Reactivity of Lattice Oxygen in Ti-Site-Substituted SrTiO3 Perovskite Catalysts.

An environmental catalyst in which a transition metal (Mn, Fe, or Co) was substituted into the Ti site of the host material, SrTiO3, was synthesized, and the reactivity of lattice oxygen was evaluated. For CO oxidation, Mn- and Co-doped SrTiO3 catalysts, which provided high thermal stabilities, exhibited higher activities than Pt/Al2O3 catalysts despite their low surface areas. Temperature-programmed reduction experiments using X-ray absorption fine structure (XAFS) measurements showed that the lattice oxygen of Co-doped catalyst was released at the lowest temperature. Isotopic experiments with CO and 18O2 revealed that the lattice oxygen was involved in CO oxidation on Fe- and Co-doped catalysts; that is, CO oxidation on these catalysts proceeded via the Mars-van Krevelen mechanism. On the other hand, for Mn-doped catalyst, the contribution of lattice oxygen to CO oxidation was relatively negligible, indicating that the reaction proceeded according to the Langmuir-Hinshelwood mechanism. This paper clearly demonstrates that the catalytic mechanism can be adjusted by substituting transition metals into SrTiO3.

Effects of a Pharmacist-Led Educational Interventional Program on Electronic Monitoring-assessed Adherence to Direct Oral Anticoagulants: A Randomized, Controlled Trial in Patients with Nonvalvular Atrial Fibrillation.

PURPOSE: Several landmark trials have reported that direct oral anticoagulants (DOACs) are more effective in preventing stroke and systemic embolism than vitamin K antagonists. However, nonadherence to DOACs worsens prognosis in patients with nonvalvular atrial fibrillation (NVAF) despite the effectiveness of the drugs. The purpose of this study was to evaluate the effects of a pharmacist-led educational interventional program involving motivational interviewing on medication adherence, as assessed by electronic monitoring, in patients receiving DOACs for the treatment of NVAF. METHODS: This prospective, randomized, interventional study was conducted at outpatient cardiology clinics at general hospitals and pharmacies in Japan. Patients with NVAF who were treated with a once-daily DOAC (edoxaban) or a twice-daily DOAC (apixaban) were randomized to receive either: (1) an educational interventional program involving motivational interviewing regarding adherence to anticoagulants; or (2) standard medication counseling. The primary end point was the change in the medication adherence rate, calculated as the number of days that patients appropriately took the drug, as assessed by an electronic monitoring device, divided by the total number of days that the drug was prescribed, from a 12-week observation period to a 12-week intervention period. The secondary end points were tolerability outcomes. The effect of the educational interventional program on the primary end point was analyzed in subgroups stratified by gender and type of DOAC received. FINDINGS: A total of 268 patients completed the observation period and were randomly assigned to one of the two study groups. The difference in the primary end point between the educational interventional program group and the standard medication counseling group was not significant (mean [SD], 2.9% [7.5%] vs 3.4% [8.3%]). On multiple linear regression analysis, the difference in DOAC adherence between the two groups was not significant, but that adherence to apixaban was significantly improved among men in the educational interventional program (ß = 0.219; P = 0.012). Two patients died of causes considered unrelated to treatment; no stroke/systemic embolism or major bleeding events were observed. IMPLICATIONS: In this randomized, controlled study of the effects of a pharmacist-led educational interventional program using motivational interviewing on adherence to DOACs among patients with NVAF, adherence to DOACs, as assessed using an electronic monitoring device, was not improved with the educational interventional program compared to standard medication counseling . However, adherence to twice-daily apixaban was improved among men, but not among women, in the educational interventional program group. In this study, the selection of DOACs was not randomized, and the lack of assessment of the association between adherence to DOACs and clinical outcomes was a limitation. Japan Registry of Clinical Trials (jRCT) indentifier: jRCTs031180142.

[History and movements of alternatives to animal experiments in Japan].

Experimental animals have been used so very often on science studies from the late 19th centuries. Especially since Wistar rat was produced in the 1890s as an experimental animal, various kinds of experimental animals have been developed and made enormous contribution to human beings. It is not an exaggeration to say that experimental animals have made us alive and rich, so to speak. However, the number of uses of experimental animals has decreased since its peak in 1990s. One of the reasons is the existence of Alternatives to animal experiments. Around 1980, Importance of 3Rs has been increased among its support, and the trend of animal experiments has moved to ones without using animals all over the world. It is because animal experiments cost and take time, but the biggest reason is the concern towards overuse of experimental animals. There is a rooting ethical doubt among many researchers that we can sacrifice other animals to save human lives. Human beings have hunted, and domesticated other animals as means of surviving. But today, we are trying to find a way to live not only for ourselves but for other animals on the whole earth. As a mean of the living, Alternatives to animal experiments have significant meanings and it will get even more important in the future. In this article, I would like to briefly explain the history and movements on Alternatives to animal experiments that took place here in Japan.

