Prospective observational study of nutritional status and oral supplement utilization in users of an elderly daycare service, employing a web-based Mini Nutritional Assessment Form (MNA plus).

Introduction: Seniors are vulnerable to frailty, a condition linked to falls, fractures, hospitalizations, and sarcopenia. Even with regular meals, senior daycare users are at risk for malnutrition. Methods: This study assessed malnutrition risk in daycare users, using the web-based Mini Nutritional Assessment Form (MNA®-SF). Individuals identified as malnourished or at risk were examined for changes in nutritional status with and without oral nutritional supplementation (ONS). Results: Of 507 subjects, 138 (27.2%) were malnourished or at risk. Discontinuation rates were 20.0% (7/35) for the ONS group and 40.0% (10/25) for the regular care (RC) group. Among 29 patients with measurable weight change after six months, 19 (ONS group) and 10 (RC group) participated. The ONS group exhibited significant increases in body weight (+1.4 ± 2.9 kg, p < 0.01), body mass index (BMI) (+0.6 ± 0.9 kg/m2, p < 0.01), calf circumference (+3.2 ± 0.2 cm, p < 0.01), and grip strength (+1.2 ± 1.9 kg, p = 0.069). Conversely, the RC group showed no significant increases in body weight (+1.0 ± 1.9 kg, p = 0.146), BMI (+0.4 ± 0.8 kg/m2, p = 0.176), or grip strength (-0.7 ± 1.7 kg, p = 0.327), with decreased grip strength and calf circumference (-0.8 ± 0.9 cm, p < 0.05). In the ONS group, 52.6% (10/19) consumed over 400 kcal/day of ONS, and 84.2% maintained this intake for three months. Malnutrition is prevalent among daycare users. Conclusion: ONS influences weight, BMI, and calf circumference, potentially reducing discontinuation rates. Clinical trial registration: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000049767, UMIN000043580.

Calculation of Human Melatonin Partial Metabolic Clearance in Healthy Adult Volunteers for Investigation of a Novel in Vivo CYP1A2 Phenotyping Method: A Pilot Study.

The method of administering caffeine as a probe to evaluate the phenotypic activity of the CYP1A2, has not yet been applied clinically. In contrast, if endogenous melatonin (MEL) metabolism can be used to assess CYP1A2 activity, it could be a simple method that does not require substance administration. The study aim was to calculate the MEL partial metabolic clearance (CLm(MEL)) from plasma MEL and its urinary metabolites and to test the potential of this approach as a novel CYP1A2 phenotyping method. Nine subjects were included in the study; 3 had 6 blood and 4 urine samples collected between 10:00 and 18:00 (collectively, the intraday sample). Nine subjects had 3 blood samples and 2-h urine samples collected between 10:00 and 12:00 once a week for 3 weeks (interday sample). The CLm(MEL) was calculated from the plasma area under the curve (AUC) of MEL (AUCMEL) and urinary MEL metabolites excretion (X6MEL). Among the intraday samples, the AUCMEL ranged from 6.45-13.17 pmol·h/L and X6MEL ranged from 0.204-0.899 nmol/2 h, showing a decrease in concentration over time. In contrast, the CLm(MEL) ranged from 30.52-69.57 L/h (within-individual percent relative standard deviation: 9.2-20.1%), showing no time-dependent variation. Large interindividual variability was observed in AUCMEL and X6MEL in the interday sample, but CLm(MEL) showed small interindividual variabilities. The CLm(MEL) was 1.8-fold higher for smokers than for nonsmokers. The results obtained in this study may be valuable in future studies of evaluating novel CYP1A2 phenotyping method.

Elucidation of clearance mechanism of TP0463518, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor: does a species difference in excretion routes exist between humans and animals?

