The antioxidant activity of an anti-ischemic agent, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), was examined. The pKa value of MCI-186 is 7.0 and the rate of oxidation of MCI-186 initiated with an azo compound increased with increasing pH, suggesting that the anionic form of MCI-186 is much more reactive than the non-ionic form. The major products were 3-methyl-1-phenyl-2-pyrazolin-4,5-dione (4,5-dione) and 2-oxo-3-(phenylhydrazono)-butanoic acid (OPB). Hydrolysis of 4,5-dione gave OPB. The minor intermediate product was 4-hydroxy-4-(3-methyl-1-phenyl-1H-pyrazolin-5-on-4-yl)-3-methyl-1-phenyl-1H-pyrazolin-5-one (BPOH). The nucleophilic attack of the anionic form of MCI-186 to 4,5-dione is likely to give BPOH. MCI-186 (50 μM) inhibited the aerobic oxidation at 37°C of 5.2 mM unilamellar soybean phosphatidylcholine (PC) liposomal membranes, initiated with a water-soluble initiator, as efficientlyas did ascorbate (100 μM). MCI-186 (50 μM) also inhibited the oxidation of the same PC liposomal membranes, this time initiated with a lipid-soluble initiator, almost as efficiently as did α-tocopherol (2 μM). Furthermore, the combination of MCI-186 with ascorbate or α-tocopherol showed almost complete inhibition of PC oxidation induced by both initiators. These data suggest that MCI-186 may work as a good antioxidant in cellular systems as well as in cell-free systems.

Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.

No abstract

The etiology of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress may be one of the major mechanisms involved. In vitro and in vivo data of edaravone suggest that it may possess broad free radical scavenging activity and protect neurons, glia, and vascular endothelial cells against oxidative stress. During the 1980s and 1990s, edaravone was developed for the treatment of acute ischemic stroke. In 2001, a clinical program in ALS was initiated and five clinical studies were conducted in Japan. Phase III studies were designed to rapidly evaluate (within a 24-week double-blind study window) functional changes using the Revised ALS Functional Rating Scale (ALSFRS-R) as a primary endpoint. The study populations were selected according to these considerations and were further refined as the studies proceeded. Although the first phase III study did not meet its primary endpoint, post-hoc analyses showed an apparent effect of edaravone, when additional patient inclusion criteria defined by ALSFRS-R score, pulmonary function, certainty of ALS diagnosis, and duration of disease were applied. This population was hypothesized not only to have retained broad functionality and normal respiratory function at study baseline but also to be likely to show measurable disease progression over 24 weeks. A second confirmatory phase III study applying these refinements in patient selection was prospectively designed and successfully documented a statistically significant difference between the edaravone and placebo groups in the ALSFRS-R primary endpoint. This paper describes and reviews data pertinent to the potential mechanism of action of edaravone, and reviews the development history of edaravone for the treatment of ALS.

No abstract

K,Na)NbO 3 (KNN) films with high transverse piezoelectric coefficients were successfully deposited onto Pt/Ti/SiO 2 /Si substrates by RF magnetron sputtering. These films were polycrystalline and had pseudo-cubic perovskite structures with preferential h001i orientation. To improve their piezoelectric properties, we investigated the effects of annealing after the deposition and the Na=ðK þ NaÞ ratio of the films. Annealing in air at 750 C led to a decrease in the residual strain in the KNN crystal and the disappearance of openings at the grain boundary, thereby improving the transverse piezoelectric coefficient and leakage current properties. We also investigated the transverse piezoelectric coefficient and dielectric constant as a function of the Na=ðK þ NaÞ ratio; both had maximum values at a ratio of approximately 0.55. For the KNN films, e à 31 ranged between À10:0 and À14:4 C/m 2 ; thus, it was superior to previously reported values for lead-free piezoelectric films and was comparable to the best commercially available Pb(Zr,Ti)O 3 films. #

This paper describes the discovery of a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, 1), as a potent antioxidant agent against lipid peroxidation. The structure-activity relationship of edaravone indicated that lipophilic substituents were essential to show its lipid peroxidation-inhibitory activity. In vivo studies revealed that edaravone showed brain-protective activity in a transient ischemia model.

We demonstrate the ultrahigh‐speed growth of thick GaN layers by hydride vapor phase epitaxy (HVPE) and present an investigation of the properties of the resulting GaN crystals. A series of GaN layers with a thickness of around 700 μm were grown homoepitaxially on freestanding GaN substrates at various growth rates ranging from 107–1870 μm/h, using a conventional atmospheric HVPE reactor. The growth rate increased almost linearly with the feed rate of source materials, reaching 1870 μm/h when the HCl flow rate is 650 sccm. The surfaces of all the homoepitaxial layers were specular, and no cracks or pits were observed. The X‐ray rocking curve measurement showed that the full width at half maximum values did not depend on the growth rate, and had small values of 23–30 arcsec for (0002) reflections and 39–58 arcsec for (30‐32) reflections. Plan‐view cathodoluminescence imaging revealed that the dislocation density had virtually no dependence on the growth rate and had small values of around 3 × 106 cm‐2 even at the highest growth rate (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)