Electronic monitoring of adherence to once-daily and twice-daily direct oral anticoagulants in patients with atrial fibrillation: Baseline data from the SMAAP-AF trial.

BACKGROUND: Nonadherence diminishes the efficacy of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation (NVAF). This report presents the baseline survey results regarding medication adherence among NVAF patients who were treated with once-daily edoxaban or twice-daily apixaban from a randomized control trial of the effect of an educational intervention on DOAC adherence. METHODS: We prospectively studied 301 NVAF patients who were treated with edoxaban (n = 175) or apixaban (n = 126) during the 12-week observation period. Adherence was measured with an electronic monitoring system and is expressed as the percentage of days with the correct doses in the measurement period (days). Adherence to DOAC therapy was defined based on the standard threshold (≥80%) or a strict threshold (≥90%). RESULTS: Of the 301 patients, 33 had incomplete data or protocol deviations, leaving 268 patients (edoxaban 158 and apixaban 110) for the per-protocol baseline analysis. There was no difference in adherence (threshold ≥80%) between the groups (edoxaban 95% vs apixaban 91%, P = .2), but there was a lower proportion of patients with strict adherence (threshold ≥90%) among apixaban users than among edoxaban users (edoxaban 87% vs apixaban 76%, P = .02). Multivariate analysis showed a negative relationship between apixaban use and an adherence rate ≥90% (odds ratio 0.49, 95% confidence interval [CI]: 0.25-0.94). CONCLUSIONS: Our study showed that the proportion of DOAC users with adherence (≥80%) did not differ between the groups, but the proportion of patients with strict adherence (≥90%) was lower among those using apixaban than among those using edoxaban.

NOx Storage Performance at Low Temperature over Platinum Group Metal-Free SrTiO3-Based Material.

Pt-based catalysts are commonly employed as NOx-trapping catalysts for automobiles, while perovskite oxides have received attention as Pt-free NOx-trapping catalysts. However, the NOx storage performance of perovskite catalysts is significantly inferior at low temperatures and with coexisting gases such as H2O, CO2, and SO2. This study demonstrates that NOx storage reactions proceed over redox site (Mn, Fe, and Co)-doped SrTiO3 perovskites. Among the examined catalysts, Mn-doped SrTiO3 exhibited the highest NOx storage capacity (NSC) and showed a high NSC even at a low temperature of 323 K. Moreover, the high NOx storage performance of Mn-doped SrTiO3 was retained in the presence of poisoning gases (H2O, CO2, and SO2). NO oxidation experiments revealed that the NSC of Co-doped SrTiO3 was dependent on the NO oxidation activity from NO to NO2 via lattice oxygen, which resulted in an inferior NSC at low temperatures. On the other hand, Mn-doped SrTiO3 successfully adsorbed NO molecules onto its surface at 323 K without the NO oxidation process using lattice oxygens. This unique adsorption behavior of Mn-doped SrTiO3 was concluded to be responsible for the high NSC in the presence of poisoning gases.

Consensus guidance of nebulizer therapy for acute rhinosinusitis.

The guidance deals with the recommended applications, procedures, and safety management of nebulizer therapy for acute rhinosinusitis. In Japan, nebulizer therapy for sinusitis has been covered by public health insurance since 1958 and has been commonly carried out nationwide. The Japan Society for Infection and Aerosol in Otorhinolaryngology and the Oto-Rhino-Laryngological Society of Japan set up a working group to draw up a consensus guidance on nebulizer therapy for acute rhinosinusitis. The device for nebulizer therapy are classified into jet, ultrasound, and mesh types. In Japan, cefmenoxime hydrochloride (CMX) was approved for use in nebulizer therapy since 1996. The widening of the obstructed lesions such as large polyps prior to nebulizer therapy were recommended. The numbers of times of nebulizer therapy is recommended for three times in a week for at least for 2 weeks (cure rate: 68%, eradication ratio: 48%). Concerns should be pay for the changes of activity of medicine due to the mixing and bacterial contamination. Pseudomonas cepacia growing in a short even in both saline and distilled water leads to contamination at high concentrations by 2 days. Nebulizer therapy is an effective treatment based on a drug delivery system (DDS) to the nasal and paranasal cavities. The therapy effectively increases the local drug concentration by promptly and uniformly delivering drugs to a targeted local site. The therapy is safe with less systemic absorption and with few adverse reactions.

Use of corticosteroids for remission induction therapy in patients with new-onset ulcerative colitis in real-world settings.

