Tracheal injury diagnosed by a sudden increase in end-tidal carbon dioxide levels during mediastinoscopic subtotal esophagectomy: a case report.

BACKGROUND: Mediastinoscopic surgery for esophageal cancer facilitates early postoperative recovery. However, it can occasionally cause serious complications. Here, we present the case of a patient with a tracheal injury diagnosed by a sudden increase in end-tidal carbon dioxide (EtCO2) during mediastinoscopic subtotal esophagectomy. CASE PRESENTATION: A 52-year-old man diagnosed with esophageal cancer was scheduled to undergo mediastinoscopic subtotal esophagectomy. During the mediastinoscopic procedure, the EtCO2 level suddenly increased above 200 mmHg, and the blood pressure dropped below 80 mmHg. We immediately asked the operator to stop insufflation and found a tracheal injury on the right side of the trachea near the carina by bronchoscopy. The endotracheal tube was replaced with a double-lumen tube, and the trachea was repaired via right thoracotomy. There were no further intraoperative complications. After surgery, the patient was extubated and admitted to the intensive care unit. CONCLUSIONS: Monitoring EtCO2 levels and close communication with the operator is important for safely managing sudden tracheal injury during mediastinoscopic esophagectomy.

A Multicenter Phase 2 Trial to Evaluate the Efficacy of mFOLFOX6 + Cetuximab as Induction Chemotherapy to Achieve R0 Surgical Resection for Advanced Colorectal Liver Metastases (NEXTO Trial).

BACKGROUND: The effect of cetuximab plus mFOLFOX on downsizing of the tumors for curative resection has yet to be assessed for patients with advanced colorectal liver metastases (CRLMs). This study aimed to assess the oncologic benefit of cetuximab plus mFOLFOX for wild-type KRAS patients with advanced CRLMs. METHODS: In this multicenter phase 2 trial, patients with technically unresectable tumor and/or five or more CRLMs harboring wild-type KRAS were treated with mFOLFOX plus cetuximab. The patients were assessed for resectability after 4 treatments, and then every 2 months up to 12 treatments. Patients with resectable disease were offered surgery after a waiting period of 1 month. The primary end point of the study was the R0 resection rate. The secondary end points were safety, progression-free survival (PFS), and overall survival (OS). The study is registered with the University Hospital Medical Information Network-Clinical Trials Registry Clinical Trials Registry (no. C000007923). RESULTS: Between 2012 and 2015, 50 patients from 13 centers were enrolled in this trial. Two patients were excluded because they had not received induction therapy. The 48 patients had a complete response rate of 0% and a partial response rate of 64.6%. For 26 R0 resections (54.2%) and 5 R1 resections (10.4%), no mortality occurred. During a median follow-up period of 31 months, the median OS for all the patients was calculated to be 41 months (95% confidence interval, 28-not reached). The 3-year OS rate was 59%. CONCLUSION: For patients with advanced CRLMs harboring wild-type KRAS, cetuximab administered in combination with mFOLFOX yields high response rates, leading to significantly high R0 resection rates and favorable prognoses.

Splenic Marginal Zone Lymphoma with Acquired von Willebrand Syndrome Diagnosed via Splenic Bleeding.

An 85-year-old woman underwent emergent splenectomy due to left abdominal pain and active bleeding in a massively enlarged spleen. The histological diagnosis was splenic marginal zone lymphoma (SMZL). A prolonged activated partial thromboplastin time (APTT) was noted, and additional tests led to the diagnosis of type 2A-like acquired von Willebrand syndrome (AVWS). An APTT cross mixing test ruled out the presence of inhibitors. She received eight courses of rituximab monotherapy. The coagulation data showed no improvement, possibly because the lymphoma showed a poor response to the treatment. AVWS rarely causes bleeding in solid organs. This is the first case of SMZL with AVWS diagnosed via splenic bleeding.

[A Case of Effective Whole-Brain Irradiation and Lapatinib/Capecitabine Combination Therapy for HER2-Positive Breast Cancer with Multiple Brain Metastases].

