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Background: We previously reported that gastrin induces expression of CXC chemokines through activation of nuclear factor κB (NFκB) in gastric epithelial cells that express gastrin receptor. Aims: To clarify gastrin [...]

Objective: The study was designed to evaluate the short-term efficacy and safety of lurasidone in the treatment of acute schizophrenia.Method: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of double-blind treatment with 40 mg of lurasidone, 120 mg of lurasidone, 15 mg of olanzapine (included to test for assay sensitivity), or placebo, dosed once daily. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (as the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (as the key secondary efficacy measure).Results: Treatment with both doses of lurasidone or with olanzapine was associated with significantly greater improvement at week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. There was no statistically significant difference in mean PANSS total or CGI-S change scores for the lurasidone groups compared with the olanzapine group. With responders defined as those with an improvement of at least 20% on the PANSS, endpoint responder rates were significant compared with placebo for olanzapine only. The incidence of akathisia was higher with 120 mg of lurasidone (22.9%) than with 40 mg of lurasidone (11.8%), olanzapine (7.4%), or placebo (0.9%). The proportion of patients experiencing ≥ 7% weight gain was 5.9% for the lurasidone groups combined, 34.4% for the olanzapine group, and 7.0% for the placebo group.Conclusions: Lurasidone was an effective treatment for patients with acute schizophrenia. Safety assessments indicated a higher frequency of adverse events associated with 120 mg/day of lurasidone compared with 40 mg/day. [ABSTRACT FROM AUTHOR]

We previously reported that treatment with 160mg/d of lurasidone improved cognitive performance in a manner superior to placebo, quetiapine XR 600mg/d, and lurasidone 80mg/d, based on a 6-week randomized trial of patients with an acute exacerbation of schizophrenia. The objective of this post-hoc analysis was to explore the cognitive and functional performance of patients whose final doses of lurasidone were 40/80mg/d, 120mg/d, and 160mg/d compared to quetiapine XR 200-800mg/d (QXR) during a 6-month, double-blind continuation study that followed a short-term trial. Subjects who received final doses of lurasidone 120mg/d (n=77) and 160mg/d (n=49) showed significantly greater improvement in overall cognitive performance compared to QXR (n=85) at week 32 (month 6 of the extension study), while those on last doses of 40/80mg/d (n=25) showed a trend towards significance at week 32. Mean changes in neurocognitive composite z-score from pre-treatment baseline were significant for the 3 lurasidone final dose groups at both weeks 19 and 32, with composite change scores of z=1.53, z=1.43, and z=1.34 for the lurasidone 40/80mg/d, 120mg/d, and 160mg/d, respectively, at week 32. In contrast, the composite change score was not statistically significant in the overall quetiapine group (z=0.46), with none of the individual quetiapine doses showing any significant improvement. Functional capacity scores improved in all treatment groups. Our findings indicate improved cognitive performance in patients treated with each of the flexible doses of lurasidone 40-160mg/d, compared to quetiapine XR 200-800mg/d. All doses of lurasidone were superior to all doses of quetiapine for cognitive performance., (Copyright © 2015. Published by Elsevier B.V.)

