Search

The purpose of these studies was to develop ex vivo tissue-based and in vitro cell-based assays using multi-electrode array (MEA) technology to predict seizure liability at the early stage of preclinical studies. Embryonic rat hippocampal neurons and adult rat hippocampal slices were used in these studies. Spontaneous activity in cultured neurons and evoked field potentials in hippocampal brain slices were recorded using MEA technology. Six seizurogenic compounds bicuculline, pentylenetetrazole, picrotoxin, gabazine, 4-Aminopyridine and BMS-A increased field potential area and peak number in brain slices and spontaneous spike activity in hippocampal neurons. Physostigmine, another seizurogenic compound, had no effect on brain slices at lower concentrations (0.1, 1, and 10 μM), and mildly increased field potential area at 100 μM. However, physostigmine induced multiple peaks in evoked field potential starting at 10 μM. Physostigmine showed greater potency in the cultured neuron assay, and increased spike rates in the nanomolar range. Two seizurogenic compounds, BMS-B and BMS-C increased the spontaneous activity in hippocampal neurons, but did not increase area and peak number of field potentials in brain slices. These findings suggest that MEA technology and rat hippocampal brain slices or rat embryonic hippocampal neurons, may be useful as early, predictive in vitro assays for seizure liability., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Preclinical assessment for alterations in cardiac ventricular function for drug candidates has not been a focus of ICH S7b guidelines for cardiovascular safety studies, but there is growing interest given that the cardiovascular risk is associated with positive and negative inotropes., Methods: From 2003 through 2013, 163 telemetry studies with left-ventricular function analyses were conducted in dogs and monkeys at Bristol Myers Squibb (BMS) in support for drug development programs. The ability of the telemetry system to detect changes in cardiac contractility was verified with positive control agents pimobendan and atenolol. Control data from a subset of studies were analyzed to determine dP/dt reference range values, and minimum detectable mean differences (control vs. treated) for statistical significance., Results: Median minimum detectable differences for dogs ranged from 14 to 21% for positive dP/dt and 11 to 21% for negative dP/dt. For monkeys, median minimum detectable differences were 25 and 14% for positive and negative dP/dt, respectively. For BMS programs, 15 drug candidates were identified that produced primary effects on contractility. Changes in contractility that were associated with, and potentially secondary to, drug-related effects on heart rate or systemic blood pressure were observed with an additional 29 drug candidates., Discussion: Changes in contractility have been observed in large animals during drug development studies at BMS over the past 10years. Model sensitivity has been demonstrated and a dP/dt beat-to-beat cloud analysis tool has been developed to help distinguish primary effects from those potentially secondary to systemic hemodynamic changes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives/hypothesis: Maxillofacial fractures often occur with serious concomitant injury in trauma patients, and knowledge of the type and severity of associated injuries can assist in rapid assessment and treatment. The objective was to identify the most commonly occurring injuries associated with facial fractures in severely injured trauma patients., Study Design: Review of medical records., Methods: A retrospective review was made of 151 patients with facial fractures presenting to a level-one trauma center over a 4-year span. All patients had an injury severity score of 12 or greater. Chart data recorded included demographics, etiology, presentation, facial fracture site, concomitant injury, imaging studies, hospital stay and course, interventions, and outcome., Results: The most common cause or origin of facial fracture was assault (41%), followed by motor vehicle accident (26.5%). Orbital fracture was the most common overall facial fracture (24.2%), with nasal fractures being the most common isolated fracture (23.2%). Cerebral hematoma occurred in 43.7% of patients, with subdural hematoma being the most frequent. Pulmonary injury was the second most commonly associated injury (31.1%) with lung contusion being the most frequent. Seventy-two patients (42%) required intubation, and 22 (14.8%) required tracheostomy during their hospital stay. The hospital complication rate was 50.3% and included primarily pulmonary complications, septicemia, renal failure, and severe anemia. Thirteen patients died during their hospital stay; 11 of them died of neurologic injuries, 1 of pulmonary failure, and 1 of overwhelming sepsis., Conclusions: Cerebral and pulmonary injuries are often associated with maxillofacial fractures in severely injured trauma patients. Knowledge of these associated injuries provides useful strategies for patient care and prevention of further complications. A multidisciplinary and coordinated approach is important for optimum stabilization and ongoing treatment of patients with facial fractures.

It has been found that the current NF identity test for microcrystalline cellulose is actually an assay of the response of the material to energy dissipation expended during the analysis procedure. The blending step needed to effect suspension of the material results in a disintegration of the microcrystalline particles and a concomitant increase in the viscosity of the slurry viscosity. These effects were shown not to be unique functions of either blender speed or blending time. The passage or failure of a given sample of microcrystalline cellulose under the conditions of the identity test was found to be a consequence of the test conditions used. Any given sample of microcrystalline cellulose can be made to pass the identity test if it is blended for a sufficiently long time or at a sufficiently high speed. The test is sufficient, however, to differentiate powdered cellulose from powdered cellulose.

A general review of the methods available for the physical characterization of pharmaceutical solids is presented. The techniques are classified as being on the molecular level (properties capable of being detected in an ensemble of individual molecules), the particulate level (properties which can be detected through the analysis of an ensemble of particles), and the bulk level (properties which can be measured only using a relatively large amount of material). The molecular-level properties discussed are infrared spectroscopy and nuclear magnetic resonance spectrometry, the particulate-level properties discussed are particle morphology, particle size distribution, powder X-ray diffraction, and thermal methods of analysis, and the bulk-level properties discussed are surface area, porosity and pore size distribution, and powder flow characteristics. Full physical characterization of three modifications of lactose (hydrous, anhydrous, and Fast-Flo) is presented to illustrate the type of information which can be obtained using each of the techniques discussed.