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A requirement, which students must satisfy, for a diploma at the Showa University School of Pharmacy is the ability to "plan, practice, and assess pharmacotherapy". To continuously assess the ability of students to meet this requirement and to provide patients with proper pharmacotherapy during student clinical rotations, we formulated the "Rubric assessment for pharmacotherapy" and evaluated its usefulness in tutorial learning classes. Clinical pharmacy faculty members created the rubric based on the Subjective, Objective, Assessment, and Plan (SOAP) note guidelines of the university. Third- (2016) and fourth-year students (2017) were required to self-assess their SOAP notes to analyze six clinical cases using the rubric. The rubric consists of three domains: (1) Evaluation of patient condition, (2) Proposal of pharmacotherapy, and (3) Plan for an assessment of pharmacotherapy. The rubric comprises 31 subdomains and is evaluated according to four levels of performance. In this study, 978 rubric sheets that were used by students to evaluate their own SOAP notes were analyzed. We found that the students were able to continuously self-assess their performance using the rubric while continuously improving their achievement level (p

Recently, a clinical study using a Chronic Liver Disease Questionnaire (CLDQ) showed that ledipasvir/sofosbuvir (LDV/SOF)-treated patients' QOL was more favorable than that of IFN/ribavirin (RBV)-treated patients. However, no study has reported QOL assessment in clinical practice. In this study, we compared the QOL between patients treated with LDV/SOF and those treated with simeprevir (SMV)/peginterferon (Peg-IFN)/RBV to provide QOL information in clinical practice. The subjects were 169 patients with type I chronic hepatitis C or compensated cirrhosis C (Child-Pugh Grade A) who were treated with SMV/Peg-IFN/RBV or LDV/SOF in Hitachi General Hospital. The QOL was assessed ≥2 weeks after the start of administration using the Japanese version of the CLDQ (Kida et al., 2008 version). The total CLDQ score in the LDV/SOF group was significantly higher than in the SMV/Peg-IFN/RBV group (6.59 vs. 6.38, respectively, p=0.007). In particular, the scores for 4 domains (abdominal symptoms, systemic symptoms, activity, and emotional function) in the former were significantly higher than in the latter (p

OBJECTIVE: We investigated factors associated with a reduction in the quality of life and their OR of patients with chronic hepatitis C who underwent ledipasvir/sofosbuvir therapy. METHODS: The subjects were 141 outpatients who had undergone ledipasvir/sofosbuvir therapy under a diagnosis of genotype I chronic hepatitis C or Child-Pugh A compensated cirrhosis at Hitachi General Hospital. The patient background before ledipasvir/sofosbuvir therapy, laboratory data and the Chronic Liver Disease Questionnaire scores during ledipasvir/sofosbuvir therapy were investigated. The Chronic Liver Disease Questionnaire consists of 29 questions, and the mean value is calculated as the overall score through a 7-step assessment by patients. Using two divisions: a Chronic Liver Disease Questionnaire score of

Riluzole blocks persistent Na + current, inhibits generation of neuronal bursts and decreases glutamate-induced excitotoxicity. In previous studies of respiratory activity, riluzole suppressed inspiratory-related burst generation activity in rat slice or en bloc preparations. We examined riluzole’s effects on inspiratory burst generation and drug-induced seizure-like activity in newborn rat en bloc preparations. Medulla-spinal cord preparations from postnatal day 0–3 Wistar rats were isolated under deep isoflurane anesthesia and were superfused with artificial cerebrospinal fluid equilibrated with 95% O 2 and 5% CO 2 , pH 7.4, at 25–26 °C. Inspiratory activity was monitored from the fourth cervical ventral root. Seizure-like activity was induced by application of 20 μM DL- threo -β-benzyloxyasparatate (TBOA, a glutamate uptake blocker preferentially acting on astrocytes) or coadministration of GABA A antagonist bicuculline (10 μM) and glycine antagonist strychnine (10 μM). Pretreatment and co-application with 10 μM riluzole abolished the seizure-like burst activity induced by TBOA or bicuculline/strychnine. N -methyl- d -aspartic acid receptor antagonist MK801 (10 μM) also depressed this activity. Riluzole may attenuate excessive glutamate action involved in pathological hyperexcitability of motor neurons with no major effect on generation of respiratory activity. Riluzole at the optimal dose could be a potential treatment to protect drug-induced epileptic brain tissue from excitotoxic damage without inducing respiratory suppression.

