Clinical decisions following implementation of asparaginase activity monitoring in pediatric patients with acute lymphoblastic leukemia: Experience from a single-center study.

We undertook this retrospective study to describe decisions made following asparaginase activity monitoring implementation at our center. Clinically apparent reactions (CARs) and asparaginase activity monitoring costs were described. Patients with acute lymphoblastic leukemia, aged <18 years who received asparaginase between April 2016 and September 2017, were included. Decisions made following receipt of asparaginase activity results were categorized as continuation, modification, premedication, or discontinuation. We included 129 patients (median age: 5.33 years) receiving 565 asparaginase doses. CARs were observed following 25 asparaginase doses (19/361 [5.3%] pegaspargase). A total of 224 asparaginase activity levels were ordered in 88 patients. Following receipt of 190 asparaginase activity results, asparaginase therapy was continued, modified, or premedicated in 188 (98.9%), 1 (0.005%), and 1 (0.005%) cases, respectively. Inadequate asparaginase activity was observed in three patients receiving Erwinia asparaginase. Asparaginase activity monitoring allowed patients with pegaspargase-associated CAR and adequate activity to continue therapy unchanged and was cost neutral.

Dermal permeation data and models for the prioritization and screening-level exposure assessment of organic chemicals.

High-throughput screening (HTS) models are being developed and applied to prioritize chemicals for more comprehensive exposure and risk assessment. Dermal pathways are possible exposure routes to humans for thousands of chemicals found in personal care products and the indoor environment. HTS exposure models rely on skin permeability coefficient (KP; cm/h) models for exposure predictions. An initial database of approximately 1000 entries for empirically-based KP data was compiled from the literature and a subset of 480 data points for 245 organic chemicals derived from testing with human skin only and using only water as a vehicle was selected. The selected dataset includes chemicals with log octanol-water partition coefficients (KOW) ranging from -6.8 to 7.6 (median=1.8; 95% of the data range from -2.5 to 4.6) and molecular weight (MW) ranging from 18 to 765g/mol (median=180); only 3% >500g/mol. Approximately 53% of the chemicals in the database have functional groups which are ionizable in the pH range of 6 to 7.4, with 31% being appreciably ionized. The compiled log KP values ranged from -5.8 to 0.1cm/h (median=-2.6). The selected subset of the KP data was then used to evaluate eight representative KP models that can be readily applied for HTS assessments, i.e., parameterized with KOW and MW. The analysis indicates that a version of the SKINPERM model performs the best against the selected dataset. Comparisons of representative KP models against model input parameter property ranges (sensitivity analysis) and against chemical datasets requiring human health assessment were conducted to identify regions of chemical properties that should be tested to address uncertainty in KP models and HTS exposure assessments.

Current and emerging drug treatment options for Alzheimer's disease: a systematic review.

Alzheimer's disease (AD) is a progressive and ultimately fatal condition that causes debilitating memory loss and extensive deterioration of cognitive and functional abilities. Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease. These therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability. The search for disease-modifying interventions has focused largely on compounds targeting the amyloid-ß pathway. To date, the treatments targeting this pathway, such as tramiprosate and semagacestat, have been unsuccessful in demonstrating efficacy in clinical stages of testing. At this point, it is likely that not only amyloid-ß aggregation but other possible neuronal mechanisms - such as hyperphosphorylated tau, neuro-inflammation and other processes - play important roles in the pathophysiology of this multifactorial disorder. Development of better disease models and biomarkers is essential for the advancement of knowledge of the disease mechanisms. This systematic review critically examines the efficacy and safety data for currently approved drugs and emerging treatments in AD, as well as discussing the present and future directions of innovation in this field.