Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results

Background: Open-label 15-month follow-up of the double-blind, placebo-controlled Glatiramer Acetate clinical Trial to assess Equivalence with Copaxone® (GATE) trial. Objective: To evaluate efficacy, safety, and tolerability of prolonged generic glatiramer acetate (GTR) treatment and to evaluate efficacy, safety, and tolerability of switching from brand glatiramer acetate (GA) to GTR treatment. Methods: A total of 729 patients received GTR 20 mg/mL daily. Safety was assessed at months 12, 15, 18, 21, and 24 and Expanded Disability Status Scale and magnetic resonance imaging (MRI) scans at months 12, 18, and 24. The presence of glatiramer anti-drug antibodies (ADAs) was tested at baseline and months 1, 3, 6, 9, 12, 18, and 24. Results: The mean number of gadolinium-enhancing lesions in the GTR/GTR and GA/GTR groups was similar at months 12, 18, and 24. The change in other MRI parameters was also similar in the GTR/GTR and GA/GTR groups. The annualized relapse rate (ARR) did not differ between the GTR/GTR and GA/GTR groups, 0.21 and 0.24, respectively. The incidence, spectrum, and severity of reported adverse events did not differ between the GTR/GTR and GA/GTR groups. Glatiramer ADA titers were similar in the GTR/GTR and GA/GTR groups. Conclusion: Efficacy and safety of GTR is maintained over 2 years. Additionally, switching from GA to GTR is safe and well tolerated

Cutoff parameter and vortex core size in d

There is some evidence that the electron-phonon mechanism is not strong enough to produce observed high critical temperatures in unconventional superconductors; this is the case in both the cuprates and Fe-based superconductors. The d-wave pairing in strongly correlated systems is consistent with the observation of nodal quasiparticles in the heavily hole doped superconductor KFe2As2 with Tc = 3 K and high-Tc cuprates. In this work the Eilenberger equations are solved for anisotropic dx2−y2-wave superconductors. The cutoff parameter ξh and vortex core size ξ2 (the distance from the vortex center to the radius where the current density reaches its maximum value) in the mixed state are investigated numerically. The cutoff parameter determines the field distribution in the generalized London equation obtained as a projection of the quasiclassical theory. It can be used for the fitting of the µSR and small-angle neutron scattering (SANS) experimental data. Field and temperature dependences of ξh/ξc2 in dx2−y2-wave superconductors are similar to those in s-wave superconductors: ξh/ξc2(B/Bc2)dependence has minimum at high temperatures and shows monotonously increasing behavior at low temperatures. Here, ξc2 is determined by the relation Bc2 =Φ0/2πξc22. The ξ2/ξc2(B/Bc2) dependence is monotonously decreasing function at intermediate and high temperatures

Účinnost a bezpečnost abobotulinumtoxinu A v tekuté formě u cervikální dystonie: randomizovaná, kontrolovaná studie.

Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA. The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia. At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P < .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events. Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA.Pozadí: Již schválené produkty botulotoxinu A vyžadují rekonstituci. Tekutý abobotulotoxin A je již připraven k přímému použití. Cíle: Cílem této studie byl průkaz vyšší efektivity tekuté formy abobotulotoxinu A proti placebu a non-inferioritní účinnost abobotulotoxinu A v tekuté formě proti abobotulotoxinu A dodávaného v práškové formě u cervikální dystonie. Metody: Jednalo se o fázi 3, multicentrickou, prospektivní, dvojitě zaslepenou, randomizovanou, aktivní a placebem kontrolovanou studii (N=369). Pacient s cervikální dystonií byli randomizováni (3:3:1) pro abobotulinumtoxin A v tekuté formě 500 U, pro abobotulinumtoxin A 500 U dodávaný v práškové formě a pro placebo. Následně po dvojitě zaslepené fázi pak nemocní dostávali tekutý abobotulinumtoxin A v otevřené fázi studie a to po dobu 4 cyklů. Primární cílem byla změna v týdnu 4 hodnocena pomocí TWSTRS (Toronto Western Spasmodic Torticollis Rating Scale) skóre. Sekundární cíle byly – změny proti bazální návštěvě či základně návštěvě cyklu (TWSTRS). Výsledky: V týdnu 4 byly oba hodnocené produkty superiorní proti placebu. Snížení TWSTRS skóre proti placebu - pro tekutou formu -12.5, pro klasickou -14.0 a pro placebo -3.9. Limit noninferiority (3 body dle TWSTRS) nebyl v týdnu 4 dosažen pro tekutou formu, ale byl dosažen ve všech cyklech extenční fáze. Bezpečnostní profil byl stejný u obou hodnocených preparátů – dysfágie a bolesti v místě aplikace. Závěr: I když nebylo dosaženo kritériu non-inferiority, je tekutá preparát podobně účinný jako klasický preparát, kdy se vytváří aplikační forma rozpuštěním suché práškové formy. Nově zkoušený tekutý preparát je určen pro chronickou léčbu a vyznačuje se zlepšenými – vyhovujícími podmínkami při přípravě preparátu k aplikaci

Innovative analytical methodologies for characterizing chemical exposure with a view to next-generation risk assessment

International audienceThe chemical burden on the environment and human population is increasing. Consequently, regulatory risk assessment must keep pace to manage, reduce, and prevent adverse impacts on human and environmental health associated with hazardous chemicals. Surveillance of chemicals of known, emerging, or potential future concern, entering the environment-food-human continuum is needed to document the reality of risks posed by chemicals on ecosystem and human health from a one health perspective, feed into early warning systems and support public policies for exposure mitigation provisions and safe and sustainable by design strategies. The use of less-conventional sampling strategies and integration of full-scan, high-resolution mass spectrometry and effect-directed analysis in environmental and human monitoring programmes have the potential to enhance the screening and identification of a wider range of chemicals of known, emerging or potential future concern. Here, we outline the key needs and recommendations identified within the European Partnership for Assessment of Risks from Chemicals (PARC) project for leveraging these innovative methodologies to support the development of next-generation chemical risk assessment

Hsp90 Regulates the Phosphorylation and Activity of Serum- and Glucocorticoid-regulated Kinase-1*

SGK-1 (serum- and glucocorticoid-regulated kinase-1), a member of the AGC protein kinase family, plays an important role in regulating ion channel expression and contributes to malignant epithelial cell proliferation and survival. SGK-1 activity is regulated on three levels: transcriptional induction following a variety of environmental and intracellular stresses, proteasomal degradation, and phosphorylation. Here we report that phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of SGK-1 requires formation of a complex between SGK-1 and heat-shock protein 90 (Hsp90). Inactivation of Hsp90 by geldanamycin led to decreased SGK-1 phosphorylation independently of increased proteasomal protein degradation, and inhibition of PI3K activity by LY294002 appeared to eliminate SGK-1 phosphorylation at the same residues as those affected by geldanamycin treatment. Interestingly, geldanamycin-targeted phosphorylation sites were not limited to the known conserved PI3K-dependent sites Thr-256 and Ser-422 in SGK-1 but included additional unknown PI3K-dependent residues. Inhibition of Hsp90 also resulted in a complete loss of SGK-1 kinase activity, suggesting that Hsp90 activity is essential for regulating the PI3K/SGK-1 pathway