Human organic anion transporter 2 (hOAT2[SLC22A7]) is a Na+-independent multispecific organic solutes (SLC) transporter. To date, several findings regarding the function and substrates of hOAT2[SLC22A7] have been reported; there are still limited data concerning the genetic variants of the hOAT2[SLC22A7] gene in Japanese, specifically, in patients with non-viral liver carcinoma (LC). In the present study, we isolated genomic DNA from a normal portion of liver cancer and screened comprehensively 88 coding single nucleotide polymorphisms (cSNPs) chosen from a database of SNPs (dbSNPs). We found genotype and allele frequencies for 1 synonymous SNP [rs2270860 (1324C > T, Ser425Ser)] to be statistically significant when compared with the SNP database ( http://www.ncbi.nlm.nih.gov/snp/ ). Our present findings suggest that, at least partly, within the entire sequence of coding region of the hOAT2[SLC22A7] gene, rs2270860 (1324C > T, Ser425Ser) might be useful as a biomarker for susceptibility for non-viral LC in Japanese.

In recent years, augmented renal clearance (ARC), in which renal function is excessively enhanced, has been reported, and its influence on β-lactam antibiotics has been investigated. In this study, we aimed to determine the optimum population pharmacokinetic model of meropenem in patients with sepsis with ARC, and evaluated dosing regimens based on renal function. Seventeen subjects (6 with ARC and 11 without) were enrolled in this study. Predicted meropenem concentrations were evaluated for bias and precision using the Bland–Altman method. To examine the dosing regimen, Monte Carlo simulation was performed to calculate the cumulative fraction of response (CFR). In patients with ARC, the bias (average of the predicted value and measured value residuals) of models constructed by Crandon et al. (2011), Roberts et al. (2009), and Jaruratanasirikul et al. (2015) were 5.96 μg/mL, 10.91 μg/mL, and 4.41 μg/mL, respectively. Following 2 g meropenem every 8 h (180 min infusion), CFR ≥ 90%, a criterion of success for empirical therapy, was achieved, even with creatinine clearance of 130–250 mL/min. For patients with sepsis and ARC, the model of Jaruratanasirikul et al. showed the highest degree of accuracy and precision and confirmed the efficacy of the meropenem dosing regimen in this patient population.

The aim was to characterise RQ-00201894, a novel non-macrolide motilin agonist, using human recombinant receptors and then investigate its ability to facilitate cholinergic activity in human stomach. A reporter gene assay assessed motilin receptor function. Selectivity of action was determined using a panel of different receptors, ion channels, transporters and enzymes. Cholinergically-mediated muscle contractions were evoked by electrical field stimulation (EFS) of human gastric antrum. The results showed that RQ-00201894, motilin and erythromycin acted as full motilin receptor agonists (EC50: 0.20, 0.11, 69 nM, respectively). In this function, RQ-00201894 had >90-fold selectivity of action over its ability to activate the human ghrelin receptor (EC50 19 nM) and greater selectivity over all other receptors/mechanisms tested. In human stomach RQ-00201894 0.1–30 μM concentration-dependently increased EFS-evoked contractions (up to 1209%; pEC50 6.0). At 0.1–10 μM this activity was usually prolonged. At higher concentrations (3–30 μM) RQ-00201894 also caused a short-lasting muscle contraction, temporally disconnected from the increase in EFS-evoked contractions. RQ-00201894 10 μM did not consistently affect submaximal contractions evoked by carbachol. In conclusion, RQ-00201894 potently and selectively activates the motilin receptor and causes long-lasting facilitation of cholinergic activity in human stomach, an activity thought to correlate with an ability to increase gastric emptying.

Continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) might differently affect iron metabolism and erythropoiesis in patients on hemodialysis (HD). This prospective study examined a cohort of patients on HD who had received either intravenous CERA every 2 or 4 weeks (N = 25) or DA once each week (N = 47). Blood was sampled before HD sessions on days 0, 2, 4, 7 and 14, and on days 0, 3, 5, 7 and 14 from patients who were injected with ESA at the beginning and end of the dialysis week, respectively. Changes in factors indicating erythropoiesis and biomarkers of iron metabolism were examined. Hemoglobin levels were maintained in the target range between 10.0 and 11.0 g/dL and ferritin levels at baseline and during the study period were similar between the DA and CERA groups. Levels of hepcidin 25 decreased from days 2-3 to day 5 and returned to the baseline at day 7 in the DA group, whereas those and transferrin saturation were serially suppressed from days 2-3 to day 14 in the CERA group. Levels of soluble transferrin receptor and reticulocyte counts were significantly elevated from days 4-5 to day 14 by CERA. Both DA and CERA stabilized erythropoiesis, but CERA might mobilize iron from body stores more effectively than DA in patients on HD.

