腎機能障害時のリネゾリドおよびその主要代謝物の薬物動態学的パラメータの解析

金沢大学附属病院本研究は,腎機能障害時のリネゾリド(LZD)およびその主要代謝物の薬物動態学的パラメータを明らかにすることを目的として実施した.MRSA感染症(疑い例を含む)と診断され,LZD1200mg/dayを投与された症例のうち同意の得られた症例についてLZDおよびその主要代謝物(MetA)の血中濃度および定常状態における尿中排泄率をLiquid Chromatography/Mass Spectrometryを用いて測定した.また電子カルテにより臨床検査値を調査した。なお腎機能障害の程度は「CKD診療ガイド」にしたがって分類し,急性腎不全症例は含まない.平成24年度までに完了した症例について中間解析をおこなったところ,eGFR区分(mL/min/1.73m^2)でG1,G2,G3,G4にあたる症例数はそれぞれ7,6,1,1例であった.LZDおよびMetAの平均トラフ濃度,投与期間中の最高血中濃度はともに腎機能障害が高度になるほど上昇する傾向が見られたLZDおよびMetAの尿中排泄率については腎機能の程度による一定の傾向は見られなかった.血小板減少率は腎機能低下例で上昇する傾向が見られ,LZDあるいはMetAの血中濃度との関連が示唆された.血小板減少の程度はGrade1～2であり,投与中止により全例で回復した.本研究の症例中に,抗結核薬のリファンピシンを併用された症例が複数存在したが,いずれもリネゾリドの血中濃度の有意な低下がみられた.この現象は2009年の添付文書の改訂でも指摘されていることから,本年度,ラットモデルを用いて予備的な検討も開始した.本研究は,LZDおよび主要代謝物の血中濃度をモニタリングすることにより有効治療域の維持や副作用回避のために有用であり,LZDの最適治療に貢献できるものと考えられる.研究課題/領域番号:24926002, 研究期間(年度):201

Comprehensive Prospective Analysis of the Factors Contributing to Aspiration Pneumonia Following Endoscopic Submucosal Dissection in Patients with Early Gastric Neoplasms

Endoscopic submucosal dissection (ESD) has become the first-line treatment for early gastric neoplasms; however, a subset of patients treated by this method develop aspiration pneumonia. We conducted a comprehensive prospective analysis of the factors contributing to post-ESD aspiration pneumonia in early gastric neoplasms in this study, with special focus on whether pre-treatment oral care can prevent aspiration pneumonia. Sixty-one patients who underwent ESD for gastric neoplasms were randomly assigned to the oral care or control groups. ESD was performed under deep sedation. Of 60 patients whose data were available for analysis, 5 (8.3%) experienced pneumonia confirmed either by chest radiography or computed tomography. Although no difference in the rate of pneumonia was found between the control and oral care groups, the post-oral care bacteria count was significantly higher in the saliva of patients who developed pneumonia compared to those without pneumonia. In addition, the presence of vascular brain diseases and the dose of meperidine were also significantly associated with the occurrence of pneumonia. These results suggest that the number of oral bacteria as well as pre-existing vascular brain diseases and high-dose narcotics can affect the incidence of post-ESD pneumonia

Epstein-Barr Virus-Positive Adrenal Diffuse Large B-Cell Lymphoma after Treatment for Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) can be complicated by Epstein-Barr virus (EBV)-positive B-cell lymphoma. B-cell lymphoma may develop simultaneously at the time of AITL diagnosis or after treatment for AITL. EBV-associated B-cell lymphoma can occur in nodal and extranodal sites. We report a case of EBV-positive diffuse large B-cell lymphoma (DLBCL) of the left adrenal gland that developed after treatment for AITL.The patient presented with systemic lymphadenopathy and biopsy of one lymph node showed AITL. A complete response (CR) was achieved after initial chemotherapy for AITL, but 9 months later the left adrenal gland was enlarged. The diagnosis of EBV-positive DLBCL was made based on the histopathological findings of the left adrenal gland biopsy. Thus, EBV-positive DLBCL developed after AITL CR was achieved. Multi-drug chemotherapy combined with rituximab was administered for adrenal DLBCL, but only a partial response was achieved. We confirmed that EBV-positive B-cell lymphoma developed after treatment for AITL. An adrenal primary is rare, and this is only the second case of EBV-positive B-cell lymphoma to be reported after treatment for AITL. Clinicians should keep in mind that when nodal and extranodal lesions are seen after AITL treatment, another biopsy should be performed for the accurate determination of whether these lesions indicate AITL relapse or new-onset EBV-positive B-cell lymphoma

Longitudinal characteristics of insight and clinical factors in patients with schizophrenia

Abstract Aims Schizophrenia is a psychiatric disorder presenting a lack of insight. Although insight changes over time, longitudinal studies of insight in schizophrenia are scarce. Furthermore, most previous studies on insight and intelligence have not measured full‐scale IQ and have not been able to examine the relationship between detailed dimensions of cognitive function and insight. In this study, we assessed insight at two time points and assessed dimensions of cognitive function. Methods A total of 163 patients with schizophrenia participated in the study. We evaluated insight at two time points to understand the patterns of change and examined the association between insight and clinical variables. Additionally, we examined the relationship between the dimensions of cognitive function and insight. Results The patients were divided into three groups based on their change in insight over time: stable at a low level of insight (poor insight), stable at a high level of insight (good insight), and changed in insight over time (unstable insight). Those in the poor insight group had lower general intelligence scores than those in the good insight and unstable insight groups. Regarding cognitive function, verbal comprehension was associated with the level of insight at baseline and follow‐up. Regarding psychiatric symptoms, the poor insight group exhibited more severe symptoms than the other two groups, especially regarding positive symptoms. Conclusions Our classification of patients based on changes in insight revealed that poor insight patients had impaired cognitive function, especially verbal comprehension, and more severe positive symptoms than good insight or unstable insight patients