We report the case of a 48-year-old female patient with HER2-positive and hormone receptor-negative breast cancer with multiple liver metastases. She underwent 6 cycles of FEC followed by docetaxel plus trastuzumab (TZB), resulting in a clinical complete response. After 15 cycles of a TZB-containing regimen, she complained of dizziness and nausea, and imaging examinations revealed multiple brain metastases. Whole-brain irradiation(33.6 Gy) was performed, and the chemotherapy regimen was changed to lapatinib (LAP: orally at 1,250 mg/day, every day) and capecitabine (CAP: orally at 2,000 mg/m2, every day for 2 weeks, followed by a 1-week rest interval, as 1 cycle). After 6 weeks of the new treatment, magnetic resonance imaging revealed marked shrinkage of brain metastases. A clinical complete response was maintained for 19 months. While brain metastasis is an important problem with treatment with TZB, LAP is drawing attention because of its ability to pass the blood-brain barrier because of its small molecular weight. LAP/CAP combination therapy may be an effective treatment option for brain metastases of HER2-positive breast cancer in which TZB essentially has no effect.

The RACHS-1 risk category can be a predictor of perioperative recovery in Asian pediatric cardiac surgery patients.

PURPOSE: The Risk Adjustment for Congenital Heart Surgery (RACHS-1) classification was originally designed to facilitate the prediction of in-hospital mortality for pediatric cardiac surgery patients. However, there have been few reports on clinical outcomes predicted by the RACHS-1 category, especially in an Asian population. The aim of this study was to determine whether RACHS-1 classification can predict patient outcomes. METHODS: A total of 580 pediatric cardiac surgery procedures performed from January 2005 to December 2009 were retrospectively classified into the six RACHS-1 categories. The association between RACHS-1 category and clinical outcomes, including length of catecholamine requirement, mechanical ventilation time, intensive care unit stay, and in-hospital mortality, were examined. RESULTS: The frequencies of RACHS-1 categories in the study population were: category 1, 10.7 %; category 2, 36.7 %; category 3, 42.8 %; category 4, 6.6 %; category 5, 0.0 %; category 6, 3.3 %. There was a significant linear correlation between RACHS-1 category and in-hospital mortality (r = 0.96, p < 0.001). Kaplan-Meier analysis demonstrated that length of catecholamine infusion, mechanical ventilation time, and ICU stay were significantly different (p < 0.05) in the different RACHS-1 categories, except for those between category 4 and 6 (p = 0.09). CONCLUSIONS: Based on the results of our analysis, we conclude that the RACHS-1 stratification system can predict in-hospital mortality and patient outcomes in patients undergoing pediatric cardiac surgery.

Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice.

The sodium-glucose cotransporter 2 (SGLT2) is responsible for most glucose reabsorption in the kidney and has been proposed as a novel therapeutic target for the treatment of type 2 diabetes. In the present study, the therapeutic effects of SGLT2 selective inhibitor ipragliflozin were examined in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice which exhibit impaired insulin secretion, insulin resistance, hyperlipidemia, hepatic steatosis, and obesity. Single administration of ipragliflozin dose-dependently increased urinary glucose excretion, reduced blood glucose and plasma insulin levels, and improved glucose intolerance. Four-week repeated administration of ipragliflozin improved not only glucose tolerance, hyperglycemia, and hyperinsulinemia but also impaired insulin secretion, hyperlipidemia, hepatic steatosis, and obesity with a concomitant increase in urinary glucose excretion. In addition, ipragliflozin reduced plasma and liver levels of oxidative stress biomarkers (thiobarbituric acid reactive substances and protein carbonyl) and inflammatory markers (interleukin 6, tumor necrosis factor α, monocyte chemotactic protein-1, and c-reactive protein), and improved liver injury as assessed by plasma levels of aminotransferases. These results demonstrate that SGLT2 selective inhibitor ipragliflozin improves not only hyperglycemia but also diabetes/obesity-associated metabolic abnormalities in type 2 diabetic mice and suggest that ipragliflozin may be useful in treating type 2 diabetes with metabolic syndrome.

Ultrasound-guided radial artery catheterization in infants and small children.