Background Dapsone (4,4′-diaminodiphenylsulfone) has been widely used for the treatment of infections such as leprosy. Dapsone hypersensitivity syndrome (DHS) is a major side effect, developing in 0.5–3.6% of patients treated with dapsone, and its mortality rate is ∼10%. Recently, human leukocyte antigen (HLA)-B*13:01 was identified as a marker of susceptibility to DHS. Objectives To investigate why HLA-B*13:01 is responsible for DHS from a structural point of view. Methods First, we used homology modeling to derive the three-dimensional structures of HLA-B*13:01 (associated with DHS) and HLA-B*13:02 (not so associated despite strong sequence identity [99%] with HLA-B*13:01). Next, we used molecular docking, molecular dynamic simulations, and the molecular mechanics Poisson-Boltzman surface area method, to investigate the interactions of dapsone with HLA-B*13:01 and 13:02. Results We found a crucial structural difference between HLA-B*13:01 and 13:02 in the F-pocket of the antigen-binding site. As Trp95 in the α-domain of HLA-B*13:02 is replaced with the less bulky Ile95 in HLA-B*13:01, we found an additional well-defined sub-pocket within the antigen-binding site of HLA-B*13:01. All three representative docking poses of dapsone against the antigen-binding site of HLA-B*13:01 used this unique sub-pocket, indicating its suitability for binding dapsone. However, HLA-B*13:02 does not seem to possess a binding pocket suitable for binding dapsone. Finally, a binding free energy calculation combined with a molecular dynamics simulation and the molecular mechanics Poisson-Boltzman surface area method indicated that the binding affinity of dapsone for HLA-B*13:01 would be much greater than that for HLA-B*13:02. Conclusions Our computational results suggest that dapsone would fit within the structure of the antigen-recognition site of HLA-B*13:01. This may change the self-peptides that bind to HLA-B*13:01, explaining why HLA-B*13:01 is a marker of DHS susceptibility.

Community pharmacies in Japan have long been advocated as effective sources of nonprescription medicines and health-related advice. Consumers sometimes self-treat symptoms of minor illnesses without consulting a pharmacist because the benefits of such consultations are not adequately recognized. The aim of this study was to investigate the use and impact of pharmacist consultations before purchase of nonprescription laxatives. An online survey was conducted July 14-22, 2012 with 500 respondents (250 men, 250 women), ranging 20-60 years old. All participants had purchased nonprescription laxatives for constipation within the past year. Stratified analysis was used to compare responses in groups that had and had not consulted a pharmacist before purchase. Consulting a pharmacist appears to improve consumers' awareness and makes them more likely to use appropriate medication. Those who consulted a pharmacist were better able to identify side effects and take appropriate action than the group that did not consult the pharmacist. Those who consulted a pharmacist were also significantly more likely to say that they would consult a pharmacist in the future. These results indicate that it is important for consumers to be able to consult with pharmacists, to improve consumers' awareness of side effects and to self-medicate appropriately, and hence improve their quality of life. Pharmacists in community pharmacy could be more active in health promotion campaigns, such as drug safety, campaigns, to raise their public profile. Increased public awareness of what pharmacists in community pharmacy do will make it easier for patients to consult with them.

We formulated mianserin suppositories for the treatment of delirium and evaluated their pharmacokinetics by measuring plasma drug concentrations in dogs and healthy human volunteers. Mianserin suppositories were prepared by a melting technique using Tetramide® tablets and Witepsol H-15 as the suppository base. Pharmacokinetics of this 30-mg mianserin preparation were evaluated in three beagle dogs and three healthy adult males, in line with ethics committee approval. Plasma mianserin levels were determined using gas chromatography–mass spectrometry. In dogs, the maximum plasma mianserin concentration (Cmax) was 1.3 ± 0.4 ng/mL, the time to Cmax (tmax) was 5.5 ± 4.3 h, and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) was 18.9 ± 1.9 h・ng/mL. In humans, the Cmax was 14.6 ± 6.3 ng/mL, the tmax was 8 h, and the AUC0-24 was 266 ± 103 h・ng/mL. The current study characterized the pharmacokinetics of mianserin suppositories in dogs and humans. As compared to oral administration, the suppositories produced a lower Cmax and a delayed tmax, although AUC0-24 values were comparable. It will be necessary to identify an appropriate dose that produces an adequate plasma mianserin concentration for effective and safe clinical use. UMIN000013853 .

