No abstract

Currently, there are limited reports available regarding the treatment and prevention of progressive age-related hearing loss. This is because age-related hearing loss is not a critical disease with direct fatalities and has several well-established countermeasures such as hearing aids and cochlear implants. This study evaluated the efficacy of Ninjinyoeito (NYT) in the treatment of age-related hearing loss. C57BL/6J mice were divided into three groups: baseline group, untreated group, and NYT-treated group, with the latter receiving NYT treatment for 2 months. The mice were fed with NYT extract mixed with 4% mouse normal chow. Hearing loss was confirmed by a reduction in intact cell density of the auditory nerve from the age of 5–7 months. The suppression of hearing loss with aging and decrease in the intact cell density of the auditory nerve were significant in mice fed with NYT for 2 months. NYT has been reported to improve blood flow and enhance mitochondrial activity and may exert its protective effects on spiral neurons through these mechanisms. There was no decrease in the size of the stria vascularis from the age of 5–7 months in C57BL/6J mice. The present model failed to reveal the effect of NYT on atrophy of the stria vascularis of the cochlear duct. In conclusion, NYT appears to have a protective effect on the auditory nerve and suppress the progression of age-related hearing loss by reducing age-related auditory nerve degeneration.

Cancer microenvironment is characterized by severe hypoxia and nutrient deprivation, especially glucose. Cancer depends largely on glycolysis for energy production (Warburg effect), therefore tumor hypoxia is mainly caused by poor blood supply despite vigorous angiogenesis. Severe tumor hypoxia and glucose deprivation promote tumor progression and affects tumor behavior especially resistance to anticancer drugs. We have focused on the invention of agents that cancel cancer cells' ability to tolerate poor oxygen and glucose supply (antiausterity) and found many agents including kigamicin, pyrvinium pamoate, and arctigenin. Because antitumor activity and safety profile were excellent in preclinical test, arctigenin was chosen for the first compound for clinical trial. Arctigenin is rich in fruit of Arctinum lappa which is filed in Japanese Pharmacopoeia, we have invented an extraction method to enrich arctigenin (GBS-01, Kracie Pharma, Ltd.) and used in clinical trial. GBS-01 contained arctigenin about 10% in weight. Pancreatic cancer is characterized for its hypovascularity and severe hypoxia in cancer tissue has been reported and, in addition, only limited benefit of chemotherapy has been achieved so far. Patients, material and design of trial: Pancreatic cancer patients refractory to gemcitabine were selected for the phase I clinical trial of GBS-01. Primary endpoint of the trial was determination of recommended dose by assessing DLT in dose escalation study from 1 g/day to 4 g/day, corresponding to 100 mg to 400 mg arctigenin/day. GBS-01 administration was continued until either unacceptable adverse effcts or evident progression of the cancer appeared. Pharmacokinetic study was also carried out as a secondary endpoint. Results:Fifteen patients were enrolled and three patients were not evaluated because of early stopping due to progression of the disease. Results: Among 12 patients evaluated, no DLT was observed. No serious adverse effects on bone marrow, liver and kidney function was observed. Pharmacokinetic study revealed that arctigenin is efficiently absorbed and rapidly conjugated with glucuronic acid. Serum concentration of arctgenin glucuronide was about 100 to several hundreds higher than that of arctigenin, indicating glucuronidation in the first pass. Urinary secretion of arctigenin and its glucuronide was more than half of administered dose in more than half of patients, indicating high bioavailability. Regarding clinical tumor response, partial response was observed in one patient at 2.5 g/day (level 2) for 2 months followed by 2four months stable disease (SD) and SD was observed in other four patients. Median progression free survival was 1.05 months and median overall survival was 5.68 months.Conclusion: Arctigenin showed high bioavailability, high safety profile, and promising clinical responses. Citation Format: Hiroyasu Esumi, Satoshi Owada, Rumi Fujioka, Katsuya Tsuchihara, Atsushi Ohtsu, Aihiro Sato, Masafumi Ikeda, Nobuo Mochizuki, Satoshi Kishino, Takanori Kawashima, Satoshi Yomoda. Arctigenin, an antiausterity agent shows high safety and promising clinical response in phase I clinical trial in patient with gemcitabine-refractory pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT213. doi:10.1158/1538-7445.AM2014-CT213

Weight loss is often temporary and is generally followed by recurrent weight gain and a relapse of metabolic complications, whose severity may be even greater upon recurrence. Preventing recurrent obesity, understanding the control of the energy balance subsequent to weight loss, and reversing the predisposition to obesity are critical factors that warrant an in-depth study. Several Kampo medicines, including daisaikoto, have traditionally been used to manage obesity, but their mechanisms of action are not well studied and their effects on weight regain are unknown. Here, we investigated the therapeutic potential and mechanism of action of daisaikoto in a mouse model of recurrent obesity. The mouse model was established by feeding mice a high-fat diet, followed by a normal chow, and a second course of the high-fat diet. Daisaikoto inhibited not only obesity and regaining of weight post-dieting, but also dysbiosis, thereby overcoming the predisposition to obesity. Furthermore, we found that recurrent obesity or long-term consumption of the high-fat diet elevated serum glucose, insulin, and corticosterone levels, and that daisaikoto lowered serum cholesterol and free fatty acid levels. These results are consistent with the hypothesis that this medication may inhibit lipid absorption by inhibiting pancreatic lipase. However, daisaikoto had no effect on the body weight of lean mice fed a normal chow, suggesting that although this medicine prevents lipid absorption, it does not cause excessive weight loss. In conclusion, our results elucidate the mechanisms underlying daisaikoto activity, and suggest that it may serve as a safe and effective anti-obesity drug.