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Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials. Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load. Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log10 copies/mL (p <0·05) and -0·82 log10 in the placebo group (P <0·05). Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42.

[Background]Heparin-induced thrombocytopenia type II (HIT II) is a rare, immune-mediated complication of heparin therapy and can cause life-threatening thromboembolism. However, perioperative anticoagulation therapy for patients with a complication of HIT II has not been established. [Case presentation]A 6-year-old boy with tetralogy of Fallot underwent radical intracardiac repair with administration of argatroban at 1 year old due to positive HIT antibody. Reoperation was scheduled for pulmonary valve insufficiency, using argatroban and nafamostat mesilate as anticoagulants. Argatroban has a long onset time and the activated coagulation time (ACT) requires 7–26 h to return to the preadministration level, making hemorrhage control difficult, while half-life of nafamostat mesilate is shorter than that of argatroban. Celite ACT reflects the effects of both argatroban and nafamostat mesilate, but kaolin ACT reflects only the effect of argatroban. Due to the early termination of argatroban administration based on Celite and kaolin ACTs, ACT recovered to ≤ 200 s at 5 h after the end of argatroban administration. [Conclusion]Celite and kaolin ACTs can be used as markers to obtain close control of the required dose of argatroban in combination with nafamostat mesilate for the management of HIT II patients.

Hui Xue,1,2 Wenping Xiang,2 Yichuan Yu,3 Guorong Liu,2 Yi Chong,2 Jiying Zhou1 1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 2Department of Neurology, Baotou Central Hospital, Inner Mongolia, Baotou, China; 3Department of Emergency, Yongchuan Hospital of Chongqing Medical University, Chongqing, China Background: Vestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder. This study was conducted to compare the efficacy and acceptability of carbamazepine (CBZ) plus betahistine mesilate tablets (BMT) (CBZ+BMT) and oxcarbazepine (OXC) plus BMT (OXC+BMT) in treating VP, and investigated whether the synergistic effect could be increased along with the increased dose of BMT.Methods: VP patients were recruited and randomly assigned to receive CBZ+BMT or OXC+BMT. The doses of CBZ and OXC were set to 200 and 300 mg/time, twice daily, respectively. The doses of BMT were set to 12 and 18 mg/time, twice daily. Half of the patients in each group received BMT 12 mg/time and the other half received BMT 18 mg/time. The treatment was continued for 12 weeks. The vertigo frequency, vertigo score, vertigo duration, response rate, and drug-related side effects were analyzed.Results: In total, 92 patients in the CBZ+BMT group and 93 patients in the OXC+BMT group completed this trial. After 12 weeks of treatment, the two groups had similar average vertigo frequency, average vertigo score, average vertigo duration, and response rate. But the incidence of side effects was significantly higher in the CBZ+BMT group than in the OXC+BMT group (p=0.04). Subgroup analysis found that patients receiving BMT (18 mg) had greater reductions in average vertigo frequency, average vertigo duration, and average vertigo score, and higher response rates than patients receiving BMT (12 mg).Conclusion: These results demonstrated that OXC+BMT may be suitable as an alternative met

学位の種類: 博士（医学）. 報告番号: 甲第4547号. 学位記番号: 新大院博（医）甲第869号. 学位授与年月日: 平成31年3月25日, 博士（医学）, 新潟大学

In this paper, the development of reversed-phase liquid chromatographic method for the analysis of dabigatran etexilate mesilate and its ten impurities supported by quality by design (QbD) approach is presented. The defined analytical target profile (ATP) was the efficient baseline separation and the accurate determination of the investigated analytes. The selected critical quality attributes (CQAs) were the separation criterions between the critical peak pairs because the mixture complexity imposed a gradient elution mode. The critical process parameters (CPPs) studied in this research were acetonitrile content at the beginning of gradient program, acetonitrile content at the end of gradient program and the gradient time. Plan of experiments was defined by Box-Behnken design. The experimental domains of the three selected factors x1 - content of the acetonitrile at the start of linear gradient, x2 - content of the acetonitrile at the end of linear gradient and x3 - gradient time (t(G)) were 110%, 30%], [48%, 60%] and [8 min, 15 min], respectively. In order to define the design space (DS) as a zone where the desired quality criteria is met providing also the quality assurance, Monte Carlo simulations were performed. The uniform error distribution equal to the calculated standard error was added to the model coefficient estimates. Monte Carlo simulation included 5000 iterations in each of 3969 defined grid points and the region having the probability pi >= 95% to achieve satisfactory values of all defined CQAs was computed. As a working point, following chromatographic conditions suited in the middle of the DS were chosen: 22% acetonitrile at the start of gradient program, 55.5% acetonitrile at the end of gradient program end and the gradient time of 11.5 min. The developed method was validated in order to prove its reliability.

The present study was designed to examine the combined effects of a synthetic protease inhibitor, gabexate mesilate, with a specific neutrophil elastase inhibitor, sivelestat sodium, on acid-induced lung injury. Adult male Sprague-Dawley rats weighing 300-350 g were anaesthetised intraperitoneally with pentobarbitone sodium and the right jugular vein was cannulated. Following tracheostomy, rats were ventilated mechanically and underwent intratracheal instillation of hydrochloric acid (HCl, 0.1 N 1.5 ml/kg) or normal saline. Gabexate mesilate (10 mg/kg, i.p.) and/or sivelestat sodium (10 mg/kg/h, i.v.) were administered 30 min before HCl instillation. Bronchoalveolar lavage fluid samples were obtained 5 h after HCl instillation. in bronchoalveolar lavage fluid, the HCl-induced increases in total nucleated cell counts, neutrophil counts, optical density at 412 nm as an index of pulmonary haemorrhage, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) were significantly attenuated by either gabexate mesilate or sivelestat sodium treatment. Gabexate mesilate or sivelestat sodium treatment also significantly attenuated the wet to dry weight ratio induced by HCl. However, combined treatment with both gabexate mesilate and sivelestat sodium did not show additive effects on HO-induced lung injury, compared with single treatments. These findings suggested that gabexate mesilate and sivelestat sodium each exhibited protective effects on acid-induced lung injury, but that synergistic effects of both agents are limited in this acid-induced lung injury model.

