In July 2017, Japan's Ministry of Health, Labor and Welfare issued a marketing authorization valid throughout Japan for N-(2,6-dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}-2-oxoethyl)-1,1-dioxothiane-4-carboxamide (amenamevir) for the first time worldwide. The decision was based on the favorable opinion of the Pharmaceuticals and Medical Device Agency (PMDA) recommending a marketing authorization of amenamevir for treatment of herpes zoster (HZ). Amenamevir has a different action mechanism from previously approved synthetic nucleoside compounds for the treatment of HZ including acyclovir, valacyclovir and famciclovir. The usual adult dose is 400 mg amenamevir p.o. once daily for 7 days. The benefit is its ability to cure HZ as well as preventing postherpetic neuralgia. The most common side-effects are increase of urine N-acetyl-b-D-glucosaminidase and a1-microglobulin levels. However, based on the detailed evaluation of the submitted clinical studies, there seems to be no serious safety concerns about amenamevir regarding the kidney of both renally normal and impaired patients. The objective of this article is to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the PMDA website (www.pmda.go.jp/PmdaSearch/iyakuSearch/).
Syndromic craniosynostosis (CS) patients exhibit early, bony fusion of calvarial sutures and cranial synchondroses, resulting in craniofacial dysmorphology. In this study, we chronologically evaluated skull morphology change after abnormal fusion of the sutures and synchondroses in mouse models of syndromic CS for further understanding of the disease. We found fusion of the inter-sphenoid synchondrosis (ISS) in Apert syndrome model mice (Fgfr2 S252W/+ ) around 3 weeks old as seen in Crouzon syndrome model mice (Fgfr2c C342Y/+ ). We then examined ontogenic trajectories of CS mouse models after 3 weeks of age using geometric morphometrics analyses. Antero-ventral growth of the face was affected in Fgfr2 S252W/+ and Fgfr2c C342Y/+ mice, while Saethre-Chotzen syndrome model mice (Twist1 +/− ) did not show the ISS fusion and exhibited a similar growth pattern to that of control littermates. Further analysis revealed that the coronal suture synostosis in the CS mouse models induces only the brachycephalic phenotype as a shared morphological feature. Although previous studies suggest that the fusion of the facial sutures during neonatal period is associated with midface hypoplasia, the present study suggests that the progressive postnatal fusion of the cranial synchondrosis also contributes to craniofacial dysmorphology in mouse models of syndromic CS. These morphological trajectories increase our understanding of the progression of syndromic CS skull growth.
-The Ames test is used for the mutagenic assessment of drugs; however, it may not provide an accurate genotoxic profile for bactericidal compounds. This study was performed to clarify 1) whether the total number of genotoxicity assays performed (#Assays) was greater during antibiotic development than during the development of other drugs, particularly antivirals, possibly due to the requirement for additional assessments, 2) whether the maximum doses of the Ames test were less when an alternative assay had been performed for antibiotics, and 3) whether some particular alternative assay had an advantage to minimize #Assays in the last decade. Genotoxicity data submitted to the Pharmaceuticals and Medical Devices Agency in Japan during 2004 -2015 were used. The #Assays was greater and the maximum doses of the Ames tests were lower for antibiotics, which was more obvious when alternative mutagenic assays had been performed. The mouse lymphoma assay or hypoxanthine-guanine phosphoribosyl transferase gene mutation assay was performed preferentially as an alternative. For antibiotic development, preferred genotoxicity test packages should be discussed in the future for a better understanding of the genotoxic potential of antibiotics.
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