1. TP0463518, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, is reportedly excreted predominantly through urinary excretion in an unchanged form in humans, with partial biliary excretion also possible. However, the clearance mechanisms remain unclear. The aim of this study was to investigate the clearance mechanisms in humans and to assess species differences in the excretion routes.2. TP0463518 was not metabolised in rat, dog, or human hepatocytes. TP0463518 is a substrate for human BCRP, OATP1B1, OATP1B3, and OAT3, suggesting that renal uptake by OAT3 is probably the predominant clearance route, with hepatic uptake by OATP1B1 and OATP1B3 contributing partially to clearance in humans.3. A species difference in excretion routes was observed. The unchanged urinary excretion rates in humans, male rats, female rats, dogs, and monkeys were 80.7%, 0.1%, 40.9%, 15.2%, and 72.6%, respectively. Urinary excretion was predominant in humans and monkeys, while only biliary excretion was observed in male rats. Uptake studies using hepatocytes showed that the hepatic uptake clearance in rats was 13.6-fold higher than that in humans. Therefore, not only reabsorption via renal tubules, but also hepatic uptake seems to be involved in the species differences in excretion routes between rats and humans.

Development and Validation of an LC-MS/MS-Based Method for Quantifying Urinary Endogenous 6-Hydroxymelatonin.

Evaluation of endogenous melatonin (MEL) secretion using its urinary metabolites is useful for the treatment of circadian rhythm sleep disorders. The primary melatonin metabolites excreted in the urine are 6-hydroxymelatonin (6-O-MEL) sulfate (S-O-MEL) and 6-O-MEL glucuronate, which result from sequential MEL metabolism by phases I and II drug metabolizing enzymes. To determine the accurate MEL secretion level, these urinary metabolites should be enzymatically deconjugated and converted into MEL. Furthermore, the use of LC-tandem mass spectrometry (LC-MS/MS) is preferable for the precision of this determination. Therefore, as part of our ongoing efforts to ultimately determine the level of MEL secretion, we herein aimed to develop an LC-MS/MS-based quantification method for 6-O-MEL and optimize deconjugation conditions. We determined the LC-MS/MS conditions of 6-O-MEL measurement and optimized the conditions of enzymatic reactions. The most efficient S-O-MEL deconjugation (102.1%) was achieved with Roche Glucuronidase/Arylsulfatase (from Helix pomatia) at 37 °C, pH-4.0 reaction buffer, and 60 min of reaction time. For human urine samples, the minimum amount of the enzyme required was 5944 units. Under these conditions, the accuracy and precision values of the 6-O-MEL determination (relative errors and standard deviation) were -3.60--0.47% and <6.80%, respectively. Finally, we analyzed the total amount of MEL metabolites excreted in 24-h urine samples; it was 6.70-11.28 µg in three subjects, which is comparable with the values reported till date. Thus, we have established a new method of measuring the total 6-O-MEL in human urine samples using an LC-MS/MS coupled with the prerequisite deconjugation reaction.

Downregulation of CYP1A2, CYP2B6, and CYP3A4 in Human Hepatocytes by Prolyl Hydroxylase Domain 2 Inhibitors via Hypoxia-Inducible Factor-α Stabilization.

Hypoxia-inducible factor (HIF) is associated with the expression of CYP, but the underlying mechanism remains uncertain. In this study, we investigated the effect of HIF-α stabilization caused by novel prolyl hydroxylase domain (PHD) 2 inhibitors, which are HIF-α stabilizers that mimic hypoxia, on the expressions of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes. An mRNA expression analysis of human hepatocytes treated with PHD2 inhibitors for 72 hours showed the downregulation of genes encoding CYP1A2, CYP2B6, and CYP3A4. The mRNA repressions were accompanied with an increase in erythropoietin protein, a marker of HIF-α stabilization, indicating that HIF-α stabilization was involved in the downregulation of the CYP isoforms. To understand the underlying mechanisms, we assessed the relationship between the expressions of the CYP isoforms and those of their regulating transcription factors [aryl hydrocarbon receptor (AhR), AhR nuclear translocator (ARNT), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoid X receptor (RXR)] in human hepatocytes treated with the HIF-α stabilizers. As a result, the mRNA level of AhR did not decrease, although ARNT expression was repressed. On the other hand, the mRNA expression levels of CAR, PXR, and RXR were repressed and closely associated with those of CYP2B6 and CYP3A4. Although the underlying mechanism of the downregulation for CYP1A2 remains unclear, the presently reported results suggest that the downregulation of CYP2B6 and CYP3A4 via HIF-α stabilization is caused by a decrease in the expressions of CAR, PXR, and RXR. SIGNIFICANCE STATEMENT: We showed that hypoxia-inducible factor (HIF)-α stabilization downregulates CYP1A2, CYP2B6, and CYP3A4 using prolyl hydroxylase domain 2 inhibitors, which are HIF-α stabilizers, as a new tool to mimic hypoxia in human hepatocytes. To understand the underlying mechanisms, we assessed the relationship between the expressions of the CYP isoforms and those of their regulating transcription factors. Our findings would contribute to a better understanding of the hypoxia-triggered regulatory mechanism of drug-metabolizing enzymes in human hepatocytes.