There is concern that radiocesium deposited in the environment after the accident at the Fukushima Daiichi Nuclear Power Plant (FDNPP) in March 2011 will migrate to paddy fields through hydrological pathways and cause serious and long-lasting damage to the agricultural activities. This study was conducted in the Towa region of Nihonmatsu in the northern part of Fukushima Prefecture, Japan, (1) to quantify (137)Cs in stream water used to irrigate paddy fields by separating the dissolved and particulate components in water samples and then fractionating the particulate components bonded in different ways using a sequential extraction procedure, and (2) to determine the amounts of radiocesium newly added to paddy fields in irrigation water relative to the amounts of radiocesium already present in the fields from the deposition of atmospheric fallout immediately after the FDNPP accident. Three catchments were studied, and the (137)Cs activity concentrations in stream water samples were 79-198 mBq L(-1) under stable runoff conditions and 702-13,400 Bq L(-1) under storm runoff conditions. The residual fraction (F4, considered to be non-bioavailable) was dominant, accounting for 59.5-82.6% of the total (137)Cs activity under stable runoff conditions and 69.4-95.1% under storm runoff conditions. The (137)Cs newly added to paddy fields in irrigation water only contributed 0.03-0.05% of the amount already present in the soil (201-348 kBq m(-2)). This indicates that the (137)Cs inflow load in irrigation water is negligible compared with that already in the soil. However, the contribution from the potentially bioavailable fractions (F1+F2+F3) was one order of magnitude larger, accounting for 0.20-0.59%. The increase in the dissolved and soluble radiocesium fraction (F1) was especially large (3.0% to infinity), suggesting that radiocesium migration in irrigation water is increasing the accumulation of radiocesium in rice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Rationale: There is an unmet need in the treatment of schizophrenia for effective medications with fewer adverse effects., Objective: This study aims to evaluate the efficacy and safety of lurasidone, an atypical antipsychotic, for the treatment of schizophrenia., Methods: Patients with an acute exacerbation of schizophrenia were randomized to 6 weeks of double-blind treatment with once-daily, fixed-dose lurasidone 40 mg (N = 50), lurasidone 120 mg (N = 49), or placebo (N = 50). The primary efficacy measure was mean change from baseline to day 42 (last observation carried forward) in the Brief Psychiatric Rating Scale derived (BPRSd) from the Positive and Negative Syndrome Scale (PANSS)., Results: Mean change in BPRSd was significantly greater in patients receiving lurasidone 40 and 120 mg/day versus placebo (-9.4 and -11.0 versus -3.8; p = 0.018 and 0.004, respectively). Treatment with lurasidone 120 mg/day was superior to placebo across all secondary measures, including PANSS total (p = 0.009), PANSS positive (p = 0.005), PANSS negative (p = 0.011), and PANSS general psychopathology (p = 0.023) subscales and Clinical Global Impression of Severity (CGI-S; p = 0.001). Treatment with lurasidone 40 mg/day was superior to placebo on the PANSS positive subscale (p = 0.018) and CGI-S (p = 0.002). The most common adverse events for patients receiving lurasidone were nausea (16.2 versus 4.0 % for placebo) and sedation (16.2 versus 10.0 % for placebo). Minimal changes in weight, cholesterol, triglyceride, and glucose levels were observed., Conclusions: In this study, which was limited by a relatively high discontinuation rate, lurasidone provided effective treatment for patients with acute exacerbation of chronic schizophrenia and had minimal effects on weight and metabolic parameters.

Background: Lurasidone is a new atypical antipsychotic agent with high affinity for D(2), 5-HT(2A) and 5-HT(7) receptors. The current study evaluated the safety and efficacy of lurasidone and ziprasidone in stable outpatients diagnosed with schizophrenia or schizoaffective disorder., Methods: Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder that was chronic (≥6 months duration) and stable were randomized to 21 days of double-blind treatment with a fixed dose of lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). Changes from baseline in efficacy measures were evaluated using mixed model for repeated measures (MMRM) analyses., Results: The proportion of patients who discontinued from the study was similar for lurasidone and ziprasidone (32.5% vs. 30.7%); the proportion who discontinued due to adverse events was similar (10.4% vs. 11.1%). Treatment with lurasidone and ziprasidone was associated with a small endpoint reduction in median weight (-0.65 kg vs. -0.35 kg) and median total cholesterol (-6.4 vs. -4.4 mg/dL); no endpoint change was observed in median triglycerides (0.0 vs. 0.0 mg/dL). There were no clinically significant changes in other laboratory or ECG parameters. Improvement was observed on an MMRM analysis of the PANSS total score for lurasidone and ziprasidone at Week 1 (-4.1 vs. -1.6; P=0.020), Week 2, (-6.1 vs. -3.6; P=0.074), and Week 3 (-6.3 vs. -4.5; P=0.229)., Conclusion: In this double-blind, fixed-dose comparison of lurasidone 120 mg and ziprasidone 160 mg, treatment with lurasidone was well-tolerated and safe, and was not associated with clinically significant changes from baseline in weight, metabolic parameters, or QTc interval. Study limitations include the relatively short trial duration and lack of placebo control., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Improving cognitive functioning in people with schizophrenia is a major treatment goal. In addition, interview-based measures have been developed to supplement performance-based assessments. However, few data are available regarding whether interview-based measures are sensitive to treatment-related changes., Methods: Adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomized to 21 days of double-blind treatment with lurasidone 120 mg once daily (N=150) or ziprasidone 80 mg BID (N=151). A similar proportion of patients completed the study on lurasidone (67.5%) and ziprasidone (69.3%). Study participants were assessed with the majority of the tests from the MATRICS Consensus Cognitive Battery (MCCB) and an interview-based assessment of cognitive functioning, the Schizophrenia Cognition Rating Scale (SCoRS). SCoRS ratings were based on the interviewer's best judgment, after interviews with the patient and a caregiver when available. The study was conducted from April 2006 to January 2007., Results: There were no between-group treatment differences in performance on the MCCB or the SCoRS ratings. Lurasidone patients demonstrated significant within group-improvement from baseline on the MCCB composite score (p=0.026) and on the SCoRS (p<0.001), but ziprasidone patients did not improve on either the MCCB composite (p=0.254) or the SCoRS (p=0.185). At endpoint there was a statistical trend (p=0.058) for lurasidone to demonstrate greater improvement from baseline in SCoRS ratings. Improvements in interview-based aspects of cognition were not related to MCCB test changes, and had minimal correlations with changes in symptoms., Conclusions: These data suggest that interview-based cognitive measures such as the SCoRS may be sensitive to changes after 3weeks of treatment in patients with schizophrenia. Lurasidone is being assessed further in ongoing clinical trials with additional outcome measures., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Lurasidone [(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D(2), 5-hydroxytryptamine 2A (5-HT(2A)), 5-HT(7), 5-HT(1A), and noradrenaline alpha(2C) receptors. Affinity for noradrenaline alpha(1), alpha(2A), and 5-HT(2C) receptors was weak, whereas affinity for histamine H(1) and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D(2) and 5-HT(7) receptors and as a partial agonist at the 5-HT(1A) receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-alpha(1)-noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant- or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects.

