This study assessed the efficacy and safety of the neuronal potassium channel opener ezogabine (US adopted name; EZG)/retigabine (international nonproprietary name; RTG) as adjunctive therapy for ...refractory partial-onset seizures.
This was a multicenter, randomized, double-blind, placebo-controlled trial in adults with ≥4 partial-onset seizures per month receiving 1 to 3 antiepileptic drugs. EZG (RTG) or placebo, 3 times daily, was titrated to 600 or 900 mg/d over 4 weeks, and continued during a 12-week maintenance phase. Median percentage seizure reductions from baseline and responder rates (≥50% reduction in baseline seizure frequency) were assessed.
The intention-to-treat population comprised 538 patients (placebo, n = 179; 600 mg, n = 181; 900 mg, n = 178), 471 of whom (placebo, n = 164; 600 mg, n = 158; 900 mg, n = 149) entered the maintenance phase. Median percentage seizure reductions were greater in EZG (RTG)-treated patients (600 mg, 27.9%, p = 0.007; 900 mg, 39.9%, p < 0.001) compared with placebo (15.9%). Responder rates were higher in EZG (RTG)-treated patients (600 mg, 38.6%, p < 0.001; 900 mg, 47.0%, p < 0.001) than with placebo (18.9%). Treatment discontinuations due to adverse events (AEs) were more likely with EZG (RTG) than with placebo (placebo, 8%; 600 mg, 17%, 900 mg, 26%). The most commonly reported (>10%) AEs in the placebo, EZG (RTG) 600 mg/d, and EZG (RTG) 900 mg/d groups were dizziness (7%, 17%, 26%), somnolence (10%, 14%, 26%), headache (15%, 11%, 17%), and fatigue (3%, 15%, 17%).
In this dose-ranging, placebo-controlled trial, adjunctive EZG (RTG) was effective and generally well tolerated in adults with refractory partial-onset seizures.
This study provides Class II evidence that adjunctive EZG/RTG reduces the occurrence of partial-onset seizures.
Summary
Aims
Ferroptosis, a new form of iron‐dependent programmed cell death, has been shown to be involved in a range of diseases. However, the role of ferroptosis in traumatic brain injury (TBI) ...has yet to be elucidated. We aimed to investigate whether ferroptosis is induced after TBI and whether the inhibition of ferroptosis would protect against traumatic brain injury in a controlled cortical impact injury (CCI) mouse model.
Methods
After establishing the TBI model in mice, we determined the biochemical and morphological changes associated with ferroptosis, including iron accumulation with Perl's staining, neuronal cell death with Fluoro‐Jade B (FJB) staining, iron metabolism dysfunction with Western blotting, reactive oxygen species (ROS) accumulation with malondialdehyde (MDA) assays, and shrunken mitochondria with transmission electron microscopy. Furthermore, a specific inhibitor of ferroptosis, ferrostatin‐1(fer‐1), was administrated by cerebral ventricular injection after CCI. We used cresyl violet (CV) staining to assess lesion volume, along with the Morris water maze and beam walk test to evaluate long‐term outcomes.
Results
TBI was followed by iron accumulation, dysfunctional iron metabolism, the upregulation of ferroptosis‐related genes, reduced glutathione peroxidase (GPx) activity, and the accumulation of lipid‐reactive oxygen species (ROS). Three days (d) after TBI, transmission electron microscopy (TEM) confirmed that the mitochondria had shrunk a typical characteristic of ferroptosis. Importantly, the administration of Fer‐1 by cerebral ventricular injection significantly reduced iron deposition and neuronal degeneration while attenuating injury lesions and improving long‐term motor and cognitive function.
Conclusion
This study demonstrated an effective method with which to treat TBI by targeting ferroptosis.
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•A series of new formylpiperazine-based ferroptosis inhibitors was designed and synthesized.•These derivatives were evaluated for their effects against Erastin-induced ferroptosis ...HUVECs.•Compound 26 to have better anti-ferroptosis activity and microsomal stability than Fer-1.•Compound 26 is a promising lead compound for treating ferroptosis-related vascular diseases.