Longitudinal reduction in brain volume in patients with schizophrenia and its association with cognitive function

Abstract Establishing a brain biomarker for schizophrenia is strongly desirable not only to support diagnosis by psychiatrists but also to help track the progressive changes in the brain over the course of the illness. A brain morphological signature of schizophrenia was reported in a recent study and is defined by clusters of brain regions with reduced volume in schizophrenia patients compared to healthy individuals. This signature was proven to be effective at differentiating patients with schizophrenia from healthy individuals, suggesting that it is a good candidate brain biomarker of schizophrenia. However, the longitudinal characteristics of this signature have remained unclear. In this study, we examined whether these changes occurred over time and whether they were associated with clinical outcomes. We found a significant change in the brain morphological signature in schizophrenia patients with more brain volume loss than the natural, age‐related reduction in healthy individuals, suggesting that this change can capture a progressive morphological change in the brain. We further found a significant association between changes in the brain morphological signature and changes in the full‐scale intelligence quotient (IQ). The patients with IQ improvement showed preserved brain morphological signatures, whereas the patients without IQ improvement showed progressive changes in the brain morphological signature, suggesting a link between potential recovery of intellectual abilities and the speed of brain pathology progression. We conclude that the brain morphological signature is a brain biomarker that can be used to evaluate progressive changes in the brain that are associated with cognitive impairment due to schizophrenia

Laparoscopic distal gastrectomy for gastric cancer patient with intestinal malrotation: report of a case

Abstract Background Intestinal malrotation, which arises from incomplete rotation of the embryonic midgut, is one of the congenital anomalies usually diagnosed in infancy. On the other hand, intestinal malrotation detected in asymptomatic adults is very rare. It is frequently diagnosed incidentally during abdominal surgery. We report a case of asymptomatic intestinal malrotation diagnosed during laparoscopic distal gastrectomy for gastric cancer. Case presentation A 59-year-old female was diagnosed with early-stage gastric cancer during health screening and admitted to our hospital for radical surgical treatment. Physical examinations and blood tests revealed nothing of note. The type 0-IIc gastric cancer was located in the posterior wall of the mid-body of the stomach. The histological type was poorly differentiated adenocarcinoma. Esophagogastroduodenoscopy and computed tomography (CT) suggested that the depth of tumor invasion was the submucosal layer without regional lymph node swelling. The clinical stage according to the TNM 7th edition was cT1b N0 M0, cStage I. Laparoscopic distal gastrectomy with D1+ lymph node dissection and Billroth-I method reconstruction was planned. During the infrapyloric lymph node dissection, a part of the pancreatic head showed unusual adherence to the first part of the duodenal wall. For safe and accurate lymphadenectomy while avoiding pancreatic injury, we deliberately focused on tracing the dissectible layer between the pancreatic parenchyma and fatty tissues including lymph nodes. Also, we changed the reconstruction procedure from Billroth-I to Roux-en-Y. After distal gastrostomy, we could not find the ligament of Treitz or jejunum on the left side below the transverse colon. Based on a review of the CT image, this patient was diagnosed with intestinal malrotation. Although the detection of malrotation during the operation was incidental, we could complete radical surgery and Roux-en-Y reconstruction safely. The type of malrotation was non-rotation (90°). She was discharged from our hospital without any complications. Conclusion We encountered a case of adult asymptomatic intestinal malrotation with gastric cancer. Even when encountering such a case during laparoscopic gastrectomy, reviewing CT images carefully to reconsider the anatomical anomalies, and tracing the dissectible layer accurately with adequate countertraction can facilitate safe and successful surgery

Effect of coadministration of rifampicin on the pharmacokinetics of linezolid: clinical and animal studies

Abstract Background Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown. Methods We conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine. Results Our clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2. Conclusions Therapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD. Trial registration UMIN, UMIN000004322. Registered 4 October 2010

Comprehensive Prospective Analysis of the Factors Contributing to Aspiration Pneumonia Following Endoscopic Submucosal Dissection in Patients with Early Gastric Neoplasms

ndoscopic submucosal dissection (ESD) has become the first-line treatment for early gastric neoplasms; however, a subset of patients treated by this method develop aspiration pneumonia. We conducted a comprehensive prospective analysis of the factors contributing to post-ESD aspiration pneumonia in early gastric neoplasms in this study, with special focus on whether pre-treatment oral care can prevent aspiration pneumonia. Sixty-one patients who underwent ESD for gastric neoplasms were randomly assigned to the oral care or control groups. ESD was performed under deep sedation. Of 60 patients whose data were available for analysis, 5 (8.3%) experienced pneumonia confirmed either by chest radiography or computed tomography. Although no difference in the rate of pneumonia was found between the control and oral care groups, the post-oral care bacteria count was significantly higher in the saliva of patients who developed pneumonia compared to those without pneumonia. In addition, the presence of vascular brain diseases and the dose of meperidine were also significantly associated with the occurrence of pneumonia. These results suggest that the number of oral bacteria as well as pre-existing vascular brain diseases and high-dose narcotics can affect the incidence of post-ESD pneumonia