Exposure-response analysis of drug-induced QT interval prolongation in telemetered monkeys for translational prediction to human.

INTRODUCTION: The preclinical in vivo assay for QT prolongation is critical for predicting torsadogenic risk, but still difficult to extrapolate to humans. This study ran preclinical tests in cynomolgus monkeys on seven QT reference drugs containing the drugs used in the IQ-CSRC clinical trial and applied exposure-response (ER) analysis to the data to investigate the potential for translational information on the QT effect. METHODS: In each of six participating facilities in the J-ICET project, telemetered monkeys were monitored for 24 h following administration of vehicle or 3 doses of test drugs, and pharmacokinetic profiles at the same doses were evaluated separately. An individual rate-corrected QT interval (QTca) was derived and the vehicle-adjusted change in QTca from baseline (∆∆QTca) was calculated. Then the relationship of concentration to QT effect was evaluated by ER analysis. RESULTS: For QT-positive drugs in the IQ-CSRC study (dofetilide, dolasetron, moxifloxacin, ondansetron, and quinine) and levofloxacin, the slope of the total concentration-QTca effect was significantly positive, and the QT-prolonging effect, taken as the upper bound of the confidence interval for predicted ∆∆QTca, was confirmed to exceed 10 ms. The ER slope of the negative drug levocetirizine was not significantly positive and the QTca effect was below 10 ms at observed peak exposure. DISCUSSION: Preclinical QT assessment in cynomolgus monkeys combined with ER analysis could identify the small QT effect induced by several QT drugs consistently with the outcomes in humans. Thus, the ER method should be regarded as useful for translational prediction of QT effects in humans.

Disaster Victim Identification: Psychological Distress and Posttraumatic Stress in Dentists After the 2011 Fukushima Disaster.

OBJECTIVE: To evaluate the correlates of psychological responses in dentists who conducted disaster victim identification (DVI) in Fukushima following the 2011 earthquake/tsunami/nuclear disaster. METHOD: Self-report questionnaires were administered to 49 male dentists six to nine months after the disaster. Psychological distress and posttraumatic stress were measured using the General Health Questionnaire-30 (GHQ-30) and Impact of Event Scale-Revised (IES-R), respectively. Independent variables included sociodemographic characteristics, participant disaster exposures, DVI-related exposures, and fear of radiation exposure during DVI. Hierarchical multiple regression analysis was performed to examine independent-dependent variable relations. RESULTS: Thirty-eight participants (77.6%) had examined ≥ 40 corpses, 20 (40.8%) reported ≥ 4 corpse-related exposures, and six (12.2%) reported ≥ 5 gruesome corpse exposures. Mean (SD) GHQ-30 and IES-R scores were 5.08 (5.31) and 9.90 (10.1), respectively. Higher levels of psychological distress were associated with younger age (adjusted ß = -0.29), extensive property loss (ß = 0.34), and anxiety for the future (ß = 0.33). Higher levels of posttraumatic stress were associated with extensive property loss (adjusted R2 = 17.7%, ß = 0.30). Neither outcome was associated with DVI-related exposures or fear of radiation exposure during DVI (p < 0.05). CONCLUSIONS: Dentists' psychological burden was associated with disaster, but not DVI, exposures.

Laser-Doppler vibrating tube densimeter for measurements at high temperatures and pressures.

A laser-Doppler vibrometer was used to measure the vibration of a vibrating tube densimeter for measuring P-V-T data at high temperatures and pressures. The apparatus developed allowed the control of the residence time of the sample so that decomposition at high temperatures could be minimized. A function generator and piezoelectric crystal was used to excite the U-shaped tube in one of its normal modes of vibration. Densities of methanol-water mixtures are reported for at 673 K and 40 MPa with an uncertainty of 0.009 g/cm3.

[Neoadjuvant chemotherapy using TS-1 and CDDP against large type 3/Type 4/Bulky N 2 advanced gastric cancer].

This study was conducted to assess therapeutic results following neoadjuvant chemotherapy (NAC) for large type 3/type 4/Bulky N 2 advanced gastric cancer having a poor prognosis following resection. The subjects consisted of cases (< or = 75 y.o.) having large type 3 (diameter > or = 8 cm), type 4 or Bulky N 2 gastric cancer curable by resection based on preoperative imaging diagnostics. The NAC regimen consisted of TS-1 at 80-120 mg/body on days 1-21 p. o. and CDDP at 60 mg/m2 on day 8 divided. Upon completion of two courses of 4 weeks per course, gastrectomy with > or = D2 lymph node dissection was carried out on days 21-34. The average age of the subjects was 60.7 years, and the therapy completion rate was 80% (8/10 cases). Five of ten cases were responders diagnosed as grade 2 by histopathological examination of excised specimens (response rate 50%). Two of five responders were histopathologically evaluated as down-staging as a result of NAC (Stage III A--> f Stage I A, Stage IV--> f Stage I A). Three of the five non-responders have relapsed, and the relapse-free interval was an average 238 days. In the five responders,one has relapsed at 331 days,while the other 4 responders have shown no relapse yet. Although NAC consisting of TS-1 and CDDP is considered to be effective against advanced gastric cancer, a phase III study with surgical treatment only will be necessary to confirm its true value.

