Disproportionality analysis of stomatitis associated with anticancer drugs using Japanese Adverse Drug Event Reporting Database.

INTRODUCTION: Anticancer drug-induced stomatitis can affect a patient's quality of life and the continuation of drug treatment. Although there have been reports of the occurrence of stomatitis associated with anticancer agents in clinical trials, few Japanese participants have been enrolled in clinical trials and have not been sufficiently investigated. In addition, there has been little attention on research on anticancer drugs associated with stomatitis by patient stratification with different carcinogenic sites. Therefore, the aim of this study was to determine the disproportionality associated with stomatitis for various types of anticancer drugs in different types of cancer patients using the Japan Spontaneous Adverse Event Reporting Database (JADER). METHODS: The aim of this study was to identify the disproportionality of stomatitis by analyzing the type of anticancer drug and cancer patients using the Japanese Pharmacovigilance Database. Data obtained from spontaneous reports of adverse events with more than 10 stomatitis outbreaks reported in the Japanese Adverse Drug Event Report database (JADER) between April 2004 and March 2023 were analyzed. The safety signal for an adverse event was defined as the lower limit of the 95% confidence interval of the reporting odds ratio of >1. RESULTS: There were 6178 reports of drugs associated with stomatitis. Among these, 41 drugs were suggested to be associated with stomatitis, and 41 drugs were detected as signals. These drugs were classified based on their efficacy: antipyrimidines (six drugs), folate metabolism antagonists (three drugs), alkylating agents (four drugs), platinum (three drugs), topoisomerase inhibitors (three drugs), microtubule inhibitors (three drugs), mTOR inhibitors (two drugs), kinase inhibitors (seven drugs), anti-growth factor antibodies (five drugs) immune checkpoint inhibitors (one drug), and others (four drugs). CONCLUSION: The drugs that may be associated with stomatitis were cell cycle-dependent drugs, epidermal growth factor receptor-tyrosine kinase inhibitors, and mTOR inhibitors. Thus, the use of JADER suggests that anti-growth factor antibodies and immune checkpoint inhibitors may be associated with stomatitis development.

Efficacy of mental practice on paralyzed upper extremity function in the acute phase of stroke: a case study.

[Purpose] Mental practice (MP) is a method of rehabilitating upper extremity function on the affected side of the body post-stroke, with the aim of improving motor task performance through the sustained repetition of motor imagery (MI). However, most studies thus far have investigated MP for post-stroke paralytic upper limb function in patients in the chronic phase. Therefore, it is necessary to obtain evidence regarding whether MP is an effective intervention modality in the acute phase of stroke. In the present study, we examined the effects of an intervention combining mirror therapy and MP initiated during the acute phase of cerebral infarction. [Participant and Methods] A female patient >80 years of age with a cerebral infarction was studied. Prior to cerebral infarction, the patient was independent in her activities of daily living. [Results] As a result of MP, sufficient improvement was observed in the upper extremity function on the paralyzed side, as assessed using the Fugl-Meyer Assessment (FMA) and Motor Activity Log (MAL). [Conclusion] In patients with MP initiated during the acute stroke phase, a combination of mirror therapy and action observation to enable vivid MI may elicit a more significant intervention effect.

Safety and blood levels of daratumumab after switching from intravenous to subcutaneous administration in patients with multiple myeloma.

The intravenous administration (IV) of daratumumab sometimes causes an infusion reaction and needs a long infusion time. Recently, a subcutaneous formulation (SC) of daratumumab, which has fewer infusion reactions and shorter administration time, was approved. However, because SC has a fixed dose, overdosing is a concern for patients with low body weights. In this study, we investigated the safety and blood levels of daratumumab after switching from IV to SC in patients with multiple myeloma (MM). Patients who switched from IV to SC of daratumumab between June 2021 and May 2022 at Kobe City Medical Center General Hospital were included in the study. Blood daratumumab levels were measured using liquid chromatography-tandem mass spectrometry. Safety after switching from IV to SC was evaluated for six months and graded according to the Common Terminology Criteria for Adverse Events, version 5.0. The median body weight of ten patients included in the analysis was 57.4 kg (range: 45.0-74.4). Blood daratumumab levels were significantly increased after switching to SC (p = 0.002); median through concentration at the last IV dose was 403.6 µg/mL (range: 96.3-776.3) and that at the third SC dose was 557.1 µg/mL (range: 288.3-997.2). Grade 1-2 injection site reactions were observed in six patients (60.0%) after switching to SC. A new grade 3 adverse event was observed in only one patient (neutropenia). The blood levels of daratumumab were significantly increased after switching from IV to SC in patients with MM; however, the dosage was tolerable.

