Phase III, open-label, single-arm study of a new MMR vaccine (JVC-001); measles AIK-C, mumps RIT 4385, rubella Takahashi, as a second vaccine dose in healthy Japanese children aged 5-6 years.

PURPOSE: This Phase III, multicenter, open-label, single-arm study evaluated the safety and immunogenicity of the measles-mumps-rubella (MMR) combined vaccine, JVC-001, as a second MMR vaccination. METHODS: Healthy Japanese children aged 5-6 years received a single dose of JVC-001 following a first measles, mumps, and rubella vaccination (measles-rubella bivalent and mumps monovalent vaccine [Hoshino or Torii strain] or JVC-001) or the MMR vaccine received between ages 1 to <4 years. Immunogenicity was evaluated using antibody titers before and after vaccination (Day 1/Day 43). The primary endpoint was the seroprotection rate of antibody titers against each virus; geometric mean titer (GMT) was also evaluated. Adverse events (AEs) and adverse drug reactions (ADRs) were monitored. RESULTS: One-hundred participants completed the study. The seroprotection rate of antibody titers against measles, rubella, and mumps virus (genotype D) were 100.0 % (95 % confidence interval [CI] 96.4 %, 100.0 %), 100.0 % (95 % CI 96.4 %, 100.0 %), and 100.0 % (95 % CI 96.3 %, 100.0 %), respectively. GMT (fold) increases (Day 1 to Day 43) were 16.0 to 55.7 for measles virus, 35.5 to 99.0 for rubella virus, and 25.7 to 89.5 for mumps virus (genotype D). Solicited ADRs occurred in 40.0 % of participants (injection site, 34.0 %; systemic, 13.0 %). CONCLUSIONS: The second MMR vaccination with JVC-001 demonstrated sufficient antibody coverage against all three viruses; the safety profile was tolerable. CLINICAL TRIAL REGISTRATION: jRCT2080225022.

Alkylsulfanyl analogs as potent α2δ ligands.

We identified novel (3R, 5S)-3-aminomethyl-5-methanesulfanyl hexanoic acid (5a: DS75091588) and (3R, 5S)-3-aminomethyl-5-ethanesulfanyl hexanoic acid (6a: DS18430756) as sulfur-containing γ-amino acid derivatives that were useful for the treatment of neuropathic pain. These two compounds exhibited a potent analgesic effect in animal models of both type I diabetes and type II diabetes, and good pharmacokinetics.

Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach.

Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.

Discovery of novel chiral diazepines as bombesin receptor subtype-3 (BRS-3) agonists with low brain penetration.

The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s.

Dietary supplementation of gamma-linolenic acid improves skin parameters in subjects with dry skin and mild atopic dermatitis.

Disruption of the skin barrier function caused by epidermal hyper-proliferation, results in the skin becoming dry and showing high transepidermal water loss (TEWL). Gamma linolenic acid (GLA) is reportedly efficacious for treating TEWL and epidermal hyper-proliferation. In this study, to elucidate the effect of GLA-rich oil on skin function, GLA-containing food was given to adults with dry skin or mild atopic dermatitis and skin parameters were evaluated. In the results, we recognized beneficial effects on the TEWL index. The efficacy of GLA was also demonstrated to be statistically significant especially in subjects with pro-inflammatory features. The results suggest that the mechanism of improvement of skin barrier has been associated with possible generation of anti-inflammatory metabolites from GLA. The clinical physician also confirmed that none of the subjects showed any noteworthy side effects. GLA-enriched food appears to be safe and to improve skin barrier function in subjects with dry skin conditions and mild atopic dermatitis.

Isolation of rice dwarf mutants with ectopic deposition of phenolic components including lignin in parenchyma cell walls of internodes.

Rice internodes must have the proper shape to support high-yielding panicles. The shape of internodes is controlled by various factors involved in their formation, such as developmental patterns, cell division, cell elongation, and cell wall biosynthesis. To understand the regulation of internode development, we screened dwarf mutants to identify those with a phenotype of ectopic deposits of phenolic components in parenchyma cell walls of internodes. We named these mutants ectopic deposition of phenolic components1 (edp1). Two alleles were identified, edp1-1 and edp1-2. Furthermore, these mutants showed disordered cell files in internode parenchyma. These abnormal phenotypes were very similar to that of a previously reported dwarf50 (d50) mutant. Genetic analyses of edp1 mutants revealed that the edp1 loci are distinct from d50. Our results indicate that analyses of edp1 mutants as well as the d50 mutant will be useful for understanding the molecular mechanisms behind ectopic deposition of cell wall phenolic components in internode parenchyma cells and the regulation of internode development.