OBJECTIVE: To determine whether ultrasound guidance increases the success rates, decreases the complication rates, and shortens the time to successful radial artery catheterization in infants and small children. DESIGN: Randomized study. SETTING: Single university-affiliated hospital. PATIENTS: Infants and children weighing 3-20 kg, undergoing cardiac surgery for congenital heart disease. INTERVENTION: We randomly assigned the right and left radial arteries of patients undergoing arterial catheterization to ultrasound-guided technique versus the usual palpation technique. MEASUREMENTS: The primary study endpoints were the rates of successful cannulation at first and within three attempts. The secondary endpoints were time to radial artery identification, number of attempts for successful cannulation, and rate of complications. MAIN RESULTS: Compared with palpation, ultrasound-guided radial artery catheterization was successful in 76.3% versus 35.6% of first attempts and in 94.9% versus 50.8% of arteries after three attempts (both comparisons, p < 0.01). The median time [interquartile range] to identification of the arteries (18.5 seconds [11.25-27.25] vs 30 seconds [17.75-39.5]) was significantly shorter (p < 0.01), the number of attempts [interquartile range] at successful cannulation (1 [1-1] vs 2 [1-2]) was significantly fewer (p < 0.01), and the proportion of hematomas (5.1% vs 25.4%) was significantly lower (p < 0.01) in the ultrasound group than those in the palpation group. CONCLUSIONS: In infants and small children, ultrasound-guided radial artery catheterization was more successful and expeditious than the usual palpation technique.

Application of fluorescent cholangiography to single-incision laparoscopic cholecystectomy.

BACKGROUND: Although the use of single-incision laparoscopic cholecystectomy (SILC) is spreading rapidly, this technique has disadvantages. It does not allow for sufficient surgical views to be obtained or for intraoperative radiographic cholangiography to be performed. Fluorescent cholangiography using a preoperative intravenous injection of indocyanine green (ICG) may be useful for identifying the biliary tract during both SILC and conventional laparoscopic cholecystectomy. METHODS: For seven patients undergoing SILC, 1 ml of ICG (2.5 mg) was administered by intravenous injection before the surgery. The prototype fluorescent imaging system consisted of a xenon light source and a 30° laparoscope (diameter, 10 mm) equipped with a charge-coupled device camera capable of filtering out light with wavelengths shorter than 810 nm. The laparoscope was introduced through an umbilical trocar. Fluorescent cholangiography then was performed by changing the color images to fluorescent images using a foot switch during dissection of the triangle of Calot. RESULTS: Fluorescent cholangiography identified the confluence between the cystic duct and the common hepatic duct in all seven patients before and throughout the dissection of the triangle of Calot. The interval from the injection of ICG to the first obtained fluorescent cholangiography before dissection of the triangle of Calot ranged from 35 to 75 min. CONCLUSIONS: Fluorescent cholangiography enabled real-time identification of the extrahepatic bile ducts during SILC without necessitating catheterization of the bile duct. Such properties of fluorescent cholangiography are expected to be helpful for ensuring the safety of SILC and expanding the indications for the procedure.

Peripheral sensitization caused by insulin-like growth factor 1 contributes to pain hypersensitivity after tissue injury.

Sensitization of primary afferent neurons is one of the most important components of pain hypersensitivity after tissue injury. Insulin-like growth factor 1 (IGF-1), involved in wound repair in injured tissue, also plays an important role in maintaining neuronal function. In the present study, we investigated the effect of tissue IGF-1 on nociceptive sensitivity of primary afferent neurons. Local administration of IGF-1 induced thermal and mechanical pain hypersensitivity in a dose-dependent manner, and was attenuated by IGF-1 receptor (IGF1R) inhibition. Tissue but not plasma IGF-1 levels, as determined by enzyme-linked immunosorbent assay, significantly increased after plantar incision. Immunohistochemistry revealed that IGF1R was predominantly expressed in neurons as well as in satellite glial cells in the dorsal root ganglion (DRG). Double-labeling immunohistochemistry showed that IGF1R expression colocalized with peripherin and TRPV1, but not with NF200 in DRG neurons. The IGF1R inhibitor successfully alleviated mechanical allodynia, heat hyperalgesia, and spontaneous pain behavior observed after plantar incision. Expression of phosphorylated Akt in DRG neurons significantly increased after plantar incision and was suppressed by IGF1R inhibition. These results demonstrate that increased tissue IGF-1 production sensitizes primary afferent neurons via the IGF1R/Akt pathway to facilitate pain hypersensitivity after tissue damage.

Vasopressin induces human mesangial cell growth via induction of vascular endothelial growth factor secretion.