Evaluation of Cardiac Adverse Events with Ponatinib Using a Spontaneous Reporting Database.

INTRODUCTION: The efficacy of ponatinib was demonstrated in patients resistant or intolerant to prior BCR-ABL tyrosine kinase inhibitors. However, cardiac adverse events (CAEs) have become a concern as a serious side effect of ponatinib administration. No reports have described the incidence of CAEs associated with ponatinib in Japanese patients. Thus, this study aimed to determine the risk of ponatinib-induced CAEs, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHODS: We analyzed data for the period between April 2004 and March 2021. Data on CAEs were extracted, and relative risk of AEs was estimated using the reporting odds ratio. RESULTS: We analyzed 1,772,494 reports and identified 1,152 reports of AEs caused by ponatinib. Of these, 163 CAEs were reportedly associated with ponatinib. Signals were detected for thirteen CAEs: hypertension, cardiac failure, acute cardiac failure, atrial fibrillation, increased blood pressure, coronary artery stenosis, myocardial infarction, angina pectoris, pulmonary hypertension, prolonged QT on electrocardiography, cardiomyopathy, cardiac dysfunction, and acute myocardial infarction. Among these, hypertension was the most frequently reported AE (27.6%). A histogram of times to onset showed occurrence from 4.5 to 150.5 days. DISCUSSION/CONCLUSION: Hypertension, cardiac failure, coronary artery stenosis, and myocardial infarction could potentially result in serious outcomes and some cases occurred earlier or even more than 1 year after starting administration. Patients should be monitored for signs of the onset of these AEs not only at the start of ponatinib administration but also over the longer term.

Cardiac Adverse Events Associated with Multiple Myeloma Patients Treated with Proteasome Inhibitors.

BACKGROUND: Proteasome inhibitors (PIs) are standard treatments for multiple myeloma (MM). The risk of cardiac adverse events (CAEs) with PIs has been documented with bortezomib and carfilzomib; however, only a few studies have been reported on ixazomib. Furthermore, the effects of concomitant medications including dexamethasone and lenalidomide remain unclear. OBJECTIVES: This study aimed to determine the safety signals of adverse events related to CAEs, the effect of concomitant medications, the time to the occurrence of CAEs, and the incidence of fatal clinical outcomes after the occurrence of CAEs for three PIs using the US Pharmacovigilance database. METHODS: We examined 1,567,240 cases of 231 drugs registered as anticancer drugs in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1997 to March 2021. We compared the odds of developing CAEs between patients who received PIs and those who received non-PI anticancer drugs. RESULTS: Bortezomib treatment resulted in significantly higher reporting odds ratios (RORs) for cardiac failure, cardiac failure congestive, and atrial fibrillation. Carfilzomib treatment resulted in significantly higher RORs for cardiac failure, congestive cardiac failure, atrial fibrillation, and QT prolonged. However, no adverse event CAE signals were observed with ixazomib treatment. A signal was detected for the safety of cardiac failure with bortezomib or carfilzomib, regardless of the presence or absence of concomitant medications. Safety signals for cardiac failure congestive with bortezomib and for cardiac failure congestive, atrial fibrillation, and QT prolonged with carfilzomib were observed only with dexamethasone combination therapy. Co-administration of lenalidomide and its derivatives did not affect the safety of bortezomib and carfilzomib. CONCLUSION: We identified CAE safety signals for bortezomib and carfilzomib exposure when compared with 231 other anticancer agents. The safety signal for developing cardiac failure for both the drugs did not differ between patients with and without concomitantly administered medications.

Evaluation of Time to Onset and Outcome of Lung Adverse Events Related to Pembrolizumab Using Marketing Surveillance.