【背景】心筋梗塞などの虚血性心疾患に対する治療は,バルーンやステントを用いて冠動脈狭窄部をカテーテル的に拡張するインターベンション治療の普及によって大きく進歩した.とはいえ少なからぬ患者では術中に起こる狭窄部血管内皮障害が原因で術後に血管内膜肥厚が起こり,結果として冠動脈再狭窄が出現し,予後改善の妨げとなっている.慢性骨髄性白血病の新薬として開発されたImatinib Mesilateは,ablやbcr/ablのチロシンキナーゼ(TK)シグナルを阻害することで慢性骨髄性白血病やPh陽性急性リンパ性白血病に有効であり,またkitのTKを阻害することで消化管間質腫瘍(GIST)に有効であるが,本剤が阻害する3つめの分子である血小板由来増殖因子(PDGF)の受容体(PDGFR)は血管平滑筋細胞に強く発現していることから,冠動脈再狭窄の予防薬として有効であると推測した.これを検討することを目的として培養血管平滑筋細胞を用いた細胞不連続性の増殖におよぼす効果を調べ,さらにラットの頸動脈バルーン障害モデルを用いたImatinib Mesilateのin vivo投与実験を行った.【方法と結果】血管平滑筋の平面培養では,増殖中の細胞はhomophilicな接着因子であるcoxsackievirus and adenovirus receptor (CAR)を強く発現し,細胞が平面の全体を覆うとともにCARの発現量が減少し増殖が終止した.スクラッチにより細胞平面に傷を付けると,傷の周囲の細胞にCARが強発現しつつ増殖を開始した.このことから,細胞の連続性が増殖シグナルに介入すること,またCAR陽性細胞同士のhomophilicな接着が細胞の増殖を負に制御している可能性が推測された.ラットの頸動脈をバルーン付きカテーテルで障害すると,血管平滑筋の中膜から内膜への遊走に引き続いてCARの強発現とともに強い増殖が誘導されるが,Imatinib Mesilateの経口投与によって内膜肥厚が用量依存性に抑制された.このことから,体内においては障害血管内腔側に接着した血小板から放出されるPDGFによる遊走・増殖シグナルをImatinib Mesilateがブロックすることがわかった.【結語】Imatinib Mesilateの投与によりインターベンション治療後の冠動脈再狭窄を予防できる可能性が示された.

Nafamostat mesilate（ FUT-175）, a synthetic serine protease inhibitor, has been reported to have antitumour activities toward solid tumours. The objective of this study was to characterize the biological activities of FUT-175 in a malignant mesothelioma cell line. We used MSTO-211H, a biphasic-type human malignant pleural mesothelioma cell line. The effect on cell growth was evaluated by 3（- 4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide assay. Secretion of urokinase-type plasminogen activator（ u-PA） and plasminogen activator inhibitor-1（ PAI-1） was analysed by enzyme-linked immunosorbent assay. The eff ects on relative mRNA expression levels were measured by reverse transcription polymerase chain reaction. The eff ect on cell invasiveness was evaluated by cell invasion assay. FUT-175 at 10-5 M signifi cantly inhibited cell growth and cell invasiveness. Cell growth reduced to 47.0 ± 2.1% compared with the control. The number of invasive cells also reduced to 16.0 ± 0.7 cells/hpf, while that of control cells was 41.4 ± 8.0 cells /hpf. U-PA and PAI-1 secreted from the cells were also reduced by FUT-175 in a dose-dependent manner. These results suggest that FUT-175 has the potential to act as a therapeutic agent against local growth and invasion, and functions by reducing PAI-1 and u-PA production of the human malignant mesothelioma（195 words）

Gabexate mesilate (GM) relaxes the papilla of Vater in addition to inhibiting the several proteases. We evaluated whether prophylactic administration of GM would prevent the occurrence of acute pancreatitis in endoscopic papillary balloon dilation (EPBD). Nineteen patients with common bile duct stones were separated into two groups according to the admission year. The group A has been administered GM intravenously at 2mg/kg/hr after EPBD till six hours later, and the group B has been administered GM before fifteen minutes of EPBD till six hours later. The mean value of sphincter of Oddi (SO) basal and peak pressure in the group B was significantly lower than that in the group A, moreover the mean value of the pancreatic pressure in the group B was significantly lower than that in the group A. However two cases had mild acute pancreatitis in the group B. GM loosened SO and pancreatic duct pressure by direct stimulation of SO, although it could not have enough effect to prevent the acute pancreatitis in EPBD.