Vasoactive hormones, growth factors, and cytokines are important in promoting mesangial cell growth, a characteristic feature of many glomerular diseases. Vascular endothelial growth factor (VEGF) is an endothelial mitogen and promoter of vascular permeability that is constitutively expressed in human glomeruli, but its role in the kidney is still unclear. In the present study, we investigated the ability of vasopressin (AVP) to stimulate VEGF secretion by and correlation with AVP-induced cell growth in human mesangial cells. AVP caused time- and concentration-dependent increases in VEGF secretion from human mesangial cells, which was in turn potently inhibited by a V(1A) receptor-selective antagonist, confirming that this secretion is a V(1A) receptor-mediated event. VEGF also induced mesangial cell growth which was completely inhibited on administration of an anti-VEGF neutralizing antibody. Further, AVP-induced mesangial cell growth was completely abolished by the V(1A) receptor-selective antagonist and partially inhibited by an anti-VEGF neutralizing antibody. These results suggest that AVP stimulates VEGF secretion by human mesangial cells via V(1A) receptors. This secreted VEGF may function as an autocrine hormone to regulate mesangial cell growth, a mechanism by which AVP might contribute to progressive glomerular diseases such as diabetic nephropathy.

Vasopressin regulates rat mesangial cell growth by inducing autocrine secretion of vascular endothelial growth factor.

Mesangial cell growth is a key feature of several glomerular diseases. Vascular endothelial growth factor (VEGF) is a potent mitogen of vascular endothelial cells and promoter of vascular permeability. Here, we examined the ability of vasopressin (AVP), which causes mesangial cell proliferation and hypertrophy, to stimulate VEGF secretion from cultured rat mesangial cells. AVP potently induced a time- and concentration-dependent increase in VEGF secretion in these cells, which was then inhibited by a V(1A) receptor-selective antagonist, confirming this is a V(1A) receptor-mediated event. VEGF also induced hyperplasia and hypertrophy in mesangial cells, which was completely abolished by an anti-VEGF antibody. In addition, AVP-induced hyperplasia and hypertrophy were completely inhibited by the V(1A) receptor-selective antagonist and partially abolished by the anti-VEGF antibody. These results indicate that AVP increases VEGF secretion in rat mesangial cells via V(1A) receptors and modulates mesangial cell growth not only by direct action but also through stimulation of VEGF secretion. This autocrine mechanism might contribute to glomerulosclerosis in renal diseases such as diabetic nephropathy.

Prediction of pediatric endotracheal tube size by ultrasonography.

BACKGROUND: Formulas based on age and height often fail to reliably predict the proper endotracheal tube (ETT) size in pediatric patients. We, thus, tested the hypothesis that subglottic diameter, as determined by ultrasonography, better predicts optimal ETT size than existing methods. METHODS: A total of 192 patients, aged 1 month to 6 yr, who were scheduled for surgery and undergoing general anesthesia were enrolled and divided into development and validation phases. In the development group, the optimal ETT size was selected according to standard age-based formulas for cuffed and uncuffed tubes. Tubes were replaced as necessary until a good clinical fit was obtained. Via ultrasonography, the subglottic upper airway diameter was determined before tracheal intubation. We constructed a regression equation between the subglottic upper airway diameter and the outer diameter of the ETT finally selected. In the validation group, ETT size was selected after ultrasonography using this regression equation. The primary outcome was the fraction of initial cuffed and uncuffed tube sizes, as selected through the regression formula, that proved clinically optimal. RESULTS: Subglottic upper airway diameter was highly correlated with outer ETT diameter deemed optimal on clinical grounds. The rate of agreement between the predicted ETT size based on ultrasonic measurement and the final ETT size selected clinically was 98% for cuffed ETTs and 96% for uncuffed ETTs. CONCLUSIONS: Measuring subglottic airway diameter with ultrasonography facilitates the selection of appropriately sized ETTs in pediatric patients. This selection method better predicted optimal outer ETT diameter than standard age- and height-based formulas.

Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice.