Complete Genome Sequence of Ceftriaxone-Resistant Neisseria gonorrhoeae SS3160, Isolated in Tokyo, Japan.

We report the complete genome sequence of ceftriaxone-resistant Neisseria gonorrhoeae SS3160, harboring the mosaic penA-60.001 allele. This Japanese isolate has a unique sequence type (ST), ST13429, which was determined by multilocus sequence typing from the chromosome sequence (2,214,955 bp). It carries two plasmids, pConjugative (39,057 bp) and pCryptic (4,207 bp).

Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, preserves renal function irrespective of acute changes in the estimated glomerular filtration rate in Japanese patients with type 2 diabetes.

Acute decline in estimated glomerular filtration rate (eGFR), a typical finding after initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors, is associated with maintaining renal function in type 2 diabetes. However, the relationship between the magnitude of acute decline in eGFR and the course of eGFR thereafter is not known. A pooled analysis of four 52-week phase III trials of luseogliflozin 2.5 mg daily (or up to 5 mg daily) in Japanese patients with type 2 diabetes was conducted and stratified according to the tertile of magnitude of acute change in eGFR during the 2 weeks after initiation. The mean age, glycated hemoglobin, eGFR, and urinary albumin were 60 years, 7.8%, 79.6 mL/min/1.73 m2, and 62.7 mg/g Cr, respectively. Acute change in eGFR varied widely between patients (N = 941; mean, -2.3; min, -35.5; max, 27.6). Patients with greater acute decline in eGFR, characterized by higher baseline eGFR and increased diuretic use, showed rapid recovery and maintenance of eGFR thereafter. Higher eGFR, longer duration of diabetes, and higher body mass index and diuretic use were associated with greater acute decline in eGFR. The course of eGFR from 12 to 52 weeks was maintained regardless of acute changes. Although acute changes in eGFR varied widely among patients with type 2 diabetes, the course of eGFR thereafter was stable regardless of the degree of acute changes.

Block copolymers containing stable radical and fluorinated blocks with long-range ordered morphologies prepared by anionic polymerization.

We report a facile synthetic approach to create stable radical block copolymers containing a secondary fluorinated block via anionic polymerization using a bulky, sterically hindered countercation composed of a sodium ion and di-benzo-18-crown-6 complex. The synthetic conditions described in this report allowed for controlled molecular weights and dispersity (<1.3) of both homopolymers: poly(2,2,6,6-tetramethyl-1-piperidinyloxy-methacrylate) (PTMA) and poly(2,2,2-trifluoroethyl methacrylate) (PTFEMA) as well as their block copolymers (PTMA-b-PTFEMA). The stable radical concentration of the polymers was determined by electron spin resonance (ESR) and showed radical content above 70%. An analysis of the microphase morphologies in PTMA-b-PTFEMA thin films via atomic force microscopy (AFM) and grazing incidence small angle X-ray scattering (GISAXS) showed clear evidence of long-range ordering of lamellar and cylindrical morphologies with 32 and 36 nm spacing, respectively. The long-range ordering of the morphologies was developed with the aid of two separate neutral layers: PTMA-ran-PTFEMA-ran-poly(hydroxyl ethyl methacrylate) (PHEMA) and poly(isobutyl methacrylate) (PiBMA)-ran-PTFEMA-ran-PHEMA, which helped us corroborate, along with the Zisman method, the surface energy estimation of PTMA to be 30.1 mJ/m2.

TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver.

Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver. The 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518) is a novel PHD 1/2/3 pan inhibitor; however, the main source of EPO production after TP0463518 administration remained to be investigated. We examined the effect of TP0463518 in inducing EPO production in the kidney and liver by measuring the hypoxia-inducible factor 2α (HIF-2α), EPO mRNA, and serum EPO levels in normal and bilaterally nephrectomized rats. Furthermore, we examined whether liver-derived EPO improved anemia in 5/6 nephrectomized (5/6 Nx) rats. TP0463518 scarcely increased the HIF-2α and EPO mRNA expression levels in the kidney cortex, whereas oral administration of TP0463518 at 40 mg/kg dramatically increased the HIF-2α level from 0.27 to 1.53 fmol/mg and the EPO mRNA expression level by 1300-fold in the livers of healthy rats. After administration of TP0463518 at 20 mg/kg, the total EPO mRNA expression level in the whole liver was 22-fold that in the whole kidney. In bilaterally nephrectomized rats, TP0463518 raised the serum EPO concentration from 0 to 180 pg/ml at 20 mg/kg. Furthermore, repeated administration of TP0463518 at 10 mg/kg increased the reticulocyte count in 5/6 Nx rats on day 7 and raised the hemoglobin level on day 14. The present study revealed that TP0463518 specifically induced EPO production in the liver and improved anemia. The characteristic feature of TP0463518 would lead to not only a more detailed understanding of the PHD-HIF2α-EPO pathway in erythropoiesis, but a new therapeutic alternative for renal anemia. SIGNIFICANCE STATEMENT: Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver; however, their effects on renal EPO production have been shown to vary depending on the experimental conditions. The authors found that 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518), a PHD 1/2/3 pan inhibitor, specifically induced EPO production in the liver and that the liver-derived EPO was pharmacologically effective. Investigation of the effects of TP0463518 may pave the way for the development of a new therapeutic alternative for renal anemia patients.

Association of ATXN2 intermediate-length CAG repeats with amyotrophic lateral sclerosis correlates with the distributions of normal CAG repeat alleles among individual ethnic populations.

Intermediate-length CAG repeats in ATXN2 have been widely shown to be a risk factor for sporadic amyotrophic lateral sclerosis (SALS). To evaluate the association of ATXN2 intermediate-length CAG repeat alleles with an increased risk of SALS, we investigated distributions of CAG repeat alleles in 394 patients with SALS and 490 control individuals in the Japanese population. In the intermediate-length repeat units of 29 or more, we identified one SALS patient with 31 repeat units and two control individuals with 30 repeat units. Thus, no significant differences in the carrier frequency of intermediate-length CAG repeat alleles were detected between patients with SALS and control individuals. When we investigated the distribution of "large normal alleles" defined as ATXN2 CAG repeats ranging from 24 up to 33 in the Japanese population compared with those in other populations in previous studies, the frequency of large normal alleles was significantly higher in the European and North American series than in the Japanese series. Moreover, these frequencies in the Turkish, Chinese, Korean, and Brazilian (Latin American) series were also higher than that in the Japanese series. These results raise the possibility that the frequencies of large normal alleles in individual populations underlie the frequencies of ALS risk alleles in the corresponding populations.

TP0463518, a novel inhibitor for hypoxia-inducible factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with a good pharmacokinetics-pharmacodynamics correlation.

Hypoxia-inducible factor prolyl hydroxylases (PHDs) inhibitor stabilizes hypoxia inducible factor alpha, which increases erythropoietin (EPO) expression via the hypoxia response element. Therefore, PHDs inhibitors have been developed as novel therapeutic agents for anemia. Here, we characterize the in vitro and in vivo pharmacological profiles of TP0463518, 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid, a novel potent PHDs inhibitor. TP0463518 competitively inhibited human PHD2 with a Ki value of 5.3 nM. TP0463518 also inhibited human PHD1/3 with IC50 values of 18 and 63 nM as well as monkey PHD2 with an IC50 value of 22 nM. In normal mice and rats, TP0463518 significantly increased the serum EPO levels at doses of 5 and 20 mg/kg, respectively. The correlation factors for serum EPO and the serum TP0463518 levels were 0.95 in mice and 0.92 in rats. TP0463518 also increased the serum EPO level in 5/6 nephrectomized chronic kidney disease model rats at a dose of 10 mg/kg, with a correlation factor for serum EPO and the serum TP0463518 levels of 0.82. Finally, the effect of TP0463518 in monkeys was investigated. TP0463518 was promptly removed with a half-life of 5.2 h and increased the area under the curve (AUC) of EPO at a dose of 5 mg/kg. The EPO and TP0463518 levels were also correlated. These results suggest that TP0463518 induces endogenous EPO with a strong pharmacokinetic-pharmacodynamic correlation and may contribute to desirable hemoglobin control in patients with renal anemia.