Previously, we reported a case of brainstem cavernous hemangioma showing false positive responses to electromyographic tracheal tube (EMG tube). We concluded that the cause was spontaneous respiration accompanied by vocal cord movement. We report a case of left vertebral artery aneurysm showing evoked potentials on bilateral electrodes by the left vagus nerve stimulation to EMG tube. An 82-year-old woman underwent clipping of a left unruptured vertebral artery-posterior inferior cerebellar artery aneurysm. General anesthesia was induced with remifentanil, propofol and suxamethonium, and was maintained with oxygen, air, remifentanil and propofol. We monitored somatosensory evoked potentials, motor evoked potentials, and electromyogram of the vocal cord. When the manipulation reached brainstem and the instrument touched the left vagus nerve, evoked potentials appeared on bilateral electrodes. EMG tube is equipped with two electrodes on both sides. We concluded that the left vagus nerve stimulation generated evoked potentials of the left laryngeal muscles, and they were simultaneously detected as potential difference between two electrodes on both sides. EMG tube is used to identify the vagus nerve. However, it is necessary to bear in mind that each vagus nerve stimulation inevitably generates evoked potentials on bilateral electrodes.

Within the secreted phospholipase A2 (sPLA2) family, group X sPLA2 (sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies using Pla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ω3 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2 (cPLA2α) protects from colitis by mobilizing ω6 arachidonic acid metabolites, including prostaglandin E2. Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizer in vivo, segregated mobilization of ω3 and ω6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization.

Background We aimed to identify associations between erythroferrone (ERFE), a regulator of hepcidin 25, and biomarkers of erythropoiesis and iron metabolism. We also aimed to determine the effects of erythropoiesis-stimulating agents (ESA), continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) on ERFE production in patients on hemodialysis (HD). Methods Blood samples were obtained from 59 patients before HD sessions on day 0 (baseline). Twenty patients who were injected with either CERA (N = 10) or DA (N = 10) at the end of the dialysis week (day 0), who had ferritin ≥ 100 ng/mL and/or transferrin saturation ≥ 20%, and hemoglobin > 9 g/dL were selected from among the 59 patients. Blood was sampled serially before HD sessions on days 3, 5, 7 from patients on DA and on the same days plus day 14 from those on CERA. Results Levels of ERFE correlated inversely with those of hepcidin 25 and ferritin, and positively with those of soluble transferrin receptor. The hepcidin 25: ERFE ratio and hepcidin 25 levels positively correlated with ferritin levels. Levels of ERFE significantly increased from day 3 of treatment with DA and CERA and decreased by days 7 and 14, respectively. Erythropoiesis-stimulating agents concomitantly decreased levels of hepcidin 25 as those of ERFE increased. Conclusion We identified a novel association between ESA and ERFE in patients on HD. Both DA and CERA increased levels of ERFE that regulated hepcidin 25 and led to iron mobilization from body stores during erythropoiesis.

Continuous erythropoietin receptor activator (CERA) and darbepoetin-α (DA) might differently affect iron metabolism and erythropoiesis in patients on hemodialysis (HD). This prospective study examined a cohort of patients on HD who had received either intravenous CERA every 2 or 4 weeks (N = 25) or DA once each week (N = 47). Blood was sampled before HD sessions on days 0, 2, 4, 7 and 14, and on days 0, 3, 5, 7 and 14 from patients who were injected with ESA at the beginning and end of the dialysis week, respectively. Changes in factors indicating erythropoiesis and biomarkers of iron metabolism were examined. Hemoglobin levels were maintained in the target range between 10.0 and 11.0 g/dL and ferritin levels at baseline and during the study period were similar between the DA and CERA groups. Levels of hepcidin 25 decreased from days 2-3 to day 5 and returned to the baseline at day 7 in the DA group, whereas those and transferrin saturation were serially suppressed from days 2-3 to day 14 in the CERA group. Levels of soluble transferrin receptor and reticulocyte counts were significantly elevated from days 4-5 to day 14 by CERA. Both DA and CERA stabilized erythropoiesis, but CERA might mobilize iron from body stores more effectively than DA in patients on HD.

Brainstem cavernous hemangioma is a complex lesion associated with hemorrhage and neurological deficit. The damage of the vagus nerve is a devastating surgical complication. Therefore, intraoperative anatomical and functional evaluation of this nerve is crucial. We used electromyographic tracheal tube (EMG tube)to monitor electromyogram from the vocal cord. We report a case of brainstem cavernous hemangioma showing false positive response to EMG tube. A 66-year-old woman underwent resection of cavernous hemangioma in the pontine tegmentum. General anesthesia was induced with remifentanl, propofol, and suxamethonium, and was maintained with oxygen, air, remifentanil and propofol. We monitored somatosensory evoked potentials, motor evoked potentials, and electromyogram of the vocal cord, orbicularis oculi, orbicularis oris and lateral rectus. When the manipulation reached brainstem, slight spontaneous respiration (SR) appeared on capnogram. Simultaneously, an alarm rang. Exposed nerves were stimulated electrically. However, there was no electromyographic response on the vocal cord. We concluded that the cause was SR accompanied by vocal cord movement. Remifentanil was increased up to 1 μg x kg(-1) x min(-1). SR did not disappear. Remifentanil was not increased any more without hindering the operation. Her operative course was uneventful. It is necessary to pay attention to false positive response caused by SR with EMG tube.

