The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise.

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n = 16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n = 18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.

Evaluation of 18F labeled glial fibrillary acidic protein binding nanobody and its brain shuttle peptide fusion proteins using a neuroinflammation rat model.

Astrogliosis is a crucial feature of neuroinflammation and is characterized by the significant upregulation of glial fibrillary acidic protein (GFAP) expression. Hence, visualizing GFAP in the living brain of patients with damaged central nervous system using positron emission tomography (PET) is of great importance, and it is expected to depict neuroinflammation more directly than existing neuroinflammation imaging markers. However, no PET radiotracers for GFAP are currently available. Therefore, neuroimaging with antibody-like affinity proteins could be a viable strategy for visualizing imaging targets that small molecules rarely recognize, such as GFAP, while we need to overcome the challenges of slow clearance and low brain permeability. The E9 nanobody, a small-affinity protein with high affinity and selectivity for GFAP, was utilized in this study. E9 was engineered by fusing a brain shuttle peptide that facilitates blood-brain barrier permeation via two different types of linker domains: E9-GS-ApoE (EGA) and E9-EAK-ApoE (EEA). E9, EGA and EEA were radiolabeled with fluorine-18 using cell-free protein radiosynthesis. In vitro autoradiography showed that all radiolabeled proteins exhibited a significant difference in neuroinflammation in the brain sections created from a rat model constructed by injecting lipopolysaccharide (LPS) into the unilateral striatum of wildtype rats, and an excess competitor displaced their binding. However, exploratory in vivo PET imaging and ex vivo biodistribution studies in the rat model failed to distinguish neuroinflammatory lesions within 3 h of 18F-EEA intravenous injection. This study contributes to a better understanding of the characteristics of small-affinity proteins fused with a brain shuttle peptide for further research into the use of protein molecules as PET tracers for imaging neuropathology.

Preclinical Characterization of the Tau PET Tracer [18F]SNFT-1: Comparison of Tau PET Tracers.

Tau PET tracers are expected to be sufficiently sensitive to track the progression of age-related tau pathology in the medial temporal cortex. The tau PET tracer N-(4-[18F]fluoro-5-methylpyridin-2-yl)-7-aminoimidazo[1,2-a]pyridine ([18F]SNFT-1) has been successfully developed by optimizing imidazo[1,2-a]pyridine derivatives. We characterized the binding properties of [18F]SNFT-1 using a head-to-head comparison with other reported 18F-labeled tau tracers. Methods: The binding affinity of SNFT-1 to tau, amyloid, and monoamine oxidase A and B was compared with that of the second-generation tau tracers MK-6240, PM-PBB3, PI-2620, RO6958948, JNJ-64326067, and flortaucipir. In vitro binding properties of 18F-labeled tau tracers were evaluated through the autoradiography of frozen human brain tissues from patients with diverse neurodegenerative disease spectra. Pharmacokinetics, metabolism, and radiation dosimetry were assessed in normal mice after intravenous administration of [18F]SNFT-1. Results: In vitro binding assays demonstrated that [18F]SNFT-1 possesses high selectivity and high affinity for tau aggregates in Alzheimer disease (AD) brains. Autoradiographic analysis of tau deposits in medial temporal brain sections from patients with AD showed a higher signal-to-background ratio for [18F]SNFT-1 than for the other tau PET tracers and no significant binding with non-AD tau, α-synuclein, transactiviation response DNA-binding protein-43, and transmembrane protein 106B aggregates in human brain sections. Furthermore, [18F]SNFT-1 did not bind significantly to various receptors, ion channels, or transporters. [18F]SNFT-1 showed a high initial brain uptake and rapid washout from the brains of normal mice without radiolabeled metabolites. Conclusion: These preclinical data suggest that [18F]SNFT-1 is a promising and selective tau radiotracer candidate that allows the quantitative monitoring of age-related accumulation of tau aggregates in the human brain.

Ulcerative colitis successfully treated with vedolizumab in the presence of comorbid opportunistic infections: a case report.