AIMS/HYPOTHESIS: It is not clear how small tyrosine kinase inhibitors, such as imatinib mesilate, protect against diabetes and beta cell death. The aim of this study was to determine whether imatinib, as compared with the non-cAbl-inhibitor sunitinib, affects pro-survival signalling events in the phosphatidylinositol 3-kinase (PI3K) pathway. METHODS: Human EndoC-βH1 cells, murine beta TC-6 cells and human pancreatic islets were used for immunoblot analysis of insulin receptor substrate (IRS)-1, Akt and extracellular signal-regulated kinase (ERK) phosphorylation. Phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] plasma membrane concentrations were assessed in EndoC-βH1 and MIN6 cells using evanescent wave microscopy. Src homology 2-containing inositol 5'-phosphatase 2 (SHIP2) tyrosine phosphorylation and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) serine phosphorylation, as well as c-Abl co-localisation with SHIP2, were studied in HEK293 and EndoC-βH1 cells by immunoprecipitation and immunoblot analysis. Gene expression was assessed using RT-PCR. Cell viability was measured using vital staining. RESULTS: Imatinib stimulated ERK(thr202/tyr204) phosphorylation in a c-Abl-dependent manner. Imatinib, but not sunitinib, also stimulated IRS-1(tyr612), Akt(ser473) and Akt(thr308) phosphorylation. This effect was paralleled by oscillatory bursts in plasma membrane PI(3,4,5)P3 levels. Wortmannin induced a decrease in PI(3,4,5)P3 levels, which was slower in imatinib-treated cells than in control cells, indicating an effect on PI(3,4,5)P3-degrading enzymes. In line with this, imatinib decreased the phosphorylation of SHIP2 but not of PTEN. c-Abl co-immunoprecipitated with SHIP2 and its binding to SHIP2 was largely reduced by imatinib but not by sunitinib. Imatinib increased total β-catenin levels and cell viability, whereas sunitinib exerted negative effects on cell viability. CONCLUSIONS/INTERPRETATION: Imatinib inhibition of c-Abl in beta cells decre

The effectiveness of continuous arterial infusion of Gabexate Mesilate (FOY-007) on experimental acute pancreatitis was investigated. Acute necrotizing pancreatitis was induced by an injection of 10% Na-taurocholate (1ml/kg) into the main pancreatic duct of mongrel dogs. Animals were divided into three groups Group A: non-treated control, Group B: after the induction of pancreatitis, injected with FOY-007 intravenously (5mg/kg/hr), Group C: after the induction of pancreatitis, injectedwithFOY-007 via the celiac artery. The changes in the values of amylase and lipase in serum and ascites etc. were examined. A histological examination was done and the FOY-007 concentration of the pancreas was measured. In both groups B and C, the serum levels of amylase and lipase reached significantly to low levels compared with those in group A. The extents of pancreatic parenchyma necrosis in each group were 36.1, 25.3 and 19.5% , respectively, and were significantly improved in group C. In addition, theFOY-007levels in pancreas specimens in the intraarterial infusion group exceeded those in the intravenous infusion group by 32 times. The results suggest that continuous FOY-007 arterial infusion therapy is useful as a local treatment for severe acute pancreatitis.

Thesis (Ph. D. in Medical Sciences)--University of Tsukuba, (B), no. 2036, 2004.4.30, Offprint. Originally published in: Annals of thoracic surgery, v. 77, no. 2, pp. 644-650, 2004, Includes bibliographical references, Includes supplementary treatises, https://www.tulips.tsukuba.ac.jp/limedio/dlam/B24/B2466242/1.pdf

This multicentre, double-blind, double-dummy, randomised trial was designed to compare the efficacy and safety of single intravenous doses of dolasetron mesilate and granisetron in the prevention of acute emesis and nausea due to high-dose (≥80 mg/m2) cisplatin. Single intravenous doses of 1.8 or 2.4 mg/kg of dolasetron mesilate or 3 mg of granisetron hydrochloride were administered in a volume of 50 ml over a 5-min period, beginning 30 min prior to cisplatin (≥80 mg/m2) administration. The number and timing of emetic episodes, time to administration of escape anti-emetic medication, severity of nausea by visual analogue scale (VAS), and safety were monitored for 24 h after the start of cisplatin-containing chemotherapy. Investigators' evaluations of overall efficacy and patients' satisfaction with therapy were recorded at the end of the 24-h study period. Of the 474 patients evaluable for efficacy, complete responses were achieved by 54, 47 and 48% of patients given dolasetron mesilate 1.8 mg/kg, dolasetron mesilate 2.4 mg/kg and granisetron, respectively. Statistically, treatment groups had comparable complete and complete plus major responses, times to first emesis, and use of escape medication; patient maximum nausea severity and treatment satisfaction ratings; and physician nausea severity and overall efficacy assessments. For the majority of efficacy endpoints, 1.8 mg/kg dolasetron mesilate produced numerically superior responses compared with the 2.4 mg/kg dose. Gender and prior chemotherapy were significant predictors of complete response; males and chemotherapy-naive patients had higher responses. The overall incidences of adverse events were comparable among the treatment groups; headache and diarrhoea were most common. In conclusion, 1.8 and 2.4 mg/kg of dolasetron mesilate and granisetron (3 mg) were equally effective in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, because no additional benef, SCOPUS: ar.j, info:eu-repo/semantics/published

We observed a case of anaphylaxis which was induced by the injection of nafamostat masilate in a patient undergoing long-term maintenance of hemodialysis. The 62-year-old male had been receiving hemodialysis for 20 years because of chronic glomer- ulonephrits. This patient also suffered from renal osteodystrophy for the last 3 years, and had undergone 5 operations for bone fracture or carpal tunnel syndromes. During surgery, nafamostat masilate was used instead of heparin sodium to avoid bleeding, and no problems occurred with respect to continuation of hemodialysis. However, anaphylaxis appeared during injection of nafamostat masilate at a dental extraction on April 17 and accompanying a thigh contusion with hematoma on August 23, 1996. The anaphylaxis was clinically more severe on August 23. The results of a lymphocyte stimulation test for nafamostat masilate were positive. There were no other factors present that might have induced hypotension (heart failure, antihypertensive drug therapy, anemia, inappropriate dry weight, etc.).We therefore report this as a case of acquired allergy to nafamostat masilate during long-term maintenance of hemodialysis.