Background: Corticosteroids may be temporarily effective for ulcerative colitis (UC), but long-term use increases the risk of adverse drug reactions. Objective: The goal of the study was to examine steroid use in remission induction therapy after diagnosis of UC. Study Design: A retrospective observational study using the Japan Medical Data Center (JMDC) Claims Database from January 2008 to December 2014. Setting: Clinics, university hospitals, and national/public hospitals. Intervention: Initiation of steroids after diagnosis of UC. Main outcome measures: Start time and annual rate of steroid use, and use during the first 6 months of remission induction therapy. Results: The subjects were 399 patients were newly diagnosed with UC in the study period. The rate of steroid use after diagnosis was 58.4% in 2009, and showed a significant decreasing trend yearly after 2010 (p ≤ 0.0001). Regarding the start time, 52.2% of patients began steroids within 60 days after diagnosis of UC. At 6 months after initiation, 23.7% continued to use steroids and 73.9% of these patients used high-dose steroids. Conclusion: In treatment of UC after diagnosis, many patients continue to use steroids for >6 months after initiation. Reduced use of steroids based on clinical practice guidelines for UC should be promoted.

[Technological development of alternative method to animal experiments in Japan].

The alternative method to animal experiments is based on 3Rs (Replacement, Reduction, Refinement) of animal experiments. The use of an alternative method to animal experiment has become a global trend in chemical substances, pharmaceuticals, medical equipment, agrochemicals, as well as cosmetics for which animal testing within the EU area was prohibited by the EU directive. Here, the progress of alternative method research to animal experiment in Japan, and recent topics on the development of "replacement" in cell culture, non mammalian, non vertebrates and in silico as technical aspects are described.

Survey on the attitudes of pharmacy students in Japan toward doping and supplement intake.

Doping is one of the most serious problems for athletes, and it is important that pharmacists have more interaction with athletes to ensure safer drug usage. Education is one of the most important roles of sports pharmacists, who are specialists regarding drug usage for athletes. We investigated pharmacy students' interests and comprehension regarding drug usage, doping and supplement intake by using the form of a questionnaire, since it is important to know how they understand these subjects as part of their greater educational program. The subjects were sophomore and junior pharmacy students at three universities. It was revealed that most of the students have negative images regarding doping violation, and they answered that they are familiar with doping. However, only sixteen percent of the students had attended lectures by specialists on doping. In addition, one third of pharmacy students did not know that some over-the-counter (OTC) drugs might contain doping substances. With regard to supplement intake, approximately two thirds of the respondents had an interest in and positive image of supplement intake. However, it was revealed that only one third of them recognized supplements as food, and their information regarding supplements was obtained from uncertain media. It was suggested that it is important for pharmacy students to have more opportunities to learn about what doping is. More education and enlightenment by sports pharmacists would be effective for pharmacy students as well as athletes, and it would help us to broaden the scope of what we can do for athletes and society.

Time-dependent interaction between differentiated embryo chondrocyte-2 and CCAAT/enhancer-binding protein α underlies the circadian expression of CYP2D6 in serum-shocked HepG2 cells.

Differentiated embryo chondrocyte-2 (DEC2), also known as bHLHE41 or Sharp1, is a pleiotropic transcription repressor that controls the expression of genes involved in cellular differentiation, hypoxia responses, apoptosis, and circadian rhythm regulation. Although a previous study demonstrated that DEC2 participates in the circadian control of hepatic metabolism by regulating the expression of cytochrome P450, the molecular mechanism is not fully understood. We reported previously that brief exposure of HepG2 cells to 50% serum resulted in 24-h oscillation in the expression of CYP3A4 as well as circadian clock genes. In this study, we found that the expression of CYP2D6, a major drug-metabolizing enzyme in humans, also exhibited a significant oscillation in serum-shocked HepG2 cells. DEC2 interacted with CCAAT/enhancer-binding protein (C/EBPα), accompanied by formation of a complex with histone deacetylase-1, which suppressed the transcriptional activity of C/EBPα to induce the expression of CYP2D6. The oscillation in the protein levels of DEC2 in serum-shocked HepG2 cells was nearly antiphase to that in the mRNA levels of CYP2D6. Transfection of cells with small interfering RNA against DEC2 decreased the amplitude of CYP2D6 mRNA oscillation in serum-shocked cells. These results suggest that DEC2 periodically represses the promoter activity of CYP2D6, resulting in its circadian expression in serum-shocked cells. DEC2 seems to constitute a molecular link through which output components from the circadian clock are associated with the time-dependent expression of hepatic drug-metabolizing enzyme.

[Primary care enlightenment to local inhabitants--cooperation of medical institution and community pharmacy in treatment of chronic hepatitis C].