BACKGROUND: Opportunistic infections associated with immunosuppressive treatments for inflammatory bowel disease pose an important safety concern. Here we report the case of a patient with active ulcerative colitis and cryptococcal pneumonia who was treated with vedolizumab combined with fluconazole. CASE PRESENTATION: A 56-year-old Japanese man with ulcerative colitis and a history of Sweet's syndrome who was taking prednisolone and azathioprine presented with a moderate exacerbation of ulcerative colitis, abdominal pain, diarrhea, and bloody stools along with cytomegalovirus infection. Increasing the prednisolone dose without using antiviral drugs improved cytomegalovirus infection; however, ulcerative colitis did not improve, and cryptococcal pneumonia occurred. Thus, treatment with fluconazole followed by vedolizumab was initiated for ulcerative colitis. The patient gradually recovered and achieved clinical remission without the exacerbation of pneumonia. CONCLUSIONS: We reported the first case of a patient with ulcerative colitis who was treated with vedolizumab and concomitant fluconazole for active cryptococcal pneumonia. Vedolizumab constitutes a high-potential treatment regimen owing to its safety in inflammatory bowel disease associated with opportunistic infections.

Super-Resolution and Feature Extraction for Ocean Bathymetric Maps Using Sparse Coding.

The comprehensive production of detailed bathymetric maps is important for disaster prevention, resource exploration, safe navigation, marine salvage, and monitoring of marine organisms. However, owing to observation difficulties, the amount of data on the world's seabed topography is scarce. Therefore, it is essential to develop methods that effectively use the limited data. In this study, based on dictionary learning and sparse coding, we modified the super-resolution technique and applied it to seafloor topographical maps. Improving on the conventional method, before dictionary learning, we performed pre-processing to separate the teacher image into a low-frequency component that has a general structure and a high-frequency component that captures the detailed topographical features. We learn the topographical features by training the dictionary. As a result, the root-mean-square error (RMSE) was reduced by 30% compared with bicubic interpolation and accuracy was improved, especially in the rugged part of the terrain. The proposed method, which learns a dictionary to capture topographical features and reconstructs them using a dictionary, produces super-resolution with high interpretability.

Swallowability of Minitablets among Children Aged 6-23 Months: An Exploratory, Randomized Crossover Study.

Minitablets have garnered interest as a new paediatric formulation that is easier to swallow than liquid formulations. In Japan, besides the latter, fine granules are frequently used for children. We examined the swallowability of multiple drug-free minitablets and compared it with that of fine granules and liquid formulations in 40 children of two age groups (n = 20 each, aged 6-11 and 12-23 months). We compared the percentage of children who could swallow minitablets without chewing with that of children who could swallow fine granules or liquid formulations without leftover. The children who visited the paediatric department of Showa University Hospital were enrolled. Their caregivers were allowed to choose the administration method. In total, 37 out of 40 caregivers dispersed the fine granules in water. Significantly more children (80%, 95% CI: 56-94%) aged 6-11 months could swallow the minitablets than those who could swallow all the dispersed fine granules and liquid formulations (22%, 95% CI: 6-47% and 35%, 95% CI: 15-59%, respectively). No significant differences were observed in children aged 12-23 months. Hence, minitablets may be easier to swallow than dispersed fine granules and liquid formulations in children aged 6-11 months.

The Role of Chirality of [18F]SMBT-1 in Imaging of Monoamine Oxidase-B.