Lung inflammation is a major adverse effect of therapy with the antitumor drug bleomycin (BLM). Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+)-permeable channel that is activated by oxidative stress through the production of ADP-ribose. We herein investigated whether TRPM2 channels contributed to BLM-induced lung inflammation. The intratracheal instillation of BLM into wild-type (WT) mice increased the number of polymorphonuclear leukocytes (PMNs) and inflammatory cytokine levels in the lung. Increases in inflammatory markers in WT mice were markedly reduced in trpm2 knockout (KO) mice, which demonstrated that the activation of TRPM2 channels was involved in BLM-induced lung inflammation. The expression of TRPM2 mRNA was observed in alveolar macrophages, alveolar epithelial cells, and lung fibroblasts. Actually, TRPM2 protein was expressed in lung tissues. Of these, TRPM2 channels in epithelial cells were activated by the addition of H2O2 following a BLM pretreatment, resulting in the secretion of macrophage inflammatory protein-2 (MIP-2). The H2O2-induced activation of TRPM2 by the BLM pretreatment was blocked by the poly(ADP-ribose) polymerase (PARP) inhibitors PJ34 and 3-aminobenzamide. The accumulation of poly(ADP-ribose) in the nucleus, a marker for ADP-ribose production, was strongly induced by H2O2 following the BLM pretreatment. Furthermore, administration of PRAP inhibitors into WT mice markedly reduced recruitment of inflammatory cells and MIP-2 secretion induced by BLM instillation. These results suggest that the induction of MIP-2 secretion through the activation of TRPM2 channels in alveolar epithelial cells is an important mechanism in BLM-induced lung inflammation, and the TRPM2 activation is likely to be mediated by ADP-ribose production via PARP pathway. TRPM2 channels may be new therapeutic target for BLM-induced lung inflammation.

Few reports exist on anesthetic management for foramen magnum decompression (FMD) of Chiari malformation type I (CM I) complicated with syringomyelia. In two such cases we monitored somatosensory evoked potentials (SEP). Case 1 : A 40-year-old woman presented with occipital headache and nuchal pain for 2 months; numbness and muscular weakness of bilateral upper limbs for a month. Magnetic resonance imaging (MRI) scan showed CM I complicated with syringomyelia. Case 2 : A 32-year-old man presented with numbness and muscular weakness of bilateral upper limbs for 5 months; numbness and muscular weakness of lower limbs for 2 months. MRI scan showed CM I complicated with syringomyelia. They underwent FMD. In both cases, general anesthesia was induced with remifentanil, propofol and rocuronium, and was maintained with oxygen, air, remifentanil and propofol. Moreover, we monitored SEP. Their operative courses were uneventful. In case 1, SEP latency became shorter after FMD. Her preoperative neurologic symptoms disappeared on first postoperative day. In contrast there was no change of SEP latency after FMD in case 2. His preoperative neurologic symptoms showed no change on fifth postoperative day. SEP monitoring may be a useful index for prediction of early recovery of neurologic symptoms after FMD.

Previously, we reported that pre- and postoperative measurement of the neck circumference might be an easy and useful measure for prediction of postoperative airway obstruction in shoulder arthroscopy. However, it is suggested that airway pressure to cause a cuff leak around the tracheal tube in a cuff deflated condition (cuff leak pressure) is a predictor of postoperative airway obstruction. We studied a correlation between the neck circumference and the cuff leak pressure.Forty patients undergoing shoulder arthroscopy in the beach-chair position were included in this study. There were 30 male and 10 female patients. All patients' neck circumference and cuff leak pressure were compared pre- and postoperatively and with each other.There was a strong correlation between the increase of neck circumference and the increase of cuff leak pressure.The rate of increase in neck circumference shows the swelling of external tissue of the neck. However, it may not reflect the swelling of the internal tissue containing pharynx, larynx and retrotracheal space. Alternatively, pre- and postoperative measurement of the cuff leak pressure could be a more substantial predictor of postoperative airway obstruction than the rate of increase in neck circumference.