Community pharmacy is evolving to provide additional services to patients such as compliance improvement, self-care and OTC consultations and advising on daily activities to supplement medical treatment. Currently in Japan, it has been estimated that 1.5 to 2 million people have chronic hepatitis C. We have attempted to increase the population's knowledge of this important issue with educational brochures about hepatitis C and placing posters encouraging them to ask medical professionals about their health problems. Peg-interferon and ribavirin combination therapy has an efficacy rate of approximately 60%. The side effects might present in different ways and frequency depending on the treatment duration; therefore, pharmacists should monitor patients carefully during the entire treatment period with particular attention to OTC drug use, daily activity, etc. Additionally, for outpatients community pharmacy has responsibility to avoid drug-related adverse events in the patients' daily life, so monitoring for clinical signs of side effects is necessary. We created the "Clinical Pathway for Healthcare Network of Chronic Hepatitis C Treatment via the Medication Notebook Type" (Clinical Pathway) for patients who received Peg-interferon and ribavirin combination therapy. We are beginning to provide the new version of this service to patients as one of the pharmaceutical care components in the community pharmacy. I would like to describe how we cooperate with other community pharmacies using the "Clinical Pathway", which is to improve patient care in the community pharmacies.

Determination of antihyperglycemic biguanides in serum and urine using an ion-pair solid-phase extraction technique followed by HPLC-UV on a pentafluorophenylpropyl column and on an octadecyl column.

An HPLC-UV method was established for the determination of metformin and buformin in biological fluids. Metformin was not retained on particles packed in conventional solid-phase extraction cartridges; in contrast, buformin was retained too firmly and not eluted with a solvent for recovery. However, both drugs were retained on particles that had been treated with an ion-pair reagent of heptanesulfonate or dodecylsulfate and recovered almost completely. The recovered fraction was subjected to HPLC on a pentafluorophenylpropyl column which was suitable for the determination of both biguanides in serum and in urine. Limits of quantitation were low enough for clinical use, and reproducibility was high with an RSD of 0.9-2.3%. HPLC on a conventional octadecyl column was suitable only for the determination of buformin in serum since interfering peaks appeared on the chromatograms of urine samples. The method was applied to analysis of some clinical specimens.

Influence of hypothyroidism induced by thiamazole on the toxicity of amitriptyline in chick embryos.

The effect of hypothyroidism induced by thiamazole on the toxicity of amitriptyline was studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. 1.2 mg/0.2 ml/egg of thiamazole was injected into the albumen of fertilized eggs on the 9th day of incubation. The control group was given 0.2 ml/egg of physiological saline in the same manner. Amitriptyline at 1 mg/egg was injected into the air sac of fertilized eggs on the 16th day of incubation. Electrocardiograms were recorded 0 to 60 min after the injection. After the injection of amitriptyline into the thiamazole-treated eggs, the heart rate was significantly decreased compared with the untreated eggs. These findings indicate that hypothyroidism induced by thiamazole has a marked influence on the toxicity of amitriptyline in chick embryos.

Influence of hypothyroidism induced by thiamazole on the toxic interaction between propranolol and disopyramide in chick embryos.

The effect of the hypothyroidism induced by thiamazole on toxic interactions between propranolol and disopyramide were studied in chick embryos. Fertilized eggs of White Leghorns were incubated and investigated. 1.2 mg/0.2 ml/egg of thiamazole was injected into the albumen of fertilized eggs on the 9th day of incubation. The control group was given 0.2 ml/egg of physiological saline in the same manner. Propranolol at 0.1 mg/egg and disopyramide at 0.3 mg/egg were injected into the air sac of fertilized eggs on the 16th day of incubation. Electrocardiograms were recorded 0 to 60 min after the injection. After the injection of propranolol and disopyramide into the thiamazole treated eggs, the heart rate was significantly decreased compared with the thiamazole untreated eggs. These findings indicate that hypothyroidism induced by thiamazole has a marked influence on the toxic interaction between propranolol and disopyramide in chick embryos.

Experimental diabetes model in chick embryos treated with streptozotocin.

The aim of the present study was to investigate whether diabetes model can be made by treatment of streptozotocin (STZ) in chick embryos and this model can be used to predict the effect of drug. When STZ (0.3 mg/egg) was injected into the albumen of fertile eggs on the 14th day of incubation, level of blood glucose significantly increased than that of the control on the 17th day of incubation, and level of serum insulin significantly decreased. In addition, the enhanced level of blood glucose in STZ-treated embryos reduced by injection of human insulin. In conclusion, STZ-treated embryos may be applicable to evaluate human insulin and anti-diabetes drugs as an experimental diabetes model.