(S)-(2-Methylpyrid-5-yl)-6-[(3-[18F]fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) was recently developed as a novel class of selective and reversible monoamine oxidase-B (MAO-B) tracers for in vivo imaging of reactive astrogliosis via positron emission tomography. To investigate the effect of the chirality of [18F]SMBT-1 on tracer performance, we synthesized (S)-[18F]6 ([18F]SMBT-1) and (R)-[18F]6 and compared their binding properties, pharmacokinetics, and metabolism. (S)-6 showed higher binding affinity to MAO-B and lower binding affinity to MAO-A than (R)-6, demonstrating a higher selectivity ratio (MAO-B/MAO-A). A pharmacokinetic study in mice demonstrated that both (S)-[18F]6 and (R)-[18F]6 showed sufficient initial brain uptake. However, (S)-[18F]6 was cleared significantly faster from the body. An abundant sulfoconjugate metabolite M2 was observed in plasma for (S)-[18F]6 but not for (R)-[18F]6. In vitro sulfation assays confirmed that (S)-6 was more reactive than (R)-6, consistent with the in vivo findings. Mefenamic acid, a selective sulfotransferase 1A1 (SULT1A1) inhibitor, strongly inhibited the in vitro sulfation of (S)-6 by mouse liver fractions, human liver cytosol fractions, and human recombinant SULT1A1 enzyme. Genetic polymorphisms of SULT1A1 did not affect the sulfation of (S)-6 in vitro. In conclusion, (S)-[18F]6 had a more favorable binding affinity and binding selectivity for MAO-B than (R)-[18F]6. Additionally, (S)-[18F]6 also possessed better pharmacological and metabolic properties than (R)-[18F]6. These results suggest that (S)-[18F]6 ([18F]SMBT-1) is a promising candidate for application in the imaging of MAO-B in vivo.

Analysis of anticholinergic adverse effects using two large databases: The US Food and Drug Administration Adverse Event Reporting System database and the Japanese Adverse Drug Event Report database.

INTRODUCTION: Anticholinergic adverse effects (AEs) are a problem for elderly people. This study aimed to answer the following questions. First, is an analysis of anticholinergic AEs using spontaneous adverse drug event databases possible? Second, what is the main drug suspected of inducing anticholinergic AEs in the databases? Third, do database differences yield different results? METHODS: We used two databases: the US Food and Drug Administration Adverse Event Reporting System database (FAERS) and the Japanese Adverse Drug Event Report database (JADER) recorded from 2004 to 2020. We defined three types of anticholinergic AEs: central nervous system (CNS) AEs, peripheral nervous system (PNS) AEs, and a combination of these AEs. We counted the number of cases and evaluated the ratio of drug-anticholinergic AE pairs between FAERS and JADER. We computed reporting odds ratios (RORs) and assessed the drugs using Beers Criteria®. RESULTS: Constipation was the most reported AE in FAERS. The ratio of drug-anticholinergic AE pairs was statistically significantly larger in FAERS than JADER. Overactive bladder agents were suspected drugs common to both databases. Other drugs differed between the two databases. CNS AEs were associated with antidementia drugs in FAERS and opioids in JADER. In the assessment using Beers Criteria®, signals were detected for almost all drugs. Between the two databases, a significantly higher positive correlation was observed for PNS AEs (correlation coefficient 0.85, P = 0.0001). The ROR was significantly greater in JADER. CONCLUSIONS: There are many methods to investigate AEs. This study shows that the analysis of anticholinergic AEs using spontaneous adverse drug event databases is possible. From this analysis, various suspected drugs were detected. In particular, FAERS had many cases. The differences in the results between the two databases may reflect differences in the reporting countries. Further study of the relationship between drugs and CNS AEs should be conducted.

Study of the compatibility of oral magnesium oxide preparations sold in Japan with the ICH-Q3D guideline for elemental impurities.

Magnesium oxide has been widely used as an antacid and constipation remedy. Currently in Japan, magnesium oxide preparations manufactured by five medical companies are marketed as prescribed generic drugs. In this study, we focused on metal elemental impurities present in 330 mg magnesium oxide tablets manufactured by each of these companies. The content of such impurities was determined by atomic absorption spectrometry and inductively coupled plasma mass spectrometry. We confirmed whether the content conformed to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Guideline for Elemental Impurities (ICH-Q3D) based on the 30% control threshold. The content of these impurities varied among the five products (preparations A-E), but in all cases met the oral permitted daily exposure (PDE) criteria stipulated in ICH-Q3D. In 5 lots of preparation C and all lots of preparation D, the equivalent cadmium (Cd) intake for a daily maximum dosage of 2 g was higher than the 30% control threshold of 1.5 µg/day. By cluster analysis, preparations A-E were classified into preparations A + B and C + D + E and/or preparations A + B, C + D and E. The present study showed that all 5 preparations sold in Japan meet the PDE value standard of ICH-Q3D, and that preparations A and B meet the 30% control threshold. It is important that for preparations failing to meet the criteria, further improvements need to be sought, and impurities in magnesium oxide preparations need to be monitored to ensure their safety.