Discovery of novel 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid derivatives as HIF prolyl hydroxylase inhibitors for treatment of renal anemia.

Prolyl hydroxylase domain-containing protein (PHD) inhibitors are useful as orally administered agents for the treatment of renal anemia. Based on the common structures of known PHD inhibitors, we found novel PHD inhibitor 1 with a 2-[(4-hydroxy-6-oxo-2,3-dihydro-1H-pyridine-5-carbonyl)amino]acetic acid motif. The PHD2-inhibitory activity, lipophilicity (CLogP), and PK profiles (hepatocyte metabolism, protein binding, and/or elimination half-life) of this inhibitor were used as the evaluation index to optimize the structure and eventually discovered clinical candidate 42 as the suitable compound. Compound 42 was demonstrated to promote the production of erythropoietin (EPO) following oral administration in mice and rats. The predicted half-life of this compound in humans was 1.3-5.6 h, therefore, this drug may be expected to administer once daily with few adverse effects caused by excessive EPO production.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Perpendicular Orientation Control without Interfacial Treatment of RAFT-Synthesized High-χ Block Copolymer Thin Films with Sub-10 nm Features Prepared via Thermal Annealing.

In this study, a series of perpendicular lamellae-forming poly(polyhedral oligomeric silsesquioxane methacrylate-block-2,2,2-trifluoroethyl methacrylate)s (PMAPOSS-b-PTFEMAs) was developed based on the bottom-up concept of creating a simple yet effective material by tailoring the chemical properties and molecular composition of the material. The use of silicon (Si)-containing hybrid high-χ block copolymers (BCPs) provides easy access to sub-10 nm feature sizes. However, as the surface free energies (SFEs) of Si-containing polymers are typically vastly lower than organic polymers, this tends to result in the selective segregation of the inorganic block onto the air interface and increased difficulty in controlling the BCP orientation in thin films. Therefore, by balancing the SFEs between the organic and inorganic blocks through the use of poly(2,2,2-trifluoroethyl methacrylate) (PTFEMA) on the organic block, a polymer with an SFE similar to Si-containing polymers, orientation control of the BCP domains in thin films becomes much simpler. Herein, perpendicularly oriented BCP thin films with a χeff value of 0.45 were fabricated using simple spin-coating and thermal annealing processes under ambient conditions. The thin films displayed a minimum domain size of L0 = 11 nm, as observed via atomic force microscopy (AFM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Furthermore, directed self-assembly (DSA) of the BCP on a topographically prepatterned substrate using the grapho-epitaxy method was used to successfully obtain perpendicularly oriented lamellae with a half pitch size of ca. 8 nm.

A Senile Case of Late-onset Pompe's Disease.

A 72-year-old, seemingly healthy, Japanese man suddenly lost consciousness. At the emergency room, the patient's Glasgow coma scale score was 10 and a thoracic breathing pattern was observed. An arterial blood gas analysis indicated acute hypercarbic respiratory failure. He was placed on non-invasive positive pressure ventilation. The next day he was alert. Manual muscle testing revealed that his face, neck and limb muscle strength were normal. He could walk, and Gowers' sign was not observed. Computed tomography showed atrophy of the paravertebral, abdominal wall and diaphragm crura muscles, without apparent limb muscle involvement. Pompe's disease was diagnosed based on the results of biochemical and genetic tests for acid alpha-glucosidase.

Palmitic acid induces interleukin-1ß secretion via NLRP3 inflammasomes and inflammatory responses through ROS production in human placental cells.

