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INTRODUCTION: Given that adverse drug effects (ADEs) have led to post-market patient harm and subsequent drug withdrawal, failure of candidate agents in the drug development process, and other negative outcomes, it is essential to attempt to forecast ADEs and other relevant drug-target-effect relationships as early as possible. Current pharmacologic data sources, providing multiple complementary perspectives on the drug-target-effect paradigm, can be integrated to facilitate the inference of relationships between these entities. OBJECTIVE: This study aims to identify both existing and unknown relationships between chemicals (C), protein targets (T), and ADEs (E) based on evidence in the literature. MATERIALS AND METHODS: Cheminformatics and data mining approaches were employed to integrate and analyze publicly available clinical pharmacology data and literature assertions interrelating drugs, targets, and ADEs. Based on these assertions, a C-T-E relationship knowledge base was developed. Known pairwise relationships between chemicals, targets, and ADEs were collected from several pharmacological and biomedical data sources. These relationships were curated and integrated according to Swanson's paradigm to form C-T-E triangles. Missing C-E edges were then inferred as C-E relationships. RESULTS: Unreported associations between drugs, targets, and ADEs were inferred, and inferences were prioritized as testable hypotheses. Several C-E inferences, including testosterone → myocardial infarction, were identified using inferences based on the literature sources published prior to confirmatory case reports. Timestamping approaches confirmed the predictive ability of this inference strategy on a larger scale. CONCLUSIONS: The presented workflow, based on free-access databases and an association-based inference scheme, provided novel C-E relationships that have been validated post hoc in case reports. With refinement of prioritization schemes for the generated C-E inferences, this workflow may provide an effective computational method for the early detection of potential drug candidate ADEs that can be followed by targeted experimental investigations.

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PURPOSE: This single-center, retrospective cohort study investigated the effects of timing of initiating home neuropsychiatric medications (NPMs) on sedation-related outcomes. MATERIALS AND METHODS: Subjects included adult medical intensive care unit (MICU) patients who had an NPM on their admission medication list; intubated before or on arrival to the intensive care unit (ICU); and were on benzodiazepine-based sedation. The intervention assessed was the timing of the initiation of home NPMs: early (≤5days) vs. late (>5days) into the ICU stay. RESULTS: There were 56 and 53 patients in the early and late restart groups, respectively. Early cohort patients maintained a median daily RASS of -1.5, while late cohort patients had a median daily RASS of -2.0 (p=0.02). The effect was driven by the subgroup of patients on home anti-depressant therapy who were restarted early on these agents. The early restart group had a higher percentage of days with RASS scores within goal (p=0.01) and less delirium (p=0.02). Early restarting of home NPMs was associated with a non-significant decrease in ventilator days compared with late restarting (p=0.11). CONCLUSIONS: Restarting home NPMs was associated with lighter sedation levels and less delirium.

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STUDY OBJECTIVE: This study was designed to prospectively evaluate the in vivo activities of drug transporters, metabolizing enzymes, and pharmacokinetics in patients with chronic kidney diseases (CKD) caused by glomerulonephritis and nonglomerular etiologies. DESIGN: A prospective study design. PARTICIPANTS: Eighteen adults with CKD. SETTING: General Clinical Research Center at the University of North Carolina and University of Pittsburgh. MEASUREMENT AND MAIN RESULTS: Blood and urine were collected and assayed for fexofenadine (transporter function) as well as flurbiprofen and 4-hydroxyflurbiprofen (CYP2C9 function). CYP3A4 activity was assessed by the erythromycin breath test. In patients with glomerulonephritis, the apparent oral clearance of fexofenadine (representing transporter activity) was 58.8 ± 34.4 L/hour, documenting a 40% reduction compared with previous data in healthy controls. The CYP2C9 pathway (4-hydroxyflurbiprofen formation clearance) was similar in all the patients with CKD and was concordant with previous reports of patients with end-stage renal disease (ESRD) and healthy controls. For flurbiprofen, patients with glomerulonephritis had higher oral clearance than those with nonglomerular CKD, suggesting higher unbound fraction and enhanced metabolism through other (non-CYP2C9) routes. No statistically significant differences in CYP3A4 activity were observed in either group of patients or when compared with results from previous studies of patients with ESRD or healthy controls. CONCLUSIONS: The current study suggests no statistically significant differences in the in vivo activity of CYP2C9 and CYP3A4 in patients with either glomerulonephritis or nonglomerular CKD. However, there are clinical differences in transporter function as defined by at least a 25% reduction in activity in glomerulonephritis as opposed to healthy controls. A similarity in the in vivo function between patients with glomerulonephritis and ESRD, and between patients with glomerulonephritis and nonglomerular CKD was present despite significant differences in kidney function. Further in vivo and in vitro studies are necessary to fully understand the physiologic and disease-specific nuances that contribute to alterations in drug disposition in patients with kidney diseases.

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