Synthesis and evaluation of 2-pyrrolopyridinylquinoline derivatives as selective tau PET tracers for the diagnosis of Alzheimer's disease.

INTRODUCTION: [18F]THK-5351 was originally developed as a positron emission tomography (PET) imaging tracer for the detection of accumulated tau proteins, the pathological hallmark of Alzheimer's disease (AD). However, clinical studies of [18F]THK-5351 revealed the existence of off-target binding to monoamine oxidase-B (MAO-B). To overcome this off-target binding, in this work, we synthesized and evaluated 2-pyrrolopyridinylquinoline (PPQ) derivatives as selective tau PET imaging tracers. METHODS: The core structure of PPQ derivatives was synthesized mainly using the Buchwald-Hartwig amination coupling reaction. All derivatives were evaluated for binding affinity towards tau and MAO-B by in vitro competitive binding assay. Radiosynthesis of PPQ derivatives was performed by 18F-radiolabeling of their tosylate precursors with activated [18F]KF/Kryptofix222 complex in dimethylsulfoxide by heating at 110 °C for 10 min. The biological properties of these [18F]PPQ derivatives were characterized by in vitro autoradiography of postmortem AD brain sections and by assay of ex vivo biodistribution in mice. RESULTS: The PPQ derivatives were synthesized, with yields of 49-84%. In vitro competitive binding assay revealed that two novel PPQ derivatives-PPQ8 and PPQ9-demonstrated high binding affinity for tau (IC50 = 4.9 and 6.9 nM, respectively). The radiosynthesis of [18F]PPQ8 and [18F]PPQ9 yielded 1.4% and 50.1% isolated non-decay corrected radiochemical yield, respectively, with >99% radiochemical purity. The molar radioactivities of [18F]PPQ8 and [18F]PPQ9 were 16.9 and 64.8 GBq/µmol, respectively. The in vitro and ex vivo biological characterization of [18F]PPQ8 and [18F]PPQ9 revealed that these tracers were selective for tau in AD brain sections without off-target binding, and they furthermore demonstrated brain uptake in normal mice. CONCLUSIONS: 18F-labeled PPQ derivatives improved binding affinity and selectivity for tau aggregates in AD. Further structural optimization to improve pharmacokinetics for potent tau PET imaging tracers is required.

18F-SMBT-1: A Selective and Reversible PET Tracer for Monoamine Oxidase-B Imaging.