BACKGROUND: Pembrolizumab has been widely used in patients since its release, but detailed information on lung-specific adverse events (AEs) from post-marketing monitoring has not been reported. OBJECTIVES: This study was undertaken to determine the risk of pembrolizumab-induced lung AEs, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHOD: We analyzed data for the period between April 2004 and March 2022. Data on lung AEs were extracted and the relative risks of AEs were estimated using reporting odds ratios. RESULTS: We analyzed 2,021,907 reports and identified 15,306 reports of AEs caused by pembrolizumab, including 3,004 lung AEs. Signals were detected for 14 lung AEs. Interstitial lung disease was the most frequently reported (62.3%) and included fatal cases. A histogram of median time to onset showed occurrence ranging from 2 to 73 days, but some cases of interstitial lung disease occurred after 2 years of administration. The AEs showing the highest fatality rates were interstitial lung disease, respiratory failure, and pneumonia aspiration. CONCLUSIONS: This study focused on lung AEs caused by pembrolizumab as post-marketing AEs. Some cases could potentially involve serious outcomes, so patients should be monitored for signs of AE onset not only at the start of administration but also over an extended period, especially for interstitial lung disease.

Evaluation of Time to Onset and Outcome of Cardiac Adverse Events Associated with Nilotinib using Post-Marketing Surveillance.

INTRODUCTION: Cardiac adverse events (CAEs) have become a concern as serious adverse events (AEs) of nilotinib administration. No reports have described the incidence of CAEs associated with nilotinib in Japanese patients. Thus, we conducted this study to evaluate the risk of nilotinib-induced CAEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database. METHODS: We analysed data for the period between April 2004 and March 2022. Data on CAEs were extracted, and relative risk of AEs was estimated using the reporting odds ratio. RESULTS: We analysed 2,021,907 reports and identified 3,545 reports of AEs caused by nilotinib. Of these, 511 reports involved CAEs. Signals were detected for 19 CAEs. Of these, electrocardiogram QT prolonged was the most frequently reported (30.9%). Fatal outcomes were observed in eight AEs: cardiac failure, atrial fibrillation, acute myocardial infarction, pericardial effusion, myocardial infarction, cardiac arrest, pericarditis, and cardiac tamponade. Of these, acute myocardial infarction, myocardial infarction, pericarditis, and cardiac tamponade exhibited mortality rates >10%. A histogram of median times to onset showed nilotinib-associated AEs occurring 3-485 days after nilotinib administration. CONCLUSION: We focused on CAEs caused by nilotinib as post-marketing AEs. Some cases resulted in serious outcomes. Patients should be monitored for signs of onset of these AEs not only at the start of administration but for a long period of time.

Adverse Event Profile of Azacitidine: Analysis by Route of Administration Using Japanese Pharmacovigilance Database.

INTRODUCTION: Azacitidine is a useful drug for myelodysplastic syndromes and acute myeloid leukemia. In clinical trials, hematologic toxicity and infection have been observed as adverse events (AEs) of this drug. However, information on the time to onset of high risk AEs and subsequent outcomes, as well as differences in the frequency of AEs due to the route of administration is lacking. In this study, we investigated azacitidine-induced AEs comprehensively using the Japanese Adverse Event Reporting Database (JADER) published by the Pharmaceuticals and Medical Devices Agency, with disproportionate analysis of AE incidence trends, time to onset, and subsequent outcomes. In addition, we analyzed the differences in AEs by route of administration and the number of days until the occurrence of AEs and generated hypotheses. METHODS: The study used JADER data reported from April 2004 to June 2022. Risk estimation was conducted using reported odds ratio. A signal was detected when the lower limit of the 95% confidence interval of the calculated ROR was ≥1. RESULTS: A total of 34 signals were detected as AEs due to azacitidine. Among them, 15 were hematologic toxicities and 10 were infections, which demonstrated a particularly high rate of death. Signals of AEs such as tumor lysis syndrome (TLS) and cardiac failure, which have been described in case reports, were also detected, and the rate of death after onset was high. In addition, more AEs generally occurred within the first month of treatment. CONCLUSION: The results of this study suggest that more attention should be paid to cardiac failure, hematologic toxicity, infection, and TLS. Because many patients in clinical trials have discontinued treatment due to serious AEs before the therapeutic effect became apparent, appropriate supportive care, dose reduction, and drug withdrawal are important for the continuation of treatment.

New Approach To Understanding the Experimental 133Cs NMR Chemical Shift of Clay Minerals via Machine Learning and DFT-GIPAW Calculations.