Výsledkem této práce bylo zkoumání fyzikálních vlastností, zejména stability a rozpustnosti ve vodě, které mají vliv na biodostupnost různých polymorfních modifikací dihydroergocristinu mesylátu. Dále bylo sledováno za jakých , přesně stanovených, podmínek určitá modifikace vzniká., Dokončená práce s úspěšnou obhajobou

The electrochemical characteristics of loprazolam mesilate have been evaluated in an aqueous solution using dc, ac, and normal and inverse pulse polarography, as well as cyclic voltammetry and controlled‐potential coulometry. This drug undergoes three different reduction steps. The first, a four‐electron transfer, corresponds to the reduction of the nitro group to give the corresponding hydroxylamine. The second, a two‐electron transfer, corresponds to the reduction of the azomethine group, either before or after (in an acidic solution) hydrolysis. The third wave corresponds to a four‐electron transfer in an acidic medium and to a two‐electron transfer in an alkaline medium. In an acidic solution, this third step involves the two‐electron reduction of the hydroxylamine group to the corresponding amine plus the two‐electron reduction of the double bond between N‐methylpiperazine and the imidazol group. In an alkaline solution, only the latter reduction takes place. Such behavior holds promise for analytical measurements of the drug. Copyright © 1990 VCH Publishers, Inc., SCOPUS: ar.j, info:eu-repo/semantics/published

In order to assess its effects on blood pressure and serum lipids, doxazosin was administered to patients with essential hypertension and a serum total cholesterol level above 220 mg/dl as part of a multicenter trial in which 7 institutions in Niigata Prefecture participated. Doxazosin was given either as monotherapy or in combination with some other antihypertensive agent. The systolic, diastolic, and mean blood pressures were all decreased significantly at weeks 4, 8 and 12 of treatment, while there was no change in the heart rate throughout the study. The antihypertensive effects in individual patients were rated according to the "Guideline for Clinical Evaluation of Antihypertensive Drugs." Moderate or improved reduction of blood pressure was attained in 29/39 patients (74%) after 12 weeks of treatment. Total cholesterol and low density lipoprotein (LDL) cholesterol levels decreased significantly after doxazosin treatment, while the cholesterol ratio (high density lipoprotein (HDL) cholesterol/total cholesterol) increased significantly. Although the apoprotein A_1 level remained unchanged, the apoprotein B level decreased significantly, and the apoprotein A_1/apoprotein B ratio increased significantly as a consequence. These results suggest that doxazosin is a useful antihypertensive drug which may be used as a first choice therapy in patients with essential hypertension and high serum cholesterol level., departmental bulletin paper

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies. Objectives: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis. Methods: Matriptase expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptaseinduced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate (CM), or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings. Measurements and Main Results: Matriptase expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-b. Furthermore, matriptase elicited signaling via protease-activated receptor-2 (PAR-2), and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic downregulation, diminished lung injury, collagen production, and transforming growth factor-b expression and signaling. Conclusions: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in

Occurrence of the residues of cytostatic drugs in the environment is, as compared to many other pharmaceuticals, much lower. However, the mechanisms of action of most cytostatic drugs are targeted to prevent growth and division of tumor cells via interference with the genetic material. Due to such mechanism they may be not selective enough to target only tumor cells, but can act on all dividing cells and tissues of exposed organisms. Thus the question is whether chronic exposure to residues of anticancer drugs at expected environmental concentrations can affect aquatic organisms, which may potentially lead to systemic environmental effects. Four cytostatic drugs (5-fluorouracil, cisplatin, etoposide and imatinib mesilate) with different mechanisms of action were selected for this study. Their ecotoxicity and genotoxicity were studied in the experimental models with algae, cyanobacteria, higher plants, crustacea, mussel and zebrafish. Their toxicity was relatively high in the reproduction assay with algae (P. subcapitata), cyanobacteria (S. leopoliensis) and crustacea (D. magna and C. dubia). The most toxic were 5-FU and cisplatin, which in crustacea showed toxic effect at concentrations below µg/L. Much lower toxicity was observed in the zebrafish embryo test. In this assay the most toxic compound was imatinib mesilate, followed by cisplatin and etoposide, while 5-FU was not toxic. The genotoxicity of the compounds was studied with the comet and/or micronucleus assay. In D. magna 5-FU, cisplatin and etoposide induced clear dose dependent increase in DNA damage with cisplatin being the most potent. Similar increase in DNA damage was observed also in mussel U. tumidus, though at higher concentrations. In plants (Allium and Tradescantia assays) etoposide and cisplatin were the strongest inducers of micronuclei formation which was observed within the concentrations 30 and 60 µg/L, respectively. In zebrafish that were exposed to 5-FU for 4 months an increase in DNA damag