In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases.
Stable isotope-assisted metabolomics (SIAM) is a powerful tool for discovering transformation products (TPs) of contaminants. Nevertheless, the high cost or lack of isotope-labeled analytes limits ...its application. In-house H/D (hydrogen/deuterium) exchange reactions enable direct
H labeling to target analytes with favorable reaction conditions, providing intuitive and easy-to-handle approaches for environmentally relevant laboratories to obtain cost-effective
H-labeled contaminants of emerging concern (CECs). We first combined the use of in-house H/D exchange and
H-SIAM to discover potential TPs of 6PPD (
-1,3-dimethylbutyl-
'-phenyl-p-phenylenediamine), providing a new strategy for finding TPs of CECs. 6PPD-
9 was obtained by in-house H/D exchange with favorable reaction conditions, and the impurities were carefully studied. Incomplete deuteride, for instance, 6PPD-
8 in this study, constitutes a major part of the impurities. Nevertheless, it has few adverse effects on the
H-SIAM pipeline in discovering TPs of 6PPD. The
H-SIAM pipeline annotated 9 TPs of 6PPD, and commercial standards further confirmed the annotated 6PPDQ (2-anilino-5-(4-methylpentan-2-ylamino)cyclohexa-2,5-diene-1,4-dione) and PPPD (
-phenyl-p-phenylenediamine). Additionally, a possible new formation mechanism for 6PPDQ was proposed, highlighting the performance of the strategy. In summary, this study highlighted a new strategy for discovering the TPs of CECs and broadening the application of SIAM in environmental studies.
Tire and road wear particles (TRWP) are polymer-based microparticles that are emitted into the environment during tire usage. Growing efforts are currently being made to quantify these emissions, ...characterize the leachates and assess their environmental impact. This study aimed to investigate the effect of aging on TRWP composition. Cryomilled tire tread particles (CMTTP) and TRWP were exposed for different durations to three aging conditions: accelerated thermal and photochemical aging and natural outdoor aging. Particles were then extracted with cyclohexane/ethanol. The time-concentration profiles of 23 additives and transformation products present in these extracts were determined by UHPLC-HRMS. Several chemicals, such as N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6-PPD) or 1,3-diphenylguanidine (DPG), decayed exponentially under all aging conditions, with half-lives of a few days under artificial photoaging versus dozens of days under pure thermal aging at 60 °C. The natural aging profiles lie between those 2 laboratory aging conditions. Other chemicals, such as 6PPD-quinone, presented bell-shaped concentration profiles within CMTTP when particles were exposed to UV light. 6PPD-quinone reached a maximal concentration within a month under natural aging. For TRWP, the initial load of 6PPD-quinone had already reached a maximum prior to the aging experiments and decreased exponentially under natural aging with a half-life below one month. Pure thermal aging induced a significantly slower decay of 6PPD-quinone within TRWP (half-life of half a year), emphasizing a greater stability and persistence in environmental compartments without light. This study highlighted that the more readily accessible CMTTP could be considered a reasonable proxy of TRWP to investigate the fate of chemicals within rubber particles, at least from a qualitative standpoint. Overall, the concentrations of 20 of the evaluated chemicals decreased by >50 % within 50 days under natural aging.
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•Time-concentration profiles of 23 chemicals were determined for 3 types of aging.•Transformation products showed different aging-induced concentration profiles.•Concentrations of most chemicals were halved within 50 days under natural aging.•The 6PPD-quinone half-life in TRWP was within a month when exposed to natural light.•Cryomilled tire tread particles can be used as TRWP surrogates to assess aging.
Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia ...reperfusion injury in mice. A chemical inhibitor discovered by high-throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.