Structural determination of adsorbed atoms on layered structures such as clay minerals is a complex subject. Radioactive cesium (Cs) is an important element for environmental conservation, so it is vital to understand its adsorption structure on clay. The nuclear magnetic resonance (NMR) parameters of 133Cs, which can be determined from solid-state NMR experiments, are sensitive to the local neighboring structures of adsorbed Cs. However, determining the Cs positions from NMR data alone is difficult. This paper describes an approach for identifying the expected atomic positions on clay minerals by combining machine learning (ML) with experimentally observed chemical shifts. A linear ridge regression model for ML is constructed from the smooth overlap of atomic position descriptor and gauge-including projector augmented wave (GIPAW) ab initio data. The constructed ML model predicts the GIPAW data to within a 3 ppm root-mean-squared error. At this stage, the 133Cs chemical shifts can be instantaneously calculated from the Cs positions on any clay layers using ML. The inverse analysis, which derives the atomic positions from experimentally observed chemical shifts, is developed from the ML model. The input data for the inverse analysis are the layer structure and the experimentally observed chemical shifts. The Cs positions for the targeted chemical shifts are then output. Inverse analysis is applied to montmorillonite, and the resultant Cs positions are found to be consistent with previous results (Ohkubo, T.; et al. J. Phys. Chem. A 2018, 122, 9326-9337). The Cs positions on saponite clay are also clarified from experimentally observed chemical shifts and inverse analysis.

Lack of clinical evidence of antiviral therapy for human monkeypox: A scoping review.

Since May 2022, many human monkeypox cases have been reported from non-endemic countries. This systematic review aimed to evaluate and summarize the existing research on the efficacy and safety of tecovirimat, brincidofovir, and cidofovir for patients with monkeypox. We searched studies that reported the efficacy and adverse events of tecovirimat, brincidofovir, or cidofovir for patients with human monkeypox in several databases including preprint servers. Only five studies were included. The efficacy and adverse events were assessed in only five and four patients, respectively. Regarding tecovirimat, all two patients recovered from monkeypox. One had no adverse event and the other has no description of an adverse event. Regarding brincidofovir, all three patients recovered from monkeypox but all of them had increased alanine transaminase, and one had nausea and abdominal discomfort. There was no study on treatment with cidofovir. Based on past studies and our results, tecovirimat might be the best choice due to ease of administration (oral drug), fewer side effects, and past treatment results for human monkeypox administration. However, very few studies were included in this scoping review. Therefore, further studies are needed to assess their efficacy and safety as possible treatments for human monkeypox.

Solution and solid-state 33 S NMR studies of 33 S-labeled taurine.

Sulfur-33(33 S) stable-isotope labeled taurine, 2-aminoethanesulfonic acid, has been synthesized, and a series of solution and solid-state 33 S nuclear magnetic resonance (NMR) experiments at 14.1 and 18.8 T, respectively, have been carried out at room temperature. The single peak of a solution 33 S NMR spectrum in 0.1-mM [33 S]-taurine in D2 O can be observed with the signal-to-noise (S/N) ratio of 9 in 40,000 scans, which paves the way toward in vivo analysis of pharmacokinetics and metabolism of 33 S-labeled taurine. Undistorted magic-angle-spinning (MAS) and static 33 S NMR spectra of polycrystalline [33 S]-taurine are observed with sufficient S/N ratios for analysis, and the magnitudes of 33 S EFG and CS tensors can be obtained.

Comprehensive Analysis of Bortezomib-Induced Adverse Events Using the Japanese Real-World Database.

