Minimizing DILI risk in drug discovery - A screening tool for drug candidates.

Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates.

Diagnostic performance of multidetector CT angiography for assessment of coronary artery disease: meta-analysis.

PURPOSE: To review the literature on the diagnostic performance of multidetector computed tomographic (CT) angiography for assessment of symptomatic coronary artery disease, with conventional coronary angiography as the reference standard. MATERIALS AND METHODS: A PubMed and manual search of the literature published between January 1998 and May 2006 on use of multidetector CT angiography compared with coronary angiography in patients with symptomatic coronary artery disease was performed. Summary estimates of diagnostic odds ratio, sensitivity, and specificity were calculated. Random-effects models were used to compare the diagnostic performance of four-, 16-, and 64-detector CT angiographic units, and the proportion of nonassessable coronary arterial segments was evaluated. RESULTS: Fifty-four studies were included in the meta-analysis: 22 studies with four-detector CT angiography, 26 with 16-detector CT angiography, and six with 64-detector CT angiography. The pooled sensitivity and specificity for detecting a greater than 50% stenosis per segment were 0.93 (95% confidence interval [CI]: 0.88, 0.97) and 0.96 (95% CI: 0.96, 0.97) for 64-detector CT angiography, 0.83 (95% CI: 0.76, 0.90) and 0.96 (95% CI: 0.95, 0.97) for 16-detector CT angiography, and 0.84 (95% CI: 0.81, 0.88) and 0.93 (95% CI: 0.91, 0.95) for four-detector CT angiography, respectively. Results of regression analysis indicated that the diagnostic performance significantly improved with the newer generations of multidetector CT scanners (64- and 16-detector vs four-detector units), adjusted for exclusion of nonassessable segments, and contrast agent concentration used (P < .05). Simultaneously, the nonassessable proportion of segments significantly decreased with the newer generations of multidetector CT scanners, adjusted for heart rate, prevalence of significant disease, and mean age. CONCLUSION: With the newer generations of multidetector CT scanners, the diagnostic performance for the assessment of coronary artery disease has significantly improved, and the proportion of nonassessable segments has decreased.

A simple method to estimate cardiac function during routine multi-row detector CT exams.

Cardiac dysfunction may be suggested at computed tomography (CT) exams by the presence of morphological abnormalities such as cardiac enlargement and thickening of the pulmonary interlobular septa. However, these morphological signs are non specific. We evaluated whether right-to-left cardiac transit time of contrast during single-level timing scans could predict the cardiac output and ejection fraction. In a consecutive group of 100 patients referred for body CT, a preliminary single-level study was used to measure the right-to-left ventricular transit time of intravenously injected contrast medium. In all these patients, the cardiac index (cardiac output corrected for body surface area, CI) and ejection fraction (EF) were calculated using cardiac magnetic resonance imaging (CMR). Data of the first half (50 patients, group A) were used to establish a method and concept to predict the cardiac index and ejection fraction with CT. The method was validated in the next half (50 patients, group B) by comparing the predicted CT results with those obtained with CMR. There was a good correlation of the observed CI with CMR and observed transit time on CT in group B (P < 0.05; R(2) 0.70 ). Functional CT estimates of CI and EF in group B correlated well with the CMR results for CI and EF (P < 0.05; R(2) 0.66 for CI and P < 0.05; R(2) 0.49 for EF). The presence of a right-to-left ventricular transit time of more than 10.5 s indicated cardiac dysfunction with a specificity and positive predictive value of 100%. Right-to-left transit time obtained during routine body CT exams can provide valuable physiological information on global cardiac function.

Coronary artery calcium scoring using ECG-gated multidetector CT: effect of individually optimized image-reconstruction windows on image quality and measurement reproducibility.

OBJECTIVE: We studied the effect of using individually optimized image-reconstruction windows on image quality and measurement reproducibility in coronary artery calcium scoring using ECG-gated multidetector CT (MDCT). SUBJECTS AND METHODS: In 50 patients, the coronary arteries were investigated twice with ECG-gated MDCT with 500-msec rotation time. Per scan, three sets of images were reconstructed, respectively, at an image-reconstruction window of 40%, 50%, and 60% of the R-R interval. Image quality was assessed, and the optimal image-reconstruction window per scan and per coronary territory was determined. The interscan variability of calcium mass measurements was calculated for different strategies (use of fixed image-reconstruction window [40%, 50%, or 60%] versus individually optimized image-reconstruction window). RESULTS: A significant improvement in image quality was obtained by selecting the best of three reconstructed data sets (mean image quality score, 4.4 vs 3.7; p < 0.001). Even with individually optimized image-reconstruction window values, we obtained high values for interscan variability (mean +/- SD, 27% +/- 22% vs 31% +/- 35% with a fixed image-reconstruction window). CONCLUSION: The use of individually optimized image-reconstruction windows leads to a significant improvement in image quality. However, interscan variability of calcium mass measurements remains high.