Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis.

PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration. METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated. FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported. IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www. CLINICALTRIALS: gov.

Edaravone Administered Orally and Via Nasogastric Tube in Healthy Adults: A Comparative Bioavailability Phase 1 Study.

Intravenous edaravone is used to treat patients with amyotrophic lateral sclerosis. This randomized, open-label, two-way crossover, single-dose phase 1 study compared the relative bioavailability of a newly developed edaravone oral suspension when administered orally and via a nasogastric tube (NGT) as a model of percutaneous endoscopic gastrostomy tube administration in healthy adult subjects. Thirty-six subjects were randomly assigned to one of two groups, with 18 per group. Blood was collected pre- and post-dose for pharmacokinetic assessments; safety was evaluated. Plasma concentration-time profiles of unchanged edaravone were similar between administration routes. Comparative bioavailability analysis revealed that geometric least squares mean ratios (NGT/oral) for maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity of unchanged edaravone were 1.052 and 0.981, respectively. No serious adverse events or adverse drug reactions were reported. These results suggest that oral edaravone suspension can be administered directly to the stomach without dose adjustment via feeding tubes; both oral and NGT administration are well tolerated.

High-Resolution Numerical Simulation of Microfiltration of Oil-in-Water Emulsion Permeating through a Realistic Membrane Microporous Structure Generated by Focused Ion Beam Scanning Electron Microscopy Images.

Owing to the limitations of visualization techniques in experimental studies and low-resolution numerical models based on computational fluid dynamics (CFD), the detailed behavior of oil droplets during microfiltration is not well understood. Hence, a high-resolution CFD model based on an in-house direct numerical simulation (DNS) code was constructed in this study to analyze the detailed dynamics of an oil-in-water (O/W) emulsion using a microfiltration membrane. The realistic microporous structure of commercial ceramic microfiltration membranes (mullite and α-alumina membranes) was obtained using an image processing technique based on focused ion beam scanning electron microscopy (FIB-SEM). Numerical simulations of microfiltration of O/W emulsions on the membrane microstructure obtained by FIB-SEM were performed, and the effects of different parameters, including contact angle, transmembrane pressure, and membrane microporous structure, on filtration performance were studied. Droplet deformation had a strong impact on filtration behavior because coalesced droplets with diameters larger than the pore diameter permeated the membrane pores. The permeability, oil hold-up fraction inside the pores, and rejection were considerably influenced by the contact angle, while the transmembrane pressure had a little impact on the permeability and oil hold-up fraction. The membrane structure, especially the pore size distribution, also had a significant effect on the microfiltration behavior and performance.

Phase-Field Simulation of the Coalescence of Droplets Permeating through a Fibrous Filter Obtained from X-ray Computed Tomography Images: Effect of the Filter Microstructure.

We numerically study the droplet coalescence of an oil-in-water (O/W) emulsion permeating through a fibrous filter. Our numerical simulation method is based on the phase-field model for capturing a free interface, the immersed boundary method used to calculate fluid-solid interactions, and the wetting model that assigns an order parameter to the solid surface according to the wettability. To represent realistic flow inside the filter during simulation, the voxel data obtained from X-ray computed tomography (CT) images of the filter microstructure are used in the simulation. The effects of the filter microstructure, such as fiber arrangement and orientation of the droplet coalescence, are investigated by using several filter domains. Our simulations demonstrate that the arrangement of closely attached fibers placed at the permeate-side surface enhances droplet coalescence. In addition, the parallel orientation of the fiber to the main flow direction suppresses droplet enlargement due to the coalescence but reduces the number of droplet passages without coalescence in the filter.

[Difficult Perioperative Glucose Management in a Type 2 Diabetic Patient with Anti-insulin Antibody Undergoing Laparoscopic Partial Liver Resection].

A 50-year-old man with type 2 diabetes mellitus was scheduled for laparoscopic partial liver resection. Six months prior to the surgery, he developed frequent hypoglycemic attacks and was diagnosed as anti-insulin antibody positive. The operation was performed under general anesthesia with epidural anesthesia. Intermit- tent and continuous insulin administration was required during liver resection due to persistent hyperglycemia. After termination of the liver resection, the patient exhibited uncontrolled hypo- and hypergly- cemia, and recovery from anesthesia was delayed due to severe hypoglycemia. He recovered immediately after 40% glucose administration. However, frequent glucose administration was required for two hours after transfer to the ICU due to hypoglycemia. It should be born in mind that preoperative poor glucose control might be caused by anti-insulin antibodies and lead to difficult perioperative glucose management.

Insights into transcription termination of Hfq-binding sRNAs of Escherichia coli and characterization of readthrough products.

The genes encoding Hfq-dependent sRNAs possess a typical Rho-independent transcription terminator. Here, we have studied the molecular events occurring at Rho-independent terminators of sRNA genes, focusing on two well-characterized Hfq-binding sRNAs, SgrS and RyhB. We constructed several hybrid genes in which the DNA sequence corresponding to a strong Rho-independent terminator was placed just downstream from the Rho-independent terminators of sRNA genes. By using this system, we demonstrate that transcripts frequently read through the Rho-independent terminators of sgrS and ryhB in normally growing cells. We show that Hfq does not affect the transcriptional readthrough event itself. We also find that the readthrough products no longer bind to Hfq in vivo. We have developed a competition assay based on a biotin-streptavidin system to analyze the interaction of Hfq and a particular RNA molecule in vitro. By using this method, we verify that the 3'-extended form of SgrS does not bind to Hfq in vitro. Finally, we demonstrate that transcription termination is significantly enhanced under stress conditions where transcription initiation of sRNA genes on the chromosome is induced. We conclude that the production of sRNAs is regulated not only at the step of transcription initiation but also at the step of transcription termination. The mechanism by which transcription termination is enhanced under stress conditions remains to be understood.

Finishing of AT-cut quartz crystal wafer with nanometric thickness uniformity by pulse-modulated atmospheric pressure plasma etching.

Quartz resonator is a very important device to generate a clock frequency for information and telecommunication system. Improvement of the productivity of the quartz resonator is always required because a huge amount of the resonator is demanded for installing to various electronic devices. Resonance frequency of the quartz resonator is decided by the thickness of the quartz crystal wafer. Therefore, it is necessary to uniform the thickness distribution of the wafer with nanometric level. We have proposed the improvement technique of the thickness distribution of the quartz crystal wafer by numerically controlled correction using atmospheric pressure plasma which is non-contact and chemical removal technique. Heating effects of the quartz wafer in the removal rate and the correction accuracy were investigated. The heating of the substrate and compensate of the scanning speed of the worktable according to the variation of the surface temperature enabled an increase of 50% in the etching rate and 10-nanometric-level accuracy in the correction of the thickness distribution of the quartz wafer, respectively.

Highly efficient damage-free correction of thickness distribution of quartz crystal wafers by atmospheric pressure plasma etching.

A new finishing method was developed to correct the thickness distribution of a quartz crystal wafer by the numerically controlled scanning of a localized atmospheric pressure plasma. The thickness uniformity level of a commercially available AT-cut quartz crystal wafer was improved to less than 50 nm without any subsurface damage by applying one correction process. Furthermore, applying a pulse-modulated plasma markedly decreased the correction time of the thickness distribution without breaking the quartz crystal wafer by thermal stress.