Development of a novel remote-controlled and self-contained audiovisual-aided interactive system for immobilizing claustrophobic patients.

In radiotherapy, only a few immobilization systems, such as open-face mask and head mold with a bite plate, are available for claustrophobic patients with a certain degree of discomfort. The purpose of this study was to develop a remote-controlled and self-contained audiovisual (AV)-aided interactive system with the iPad mini with Retina display for intrafractional motion management in brain/H&N (head and neck) radiotherapy for claustrophobic patients. The self-contained, AV-aided interactive system utilized two tablet computers: one for AV-aided interactive guidance for the subject and the other for remote control by an operator. The tablet for audiovisual guidance traced the motion of a colored marker using the built-in front-facing camera, and the remote control tablet at the control room used infrastructure Wi-Fi networks for real-time communication with the other tablet. In the evaluation, a programmed QUASAR motion phantom was used to test the temporal and positional accuracy and resolution. Position data were also obtained from ten healthy volunteers with and without guidance to evaluate the reduction of intrafractional head motion in simulations of a claustrophobic brain or H&N case. In the phantom study, the temporal and positional resolution was 24 Hz and 0.2 mm. In the volunteer study, the average superior-inferior and right-left displacement was reduced from 1.9 mm to 0.3 mm and from 2.2 mm to 0.2 mm with AV-aided interactive guidance, respectively. The superior-inferior and right-left positional drift was reduced from 0.5 mm/min to 0.1 mm/min and from 0.4 mm/min to 0.04 mm/min with audiovisual-aided interactive guidance. This study demonstrated a reduction in intrafractional head motion using a remote-controlled and self-contained AV-aided interactive system of iPad minis with Retina display, easily obtainable and cost-effective tablet computers. This approach can potentially streamline clinical flow for claustrophobic patients without a head mask and also allows patients to practice self-motion management before radiation treatment delivery.

Preclinical strategy to reduce clinical hepatotoxicity using in vitro bioactivation data for >200 compounds.

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.