Background: Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments. Methods: In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to eribulin mesilate (1.4 mg/m 2 administered intravenously during 2-5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726. Findings: 762 women were randomly allocated to treatment groups (508 eribulin, 254 TPC). Overall survival was significantly improved in women assigned to eribulin (median 13.1 months, 95% CI 11.8-14.3) compared with TPC (10.6 months, 9.3-12.5; hazard ratio 0.81, 95% CI 0.66-0.99; p=0.041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) of 503 patients. Interpretation: Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated m, SCOPUS: ar.j, info:eu-repo/semantics/published

The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi. Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies against tumor necrosis factor-alpha (TNF-alpha) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta-lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted Udgivelsesdato: 2008/5/21, The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL) is a nitrogen oxide (NO) donor, which relaxes the sphincter of Oddi. Studies show conflicting results when applied prior to ERCP and a large multicenter randomized study is warranted. Steroids administered as prophylaxis against PEP has been validated without effect in several randomized trials. The non-steroidal anti-inflammatory drugs (NSAID) indomethacin and diclofenac have in randomized studies showed potential as prophylaxis against PEP. Interleukin 10 (IL-10) is a cytokine with anti-inflammatory properties but two trials testing IL-10 as prophylaxis to PEP have returned conflicting results. Antibodies against tumor necrosis factor-alpha (TNF-alpha) have a potential as rescue therapy but no clinical trials are currently being conducted. The antibiotics beta-lactams and quinolones reduce mortality when necrosis is present in pancreas and may also reduce incidence of infected necrosis. Evidence based pharmacological treatment of AP is limited and studies on the effect of potent anti-inflammatory drugs are warranted.

Backgrounds: Prior studies have suggested that drain amylase level is a predictive marker for developing pancreatic fistulas (PFs) after pancreaticoduodenectomy (PD). However, means of preventing PF after discovering high drain amylase levels have not been previously established. The purpose of this study was to evaluate the efficacy of a combination drug therapy (using three drugs; gabexate mesilate, octreotide, and carbapenem antibiotics, named as triple-drug therapy [TDT]) regimen in preventing PF for patients with high drain amylase levels on postoperative day (POD) 1 after PD. Materials and methods: We divided the 183 patients who underwent PD into two groups in accordance with their enrollment in the study: for those enrolled early in the study (early period), TDT was not administered to patients with high drain amylase level; however, for those enrolled later in the study (late period), TDT was administered if drain amylase levels were over 10,000 IU/L on POD 1. We retrospectively compared the incidence of PF between the two groups. Results: Incidences of PFs were statistically, significantly prevented in the late group (early 17% versus late 6%; P = 0.01). For patients with low levels of drain amylase (<10,000 IU/L), the PF ratio was equivalent between two groups (early 8% versus late 5%; P = 0.56); however, PFs in patients with high drain amylase levels in the late period group were dramatically prevented by TDT administration (early 89% versus late 11%; P < 0.001). Conclusions: TDT may be a promising therapy to prevent PFs in patients with high drain amylase levels after PD., Journal of Surgical Research, 234, pp.77-83; 2019

Background : The treatment strategy for jaundiced patients with hilar cholangiocarcinoma (HC) is not well established. In this study, we evaluate the feasibility of our perioperative protocol for jaundiced patients with HC. Methods : Twenty patients with HC who underwent hepatic resection at our institute were enrolled, and patients were divided into icteric(n=6) and normal(n=14) group. As a perioperative protocol, Oral administration of Inchinkoto(ICKT), steroid and nafamostat mesilate were introduced. The evaluation of functional future remnant liver(FRL) by asiaroscintigraphy, and postoperative outcomes were retrospectively compared. Results : Indocyanine green dye retention rate at 15 minutes was higher, and LHL15 values was lower in icteric group. However, in the functional evaluation of FRL, which was the sum of GSA uptake of the future FRL, there was no significant difference of LHL15 values of the remnant liver functional reserve between the two groups. As results, according to the difference of liver function, serum AST level was not different between two groups. The number of patients with postoperative morbidity in the two groups was comparable. Conclusions : Even in HC patients with icteric liver, accurate assessment of liver functional reserve and effective perioperative treatment may attribute to successful hepatectomy and favorable post-operative outcomes.

Objective Prior studies suggested that early drain removal prevented the development of pancreatic fistula (PF) after pancreaticoduodenectomy (PD), but there has been no corresponding prospective trial for distal pancreatectomy (DP). The purpose of this study was to determine the safety and efficacy of early drain removal and triple-drug therapy (TDT) with gabexate mesilate, octreotide and carbapenem antibiotics to prevent PF after DP in patients at high-risk of developing PF. Methods A total 71 patients who underwent a DP were enrolled. We prospectively divided them into two groups: the late-removal group, in which the drain remained in place for at least for 5 days postoperatively (n = 30) and the early-removal group in which the drain was removed on postoperative day 1 (POD1) (n = 41). For the patients with a high drain amylase level (?10,000 IU/L) and patients with symptomatic intraperitoneal fluid collection, our original TDT was introduced. The primary endpoint was the safety and efficacy of this management, and the secondary endpoint was the incidence of PF. Results The incidence of clinical PF was significantly lower in the early-removal group (0% vs. The late removal 16%; p < 0.001). In the early-removal group, TDT was administered to 12 patients (29%) and none of the patients needed additional treatment after TDT. Conclusions Postoperative management after DP with early drain removal and TDT was safe and effective for preventing PF., Pancreatology, 15(4), pp.411-416; 2015

