Qualitative analysis of actual Standard for Exchange of Nonclinical Data (SEND) datasets for Data Domains: Proposition from Japan Pharmaceutical Manufacturers Association SEND Taskforce Team on standardization of nonclinical data.

The Standard for Exchange of Nonclinical Data (SEND) has been adopted by the US FDA, which has required pharmaceutical companies who are developing new drugs for the US market to implement SEND. The Japan Pharmaceutical Manufacturers Association (JPMA) SEND Taskforce Team responded to this situation by starting a project to better understand the contents of SEND datasets. The project focused on domains generally included in the SEND domains for single- and repeat-dose general toxicology studies, and surveyed what kind of information are populated in which domains and in what way. The qualitative analysis of the results indicated that variations exist based on whether or not an individual variable was populated and on how the variable was populated. The Taskforce Team recommends reducing variations not only in the SEND datasets but also in the descriptions in the study protocol and/or final study report. Reduction of such variations should lead to higher quality datasets with powerful and increased searchability so that accumulated SEND datasets should become more valuable. These efforts would provide regulatory agencies with easier review of SEND datasets, which contributes to efficient development of new drug candidates.

Toxicologic Pathology Forum: Current Status on the Use of Animal Models of Human Disease in the Pharmaceutical Industry in Japan in Nonclinical Safety Assessment-Opinion Paper.

In nonclinical safety studies for new drug development, healthy animals have been commonly used. However, in some cases, the use of animal models of human disease is considered to be more favorable in evaluating risks in patients. To elucidate the current status of the use of animal models for nonclinical safety assessment, an internal questionnaire from the Japan Pharmaceutical Manufacturers Association and surveys (questionnaire period: August 27 to September 30, 2015) of both common technical documents and review reports of approved drugs (approval period: May 1999 to May 2017) disclosed by the Pharmaceutical and Medical Devices Agency were conducted. Although there were some concerns and limitations raised, the survey results revealed that animal models have been used in nonclinical safety assessment on a case-by-case basis and that nonclinical safety studies using animal models were included in the data packages of several approved drugs in Japan. The survey results also revealed that nonclinical safety studies using animal models have become more frequent in the past few years. In almost all cases, useful information, such as signs of toxicity under disease conditions and mechanisms of toxic change, was obtained from the results of nonclinical studies using animal models. Note: This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the author(s). It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

Social isolation stress induces hepatic hypertrophy in C57BL/6J mice.

We previously reported that social isolation stimulated a stress response leading to increasing plasma corticosterone level and disruption of the hepatic lipid metabolism-related pathway, without changing body and organ weights, in mice after 4 weeks of social isolation stress, compared with the grouped-housing control (5 mice/cage). In this study, we evaluated the effects of social isolation stress for an extended period on physiologic changes in male C57BL/6J mice. Plasma corticosterone was reduced after 13 weeks, indicating mice might adapt to social isolation stress. However, body and visceral fat weights were significantly increased in combination with hepatic hypertrophy, and significant decreases in levels of triglyceride and adiponectin in plasma were observed. In conclusion, it is tempting to speculate that mice exposed to social isolation stress for 13 continuous weeks could be at an increased risk of overweight with hepatic hypertrophy. Our results also imply that physiological changes, at least fatty acid metabolism, under stress exposure might be an important factor when evaluating the chronic effects of environmental chemicals.

Photo- and electro-chromic organometallics with dithienylethene (DTE) linker, L2CpM-DTE-MCpL2: dually stimuli-responsive molecular switch.

Photochromic dithienylethene (DTE) derivatives, M-DTE-M (M: M(η(5)-C(5)R(5))L(2); M = Fe, Ru; R = H, Me; L = CO, phosphine), with direct σ-bonded, redox-active organometallic attachments are prepared and their response to photo- and electro-chemical stimuli as well as wire-like and switching performance has been investigated. These properties turn out to be dependent on the metal and the auxiliary ligands. The DTE complexes with the MCp(CO)(2) and RuCp(CO)(PPh(3)) fragments undergo reversible photochemical ring-closing and -opening of the DTE moiety upon UV and visible-light irradiation, respectively, whereas the other FeCp(CO)(PPh(3)) and Fe(η(5)-C(5)R(5))(dppe) derivatives are virtually inert with respect to the photochemical ring closing process. Electrochemical analysis of the DTE complexes reveals that 2e-oxidation of the open isomer O also brings about the ring closure of the DTE moiety to afford the Fischer-carbene-type, dicationic closed derivatives C(2+) with the π-conjugated system different from that in the neutral ones C obtained photochemically. Subsequent reduction of C(2+) furnishes the neutral closed species C. Thus the ring closure is mediated not only by the conventional photochemical process but also by the sequential oxidation-reduction process, i.e. the organometallic DTE complexes are found to be dually photo- and electro-chromic. It is notable that the oxidative procedures are viable for the photochemically inert derivatives. Wire-like and switching performance has been evaluated on the basis of the comproportionation constant K(C) for the 1e-oxidized mixed valence monocationic species obtained by the electrochemical analysis and the switching factor SF (K(C)(C)/K(C)(O)), respectively. The K(C)(C) (7.5 × 10(4)) and SF values (5.4 × 10(3)) for phosphine-substituted derivatives are significantly large, as a result of the distinct π-conjugated systems of the DTE moieties involved in the O- (with cross-conjugation) and C-forms (fully conjugated). Compared to the previously reported acetylide-type complexes bridged by a DTE linker, (dppe)Cp*M-C≡C-DTE-C≡C-MCp*(dppe), both parameters have been significantly improved by factors of ~150. Time-dependent DFT analysis for the photochemical processes has revealed that the ring-closing process occurs not only via the ligand centered singlet excited state but also via the ligand centered triplet state resulting from energy transfer processes between the ligand- and metal-centered excited states and that this proposed mechanism can account for the photochemical reactivity of ruthenium complexes superior to that of the corresponding iron derivatives.