This work presents an alternative device for cancer screening in liquid biopsies. It combines a biomimetic film (i) with electrochemical detection (ii). The biomimetic film (i) was obtained by ...electro-polymerizing amine-substituted benzene rings around a CA 15-3 target. This protein target was previously adsorbed on a gold (Au) support and incubated in charged monomers (4-Styrenesulfonate sodium and 3-Hydroxytyraminium chloride). The protein was further eliminated by enzymatic activity, leaving behind vacant sites for subsequent rebinding. Electrochemical detection (ii) was achieved on an Au working electrode, designed on commercial screen-printed electrodes. Raman spectroscopy, atomic force microscopy and ellipsometric readings were used to follow the chemical modification of the Au surface. The ability of the material to rebind CA15-3 was monitored by electrochemical techniques. The device displayed linear responses to CA15-3 ranging from 0.25 to 10.00 U/mL, with detection limits of 0.05 U/mL. Accurate results were obtained by applying the sensor to the analysis of CA15-3 in PBS buffer and in serum samples. This biosensing device displayed successful features for the detection of CA 15-3 and constitutes a promising tool for breast cancer screening procedures in point-of-care applications. Moreover, its scale-up seems feasible as it contains a plastic antibody assembled in situ, in less than 1 minute, and the analysis of serum takes less than 30 minutes.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using ...transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.
To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.
This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.
Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.
The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.
A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).
Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.
ClinicalTrials.gov Identifier: NCT02450552.
In this research work, poly(o-phenylenediamine) was incorporated into the hydrous zirconium oxide matrix to form poly(o-phenylenediamine)/hydrous zirconium oxide composite which is used for the ...removal of Cd(II) from aqueous solution. The characterization of the material was done based on FTIR, XRD, SEM, and TGA-DTA. The effects of contact time, pH, adsorbent dose, and initial concentration of Cd(II) on the removal of Cd(II) were studied by performing 29 sets of sorption runs using Box–Behnken design combined with response surface methodology (RSM). Various isotherm models were tested to describe the adsorption equilibrium. The adsorption equilibrium data fitted well with Freundlich isotherm model. The maximum adsorption capacity of 66.66 mg g
−1
was obtained from Langmuir isotherm. The pseudo-second-order kinetic model described the adsorption kinetics more accurately. Diffusion-based kinetics such as intraparticle diffusion and Bangham’s model suggested that both film and intraparticle pore diffusion were involved in the adsorption process. The Elovich model pointed towards the chemisorption. The investigation of desorption and regeneration suggested that the material can be used as an effective sorbent for removal of Cd(II) from aqueous system.
Praziquantel is the only drug available for the treatment of Opisthorchis viverrini infections. Tribendimidine has emerged as a potential treatment alternative; however, its pharmacokinetic (PK) ...properties have not been sufficiently studied to date. Via two phase IIa dose-finding studies, 68 O. viverrini patients were treated with 25- to 600-mg doses of tribendimidine using 50- and 200-mg tablet formulations. Plasma, blood, and dried blood spots (DBS) were sampled at selected time points. The two main metabolites of tribendimidine, active deacetylated amidantel (dADT) and acetylated dADT (adADT), were analyzed in plasma, blood, and DBS. PK parameters were estimated by noncompartmental analysis. An acceptable agreement among plasma and DBS concentrations was observed, with a mean bias of ≤10%, and 60% dADT and 74% adADT concentrations being within ±20% margins. We found that 200-mg tribendimidine tablets possess immediate floating characteristics, which led to variable time to maximal concentration of drug (Tmax) values (2 to 24 h) between individuals. Dose proportionality was observed for dADT from 25 to 200 mg using 50-mg tablets, but at higher dosages (200 to 600 mg), saturation occurred. The median ratio of the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) of dADT to the AUC0- 24 of adADT ranged from 0.8 to 26.4, suggesting substantial differences in acetylation rates. Cure rates ranged from 11% (25-mg dose) to 100% (400-mg dose). Cured patients showed significantly higher dADT maximal serum concentrations (Cmax) and AUC0-24 values than uncured patients. Tribendimidine is a promising drug for the treatment of opisthorchiasis. However, the tablet formulation should be optimized to achieve consistent absorption among patients. Further studies are warranted to assess the large differences between individuals in the rate of metabolic turnover of dADT to adADT. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.).
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