ABSTRACT
The diastereoselective synthesis and biological activity of piperidine-3,4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans-4-aryl-piperidine-3-ols (22) were more potent than the cis diastereomers (20).
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Lymphoma, Large-Cell, Anaplastic/drug therapy , Pyrroles/chemistry , Pyrroles/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazines/chemistry , Triazines/therapeutic use , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Crystallography, X-Ray , Humans , Lymphoma, Large-Cell, Anaplastic/enzymology , Mice, SCID , Models, Molecular , Piperidines/chemistry , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrroles/pharmacokinetics , Rats, Sprague-Dawley , Receptor Protein-Tyrosine Kinases/metabolism , Triazines/pharmacokineticsABSTRACT
Background: Didactics play a key role in medical education. There is no standardized didactic evaluation tool to assess quality and provide feedback to instructors. Cognitive load theory provides a framework for lecture evaluations. We sought to develop an evaluation tool, rooted in cognitive load theory, to assess quality of didactic lectures. Methods: We used a modified Delphi method to achieve expert consensus for items in a lecture evaluation tool. Nine emergency medicine educators with expertise in cognitive load participated in three modified Delphi rounds. In the first two rounds, experts rated the importance of including each item in the evaluation rubric on a 1 to 9 Likert scale with 1 labeled as "not at all important" and 9 labeled as "extremely important." In the third round, experts were asked to make a binary choice of whether the item should be included in the final evaluation tool. In each round, the experts were invited to provide written comments, edits, and suggested additional items. Modifications were made between rounds based on item scores and expert feedback. We calculated descriptive statistics for item scores. Results: We completed three Delphi rounds, each with 100% response rate. After Round 1, we removed one item, made major changes to two items, made minor wording changes to nine items, and modified the scale of one item. Following Round 2, we eliminated three items, made major wording changes to one item, and made minor wording changes to one item. After the third round, we made minor wording changes to two items. We also reordered and categorized items for ease of use. The final evaluation tool consisted of nine items. Conclusions: We developed a lecture assessment tool rooted in cognitive load theory specific to medical education. This tool can be applied to assess quality of instruction and provide important feedback to speakers.
ABSTRACT
INTRODUCTION: Perimortem cesarean section is a rare, time-critical, and potentially life-saving procedure for both the fetus and mother. This makes perimortem cesarean section an ideal and recommended subject for simulation learning and practice. METHODS: Various attempts have been made to produce models to simulate emergency caesarian sections. We designed a cost-effective and easy to assemble model that can be used with any high fidelity simulator.The model was used as part of a simulation education module that is part of resident educational conferences. After the simulation day, residents were asked to fill out an anonymous online survey using a 5-point Likert scale. RESULTS: Thirty-four emergency medicine residents took part in a perimortem caesarian section case. Nine (26%) completed the online survey. Eight respondents agreed or strongly agreed [4.33 (0.71)] that the model helped to familiarize them with a perimortem cesarean section. Eight residents also agreed or strongly agreed [4 (0.87)] that they were better prepared to perform this procedure, and 9 residents felt that knowledge from this session would help with their emergency department rotations [4.11 (0.33)]. Six residents agreed or strongly agreed that this model was a good replication of human anatomy [3.78 (0.97)]. All respondents agreed or strongly agreed [4.56 (0.53)] that this session enhanced learning more than traditional lectures and reading alone. CONCLUSION: We present here an inexpensive, easy to make, and portable model, which can be used to simulate an emergency caesarian section.
Subject(s)
Cesarean Section/education , Emergency Medical Services , Maternal Death/prevention & control , Models, Anatomic , Female , Humans , Infant, Newborn , Medical Staff, Hospital/education , Pregnancy , Surveys and QuestionnairesABSTRACT
Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.