Maternal obesity, a major risk factor for adverse pregnancy complications, results in inflammatory cytokine release in the placenta. Levels of free fatty acids are elevated in the plasma of obese human. These fatty acids include obesity-related palmitic acids, which is a major saturated fatty acid, that promotes inflammatory responses. Increasing evidence indicates that nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasomes mediate inflammatory responses induced by endogenous danger signals. We hypothesized that inflammatory responses associated with gestational obesity cause inflammation. To test this hypothesis, we investigated the effect of palmitic acid on the activation of NLRP3 inflammasomes and inflammatory responses in a human Sw.71 trophoblast cell line. Palmitic acid stimulated caspase-1 activation and markedly increased interleukin (IL)-1ß secretion in Sw.71 cells. Treatment with a caspase-1 inhibitor diminished palmitic acid-induced IL-1ß release. In addition, NLRP3 and caspase-1 genome editing using a CRISPR/Cas9 system in Sw.71 cells suppressed IL-1ß secretion, which was stimulated by palmitic acid. Moreover, palmitic acid stimulated caspase-3 activation and inflammatory cytokine secretion (e.g., IL-6 and IL-8). Palmitic acid-induced cytokine secretion were dependent on caspase-3 activation. In addition, palmitic acid-induced IL-1ß, IL-6, and IL-8 secretion was depended on reactive oxygen species (ROS) generation. In conclusion, palmitic acid caused activation of NLRP3 inflammasomes and inflammatory responses, inducing IL-1ß, IL-6, and IL-8 secretion, which is associated with ROS generation, in human Sw.71 placental cells. We suggest that obesity-related palmitic acid induces placental inflammation, resulting in association with pregnancy complications.

Intracerebral Hematoma Occurring During Warfarin Versus Non-Vitamin K Antagonist Oral Anticoagulant Therapy.

The neuroradiological findings and its outcomes of intracerebral hemorrhage (ICH) were compared between the non-vitamin K antagonist oral anticoagulant (NOAC) therapy and warfarin therapy. In the latest 3 years, 13 cases of nonvalvular atrial fibrillation on NOAC therapy were admitted for ICH. For comparison, 65 age- and gender-comparable patients with ICH on warfarin therapy were recruited. Three NOACs had been prescribed: dabigatran (n = 4), rivaroxaban (n = 2), and apixaban (n = 7). The average ages were 76 ± 9 and 78 ± 8 years in the warfarin (n = 65) and NOAC groups (n = 13), respectively. There was no difference in the clinical features, including the CHADS2 score or HAS-BLED score: 2.62 ± 1.31 versus 2.62 ± 1.33, or 1.09 ± 0.43 versus 1.00 ± 0.41, for the warfarin and NOAC groups, respectively. The volume of ICH <30 ml was found in 84.6% of the patients on NOACs, but it was found in 53.8% of the patients on warfarin (p = 0.0106). The expansion of hematoma was limited to 7 patients (10.8%) of the warfarin group. A lower hospital mortality and better modified Rankin Scale were observed in the NOAC group than in the warfarin group: 1 (7.7%) versus 27 (41.5%; p = 0.0105) and 3.2 ± 1.4 versus 4.5 ± 1.6 (p = 0.0057), respectively. In conclusion, ICH on NOAC therapy had smaller volume of hematoma with reduced rate of expansion and decreased mortality compared with its occurrence on warfarin.

Long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome receiving adjunctive rufinamide therapy: An open-label study following a randomized clinical trial.

PURPOSE: To evaluate the long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome (LGS) receiving adjunctive rufinamide therapy. SUBJECTS AND METHODS: We conducted an open-label extension study following a 12-week multicenter, randomized, double-blind, placebo-controlled study of adjunctive rufinamide therapy in Japanese patients with LGS. Fifty-four patients participated in the extension study. Seizure frequency was evaluated until 52 weeks after the start of the extension study. Adverse events (AEs) were evaluated throughout both studies. KEY FINDINGS: Of the 54 patients, 41 (75.9%) completed the extension study. The median duration of exposure to rufinamide was 818.0 days in all 54 patients, and 38 patients (70.4%) received rufinamide for 2 years or more. The median percent change in the frequency of tonic-atonic seizures relative to the frequency at the start of the double-blind study was -39.3% (12 weeks), -40.6% (24 weeks), -46.8% (32 weeks), -47.6% (40 weeks), and -36.1% (52 weeks). Reduction of total seizure frequency was also maintained until 52 weeks. Frequent treatment-related AEs were somnolence (20.4%), decreased appetite (16.7%), transient seizure aggravation including status epilepticus (13.0%), vomiting (11.1%), and constipation (11.1%). Adverse events were mild or moderate, except for transient seizure aggravation in three patients. Adverse events resulting in discontinuation of rufinamide were decreased appetite, drug eruption, and worsening of underlying autism. When clinically notable weight loss was defined as a decrease ≥ 7% relative to baseline, 22 patients (40.7%) experienced weight loss at least once during long-term observation, although weight loss was reported as an AE in only three patients. SIGNIFICANCE: This study demonstrated a long-term benefit of rufinamide as adjunctive therapy for Japanese patients with LGS. Exacerbation of seizures and decreased appetite/weight loss should be monitored carefully.