BACKGROUND: Bortezomib is used as first-line therapy for multiple myeloma. Observational studies based on the FDA Adverse Event Reporting System database analysis and systematic reviews indicate that the incidence of peripheral neuropathy (PN) and tumor lysis syndrome (TLS) tends to be higher with bortezomib than that of other drugs. In a comprehensive analysis assessing drugs that cause PN in Japanese patients, the incidence of bortezomib-induced adverse events (AEs) was reportedly high. However, a comprehensive assessment of bortezomib is lacking. OBJECTIVES: The purpose of this study was to determine the frequency of bortezomib AEs in Japanese patients and to determine the incidence, time to onset, and post hoc outcomes of unique AEs using the Japanese Adverse Drug Event Report database. METHOD: To investigate the association between bortezomib and AEs, we analyzed the Japanese Adverse Drug Event Report database, which contains spontaneous AE reports submitted to the Pharmaceuticals and Medical Devices Agency from April 2004 to December 2020. Criteria indicating the presence of an AE signal were met when the following requirements were fulfilled: proportional reporting ratios ≥2 and χ2 ≥ 4. Time to onset and post-event outcomes were analyzed for characteristic AEs. RESULTS: Among 26 extracted AEs, 13 presented AE signals. The post-exposure outcomes of 12 AEs showed fatal outcomes at rates exceeding 10%, including cardiac failure (30%), lung disorder (24%), pneumonia (18%), and TLS (10%). Furthermore, a histogram of time to onset revealed that the 12 AEs were concentrated from the beginning to approximately 1 month after bortezomib administration. The median onset times for cardiac failure, lung disorder, pneumonia, and TLS were 28, 13, 42, and 5 days, respectively. CONCLUSIONS: Cardiac failure, lung disorder, pneumonia, and TLS had a higher rate of fatal clinical outcomes after onset than other AEs. These AEs exhibited a greater onset tendency in the early post-dose period. This study suggests that there is a need to monitor signs of cardiac failure, lung disorder, pneumonia, and TLS, potentially resulting in serious outcomes.

Evaluation of Cardiac Adverse Events Associated with Carfilzomib Using a Japanese Real-World Database.

BACKGROUND: Carfilzomib is a proteasome inhibitor widely used for the treatment of multiple myeloma. However, cardiac adverse events (CAEs) are a serious side effect of carfilzomib administration. Observational studies based on systematic reviews and real-world data have revealed that the risk of CAEs tends to be high. However, there have been no reports on the incidence of CAEs associated with carfilzomib in Japanese patients. Furthermore, there have been no reports on the timing and post-event outcomes of CAEs. OBJECTIVES: The purpose of this study was to identify the trends in carfilzomib-associated adverse events, the time to onset of CAEs, and the clinical outcomes after the occurrence of CAEs using the Japanese Adverse Drug Event Report (JADER) database. METHOD: We analyzed data from the JADER database, which contains reports of spontaneous adverse events submitted to the Pharmaceutical and Medical Device Agency, between April 2004 and December 2020. The relative risk of adverse events was estimated using the reporting odds ratio. The time to onset and post-event outcomes were evaluated for adverse cardiotoxic events with >10 reports. RESULTS: The reporting rate was significantly higher for all 6 detected CAEs. A time-to-onset histogram of the 6 CAEs showed that they all occurred early after carfilzomib administration. The median time of onset of heart failure, congestive heart failure, and acute heart failure was approximately 2 weeks after treatment. The adverse events with the largest proportion of fatal clinical outcomes were acute heart failure (26%) and heart failure (9.5%). CONCLUSIONS: This study suggests that the early signs and symptoms of potential fatal heart failure should be monitored during carfilzomib treatment.

Comprehensive Analysis of Ixazomib-Induced Adverse Events Using the Japanese Pharmacovigilance Database.

BACKGROUND: Ixazomib is an orally available proteasome inhibitor for multiple myeloma with adverse effects such as gastrointestinal symptoms, skin rashes, and thrombocytopenia reported in clinical trials and post-marketing surveillance, resulting in treatment discontinuation. However, comprehensive adverse event (AE) assessments for ixazomib are lacking. OBJECTIVES: Herein, we aimed to determine the frequency and risk of AEs associated with ixazomib in Japanese patients using the Japanese Adverse Event Reporting Database (JADER). Additionally, the time to onset and post hoc outcomes of unique AEs were clarified. METHODS: To investigate the association between ixazomib and AEs, we analyzed the JADER database, comprising voluntary AE reports submitted to the Pharmaceuticals and Medical Devices Agency, between April 2004 and June 2021. AEs with ≥10 reports were included in the analysis, and criteria for the presence of AE signals were defined as meeting the requirements of proportional report ratio ≥2 and χ2 ≥ 4. Characteristic AEs were analyzed considering time to onset and onset outcomes. RESULTS: Of 34 extracted AEs, 18 presented AE signals. The 12 post hoc outcomes with fatality rates ≥10% included septic shock (50.0%), infection (41.2%), heart failure (16.7%), pneumonia (14.2%), and tumor necrosis syndrome (13.3%). A median of the time to onset showed that 11 of the 18 AEs occurred from ixazomib initiation to approximately 1 month later. CONCLUSION: Our results suggest that ixazomib may increase the incidence of 18 AEs, 11 of which occurred within the first month of treatment. Furthermore, 8 AEs were found to have potentially fatal outcomes at a rate of ≥10%. Therefore, monitoring AEs during the first month of treatment appears necessary.