Reactive astrocytes play a key role in the pathogenesis of various neurodegenerative diseases. Monoamine oxidase-B (MAO-B) is one of the promising targets for the imaging of astrogliosis in the human brain. A novel selective and reversible MAO-B tracer, (S)-(2-methylpyrid-5-yl)-6-[(3-18F-fluoro-2-hydroxy)propoxy]quinoline (18F-SMBT-1), was successfully developed via lead optimization from the first-generation tau PET tracer 18F-THK-5351. Methods: SMBT-1 was radiolabeled with 18F using the corresponding precursor. The binding affinity of radiolabeled compounds to MAO-B was assessed using saturation and competitive binding assays. The binding selectivity of 18F-SMBT-1 to MAO-B was evaluated by autoradiography of frozen human brain tissues. The pharmacokinetics and metabolism were assessed in normal mice after intravenous administration of 18F-SMBT-1. A 14-d toxicity study after the intravenous administration of 18F-SMBT-1 was performed using rats and mice. Results: In vitro binding assays demonstrated a high binding affinity of 18F-SMBT-1 to MAO-B (dissociation constant, 3.7 nM). In contrast, it showed low binding affinity to MAO-A and protein aggregates such as amyloid-ß and tau fibrils. Autoradiographic analysis showed higher amounts of 18F-SMBT-1 binding in the Alzheimer disease brain sections than in the control brain sections. 18F-SMBT-1 binding was completely displaced with the reversible MAO-B inhibitor lazabemide, demonstrating the high selectivity of 18F-SMBT-1 for MAO-B. Furthermore, 18F-SMBT-1 showed a high uptake by brain, rapid washout, and no radiolabeled metabolites in the brain of normal mice. 18F-SMBT-1 showed no significant binding to various receptors, ion channels, or transporters, and no toxic effects related to its administration were observed in mice and rats. Conclusion:18F-SMBT-1 is a promising and selective MAO-B PET tracer candidate, which would be useful for quantitative monitoring of astrogliosis in the human brain.

Pneumothorax during lenvatinib treatment for hepatocellular carcinoma with lung metastasis.

Lenvatinib is an inhibitor of tyrosine kinases, such as vascular endothelial growth factor receptor and fibroblast growth factor receptor, and was first approved for use in thyroid cancer in 2015 in Japan. Additional approval was given in March 2018 for its use as a first-line treatment for advanced or unresectable hepatocellular carcinoma. Herein, we report a case of pneumothorax during lenvatinib treatment for multiple lung metastases of hepatocellular carcinoma in a 71-year-old man. Although the development of pneumothorax during treatment with anticancer agents for lung metastases is well-known, this is the first report of pneumothorax induced by lenvatinib during treatment for lung metastases of hepatocellular carcinoma.

A concentration-based microscale method for 18F-nucleophilic substitutions and its testing on the one-pot radiosynthesis of [18F]FET and [18F]fallypride.

When applied to a radiosynthesis, a microscale approach can help to save precursor and improve yields. Thus, a 5-10 µL microscale method based on a concentration procedure was developed and applied to the radiosynthesis of [18F]FET and [18F]fallypride. In spite of using an amount of precursor ca. 100 times smaller, radiochemical yields were comparable or even higher than those reported in literature. Because of the very low reaction volumes, the possible effects of concentrated dose of activity and carrier fluoride were also investigated.

Identification of skipjack tuna (Katsuwonus pelamis) pelagic hotspots applying a satellite remote sensing-driven analysis of ecological niche factors: A short-term run.

Skipjack tuna (SJT) pelagic hotspots in the western North Pacific (WNP) were modelled using fishery and satellite remotely sensed data with Ecological Niche Factor Analysis (ENFA) models. Our objectives were to model and predict habitat hotspots for SJT and assess the monthly changes in sub-surface temperatures and mixed layer depths at fishing locations. SJT presence-only monthly resolved data, sea surface temperature, chlorophyll-a, diffuse attenuation coefficient, sea surface heights and surface wind speed were used to construct ENFA models and generate habitat suitability indices using a short-term dataset from March-November 2004. The suitability indices were then predicted for July-October (2007 and 2008). Monthly aggregated polygons of areas fished by skipjack tuna pole and line vessels were also overlaid on the predicted habitat suitability maps. Distributions of sub-surface temperatures and mixed layer depths (MLD) at fishing locations were also examined. Our results showed good fit for ENFA models, as indicated by the absolute validation index, the contrast validation index and the continuous Boyce index. The predicted hotspots showed varying concurrences when compared with 25-degree polygons derived from fished areas. Northward shifts in SJT hotspots corresponded with declining MLDs from March to September. The MLDs were shallower in summer and deeper in autumn and winter months. The habitat hotspots modeled using ENFA were consistent with the known ecology and seasonal migration pattern of SJT. The findings of this work, derived from a short-term dataset, enable identification of SJT hotspots in the WNP, thus contributing valuable information for future research on SJT habitat prediction models.