The purpose of this investigation was to determine the effects of dual task performance on postural instability in subjects with idiopathic Parkinson's disease (PD) compared with healthy elderly people. In particular, we aimed to divert attention to a secondary task so the full extent of balance disturbance could be revealed without compensation by attentional mechanisms. Forty-five subjects were tested: 15 PD subjects with a past history of falls; 15 PD subjects with no history of falls; and 15 unimpaired individuals. Groups were matched for age and sex and subjects with PD were tested at peak dose in the levodopa medication cycle. Each subject was tested on their ability to maintain stability in three conditions: (1) steady standing (feet apart, feet together, step stance, tandem stance, single leg stance); (2) in response to perturbations generated by self-initiated movements (arm raise test, step test); and (3) in response to an unexpected external perturbation in upright stance, the shoulder tug test. The concurrent task was verbal-cognitive and required subjects to recite the days of the week backwards. The concurrent task produced a significant deterioration in performance for the arm raise test in all groups, the step test for the PD fallers and controls and for tandem stance in the PD fallers. Ceiling effects were evident for timed tests with feet apart and feet together resulting in poor discriminative validity for these tests. The external perturbation test showed differences between the three groups for both unitask and concurrent task conditions, yet similar rates of change from unitask to dual task conditions. Because PD fallers had a more severe initial deficit than controls, deterioration placed them in that part of the balance continuum at high risk of losing equilibrium. Copyright © 2000 Elsevier Science B.V.

In healthy adults, deficits in identifying a second target following a previously attended target in Rapid Serial Visual Presentation (RSVP) occur between intertarget intervals of approximately 100-500 ms. This Attentional Blink (AB) is investigated in nondemented medicated Parkinson's patients using a modification of the standard paradigm that required the identification of two red letters embedded in a black letter distractor stream. Parkinson's patients and controls produced an equivalent AB, although with a different pattern of errors. Thus, the processing and clearance of information was largely preserved in nondemented Parkinson's patients, without evidence of bradyphrenia. However, perseveration of earlier RSVP items in short-term memory was thought to explain the different pattern of errors.

Although a variety of medications are used in the treatment of Parkinson's disease, all have short term effects. As a result, motor performance varies over time. A key role of the physiotherapist is to measure fluctuations in the severity of movement disorders in relation to the dose and timing of anti-Parkinsonian medication with a view to: (i) optimising motor performance; (ii) targeting therapeutic interventions for times of greatest need; and (iii) communicating findings to the interprofessional team. For an informed approach to the measurement of medication-induced motor fluctuations, clinicians require an understanding of the pathophysiology of Parkinson's disease, the mode of action of medications and the validity of existing methods used to quantify changes in performance resulting from pharmaceuticals and rehabilitation.

We examined whether people with Parkinson's disease (PD) have a central amplitude regulation disorder using three-dimensional (3-D) gait analyses to compare the effects of medication and attentional strategies on gait in 12 PD subjects and 12 matched comparison subjects. Subjects with PD first performed several 10-m gait trials at preferred speed while off levodopa. They then walked at preferred speed on levodopa; off levodopa with cues; and on levodopa with cues. Control subjects walked at preferred speed and then with visual cues to match their stride length to PD values. As well as spatiotemporal footstep data, pelvic and lower limb kinematic profiles and angle-angle diagrams were produced for sagittal, coronal, and transverse plane movements using a 3-D motion analysis system. In people with PD, decreased step length was accompanied by reduced movement amplitude across all lower limb joints, in all movement planes. When control subjects were required to walk with short steps matched to the size of PD comparisons, they displayed a similar multijoint reduction in amplitude. For PD subjects, both levodopa and visual cues increased movement amplitude across all lower limb joints. Amplitude increased further when levodopa and visual cues were combined, resulting in normalization of step length. This finding suggested that reduced step length is due to a mismatch between cortically selected movement amplitude and basal ganglia maintenance mechanisms. Levodopa and cues normalized amplitude across all joints by altering motor set and bypassing defective basal ganglia mechanisms. © 2004 Movement Disorder Society.

Background: FUT-175 (nafamostat mesilate) has a variety of pharmacological effects; in addition to its stable potent serine protease inhibitory activity, it exerts far stronger anti-complement activity than other protease inhibitors. Here, we evaluated the protective effect of FUT-175 on pulmonary function of xenografts in an ex vivo guinea pig-to-rat lung perfusion model, using a device for analyzing pulmonary function in small animals. Methods: Animals were divided into three groups (n = 6 each), Isograft (Group I), Xenograft (Group X), and Xenograft with FUT-175 (Group XF). In the latter, 10 mg of FUT-175 was added to the extracorporeal circuit before perfusion with xenogeneic blood was started. The following parameters were serially measured in these three groups: complement activity causing 50% hemolysis (CH50 units) in the perfusion blood either before or during perfusion, pulmonary arterial pressure, dynamic pulmonary compliance, and airway resistance. In addition, Hematoxylin and Eosin staining of the lungs and assays of rat IgM, IgG, and anti-C3 deposition were carried out after perfusion. Results: The duration of satisfactory pulmonary function after the start of perfusion was significantly increased in Group XF. CH50 in Group XF decreased significantly than in Group X. In addition, FUT-175 suppressed both the increase in pulmonary arterial pressure and airway resistance, and the decrease in dynamic pulmonary compliance. In Group XF, intraalveolar hemorrhage and the thickening of the arterial wall were not observed. Groups X and XF showed deposition of IgM, IgG, and C3 at the endothelium of the pulmonary arteries but less in Group I. Conclusions: This study suggests that FUT-175 inhibited complement activation including the alternative pathway and improved lung xenograft pulmonary function. FUT-175 ameliorates hyperacute rejection in a guinea pig-to-rat ex vivo xenogeneic lung perfusion model., Acta Medica Nagasakiensia, 56(2), pp.43-48; 2011