Objective: Lurasidone is a novel psychotropic agent with high affinity for D(2) and 5-HT(2A) receptors, as well as for receptors implicated in the enhancement of cognition and mood and the reduction of negative symptoms (5-HT(7), 5-HT(1A), and alpha(2c)). The objective of the study was to evaluate the safety and efficacy of lurasidone in patients hospitalized for an acute exacerbation of DSM-IV-defined schizophrenia., Method: Patients were randomly assigned to 6 weeks of double-blind treatment with a fixed dose of lurasidone 80 mg (N = 90, 75.6% male, mean age = 39.7 years, mean baseline score on the Brief Psychiatric Rating Scale derived from the Positive and Negative Syndrome Scale [BPRSd] = 55.1) or placebo (N = 90, 77.8% male, mean age = 41.9 years, mean BPRSd score = 56.1). The primary efficacy measure was the BPRSd. The study was conducted from May to December 2004., Results: At day 42, last-observation-carried-forward endpoint, treatment with lurasidone was associated with significant improvement compared to placebo on the BPRSd (least squares mean +/- SE = -8.9 +/- 1.3 vs. -4.2 +/- 1.4; p = .012), as well as on all secondary efficacy measures, including the PANSS total score (-14.1 +/- 2.1 vs. -5.5 +/- 2.2; p = .004) and the PANSS positive (-4.3 +/- 0.7 vs. -1.7 +/- 0.7; p = .006), negative (-2.9 +/- 0.5 vs. -1.3 +/- 0.5; p = .025), and general psychopathology (-7.0 +/- 1.1 vs. -2.7 +/- 1.2; p = .0061) subscales. Significant improvement was seen as early as day 3, based on BPRSd, PANSS, and Clinical Global Impressions-Severity of Illness assessments. Treatment with lurasidone was generally well tolerated and was not associated with adverse changes in metabolic or electrocardiogram parameters. There were no clinically significant differences between lurasidone and placebo in objective measures of extrapyramidal symptoms., Conclusions: The results of this study suggest that the novel psychotropic agent lurasidone is a safe and effective treatment for patients with an acute exacerbation of schizophrenia., Trial Registration: (ClinicalTrials.gov) Identifier: NCT00088634., (Copyright 2009 Physicians Postgraduate Press, Inc.)

Background: Hypereosinophilia commonly reflects an allergic, infectious, or neoplastic disease, and is a rare complication during pregnancy., Case: A 27-year-old pregnant woman was referred to our hospital due to dyspnea at 10 weeks' gestation. Ultrasound examination showed the presence of pericardial effusion, pleural effusion, and ascites. Fluid transfusion, diuretic administration, and oxygen supplementation gradually improved the symptoms. Thereafter, the blood eosinophil count increased acutely and the fetus died. Following cessation of pregnancy the blood eosinophil count gradually decreased. Laboratory examinations did not assist the diagnosis of eosinophilia., Conclusion: This is the first case of hypereosinophilia associated with the life-threatening hyperpermeability symptoms, i.e., pericardial effusion, pleural effusion, and ascites, during early pregnancy., (2006 S. Karger AG, Basel)

Epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. In the experiments described here using AGS gastric cancer cells, SN38 (the active metabolite of CPT-11) induced tyrosine phosphorylation of EGFR within 5 min, and this was followed by the induction of transcripts and/or proteins of heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-alpha, and interlukin-8 (IL-8). SN38 also activates nuclear factor-kappaB and activator protein-1, both of which are critical for the transcription of the IL-8 gene. However, the blocking of EGFR activation by gefitinib (Iressa, ZD1839), an EGFR-TKI (tyrosine kinase inhibitor), abrogates all the above reactions. The SN38-triggered mechanisms include the generation of reactive oxygen species (ROS) and the activation of protein kinase C (PKC), followed by metalloproteinase activation and the sequential ectodomain shedding of EGFR ligands. These findings suggest that EGF signaling is enhanced by CPT-11 and point to the potential benefit of the use of a combination of CPT-11 with gefitinib in the treatment of certain gastric cancers.