Many environmental chemicals caused rat hyperactivity, a key feature of attention deficit hyperactivity disorder (ADHD). These were confirmed by many epidemiological studies, showing the correlation in their exposure levels in patients with ADHD. The nanomaterials have been difficult to be evaluated health risk because of its physicochemical nature. In this study, we examined the possibility that silver nanoparticle might be ADHD related chemical. Oral exposure of rat pups to silver nanoparticles (3mg/kg) with 1% bovine serum albumin as a carrier protein at 5 days old increased 1.3~1.4 fold spontaneous motor activity while without carrier proteins, it failed to do so. Thus, dispersion of silver nanoparticle solution by carrier proteins was necessary to examine the toxicological action of silver nanoparticles in the animal experiment.

TTA-121 is a novel oxytocin nasal spray with high bioavailability and is expected to increase oxytocin delivery to the brain by adjusting osmolality and viscosity of the formulation. As nonclinical safety studies to support the conduct of the Phase 1 and Phase 2 studies of TTA-121, a 6-week repeated intranasal dose toxicity study of TTA-121 in monkeys was conducted. In the present study, TTA-121 was administered intranasally to male and female cynomolgus monkeys once daily for 6 weeks at 0, 26.88, 134.4, and 672.0 U/body/day followed by a 4-week recovery period to investigate the toxicity of oxytocin and systemic exposure to oxytocin. No animal died or was euthanized due to moribundity. There were no test article-related changes in clinical signs, body weight, food consumption, ophthalmology, electrocardiography, urinalysis, hematology, blood chemistry, necropsy, organ weights, or histopathology at any dose level during the dosing or recovery periods. The toxicokinetic analysis indicated that systemic exposures of oxytocin increased with the dose ranging from 26.88 to 672.0 U/body/day on the first and final day of dosing. Based on these results, the no-observed adverse effect level (NOAEL) of TTA-121 was 672.0 U/body/day.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder. Although there is no established treatment for the core symptoms of ASD, recent research has indicated a potentially therapeutic effect of intranasally administered oxytocin. TTA-121 is a novel oxytocin nasal spray with high bioavailability and is expected to increase oxytocin delivery to the brain by adjusting osmolality and viscosity of the formulation. As nonclinical safety studies to support the conduct of the Phase 1 and Phase 2 studies of TTA-121, a 6-week repeated intranasal dose toxicity study of TTA-121 in rats was conducted. In the present study, TTA-121 was administered intranasally to male and female rats at 0 (placebo), 1.2, 6, and 30 U/body/day once daily for 6 weeks followed by a 4-week recovery period to evaluate potential toxicity and systemic exposure to oxytocin. The toxicokinetic analysis indicated that systemic exposure of oxytocin increased with a dose ranging from 1.2 to 30 U/body/day at the first and last dosing. No deaths or moribundity were observed. There were no toxicologically significant changes in clinical signs, functional observational battery, body weight, food consumption, water consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weights, necropsy or histopathology at any dose during the dosing or recovery period. Based on these results, the no-observed-adverse-effect level of TTA-121 was 30 U/body/day for male and female rats, suggesting that there is a sufficient safety margin. We believe that TTA-121 is expected to be sufficiently safe to treat males and females with ASD.

Ovariectomized rats were used as an animal model of osteoporosis in this study. They were given ad libitum access to a diet with high or low calcium to phosphorus ratio, or a normal diet, for a period of 10 weeks and effects on osteoporosis were assessed. Our results showed that the experimental diets affect urine levels of calcium and phosphorus, but do not affect the levels of biochemical, histopathological, or bone-related biomarkers. These results indicate that the administration of feed with different ratios of calcium to phosphorus (the phosphorus content was kept constant and the calcium content varied from 0.2× to 5× relative to the phosphorus content) over a period of 10 weeks does not accelerate the development of osteoporosis in ovariectomized rats with normal renal function to maintain homeostasis.

S-(1, 2-Dichlorovinyl)-L-cysteine (DCVC) is derived from trichloroethylene (TCE) and known to cause renal cell injury after metabolic activation by cysteine conjugate β-lyase. We examined the in vivo disposition of [³⁵S] DCVC in mice after intraperitoneal administration at a dose of 30 mg/kg (2.42 MBq/6 mg/mL). DCVC and its related-substances were absorbed rapidly and distributed highly in the kidneys. Whole-body autoradiography analyses revealed high accumulation of DCVC and its relatedsubstances in hyaline cartilage of growth plates of the femoral epiphysis, vertebral endplates of the spinal column, costal cartilage, and tracheal cartilage, in addition to the kidneys. These findings suggest that TCE and DCVC are likely to be a cause of damaged cartilage.

In the therapy of ocular diseases, different active pharmaceutical ingredients are often instilled concomitantly as different ophthalmic solutions at an appropriate interval (unfixed-combination therapy) or simultaneously as one formulation (fixed-combination therapy). In this study, we aimed to compare the in vitro cytotoxicity of fixed- and unfixed-combination ophthalmic solutions using the glaucoma therapeutic agents, timolol and brimonidine. Cultured human corneal epithelial cell line was used as a test system. Exposure period was set at 5 min. Compared with the fixed-combination treatment, the unfixed-combination treatment (timolol followed by brimonidine, and vice versa) led to a significant reduction in the percentage of cell viability. In conclusion, it was suggested that a fixed-combination ophthalmic solution was expected to cause less cellular damage to the ocular surface, compared to an unfixed-combination ophthalmic solution.