A 59-year old woman with SLE was admitted to our hospital for the treatment of pulmonary miliary tuberculosis. She was given isoniazid and rifampicin, as an initial treatment regimen. On the 10th hospital day, she suddenly developed nausea, vomiting, diarrhea and left back pain. Furthermore, marked elevation of serum amylase level was observed. From her symptoms and laboratory findings, she was diagnosed as having acute pancreatitis and administered gabexate mesilate and antibiotics. In spite of treatment, her pancreatitis became worse gradually, and she developed respiratory distress. Methylprednisolone pulse therapy was performed, but she was complicated with pulmonary hemorrhage and died of respiratory failure. Autopsy findings suggested that acute pan- creatitis was associated with the vasculitis of SLE. To our knowledge, there have been few SLE patients complicated with acute pancreatitis, and the pathophysiology of SLE pan- creatitis is still unclear. The purpose of this paper is to discuss the relation between pancreatitis and SLE.

We report a rare case of acute pancreatitis with hepatic infarction. A 71- year-old woman was admitted to our hospital because of sudden upper abdominal pain and severe nausea. Physical examination revealed upper abdominal tenderness with mild muscle defense, and hepatomegaly. Blood examination revealed high levels of serum amylase and lipase. Abdominal echography showed swelling of the entire pancreas and bright lever. The patient was diagnosed as having acute pancreatitis. Abdominal CT scan on admission showed swelling of the pancreas and bilateral fluid collection behind the kidneys without liver abnormalities. The patient was treated with continuous intravenous drip injection of gabexate mesilate(30 mg/kg)and ulinastatin(150,000 IU)daily. On the 6th hospital day, serum amylase and lipase levels and liver dysfunction were normalized, and the patient's, subjective symptoms were diminished. However, on the 16th hospital day, she had right hypochondralgia, high grade fever, and mild liver dysfunction. A contrast- enhanced abdominal CT scan showed a small, wedge-shaped, low-attenuation area in the right lobe of the liver. Hepatic infarction was diagnosed. Although the patient was not treated because the infarction was small, she recovered quickly.

平成13年度-平成15年度年度科学研究費補助金 (基盤研究(B)(1) 課題番号13557048) 研究成果報告書, 6-12p: Matsushima-Nishiwaki R. et al., Molecular mechanism for growth suppression of human hepatocellular carcinoma cells by acyclic retinoid. Carcinogenesis. 2003 24(8): 1353-1359, 13-19p: Moriwaki H. , Prevention of liver cancer: basic and clinical aspects. Experimental and molecular medicine. 2002 34(5): 319-325, 20-28p: Adachi S. et al., Phosphorylation of Retinoid X Receptor Suppresses its Ubiquitination in Human Hepatocellular Carcinoma. Hepatology. 2002 35(2): 332-340, 29-40p: Yasuda I. et al., Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and telomerase activity, and induces apoptosis in human hepatoma-derived cell lines. Journal of Hepatology. 2002 36: 660-671, 41-50p: Obora A. et al., Synergistic Induction of Apoptosis by Acyclic Retinoid and Interferon-β in Human Hepatocellular Carcinoma Cells. Hepatology. 2002 36(5): 1115-1124, 51-65p: Okuno M. et al., Retinoids in Liver Fibrosis and Cancer. Frontiers in Bioscience. 2002 7: d204-218, 66-78p: Okuno M. et al., Retinoids in Liver Fibrosis: Induction of Proteolytic Activation of Transforming Growth Factor-β by Retinoic Acid and Its Therapeutic Control by Protease Inhibitors. Extracellular Matrix and the Liver. 2003 : 391-403, 79-89p: Suzui M. et al., Enhanced colon carcinogenesis induced by azoxymethane in min mice occurs via a mechanism independent of β-catenin mutation. Cancer Letters. 2002 183: 31-41, 90-96p: Suzui M. et al., Different Mutation Status of the β-Catenin Gene in Carcinogen-Induced Colon, Brain, and Oral Tumors in Rats. Molecular Carcinogenesis. 2001 32: 206-212, 97-109p: Akita K. et al., Impaired Liver Regeneration in Mice by Lipopolysaccharide Via TNF-α/Kallikrein-Mediated Activation of Latent TGF-β. Gastroenterology. 2002 123: 352-364, 110-115p: Fukutomi Y. et al., Metachronous colon tumors: risk factors and rationale for the surveillance colonoscopy after initial polypectomy. Journal of Cancer Research and Clinical Oncology. 2002 128: 569-574, 116-123p: Matsushima-Nishiwaki R. et al., Phosphorylation of Retinoid X Receptor α at Serine 260 Impairs Its Metabolism and Function in Human Hepatocellular Carcinoma. Cancer Research. 2001 61: 7675-7682, 124-130p: Okuno M. et al., Chemoprevention of hepatocellular carcinoma: Concept, progress and perspectives. Journal of Gastroenterology and Hepatology. 2001 16: 1329-1335, 131-134p: Okuno M. et al., Apoptosis Induction by Acyclic Retinoid: a Molecular Basis of 'Clonal Deletion' Therapy for Hepatocellular Carcinoma. Japanese Journal of Clinical Oncology. 2001 31(8): 359-362, 135-141p: Okuno M. et al., Retinoid-Induced Apoptosis in Hepatocellular Carcinoma: A Molecular Basis for "Clonal Deletion" Therapy. Frontiers in Hepatology. 2002: 33-39, 142-158p: Okuno M. et al., Prevention of Rat Hepatic Fibrosis by the Protease Inhibitor, Camostat Mesilate, via Reduced Generation of Active TGF-β. Gastroenterology . 2001 120: 1784-1800, 159-166p: Shimizu M. et al., Mechanism of Retarded Liver Regeneration in Plasminogen Activator-Deficient Mice: Impaired Activation of Hepatocyte Growth Factor After Fas-Mediated Massive Hepatic Apotosis. Hepatology. 2001 33(3): 569-576, 167-169p: Okuno M. et al., Protease Inhibitors: Suppression of Activation of Hepatic Stellate Cells by Inhibiting TGFβ Generation. Trends in Gastroenterology and Hepatology. 2001: 361-363