Excessive hepatic glucose production through the gluconeogenesis pathway is partially responsible for the elevated glucose levels observed in patients with type 2 diabetes mellitus (T2DM). The forkhead transcription factor forkhead box O1 (Foxo1) plays a crucial role in mediating the effect of insulin on hepatic gluconeogenesis. Here, using a db/db mouse model, we demonstrate the effectiveness of Foxo1 inhibitor, an orally active small-molecule compound, as a therapeutic drug for treating T2DM. Using mass spectrometric affinity screening, we discovered a series of compounds that bind to Foxo1, identifying among them the compound, 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (AS1842856), which potently inhibits human Foxo1 transactivation and reduces glucose production through the inhibition of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase mRNA levels in a rat hepatic cell line. Oral administration of AS1842856 to diabetic db/db mice led to a drastic decrease in fasting plasma glucose level via the inhibition of hepatic gluconeogenic genes, whereas administration to normal mice had no effect on the fasting plasma glucose level. Treatment with AS1842856 also suppressed an increase in plasma glucose level caused by pyruvate injection in both normal and db/db mice. Taken together, these findings indicate that the Foxo1 inhibitor represents a new class of drugs for use in treating T2DM.

Effects of the novel Foxo1 inhibitor AS1708727 on plasma glucose and triglyceride levels in diabetic db/db mice.

Recent evidence suggests that the forkhead transcription factor Foxo1 plays an important role in the regulation of glucose and triglyceride metabolism at the gene transcription level for glucose-6 phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and apolipoprotein C-III (apoC-III). Here, we report on the pharmacological effects of the novel Foxo1 inhibitor AS1708727, which we identified by compound screening. Chronic treatment of diabetic db/db mice with AS1708727 for four days significantly reduced blood glucose and triglyceride levels with decrease of gene expression levels of hepatic G6Pase, PEPCK, and apoC-III. No reports have yet examined the influence of Foxo1 inhibitors on these pharmacological effects. In this study, we newly identified a Foxo1 inhibitor compound capable of exerting both an anti-hypertriglyceridemic and anti-hyperglycemic effect. These effects were dependent on maintaining a stable blood concentration of AS1708727 and achieving a high rate of compound transition to the liver. We also investigated the action mechanism of AS1708727 on gluconeogenesis in vitro and in vivo. The compound inhibited gene expression of key gluconeogenic molecules and suppressed gluconeogenesis in Fao hepatocyte cells in vitro. Further, in the pyruvate challenge study using db/db mice in vivo, AS1708727 suppressed increases in blood glucose level by inhibiting gluconeogenic gene expression. These results indicate that the novel Foxo1 inhibitor AS1708727 may exert anti-diabetic and anti-hypertriglyceridemic effects by improving blood glucose and triglyceride metabolism at the gene expression level, and may represent a new class of drugs useful for treating type 2 diabetes mellitus and hypertriglyceridemia.

[How much dosage of heparin do you administer? The relationship between heparin dosage and activated coagulation time (ACT) value during cardiovascular surgery: a multi center investigations].

BACKGROUND: In cardiac surgery, unfractionated heparin is widely used for anticoagulation. There are differences of heparin dosages among institutions for cardiac surgery with and without cardiopulmonary bypass (CPB). The aim of this clinical investigation is to find out the optimal dosage of heparin for initiation of CPB. METHODS: In cardiac cases with CPB, patients' weight, initial dosage of heparin, ACT values after heparin administration, product name of heparin and ACT measurement devices were recorded. RESULTS: There were significant differences in initial dosages of heparin, basal ACT values and increment of ACT values per units of heparin among institutions. CONCLUSIONS: A significant difference was revealed among institutions regarding the initial heparin dosage for CPB, in spite of the same target of ACT. There was no evidence to determine the optimal dosage of heparin for initiation of CPB.

Phosphodiesterase 3 inhibition reduces platelet activation and monocyte tissue factor expression in knee arthroplasty patients.