Rufinamide as an adjunctive therapy for Lennox-Gastaut syndrome: a randomized double-blind placebo-controlled trial in Japan.

PURPOSE: To evaluate the efficacy, safety, and pharmacokinetics of rufinamide as an adjunctive therapy for patients with Lennox-Gastaut syndrome (LGS) in a randomized, double-blind, placebo-controlled trial. METHODS: We conducted a multicenter clinical trial with a 4-week baseline, a 2-week titration, a 10-week maintenance, and either a follow-up visit or entry into an open-label extension. Patients with LGS (4 to 30 years old) taking between one and three antiepileptic drugs were recruited. After the baseline period, patients were randomly assigned to rufinamide or placebo. The primary efficacy variable was the percent change in the tonic-atonic seizure frequency per 28 days. KEY FINDINGS: Of the 59 patients, 29 were randomized to the rufinamide group and 30 to the placebo group. The frequency of epileptic seizures was significantly decreased in the rufinamide group than in the placebo group; the median percent change in frequency of tonic-atonic seizures was -24.2% and -3.3%, respectively, (p=0.003) and that of total seizures was -32.9% and -3.1%, respectively (p<0.001). Subgroup analyses indicated that the efficacy of rufinamide was consistent independent of clinical background characteristics. The common treatment-related adverse events in the rufinamide group were decreased appetite (17.2%), somnolence (17.2%), and vomiting (13.8%). Transient seizure aggravations were observed in 13 (22.0%) of the 59 patients, though a causal relationship with rufinamide was suspected in only one patient. All adverse events were mild to moderate in severity. The mean plasma concentration of rufinamide between 1 and 9 within 12h after administration was 17.2 µg/mL. SIGNIFICANCE: The present results showed a favorable risk-benefit profile for rufinamide as an adjunctive therapy for patients with LGS.

Clinical and cardiac features of patients with subarachnoid haemorrhage presenting with out-of-hospital cardiac arrest.

BACKGROUND: Subarachnoid haemorrhage (SAH) is known as one of the aetiologies of out-of-hospital cardiac arrest (OHCA). However, the mechanisms of circulatory collapse in these patients have remained unclear. METHODS AND RESULTS: We examined 244 consecutive OHCA patients transferred to our emergency department. Head computed tomography was performed on all patients and revealed the existence of SAH in 14 patients (5.9%, 10 females). Among these, sudden collapse was witnessed in 7 patients (50%). On their initial cardiac rhythm, all 14 patients showed asystole or pulseless electrical activity, but no ventricular fibrillation (VF). Return of spontaneous circulation (ROSC) was obtained in 10 of the 14 patients (14.9% of all ROSC patients) although all resuscitated patients died later. The ROSC rate in patients with SAH (71%) was significantly higher than that of patients with either other types of intracranial haemorrhage (25%, n=2/8) or presumed cardiovascular aetiologies (22%, n=23/101) (p<0.01). On electrocardiograms, ST-T abnormalities and/or QT prolongation were found in all 10 resuscitated patients. Despite their electrocardiographic abnormalities, only 3 patients showed echocardiographic abnormalities. CONCLUSIONS: The frequency of SAH in patients with all causes of OHCA was about 6%, and in resuscitated patients was about 15%. The initial cardiac rhythm revealed no VF even though half had a witnessed arrest. A high ROSC rate was observed in patients with SAH, although none survived to hospital discharge.