A case of acute pancreatitis with hyperlipemia and hyperglycemia induced by alcohol abuse is reported. The case is a 34-year-old man who was admitted to our hospital with a complaint of severe abdominal pain. He had been drinking 700ml~ 1400ml of whisky daily prior to admission. At the time of admission, his serum amylase was elevated to 1833 U. Abdominal computerized tomography revealed edematous swelling of the pancreas. His serum glucose level was 926 mg/dl, cholesterol 754 mg/dl and triglyceride 3,530 mg/dl. Following successful treatment of acute pancreatitis and hyperglycemia with gabexate mesilate and insulin, his serum glucose, lipid and pancreatic enzyme levels decreased to the normal range. This case is considered to be one of acute pancreatitis with diabetic lipemia induced by alcohol abuse.

Four studies were conducted to investigate the effect and site of action of exogenous and endogenous opioids on pituitary growth hormone (GH) and prolactin (PRL) secretion in Holstein calves. In the first study, the effect of the opioid agonist DAMME (D-Ala²⁺,N-Me-Phe⁴,Met(O)⁵-01 enkephalin) on plasma GH and PRL secretion was measured in Holstein calves in fall season. Plasma concentrations of both GH and PRL increased in response to DAM ME injection. Pretreatment with either the lipid soluble opioid antagonist naloxone (NAL), which readily penetrates the blood brain barrier (BBB), or the peripherally acting antagonist methyl levallorphan mesiltate (MLM), blocked the PRL response to DAMME. Naloxone, but not MLM, negated the GH response to DAMME. In spring, the experiment was repeated with similar results. In the second experiment, the opioid antagonists NAL and MLM were administered alone to detennine whether endogenous opioids mediate basal GH and PRL secretion, and the site of action of any of opioid-mediation of basal GH and PRL. In fall, NAL administration increased both plasma GH and PRL secretion. Methyl levallorphan mesilate did not affect PRL, but increased plasma GH concentrations. In spring, a second trial using 5 different doses of each antagonist was conducted. Naloxone did not affect GH levels at any dose in spring, but decreased plasma PRL at the same dose which increased plasma PRL in fall. Plasma PRL was again unaffected by MLM, but plasma GH was increased by 3 separate doses of MLM. The third experiment was designed to determine if the increases in plasma PRL seen after DAMME administration were mediated via dopaminergic mechanisms. Plasma PRL in calves again increased in response to DAMME injection alone. In calves pre-treated with the long-acting dopamine agonist 2-Br-&alp. ergocryptine (CB 154), plasma PRL was unresponsive to DAMME injection. The pituitaries of calves treated with CB 154 in this experiment were able to respond to thyrotropin-rele

A case of acute pancreatitis with hyperlipemia and hyperglycemia induced by alcohol abuse is reported. The case is a 34-year-old man who was admitted to our hospital with a complaint of severe abdominal pain. He had been drinking 700ml~ 1400ml of whisky daily prior to admission. At the time of admission, his serum amylase was elevated to 1833 U. Abdominal computerized tomography revealed edematous swelling of the pancreas. His serum glucose level was 926 mg/dl, cholesterol 754 mg/dl and triglyceride 3,530 mg/dl. Following successful treatment of acute pancreatitis and hyperglycemia with gabexate mesilate and insulin, his serum glucose, lipid and pancreatic enzyme levels decreased to the normal range. This case is considered to be one of acute pancreatitis with diabetic lipemia induced by alcohol abuse.

The basal ganglia may be involved in bimanual co-ordination. Parkinson's disease (which impairs basal ganglia output) is clinically reported to cause difficulties in the performance of co-ordinated bimanual movements. Nevertheless, any bimanual co-ordination difficulties may be task specific, as experimental observations are equivocal. To infer the role of the basal ganglia in co-ordinating the two arms, this study investigated the bimanual co-ordination of patients with Parkinson's disease. Sixteen Parkinson's disease patients and matched control subjects performed a bimanual cranking task, at different speeds (1 and 2 Hz) and phase relationships. All subjects performed the required bimanual in-phase movement on a pair of cranks, at fast (2 Hz) and slow (1 Hz) speeds. However, the Parkinson's disease patients were unable to perform the asymmetrical anti-phase movement, in which rotation of the cranks differed by 180degree, at either speed; but instead reverted to the in-phase symmetrical movement. For Parkinson's disease patients, performance of the in-phase movement was more accurate and stable when an external timing cue was used; however; for anti-phase movement, the external cue accentuated the tendency for patients to revert to more symmetrical, in-phase movements.