BACKGROUND: Tissue damage during surgery activates platelets and provokes a prothrombic state. The current study attempted to determine the impact of phosphodiesterase 3 inhibitors on platelet activation, platelet-leukocyte aggregate formation, and monocyte tissue factor expression during and after total knee arthroplasty. METHODS: Thirty-four patients undergoing scheduled total knee arthroplasty were randomly assigned to receive either the phosphodiesterase 3 inhibitor milrinone or the same amount of saline perioperatively. The effects of milrinone on platelet and leukocyte function in vitro were then assessed in healthy volunteers. RESULTS: Perioperative infusion of milrinone significantly attenuated platelet activation; phosphorylation of intraplatelet p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Akt; and platelet-leukocyte aggregation. Furthermore, perioperative tissue factor expression on monocytes and fibrin monomer complex production were reduced by milrinone infusion in patients undergoing total knee arthroplasty. In vitro studies using adenosine diphosphate- and collagen-stimulated blood samples from healthy volunteers confirmed the antiplatelet effects and reduced monocyte tissue factor expression by milrinone. These studies further showed that platelet aggregation and integrin alpha(IIb)beta(3) activation were modified by intraplatelet phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways, and that P-selectin expression on platelets and platelet-leukocyte aggregation were modulated by intraplatelet p38 mitogen-activated protein kinase pathway. CONCLUSION: Continuous milrinone infusion has the potential to reduce platelet activation and monocyte tissue factor expression during the perioperative period in total knee arthroplasty. These events may be mediated in part by the ability of milrinone to reduce activation of intraplatelet mitogen-activated protein kinases and phosphatidylinositol 3-kinase. The clinical impact of phosphodiesterase 3 inhibition on perioperative hemostasis remains to be elucidated.

Ultrasound evidence of the optimal wrist position for radial artery cannulation.

PURPOSE: Radial artery cannulation is a common medical procedure for anesthesia and critical care. To establish the ideal wrist position for radial artery cannulation, we performed ultrasound examinations of the radial artery to investigate the effect of the angle of wrist extension on radial artery dimensions. CLINICAL FEATURES: Measurements were performed in 17 healthy subjects and 17 surgical patients scheduled for coronary artery bypass graft (CABG) surgery. The radial artery was echographically visualized near the styloid process of the radius at the wrist. Radial artery dimensions were measured at wrist joint angles of 0, 15, 30, 45, 60 and 75 degrees . OBSERVATIONS: In both groups, radial artery height was affected by the wrist joint angle. Vessel height was decreased at 60 degrees (one way ANOVA P = 0.027 vs 0 degrees ) and 75 degrees (P < 0.001 vs 0, 15, 45 degrees ) in healthy subject and at 75 degrees in CABG patients (P < 0.001 vs 0 degrees ). The mean differences in radial artery height at 0 and 75 degrees were 0.33 +/- 0.09 mm and 0.20 +/- 0.06 mm for healthy and CABG patients, respectively. Vessel width was not affected by wrist joint angulation up to 75 degrees of extension. CONCLUSION: Our results demonstrate that in healthy subjects, radial artery dimensions are unaltered when the wrist joint is extended up to an angle of 45 degrees . Extension at 60 degrees for healthy subjects and 75 degrees for CABG patients, however, results in a decrease in the height of the radial artery, which could possibly render arterial catheterization more difficult.

Evaluation of the antidiabetic effects of dipeptidyl peptidase-IV inhibitor ASP8497 in streptozotocin-nicotinamide-induced mildly diabetic mice.

Gastrointestinal hormone glucagon-like peptide-1 (GLP-1) has a potent glucose-dependent insulinotropic effect and is rapidly degraded by dipeptidyl peptidase (DPP)-IV. Therefore, the use of DPP-IV inhibitors is being actively explored as a novel approach to the treatment of type 2 diabetes. The present study investigated the antidiabetic effects of the DPP-IV inhibitor ASP8497 in streptozotocin-nicotinamide-induced mildly diabetic mice which possess aggravation of glucose tolerance due to loss of early-phase insulin secretion. ASP8497 exhibited good oral bioavailability with potent inhibition of plasma DPP-IV activity. This inhibitory activity lasted up to 24 h when administered at 5 mg/kg twice a day or 10 mg/kg once a day. A single oral administration of ASP8497 (0.3-3 mg/kg) significantly improved glucose tolerance by increasing plasma insulin and GLP-1 levels during the oral glucose or liquid meal tolerance tests. These effects were seen not only immediately, but also 8 h after administration. In contrast, ASP8497 (0.3-10 mg/kg) had no significant effect on blood glucose and plasma insulin levels under fasting conditions. Furthermore, repeated administration of ASP8497 (5 mg/kg twice a day or 10 mg/kg once a day) for 25 days significantly decreased nonfasting blood glucose and HbA(1c) levels. These results suggest that ASP8497 is a potent and long-acting DPP-IV inhibitor that improves glucose tolerance through glucose-dependent insulinotropic action via the elevation of the GLP-1 level in streptozotocin-nicotinamide-induced mildly diabetic mice. It is expected to be useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes.