Different Development Strategies Affecting Japan's Drug lag between Japan-Based and Foreign-Based Companies.

We examined the development strategies of new molecular entities approved during a 10-year period (fiscal years of 2012-2021) in Japan to determine the differences in drug lag between Japan and foreign companies. The results demonstrated a clear difference in development strategies. For example, products were usually developed through a "only-Japan" strategy by Japan companies (51.1% of products), compared to a "MRCT (multi-regional clinical trials)" strategy by foreign companies (54.9% of products). Regarding types of licenses, for Japan companies, the percentage of original products was higher in the category of less drug lag, such as "no approval in the US and EU" (59.1%), whereas the percentage of "license-in" products was markedly higher in the "drug lag ≥ 5 years" category (52.5%). Such differences were not observed for products developed by foreign companies. Of 64 license-in products developed by Japan companies with a drug lag > 5 years, 51 (79.7%) had already been approved in the US or EU at initiation of clinical development in Japan. The origin of approximately half (34) of the products was from the emerging companies (non-member foreign companies of the Japan Pharmaceutical Manufacture Association). These results suggest that more global cooperation of Japan companies, particularly with emerging foreign companies, is necessary in terms of the earlier timing of license-in and development strategies of products to promote drug development without drug lag or drug loss in Japan.

Bioremediation of heavily oil-polluted seawater by a bacterial consortium immobilized in cocopeat and rice hull powder.

We examined the effectiveness of cocopeat and rice hull powder obtained from agricultural wastes as biocarriers for an oil-degrading bacterial consortium. Scanning electron microscopy revealed colonization and strong attachment of bacterial cells on the surface of both carriers. Results of a 60-day in vitro seawater bioremediation trial showed significant oil reduction and high cultivable bacterial counts in treatments augmented with the carrier-attached bacterial consortia compared to treatments supplemented with the same consortium in free living and encapsulated forms. Significant degradations in both aliphatic and aromatic fractions were obtained in treatments augmented with carrier-immobilized consortia. The developed immobilized cells showed sustained activities and viabilities during storage for six months. Results of this study demonstrated that inexpensive waste materials can be utilized as biocarriers of an oil-degrading consortium and that immobilization on biocarriers can enhance the bioremediation of oil-contaminated seawater.

Characterization of the bacterial community in the sediment of a brackish lake with oyster aquaculture.

The physicochemical properties and bacterial community in sediments of Lake Shiraishi, a lake with brackish water, were characterized to elucidate the influence of oyster farming and seawater and freshwater inflow. Physicochemical analyses suggested the marine origin of the sediment at the mouth of the lake, while higher organic matter load and the resultant anaerobic, reductive condition of the sediments of the inner part were observed. The bacterial community in the sediments reflects these sediment environments: the bacterial community in the vicinities of oyster farms included sulfate-reducing bacteria (SRB) , although sulfur-oxidizing bacteria (SOB) were found at all the sampling sites. In addition, similarity of the band profiles obtained with 16S ribosomal RNA gene (16S rDNA) -denaturing gradient gel electrophoresis (DGGE) decreased in proportion to the distance from the mouth of the lake to the oyster farms in the inner part. This study was able to characterize the microbial community shift in brackish lake sediments with an oyster aquaculture system through the molecular fingerprinting technique, DGGE, in relation to their physicochemical characteristics.

Effect of magnesium peroxide biostimulation of fish feed-loaded marine sediments on changes in the bacterial community.

The effect of an oxygen-releasing compound (ORC) magnesium peroxide (MgO(2)) on the changes in the bacterial community in organically polluted sediment of aquaculture farms was tested in a microcosm experiment. The sediment, to which fish feed was added, was treated with 1% or 5% MgO(2). The addition of fish feed induced a highly reduced environment with low redox potential, high total sulfides, and abundance of sulfate-reducing bacteria (SRB) . Although the sediment remained highly reduced at 1% MgO(2), there was a significant reduction of total sulfides, increase of redox potential, and resultant reduction of SRB. The bacterial community clearly changed with the treatments according to denaturing gradient gel electrophoresis (DGGE) analysis of 16S ribosomal RNA gene (16S rDNA) . Aerobes disappeared in the fish feed-added sediment, and some SRB emerged in place of these aerobes. On the other hand, the SRB disappeared in the ORC-amended sediment due to its highly oxic condition. This study revealed the bacterial community in the sediments was affected mainly by the redox potential and resultant sulfides produced by SRB, but total organic carbon and nitrogen were not determinants of the microbial population.

Identification of novel and orally active spiroindoline NPY Y5 receptor antagonists.

A series of spiroindoline-3,4'-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10mg/kg.

A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice.

Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, the NPY Y5 receptor (Y5R) is a prime candidate to mediate some of the effects of NPY on energy homeostasis, although its role in physiologically relevant rodent obesity models remains poorly defined. We examined the effect of a potent and highly selective Y5R antagonist in rodent obesity and dietary models. The Y5R antagonist selectively ameliorated diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving the DIO-associated hyperinsulinemia. The compound did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y5R receptor occupancy. The Y5R antagonist acts in a mechanism-based manner, as the compound did not affect DIO of Y5R-deficient mice. These results indicate that Y5R is involved in the regulation and development of DIO and suggest utility for Y5R antagonists in the treatment of obesity.

Blockade of body weight gain and plasma corticosterone levels in Zucker fatty rats using an orally active neuropeptide Y Y1 antagonist.

1. An experiment was conducted to examine whether a potent, orally active and highly selective neuropeptide Y Y1 receptor antagonist attenuates hyperphagia and obesity in genetically obese Zucker fatty rats. 2. Oral administration of the Y1 antagonist (30 and 100 mg x kg(-1), once daily for 2 weeks) significantly suppressed the daily food intake and body weight gain in Zucker fatty rats accompanied with a reduction of fat cell size and plasma corticosterone levels. 3. Despite the fact that food intake was gradually returned to near the control level, the body weight of the treated animals remained significantly less when compared to that of the controls for the duration of the treatment. 4. These results suggest that the Y1 receptor, at least in part, participate in pathophysiological feeding and/or fat accumulation observed in Zucker fatty rats. Y1 antagonists might be useful for the treatment of obesity.