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- Ben-Menachem, Elinor, 1945, et al.
(författare)
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Safety, tolerability, and efficacy of brivaracetam as adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease: An open-label, long-term follow-up trial
- 2021
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Ingår i: Epilepsy Research. - : Elsevier BV. - 0920-1211. ; 170
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Tidskriftsartikel (refereegranskat)abstract
- This long-term open-label extension (OLE) trial was conducted to evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses in patients with epilepsy and focal (partial-onset) or generalized onset seizures, or Unverricht-Lundborg disease (ULD). A secondary objective was to evaluate efficacy of BRV in the subgroups of patients with focal or generalized onset seizures. Patients with epilepsy were eligible to enroll in this OLE (N01125; NCT00175916) and were analyzed if they had completed a previous double-blind BRV trial (N01114 [NCT00175929], N01252 [NCT00490035], N01254 [NCT00504881], N01187 [NCT00357669], and N01236 [NCT00368251]), and were expected to obtain a reasonable benefit from long-term BRV treatment. Patients entered the OLE at the BRV dose recommended at the end of the previous trial, with dose adjustments of BRV and concomitant antiseizure medications permitted. Safety variables included treatment-emergent adverse events (TEAEs). Efficacy variables in patients with focal seizures were percent reduction in focal seizure frequency, 50 % responder rates, and 6- and 12-month seizure-freedom. Eight hundred and fifty-three patients (729 [85.5 %] with focal seizures, 30 [3.5 %] with generalized onset seizures, and 94 [11.0 %] with ULD) were enrolled and included in the Safety Set. Overall, 619 (72.6 %) patients discontinued the trial, mainly due to lack of efficacy (354 [41.5 %]), adverse events (100 [11.7 %]), and patient choice (98 [11.5 %]). During the OLE, 588 (68.9 %) patients received BRV for >= 12 months, 403 (47.2 %) for >= 36 months, and 223 (26.1 %) for >= 96 months. The most common modal dose of BRV was 150 mg/day (415 [48.7 %] patients). In the ULD subgroup, the most common modal BRV dose was 100 mg/day (44/94 [46.8 %] patients), and 37/94 (39.4 %) patients had >= 96 months of BRV exposure. Overall, 720/853 (84.4 %) patients reported TEAEs, 451 (52.9 %) had a drug-related TEAE, and 95 (11.1 %) discontinued BRV due to a TEAE. In the ULD subgroup, 87/94 (92.6 %) patients reported TEAEs, 60 (63.8 %) had a drug-related TEAE, and 16 (17.0 %) discontinued due to a TEAE. In patients with focal seizures, the median reduction in focal seizure frequency from Baseline was 43.1 % (n = 728), the 50 % responder rate was 43.6 % (n = 729), and 6-and 12-month seizure freedom rates were 22.2 % and 15.8 %, respectively (n = 595). Overall, BRV was well-tolerated as long-term adjunctive therapy in patients with focal seizures, generalized onset seizures, or Unverricht-Lundborg disease, with improvements in focal seizure frequency maintained over time.
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- Loryan, Irena, Associate Professor (Docent), 1977-, et al.
(författare)
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Unbound Brain-to-Plasma Partition Coefficient, K-p,K-uu,K-brain-a Game Changing Parameter for CNS Drug Discovery and Development
- 2022
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Ingår i: Pharmaceutical research. - : Springer Nature. - 0724-8741 .- 1573-904X. ; 39:7, s. 1321-1341
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Tidskriftsartikel (refereegranskat)abstract
- Purpose More than 15 years have passed since the first description of the unbound brain-to-plasma partition coefficient (K-p,K-uu,K-brain) by Prof. Margareta Hammarlund-Udenaes, which was enabled by advancements in experimental methodologies including cerebral microdialysis. Since then, growing knowledge and data continue to support the notion that the unbound (free) concentration of a drug at the site of action, such as the brain, is the driving force for pharmacological responses. Towards this end, K-p,K-uu,K-brain is the key parameter to obtain unbound brain concentrations from unbound plasma concentrations. Methods To understand the importance and impact of the K-p,K-uu,K-brain concept in contemporary drug discovery and development, a survey has been conducted amongst major pharmaceutical companies based in Europe and the USA. Here, we present the results from this survey which consisted of 47 questions addressing: 1) Background information of the companies, 2) Implementation, 3) Application areas, 4) Methodology, 5) Impact and 6) Future perspectives. Results and conclusions From the responses, it is clear that the majority of the companies (93%) has established a common understanding across disciplines of the concept and utility of K-p,K-uu,K-brain as compared to other parameters related to brain exposure. Adoption of the K-p,K-uu,K-brain concept has been mainly driven by individual scientists advocating its application in the various companies rather than by a top-down approach. Remarkably, 79% of all responders describe the portfolio impact of K-p,K-uu,K-brain implementation in their companies as 'game-changing'. Although most companies (74%) consider the current toolbox for K-p,K-uu,K-brain assessment and its validation satisfactory for drug discovery and early development, areas of improvement and future research to better understand human brain pharmacokinetics/pharmacodynamics translation have been identified.