Retrospective survey of compounded medications for children in Japan.

Compounding of medications, such as crushing tablets and dispersing the contents of capsules, is a common practice in pharmacies and hospitals worldwide and is often done to provide age-appropriate formulations for oral use in pediatric patients. In the present study, a retrospective, descriptive, questionnaire-based survey was conducted to clarify the current status of drug compounding for pediatric patients in Japan. An electronic questionnaire was distributed to 740 hospitals in Japan with pediatric beds, and 208 (28.1%) of these hospitals responded. The total instances of compounding numbered 14,864 (9.6% of the total pediatric oral prescriptions) and comprised 266 active pharmaceutical ingredients (APIs), one-third of which (98 APIs) were compounded even though flexible dosage forms were available. The three most frequently compounded drugs were dantrolene sodium capsules (1152 prescriptions), ramelteon tablets (726 prescriptions), and hydrocortisone tablets (652 prescriptions), all of which were prescribed and administered in powder form. Although compounding of medications frequently varied by the patients' age, steroids such as prednisolone, dexamethasone, and hydrocortisone were commonly compounded in all age groups. To ensure the quality and safety of these compounded medications, developing a standard protocol for compounding methods is urgently needed in Japan.

Estimation of tsunami debris on seafloors towards future disaster preparedness: Unveiling spatial varying effects of combined land use and oceanographic factors.

A large amount of tsunami debris from the Great East Japan Earthquake in 2011 was sunk on the seafloor and threatened the marine ecosystem and local communities' economy, especially in fisheries. However, few studies estimated spatial accumulations of tsunami benthic debris, comparing to their flows on the ocean surface. Here, a spatially varying coefficient model was used to estimate tsunami debris accumulation considering the spatial structure of the data off the Tohoku region. Our model revealed the number of vessels nearest the coast at the tsunami event had the highest positive impact, whereas the distance from the coast and kinetic energy influenced negatively. However, the effect of the proximity to the coast wasn't detected in the Sendai bay, indicating spatial dependency of these effects. Our model estimation provides the fundamental information of tsunami debris accumulation on the seafloor, supporting early reconstruction and risk reduction in marine ecosystems and local communities.

Brain histamine H1 receptor occupancy after oral administration of desloratadine and loratadine.

Some histamine H1 receptor (H1R) antagonists induce adverse sedative reactions caused by blockade of histamine transmission in the brain. Desloratadine is a second-generation antihistamine for treatment of allergic disorders. Its binding to brain H1Rs, which is the basis of sedative property of antihistamines, has not been examined previously in the human brain by positron emission tomography (PET). We examined brain H1R binding potential ratio (BPR), H1R occupancy (H1RO), and subjective sleepiness after oral desloratadine administration in comparison to loratadine. Eight healthy male volunteers underwent PET imaging with [11C]-doxepin, a PET tracer for H1Rs, after a single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double-blind crossover study. BPR and H1RO in the cerebral cortex were calculated, and plasma concentrations of loratadine and desloratadine were measured. Subjective sleepiness was quantified by the Line Analogue Rating Scale (LARS) and the Stanford Sleepiness Scale (SSS). BPR was significantly lower after loratadine administration than after placebo (0.504 ± 0.074 vs 0.584 ± 0.059 [mean ± SD], P < 0.05), but BPR after desloratadine administration was not significantly different from BPR after placebo (0.546 ± 0.084 vs 0.584 ± 0.059, P = 0.250). The plasma concentration of loratadine was negatively correlated with BPR in subjects receiving loratadine, but that of desloratadine was not correlated with BPR. Brain H1ROs after desloratadine and loratadine administration were 6.47 ± 10.5% and 13.8 ± 7.00%, respectively (P = 0.103). Subjective sleepiness did not significantly differ among subjects receiving the two antihistamines and placebo. At therapeutic doses, desloratadine did not bind significantly to brain H1Rs and did not induce any significant sedation.

