[Trials for early intervention in Mie Prefectural Mental Care Center].

Mie Prefectural Mental Care Center is a public psychiatric hospital that has 400 beds and 250 outpatients a day. The main catchment area is Tsu City (population: 290,000). Our hospital started early intervention in Aug 2008, and opened the Youth Mental Support Center MIE (YMSC MIE) in Oct 2008. This article reports an early intervention trial in a regional area of Japan. The mission of YMSC MIE is the education, consultation, staff training, and intervention for mental health problems and early psychosis of youths. In Jul 2009, we set up the Youth Assist Clinic (YAC) to support youths with mental health problems and early psychoses. Our activities consist of school-based, community-based, and hospital-based approaches. Specific programs are as follows: 1) School-based approaches: Outreach consultation to school. Mental health lessens. Creating mental health textbooks. Education for parents and teachers. 2) Community-based approaches: To enlighten primary physicians and mental clinic psychiatrists about the importance of early psychosis. To survey their concerns regarding early psychosis. Promoting awareness of community staff and the general public. 3) Hospital-based approaches: YAC. Case manager system. Family meetings for the family including the young with mental disorders. Peer group. Looking back over our 3-year trials, especially in school and the community, we find several problems, as follows: 1) Lack of consultation skills of medical staff outside the hospital. 2) Limiting number of schools which have mental support system. 3) Support for school attendance and learning. 4) Lack of concern about early psychosis of primary physicians and mental clinic psychiatrists. 5) Staff training for early intervention. We are now getting close to improving these issues.

Safety, Tolerability, and Immunogenicity of V160, a Conditionally Replication-Defective Cytomegalovirus Vaccine, in Healthy Japanese Men in a Randomized, Controlled Phase 1 Study.

Cytomegalovirus (CMV) infection can cause newborn morbidity and mortality; no pharmacological method of reducing CMV infection during pregnancy is currently available. In a phase 1 study in the United States, V160, a conditionally replication-defective CMV vaccine, was immunogenic and well tolerated. This placebo-controlled study (NCT03840174) investigated the safety and immunogenicity of a three-dose V160 vaccine administered over six months. A total of 18 healthy adult Japanese males (9 seronegative and 9 seropositive) were enrolled at a single center and randomized 2:1 to intramuscular V160 or placebo. In vitro, V160 induced high CMV-specific neutralizing antibody (NAb) titers (50% neutralization titer [NT50], 3651; 95% confidence interval [CI], 1688-7895) in the CMV-seronegative per-protocol immunogenicity (PPI) population one month after the third vaccine dose was administered compared with no change in the placebo arm (NT50, <94; 95% CI <94-115). The geometric mean titer ratio in the seronegative population versus baseline was 77.7 (95% CI, 23.9-252.4). CMV NAb titers in the CMV-seropositive PPI population were similar to baseline NAb titers observed in the CMV-seropositive population. V160 was well tolerated, and no vaccine viral DNA shedding was observed. In conclusion, the immunogenicity and safety profile of V160 in Japanese participants was consistent with other populations.

Model-Informed Dose Justifications of Posaconazole in Japanese Patients for Prophylaxis and Treatment Against Fungal Infection.

Posaconazole is a globally approved broad-spectrum triazole antifungal compound. In Japanese patients, posaconazole has identical dosing regimens as those approved globally for both tablet and intravenous formulations. This article aims to describe a model-informed approach for dose justification of posaconazole in the Japanese population as either high-risk patients with fungal infections (prophylaxis patients) or patients with fungal infections (treatment patients). A simultaneous population pharmacokinetic (PK) model for tablet and intravenous formulation was developed on the basis of a data set including Japanese data from healthy participants and treatment patients. The PK profiles and exposure distributions in Japanese patients were predicted and compared against foreign patients, that is, patients outside of Japan. Relationships between the post hoc posaconazole exposures and frequently observed clinical adverse events were evaluated. Although clinical trials for Japanese prophylaxis patients were not conducted, PK profiles in Japanese prophylaxis patients were predicted using the population PK model and demographic covariate information obtained from the published literature. Based upon the globally approved dosing regimen, posaconazole exposure distribution was predicted to be the highest in Japanese treatment patients, and generally similar between Japanese and foreign prophylaxis patients. Exposures in Japanese patients exceeded the efficacy target level (500 ng/mL). Safety profiles in Japanese treatment patients with the highest exposures were clinically acceptable without specific concerns to Japanese patients and appeared to have no relationship with posaconazole exposures. From PK, safety, and efficacy perspectives, the use of the same dosing regimen as in foreign patients was justified in Japanese prophylaxis and treatment patients.

Phase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors.

Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in non-Japanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25-72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7-day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once-daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Dose-limiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100-500 mg dose range, vorinostat area under the concentration-time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non-Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7-day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached.

Application of Physiologically Based Pharmacokinetic Modeling to Predict Pharmacokinetics in Healthy Japanese Subjects.

