1 mg/kg/jour ± 6,6). Le taux plasmatique de VPA est significativement plus bas dans le groupe experimental (63,0 Μg/ml ± 21,8) contre 99,3 Μg/ml ± 23,3 dans le groupe tÉmoin ( p < 0,01). Le rapport taux plasmatique/posologie (LDR) a ÉtÉ diminuÉ dans le groupe expÉrimental (1,92 ± 0,75) par rapport au groupe tÉmoin (3,26 ± 0,65), p < 0,01 en particulier chez les malades recevant de la phÉnytoÏne ou du phÉnobarbital. La posologie moyenne du VPA n'Étant pas significativement diffÉrente dans les deux groupes, les faits observÉs suggÈrent que l'addition d'autres antiÉpileptiques est capable de modifier le taux À l'Équilibre du VPA plasmatique en fonction de la dose administrÉe. RESUMEN Se analizaron los niveles estables de valproato en plasma (VPA) en 37 niÑos despuÉs de 6 semanas de terapia con VPA. Ventiseis pacientes recibÍan otros fÁrmacos ademÁs de VPA (grupo experimental) y once sÓlo tomaban VPA y sirvieron como controles. La dosis media de VPA no fue significativamente distinta en los dos grupos (grupo experimental: 35,4 mg/kg/dÍa, DS 11,6; grupo control: 31.1 mg/kg/dÍa, DS 6,6). El nivel plasmÁtico medio de VPA fue significativamente inferior en el grupo experimental (63,0 Μg/ml, DS 21,8) que en el control (99,3 Μg/ml, DS 23,3), p < 0,01. La relaciÓn nivel de VPA: dosis (LDR) estaba tambiÉn reducida en el grupo experimental (1,92, DS 0,75) al compararla con los controles (3,26, DS 0,65), p < 0,01. Dentro del grupo experimental los niveles de VPA y la LDR estaban significativamente reducidos en pacientes que tomaban fenitoÍna o fenobarbital. La dosis media no fue diferente entre los grupos experimental y control. Estos datos sugieren que la ingestiÓn de otros fÁrmacos alteran de modo significativo los niveles estables de VPA en relaciÓn con la dosis. ZUSAMMENFASSUNG In steady-state befindliche Plasma Valproatspiegel (VPA) wurden bei 37 Kindern nach 6 wÖchiger VPA-Therapie analysiert. 26 Patienten erhielten zusÄtzlich zum VPA andere Antiepileptika (experimentelle Gruppe). 11 Patienten, die VPA alleine bekamen, dienten als Kontrollen. Die mittlere VPA-Dosis war in beiden Gruppen nicht signifikant Vunterschiedlich (experimentelle Gruppe 35,4 mg/kg pro Tag, 11,6 SD; Kontrollgruppe 31,1 mg/kg pro Tag, SD 6,6). Der mittlere Plasma VPA-Spiegel war signifikant niedriger in der experimentellen Gruppe (63,0 Μg/ml, SD 21,8) als in der Kontrollgruppe (99,3 Μg/m1, SD 23,3), p < 0.01. Das VerhÄltnis VPA-Spiegel: Dosis (LDR) war in der experimentellen Gruppe ebenfalls reduziert (1,92, SD 0,75) gegenuber der Kontrollgruppe (3,26, SD 0,65), p < 0.01. Innerhalb der experimentellen Gruppe waren die VPA-Spiegel und die VPA/LDR bei Patienten, die entweder Phenytoin oder Phenobarbital bekamen, signifikant erniedrigt. Die mittlere VPA-Dosis war nicht signifikant unterschiedlich in der experimentellen und in der Kontrollgruppe. Diese Daten lassen vermuten, daß andere Antiepileptika signifikanterweise den Steady-state-Spiegel im Hinblick auf die verabfolgte Dosis VPA Ändern.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66058/1/j.1528-1157.1981.tb06154.x.pd

Polymer Light‐Emitting Transistors With Charge‐Carrier Mobilities Exceeding 1 cm2 V−1 s−1

The vast majority of conjugated polymer-based light emitting field-effect transistors (LEFETs) are characterized by low charge carrier mobilities typically in the range 10-5 to 10-3 cm2 V-1 s-1 range. Fast carrier transport is a highly desirable characteristic for high frequency LEFET operation and, potentially, for use in electrically-pumped lasers. Unfortunately, high mobility organic semiconductors are often characterised by strong intermolecular π-π interactions that reduce luminescence. Development of new materials and/or device concepts that overcome this hurdle are therefore required. We report single organic semiconductor layer, light-emitting transistors that combine the highest hole mobilities reported to date for any polymer-based LEFET, with encouraging light emission characteristics. We achieve this in a single polymer layer LEFET, which was further enhanced through the use of a small-molecule/conjugated polymer blend system that possesses a film microstructure which supports enhanced charge carrier mobility (3.2 cm2 V-1 s-1) and promising light emission characteristics (1600 cd m-2) as compared to polymer-only based LEFETs. This simple approach represents an attractive strategy to further advance the performance of solution-processed LEFETs

Brand-to-generic levetiracetam switch in patients with epilepsy in a routine clinical setting

Purpose: The therapeutic equivalence of generic and brand antiepileptic drugs, based on studies performed on healthy volunteers, has been questioned. We compare, in a routine clinical setting, brand versus generic levetiracetam (LEV) bioequivalence in patients with epilepsy and also the clinical efficacy and tolerability of the substitution. / Methods: A prospective, open-label, non-randomized, steady-state, multiple-dose, bioequivalence study was conducted in 12 patients with epilepsy (5 females), with a mean age of 38.4 ± 16.2 years. Patients treated with the brand LEV (Keppra; UCB Pharma) were closely followed for a four-week period and subsequently switched to a generic LEV (Pharmaten) and followed for another four-week period. Blood samples were collected at the end of each 4-week period, during a dose interval for each formulation, for LEV concentration measurements by liquid chromatography mass spectrometry. Steady-state area under the curve (AUC) and peak plasma concentration (Cmax) data were subjected to conventional average bioequivalence analysis. Secondary clinical outcomes, including seizure frequency and adverse events, were recorded. / Results: Patients had epilepsy for a mean period of 14.1 ± 10.6 years and the mean daily LEV dose was 2583.3 ± 763.7 mg. The mean AUC ± SD and Cmax ± SD was 288.4 ± 86.3 (mg/L) h and 37.8 ± 10.4 mg/L respectively for brand LEV and 319.2 ± 104.7 (mg/L) h and 41.6 ± 12.3 mg/L respectively for the generic LEV. Statistic analysis showed no statistical significant difference in bioequivalence. Also, no change in seizures frequency and/or adverse events was recorded. / Conclusions: In our clinical setting, generic LEV was determined to be bioequivalent to brand LEV. Furthermore, seizures frequency or/and adverse events were not affected upon switching from brand to generic LEV

Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

<p>Abstract</p> <p>Background</p> <p>Therapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects. This is most commonly accomplished by measurement of total phenytoin plasma concentrations. However, total phenytoin levels can be misleading in patients with factors such as low plasma albumin that alter the free (unbound) concentrations of phenytoin. Direct measurement of free phenytoin concentrations in plasma is more costly and time-consuming than determination of total phenytoin concentrations. An alternative to direct measurement of free phenytoin concentrations is use of the Sheiner-Tozer equation to calculate an adjusted phenytoin that corrects for the plasma albumin concentration. Innovative medical informatics tools to identify patients who would benefit from adjusted phenytoin calculations or from laboratory measurement of free phenytoin are needed to improve safety and efficacy of phenytoin pharmacotherapy. The electronic medical record for an academic medical center was searched for the time period from August 1, 1996 to November 30, 2010 for patients who had total phenytoin and free phenytoin determined on the same blood draw, and also a plasma albumin measurement within 7 days of the phenytoin measurements. The measured free phenytoin plasma concentration was used as the gold standard.</p> <p>Results</p> <p>In this study, the standard Sheiner-Tozer formula for calculating an estimated (adjusted) phenytoin level more frequently underestimates than overestimates the measured free phenytoin relative to the respective therapeutic ranges. Adjusted phenytoin concentrations provided superior classification of patients than total phenytoin measurements, particularly at low albumin concentrations. Albumin plasma concentrations up to 7 days prior to total phenytoin measurements can be used for adjusted phenytoin concentrations.</p> <p>Conclusions</p> <p>The results suggest that a measured free phenytoin should be obtained where possible to guide phenytoin dosing. If this is not feasible, then an adjusted phenytoin can supplement a total phenytoin concentration, particularly for patients with low plasma albumin.</p

A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte-derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage-derived factors coordinate tissue repair. Gene expression kinetics-based clustering of blood circulating Ly6C(high), infiltrating inflammatory Ly6C(high), and reparative Ly6C(low) macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration-associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor-expressing macrophages [GFEMs])

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

Requirements for generic anti-epileptic medicines: a regulatory perspective

Contains fulltext : 81660.pdf (publisher's version ) (Closed access

Pharmacokinetic Modeling of Non-Linear Brain Distribution of Fluvoxamine in the Rat

Introduction. A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. Materials and methods. Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg j1 of fluvoxamine. Analysis. With increasing dose a disproportional increase in brain concentrations was observed. Th

Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study

Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs

Impact of a pharmaceutical care programme on health-related quality of life among women with epilepsy: a randomised controlled trial (IPHIWWE study)

This paper was presented in part at the II Congreso Colombiano de Atención Farmacéutica, Medellín, Colombia, September 27, 2013.Background: Epilepsy is a complex chronic disorder which affects health-related quality of life (HRQOL), especially in women. Pharmaceutical care (PC) allows direct intervention between the pharmacist, the patient and the other healthcare team members to optimise treatments in order to reduce negative outcomes related to medication and contribute to improving HRQOL. The aim of the study was to establish the impact of the application of a pharmaceutical care programme on the HRQOL of women with epilepsy.Methods: This study is a pragmatic randomised controlled trial involving women with epilepsy (WWE) over 18 years of age. The intervention group (IG) received a pharmaceutical care programme consisting of medication review follow-up according to Dáder’s method, health education and therapeutic drug monitoring of anticonvulsants. The impact was assessed by changes in seizure frequency, in the self-administered questionnaires (the QOLIE-31, Liverpool AEP, CES-D, Haynes-Sackett test and Moriski-Green test) and between the first interview and the one at the end of six months of follow-up. A Student’s t-test was performed to compare the final QOLIE-31 score between groups and a paired Student’s t-test was used to determine the change in each group between the start and the end of follow-up.Results: One hundred eighty-two WWE entered the study and 144 (79.1%) completed it. The t-test for comparing the final QOLIE-31 scores between groups yielded a t = −2.166 and confidence interval (CI) (95%): −10.125; −0.4625, p-value =0.0319. The change (Δ) in the QOLIE-31 score for the IG was 12.45 points (p-value <0.001) and for the control group it was 2.61 (p-value =0.072). With 10.7 as the minimally important change we found a relative risk of 2.17 (CI: 1.37; 3.43) and a number needed to treat (NNT) of 3.5.Conclusions: The study demonstrated that the application of a pharmaceutical care programme significantly improves HRQOL in WWE. The NNT we found allows a recommendation to implement the PC programme for the additional benefit that would be obtained in patients’ HRQOL.This study was funded by a competitive investigator grant award from the Universidad Nacional de Colombia (Colombia) - Research Division of Bogotá (ref: 202010011419 Quipu Code)