[Current State of Process of Dispensing Prescription for Pediatric Patients Who Need Home Visiting for Intervention for Pharmaceutical Management].

Medical advances have made it possible to save lives of children with severe refractory diseases. As a result, the number of children who need continuous medical care at home has increased. However, there are concerns that many pharmacies are not actively involved in, because the dispensing fee does not match their prescriptions, which are very complicated and contain some high-risk medicines. We analyzed the burden of dispensing prescribed medicines so that we can quantitatively discuss from prescription contents. The essence of the burden of a pharmacy regarding home medical care for children is to cover the transportation of heavy pharmaceuticals and the combination of multiple medication including high-risk medicines and lack of pediatric drug formulations with the efforts of the on-site pharmacist. It became clear that the pharmacist's objective work supports pediatric pharmacotherapy.

Alternating electric field application induced non-contact and enzyme-free cell detachment.

Low intensity (< 2 Vpp/cm (peak to peak voltage/cm)), high frequency (10-30 MHz), and 10 min alternating electric fields (sine wave with no DC component) induce non-contact and enzyme-free cell detachment of anchorage-dependent cells directly from commercially available cell culture flasks and stack plates. 0.25 Vpp/cm, 20 MHz alternating electric field for 10 min at room temperature (RT) induced maximum detachment and separated 99.5 ± 0.1% (mean ± SEM, n = 6) of CHO-K1 and 99.8 ± 0.2% of BALB/3T3 cells from the culture flasks. Both vertical and lateral alternating electric field applications for 10 min at RT detach the CHO-K1 cells from 25 cm2 culture flasks. The alternating electric field application induced cell detachment is almost noncytotoxic, and over 90% of the detached cells remained alive. The alternating electric field applied CHO-K1 cells for 90 min showed little or no lag phase and immediately enter exponential phase in cell growth. Combination of the 20 MHz alternating electric field and enzymatic treatment for 4 min at 37 °C showed synergetic effect and quickly detached human induced pluripotent stem cells from a laminin-coated culture flask compared with the only enzymatic treatment. These results indicate that the rapid cell detachment with both the electric field application and the enzymatic treatment could be applied to subcultures of cells that are susceptible to prolonged enzymatic digestion damage for mass culture of sustainable clinical use.

Age-Appropriate Pediatric Dosage Forms in Japan: Insights into End-User Perceptions From an Observational Cross-Sectional Survey Assessing the Acceptability of Oral Formulation.

BACKGROUND: The lack of appropriate pediatric formulations is a global issue and information on acceptability is urgently needed to develop standard pediatric formulations. This study aimed to assess perceptions of acceptability of several oral dosage forms among pediatric patients at a community and a pediatric hospital in Japan and collected information about age-appropriate pediatric formulations, aiming to contribute to drug development promotion worldwide. METHODS: A cross-sectional observational study was performed. A convenience sample of caregivers was recruited from available chain-owned retail pharmacies and inpatient pediatric units. The questionnaire was composed of 3 parts: (1) acceptability of the 5 dosage forms (tablets, capsules, powders, liquids, and orally disintegrating tablet) by age; (2) acceptability of dosage size, amount, and volume by age; and (3) the actual method of administration. Face-to-face interviews were conducted at 3 independent community pharmacies (324 parents) and tertiary care pediatric hospital wards (112 nursing staff). Acceptability scores and acceptable dosages were then determined. The survey was conducted from October 1 to December 1, 2017, for the hospital setting and November 1 to 30, 2017, for the outpatient setting. RESULTS: The acceptability of oral dosage forms was roughly similar to the matrix drafted by the European Medical Agency. Differences in perception of the powder forms between communities and hospitals were also observed, with the nursing staff perceiving powder as being acceptable from the neonatal period. CONCLUSIONS: The difference in caregivers' perception of the acceptability of oral formulations between Japan and Europe was small. The powder form was found to be more acceptable in Japan. Further intervention studies are needed to assess the preferred pediatric formulation worldwide.