QT PRODACT: in vivo QT assay in the conscious dog for assessing the potential for QT interval prolongation by human pharmaceuticals.

The goal of the present study was to examine the utility of the conscious dog model by assessing the QT-interval-prolonging potential of ten positive compounds that have been reported to induce QT interval prolongation in clinical use and seven negative compounds considered not to have such an effect. Three doses of test compounds or vehicle were administered orally to male beagle dogs (n=4), and telemetry signals were recorded for 24 h after administration. All positive compounds (astemizole, bepridil, cisapride, E-4031, haloperidol, MK-499, pimozide, quinidine, terfenadine, and thioridazine) caused a significant increase in the corrected QT (QTc) interval, with a greater than 10% increase achieved at high doses. In contrast, administration of negative compounds (amoxicillin, captopril, ciprofloxacin, diphenhydramine, nifedipine, propranolol, and verapamil) did not produce any significant change in the QTc interval, with the exception of nifedipine that may have produced an overcorrection of the QTc interval due to increased heart rate. The estimated plasma concentrations of the positive compounds that caused a 10% increase in the QTc interval were in good agreement with the plasma/serum concentrations achieved in humans who developed prolonged QT interval or torsade de pointes (TdP). Although careful consideration should be given to the interpretation of QT data with marked heart rate change, these data suggest that an in vivo QT assay using the conscious dog is a useful model for the assessment of QT interval prolongation by human pharmaceuticals.

QT PRODACT: in vivo QT assay with a conscious monkey for assessment of the potential for drug-induced QT interval prolongation.

In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n=3-4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett's formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and/or disagreement with Bazett's formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation.

Malignant lymphoma occurring in the residual stomach following gastrectomy: plus discussion based on the literature in Japan.

Malignant lymphoma of the remnant stomach was diagnosed in a 53-year-old man 8 years after gastrectomy for a perforated gastric ulcer. Endoscopic examination demonstrated protruding lesions spreading over the entire residual stomach, and biopsy revealed malignant lymphoma. Rectal cancer was diagnosed simultaneously. The residual stomach was completely excised, with splenectomy, in parallel with low anterior resection of the rectum. Histological studies revealed that the lesion in the residual stomach was a lymphoma of the diffuse, large-cell type, according to the Lymphoma-Leukemia Study Group (LSG) classification, with positivity for CD20 and CD45RA, leading to a diagnosis of B-cell lymphoma. Helicobacter pylori microorganisms were found on the luminal surface of the tumor. Despite postoperative chemotherapy, the patient died of disseminated lymphoma 34 months later. Although malignant lymphoma occurring in the residual stomach following gastrectomy is rare, particular attention should be given to the possible presence of a malignant tumor when examining the residual stomach following gastrectomy.

A patient with small-cell carcinoma of the stomach with long survival after percutaneous microwave coagulating therapy (PMCT) for liver metastasis.

A 66-year-old man was admitted to our hospital with epigastralgia. Preoperative examinations revealed an 8.0 x 8.0-cm, Borrmann type 2 tumor in the posterior wall of the cardia, without distant metastases. Total gastrectomy with pancreato-splenectomy and regional lymph node dissection was performed curatively. Histologically, the tumor was composed mainly of small cells with hyperchromatic nuclei and scant cytoplasm, which showed positive staining for Grimelius, gamma-neuron-specific enolase (gamma-NSE), chromogranin A, and serotonin. About 10 months after the operation, a solitary tumor was revealed in S8 of the liver by abdominal computed tomography (CT), and it was histologically confirmed by needle biopsy to be a metastasis of the small-cell carcinoma from the stomach. Instead of hepatectomy, percutaneous microwave coagulating therapy (PMCT) was indicated, because of the patients' liver dysfunction (ICG R15, 39.9%); CT showed complete necrosis of the metastatic focus in the liver after the PMCT. Now, 33 months after the first detection of the liver metastasis (43 months after the gastrectomy), the patient is still alive without any growth of the liver metastasis. The 67 previously reported cases of small-cell carcinoma of the stomach in Japan, including ours, are also reviewed.