Comprehensive analysis of everolimus-induced adverse events using the Japanese real-world database.

WHAT IS KNOWN AND OBJECTIVES: As for adverse events (AEs) caused by everolimus, findings from clinical trials and post-marketing surveillance have reported interstitial lung disease, hyperglycaemia, cardiovascular disease, etc. However, these reports are limited to incidence, and detailed studies on the risk of occurrence, time to onset and post-event clinical outcomes are only related to hyperglycaemia. The purpose of this study was to perform a comprehensive analysis of adverse events during everolimus therapy in patients with renal cell carcinoma (RCC) using the Japanese Adverse Event Report database. METHODS: Data reported between April 2004 and June 2021 in the Japanese Adverse Drug Event Report database were extracted for use. The reported odds ratio, time to onset and post-event course were analysed for the top 30 adverse events reported. RESULTS AND DISCUSSION: Among the top 30 adverse events, 23 adverse event signals were detected and classified into seven categories: lung-related AEs, haematological-related AEs, cancer progression, blood glucose-related AEs, hepatic-related AEs, renal-related AEs and others. The lung-related adverse events category was the most common, and the proportion of fatal outcomes after the occurrence of two adverse events related to infectious pneumonia was more than 10%. WHAT IS NEW AND CONCLUSION: A comprehensive survey of adverse events associated with everolimus administration using the pharmacovigilance database revealed that pulmonary and haematological AEs are frequently reported. The results suggest that attention should be paid to the occurrence of lung disorders because they may lead to fatal outcomes.

Quaternary Wurtzitic Nitrides (1 - x)ZnGeN2-2xGaN (x = 0.02, 0.05): Disorder-Induced Band-Gap Narrowing and Potentiality as a Solar-Active Photocatalyst.

We examined the ZnGeN2-GaN solid-solution system (Zn1-xGe1-xGa2xN2) in the unexplored compositional region of x < 0.10 to reveal the transitional structural and optical properties caused by the introduction of Ga. Fairly stoichiometric fine powder specimens with compositions of x = 0.02 and 0.05 were prepared by the gas-reduction-nitridation method, and their partially ordered Pna21 structure was identified by solid-state 71Ga NMR spectroscopy and time-of-flight neutron powder diffraction. The Rietveld refinement results of the neutron diffraction data showed that the introduction of 2 atom % Ga readily retards the cation ordering in ZnGeN2, and this composition-induced transition to the wurtzite disordered phase proceeds mostly in the range of x < 0.10. The synthesized samples showed gradual red shifts of the absorbance and photoluminescence excitation spectra with their x value, consistent with their degree of disorder, indicating that the narrowing of the band gap achieved in the current system results primarily from the disorder of the cation sublattice accompanied by octet-rule violation, as has been predicted theoretically. The test reactions for photocatalytic water splitting resulted in improved H2 evolution rates of 6.1-72.6 µmol/h under UV-visible-light irradiation, and stable solar H2 evolution of up to 5 days was demonstrated.

Disposable Nitric Oxide Generator Based on a Structurally Deformed Nitrite-Type Layered Double Hydroxide.

The inhalation of nitric oxide (NO), which acts as a selective vasodilator of pulmonary blood vessels, is an established medical treatment. However, its wide adoption has been limited by the lack of a convenient delivery technique of this unstable gas. Here we report that a solid mixture of FeIISO4·7H2O and a layered double hydroxide (LDH) containing nitrite (NO2-) in the interlayer spaces (NLDH) stably generates NO at a therapeutic level (∼40 ppm over 12 h from freshly mixed solids; ∼80 ppm for 5-10 h from premixed solids) under air flow (0.25 L min-1) if the NLDH has been prepared by using a reconstruction method. Mg/Al-type LDH was calcined at 550 °C to remove interlayer CO32- and then treated with NaNO2 in water to reconstruct the NLDH. This one-pot, organic solvent-free process can be performed at large scales and is suitable for mass production. Humid air promotes anion exchange between NO2- and SO42- in the solid mixture, resulting in persistent interactions of NO2- and Fe2+, generating NO. In contrast to the previously reported NLDH prepared using an anion-exchange method, the reconstructed NLDH exhibits stable and persistent generation of NO because of partial deformation of the layered structures (e.g., particle aggregation, reduced crystallinity, and enhanced basicity). Degradation of the solid mixture is suppressed under dry conditions, so that a portable cartridge column that is readily available as an NO source for emergency situations can be prepared. This work demonstrates that the interlayer nanospace of LDH serves as a reaction mediator for excellent controllability of solid-state reactions. This inexpensive and disposable NO generator will facilitate NO inhalation therapy in developing countries and nonhospital locations.

Identification of HUHS190, a human naftopidil metabolite, as a novel anti-bladder cancer drug.

We carried out structure-activity relationship study on anti-cancer effects of naftopidil (1) and its metabolites, resulted in identification of 1-(4-hydroxy-2-methoxyphenyl)piperazin-1-yl)-3-(naphthalen-1-yloxy) propan-2-ol (2, HUHS190), a major human metabolite of 1, which exhibited the most selective toxicities between against normal and cancer cells (Table 1). 2 was more hydrophilic compared to 1, was enough to be prepared in high concentration solution of more than 100 µM in saline for an intravesical instillation drug. Moreover, serum concentration of 2 was comparable to that of 1, an oral preparation drug, after oral administration at 32 mg/kg (Fig. 3). Both of 1 and 2 showed broad-spectrum anti-cancer activities in vitro, for example, 1 and 2 showed inhibitory activity IC50 = 21.1 µM and 17.2 µM for DU145, human prostate cancer cells, respectively, and IC50 = 18.5 µM and 10.5 µM for T24 cells, human bladder cancer cells. In this study, we estimated anticancer effects of 2 in a bladder cancer model after intravesical administration similar to clinical cases. A single intravesical administration of 2 exhibited the most potent inhibitory activities among the clinical drugs for bladder cancers, BCG and Pirarubicin, without obvious side effects and toxicity (Fig. 4). Thus, HUHS190 (2) can be effective for patients after post-TURBT therapy of bladder cancer without side effects, unlike the currently available clinical drugs.

Field-stepwise-swept QCPMG solid-state 115In NMR of indium oxide.

Experimental and theoretical investigations of indium-115 electric-field-gradient (EFG) tensors of indium(III) oxide, In2O3, have been presented. Field-stepwise-swept QCPMG solid-state 115In NMR experiments are carried out at T â€‹= â€‹120 â€‹K, observed at 52.695 â€‹MHz, and in the range of external magnetic fields between 4.0 and 6.5 â€‹T. The spectral simulations yield the quadrupolar coupling constant, CQ value, of 183(2) MHz and the asymmetry parameter, ηQ, of 0.05(5), for In(1), and that of 126(2) MHz and ηQ of 0.86(5) for In(2). Quantum chemical calculations are carried out to provide 115In EFG tensor orientations with respect to the molecular structure. A relationship between operative frequencies and variable ranges of external magnetic fields is briefly discussed for field-swept solid-state 115In NMR.

Why Do Carbonate Anions Have Extremely High Stability in the Interlayer Space of Layered Double Hydroxides? Case Study of Layered Double Hydroxide Consisting of Mg and Al (Mg/Al = 2).

Layered double hydroxides (LDHs) are promising compounds in a wide range of fields. However, exchange of CO32- anions with other anions is necessary, because the CO32- anions are strongly affixed in the LDH interlayer space. To elucidate the reason for the extremely high stability of CO32- anions intercalated in LDHs, we investigated in detail the chemical states of CO32- anions and hydrated water molecules in the LDH interlayer space by synchrotron radiation X-ray diffraction, solid-state NMR spectroscopy, and Raman spectroscopy. We found the rigidity of the network structure formed between the CO32- anions, hydrated water molecules, and the hydroxyl groups on the metal hydroxide layer surface to be a crucial factor underlying the stability of CO32- anions in the LDH interlayer space.