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- Niarchos, D., et al.
(författare)
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Toward Rare-Earth-Free Permanent Magnets : A Combinatorial Approach Exploiting the Possibilities of Modeling, Shape Anisotropy in Elongated Nanoparticles, and Combinatorial Thin-Film Approach
- 2015
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Ingår i: JOM. - : Springer Science and Business Media LLC. - 1047-4838 .- 1543-1851. ; 67:6, s. 1318-1328
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Tidskriftsartikel (refereegranskat)abstract
- The objective of the rare-earth free permanent magnets (REFREEPM) project is to develop a new generation of high-performance permanent magnets (PMs) without rare earths. Our approach is based on modeling using a combinatorial approach together with micromagnetic modeling and the realization of the modeled systems (I) by using a novel production of high-aspect-ratio (> 5) nanostructrures (nanowires, nanorods, and nanoflakes) by exploiting the magnetic shape anisotropy of the constituents that can be produced via chemical nanosynthesis polyol process or electrodeposition, which can be consolidated with novel processes for a new generation of rare-earth free PMs with energy product in the range of 60 kJ/m(3) < (BH)max < 160 kJ/m(3) at room temperature, and (II) by using a high-throughput thin-film synthesis and high-throughput characterization approach to identify promising candidate materials that can be stabilized in a tetragonal or hexagonal structure by epitaxial growth on selected substrates, under various conditions of pressure, stoichiometry, and temperature. In this article, we report the progress so far in selected phases.
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- Saupe, Falk, et al.
(författare)
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Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously
- 2017
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Ingår i: The FASEB Journal. - 0892-6638 .- 1530-6860. ; 31:3, s. 1204-1214
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Tidskriftsartikel (refereegranskat)abstract
- With the aim to improve the efficacy of therapeutic vaccines that target self-antigens, we have developed a novel fusion protein vaccine on the basis of the C-terminal multimerizing end of the variable lymphocyte receptor B (VLRB), the Ig equivalent in jawless fishes. Recombinant vaccines were produced in Escherichia coli by fusing the VLRB sequence to 4 different cancer-associated target molecules. The anti-self-immune response generated in mice that were vaccinated with VLRB vaccines was compared with the response in mice that received vaccines that contained bacterial thioredoxin (TRX), previously identified as an efficient carrier. The anti-self-Abswere analyzed with respect to titers, binding properties, and duration of response. VLRB-vaccinatedmice displayed a 2-to 10-fold increase in anti-self-Ab titers and a substantial decrease in Abs against the foreign part of the fusion protein compared with the response in TRX-vaccinated mice (P < 0.01). VLRB-generated Ab response had duration similar to the corresponding TRX-generatedAbs, but displayed a higher diversity in binding characteristics. Of importance, VLRB vaccines could sustain an immune response against several targets simultaneously. VLRB vaccines fulfill several key criteria for an efficient therapeutic vaccine that targets self-antigens as a result of its small size, its multimerizing capacity, and nonexposed foreign sequences in the fusion protein.- Saupe, F., Reichel, M., Huijbers, E. J. M., Femel, J., Markgren, P.- O., Andersson, C. E., Deindl, S., Danielson, U. H., Hellman, L. T., Olsson, A.- K. Development of a novel therapeutic vaccine carrier that sustains high antibody titers against several targets simultaneously.
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