Quantitative risk assessment of Vibrio parahaemolyticus in finfish: a model of raw horse mackerel consumption in Japan.

The aim of this study was to evaluate the effects of implemented control measures to reduce illness induced by Vibrio parahaemolyticus (V. parahaemolyticus) in horse mackerel (Trachurus japonicus), seafood that is commonly consumed raw in Japan. On the basis of currently available experimental and survey data, we constructed a quantitative risk model of V. parahaemolyticus in horse mackerel from harvest to consumption. In particular, the following factors were evaluated: bacterial growth at all stages, effects of washing the fish body and storage water, and bacterial transfer from the fish surface, gills, and intestine to fillets during preparation. New parameters of the beta-Poisson dose-response model were determined from all human feeding trials, some of which have been used for risk assessment by the U.S. Food and Drug Administration (USFDA). The probability of illness caused by V. parahaemolyticus was estimated using both the USFDA dose-response parameters and our parameters for each selected pathway of scenario alternatives: washing whole fish at landing, storage in contaminated water, high temperature during transportation, and washing fish during preparation. The last scenario (washing fish during preparation) was the most effective for reducing the risk of illness by about a factor of 10 compared to no washing at this stage. Risk of illness increased by 50% by exposure to increased temperature during transportation, according to our assumptions of duration and temperature. The other two scenarios did not significantly affect risk. The choice of dose-response parameters was not critical for evaluation of control measures.

Isolation stress for 30 days alters hepatic gene expression profiles, especially with reference to lipid metabolism in mice.

To elucidate the physiological responses to a social stressor, we exposed mice to an isolation stress and analyzed their hepatic gene expression profiles using a DNA microarray. Male BALB/c mice were exposed to isolation stress for 30 days, and then hepatic RNA was sampled and subjected to DNA microarray analysis. The isolation stress altered the expression of 420 genes (after considering the false discovery rate). Gene Ontology analysis of these differentially expressed genes indicated that the stress remarkably downregulated the lipid metabolism-related pathway through peroxisome proliferator-activated receptor-alpha, while the lipid biosynthesis pathway controlled by sterol regulatory element binding factor 1, Golgi vesicle transport, and secretory pathway-related genes were significantly upregulated. These results suggest that isolation for 30 days with a mild and consecutive social stress regulates the systems for lipid metabolism and also causes endoplasmic reticulum stress in mouse liver.

Remarkable switching behavior of bimodally stimuli-responsive photochromic dithienylethenes with redox-active organometallic attachments.

Organometallic dithienylethenes with the redox-active M(eta(5)-C(5)H(5))L(2)-type attachments (M = Fe, Ru; L = CO, PR(3)) exhibit bimodally stimuli-responsive, photo- and pseudo-electrochromic behavior with the remarkable switching factors [K(C)(closed)/K(C)(open)] up to 5.4 x 10(3).

Social stress increases biopyrrins, oxidative metabolites of bilirubin, in mouse urine.

We investigated whether or not three kinds of social stress (isolation, crowding, and confrontation) increase urinary excretion of biopyrrins, oxidative metabolites of bilirubin, in mice. Male BALB/c mice (4 weeks old) were housed 5 per cage for 10 days. After acclimatization, mice were exposed to the above mentioned three kinds of psychosocial stress. Mouse blood and urine samples were collected after 2, 7, and 30 days of stress. Serum levels of corticosterone and urinary levels of biopyrrins were determined by EIA and ELISA, respectively. Adrenal hypertrophy, significant increases in serum concentration of corticosterone and in urinary excretion of biopyrrins were observed in mice exposed to these types of social stress for 7 days. These levels decreased after 30 days, though they were still rather high compared to the control group. These results suggested that social stress causes oxidative stress and that biopyrrins could be useful biomarkers of psychosocial stress.