Pharmacokinetics (PKs) in Japanese healthy subjects were simulated for nine compounds using physiologically based PK (PBPK) models parameterized with physicochemical properties, preclinical absorption, distribution, metabolism, and excretion (ADME) data, and clinical PK data from non-Japanese subjects. For each dosing regimen, 100 virtual trials were simulated and predicted/observed ratios for peak plasma concentration (Cmax ) and area under the curve (AUC) were calculated. As qualification criteria, it was prespecified that >80% of simulated trials should demonstrate ratios to observed data ranging from 0.5-2.0. Across all compounds and dose regimens studied, 93% of simulated Cmax values in Japanese subjects fulfilled the criteria. Similarly, for AUC, 77% of single-dosing regimens and 100% of multiple-dosing regimens fulfilled the criteria. In summary, mechanistically incorporating the appropriate ADME properties into PBPK models, followed by qualification using non-Japanese clinical data, can predict PKs in the Japanese population and lead to efficient trial design and conduct of Japanese phase I studies.

Anti-stress effects of simplified aroma hand massage.

In order to be able to use the aroma hand massage as a skill that can be done by a nurse who does not have a special aromatherapy technique, we examine antistress effects of simplified aroma hand massage for healthy subjects. We evaluated the anti-stress action of aroma hand massage and the different components of the procedure in 20 healthy women in their twenties. We used autonomic nervous function measured via electrocardiogram as an index of stress. After conducting a baseline electrocardiogram, we induced stress in the participants by asking them to spend 30 minutes completing Kraepelin's arithmetic test. We then administered various treatments and examined the anti-stress effects. Kraepelin's test significantly increased sympathetic nervous function and significantly reduced parasympathetic nervous function. Compared with massage without essential oil or aroma inhalation, aroma hand massage significantly increased parasympathetic nervous function and significantly decreased sympathetic nervous function. The effect of the aroma hand massage persisted when the procedure was simplified. The anti-stress action of the aroma hand massage indicates that it might have beneficial application as a nursing technique. There are several limitations in this study; ambiguities of low component/high component ratio of heart rate variability and bias by small subjects groups of the same women.

The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study.

BACKGROUND: Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis. METHODS: The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment. RESULTS: In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (n = 31) or 100 mg (n = 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (n = 227) or deferred treatment (n = 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment. CONCLUSION: Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection. CLINICALTRIALS. GOV IDENTIFIER: NCT02203149.

Absolutely exponential stability of a class of neural networks with unbounded delay.

In this paper, the existence and uniqueness of the equilibrium point and absolute stability of a class of neural networks with partially Lipschitz continuous activation functions are investigated. The neural networks contain both variable and unbounded delays. Using the matrix property, a necessary and sufficient condition for the existence and uniqueness of the equilibrium point of the neural networks is obtained. By constructing proper vector Liapunov functions and nonlinear integro-differential inequalities involving both variable delays and unbounded delay, using M-matrix theory, sufficient conditions for absolutely exponential stability are obtained.

Perspectives on non-clinical safety evaluation of drug metabolites through the JSOT workshop.

The prompt and appropriate safety assessment of drug metabolite(s) was mentioned in regulatory guidances such as an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance, entitled "Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" (ICH M3(R2)) implemented in January 1 of 2011 in Japan, and has become a significant issue in the drug development. Upon release of ICH M3(R2) Step 4, a survey was conducted between March and April 2010 on the safety assessment of drug metabolites in 63 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). The Pharmacokinetics Team in the Non-Clinical Evaluation Expert Committee in JPMA conducted a questionnaire survey and compiled the results to comprehend how safety of drug metabolites are currently assessed at research-based pharmaceutical companies in Japan. The assessment of "Metabolites in Safety Testing" (MIST) can be divided into three stages based on the research purpose as follows: MIST 1 is a stage of estimating human drug metabolites and predicting their potential risks, MIST 2 is a stage of deciding the necessity for non-clinical safety studies, and MIST 3 is a stage of conducting non-clinical safety studies. In this paper, we propose typical approaches on safety assessment of metabolites that meet the purpose of each stage, considering the current level of scientific technology. Our proposals are based on the results from our survey and a symposium about the safety assessment of drug metabolites at the 37th annual meeting of the Japanese Society of Toxicology held in June 2010.

Early weaning decreases play-fighting behavior during the postweaning developmental period of Wistar rats.

We examined the influence of early weaning on the development of play-fighting behaviors and anxiety status in Wistar rats. Pups were divided into two groups, those weaned at postnatal day (PD) 16 (early-weaned group) and those weaned at PD30 (normally weaned group), and were housed in pairs of the same sex. Playful interactions were measured for each pair once a week from 4 to 7 weeks of age. Thereafter, during early adulthood, all the rats were subjected to the elevated plus-maze test. The frequencies of pinning and playful attack were less in the early-weaned group than in the normally weaned group. In the elevated plus-maze test, rat pups in the early-weaned group had higher anxiety levels. The results showed that deprivation of mother-pup interactions during the preweaning period decreases affiliative interactions between cage mates, including play-fighting behaviors during the postweaning developmental period, and increases anxiety levels during early adulthood.