Browsing by Subject "Cardiac glycosides"

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    Controversial COVID-19 Cures: Hydroxychloroquine and Oleander Pediatric Ingestion Simulation Cases
    (Springer, 2022-06-21) Solano, Joshua J.; Mendelsohn, Rebecca A.; Ahmed, Rami A.; Shih, Richard D.; Clayton, Lisa M.; Alter, Scott M.; Hughes, Patrick G.; Emergency Medicine, School of Medicine
    Introduction: The use of hydroxychloroquine has dramatically increased since being touted as a potential therapeutic in combating coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus. This newfound popularity increases the risk of accidental pediatric ingestion, whereby just one or two tablets causes morbidity and mortality from seizures, cardiac dysrhythmias, and cardiogenic shock. The unique management of hydroxychloroquine overdose makes it imperative for emergency medicine physicians to have familiarity with treating this condition. Similarly, ​​during the COVID-19 pandemic, there have been publicized cases touting extracts of oleander as being a potential therapeutic against the illness. Since it is commonly available and potentially lethal ingestion with a possible antidote, we developed a simulation case based on the available literature. The two cases were combined to create a pediatric toxicology curriculum for emergency medicine residents and medical students. Both of these treatments were selected as simulation cases since they were being touted by prominent national figures as potential cures for COVID-19. Methods: Two series of simulation cases were conducted in a high-fidelity simulation lab with emergency medicine residents and medical students. The hydroxychloroquine simulation case involved the management of a four-year-old male who presented to the emergency department with nausea, vomiting, and tachycardia after ingesting hydroxychloroquine tablets. As the case unfolded, the child became increasingly unstable, eventually experiencing QT prolongation, torsades de pointes, and ventricular fibrillation arrest requiring appropriate resuscitation to achieve a return of spontaneous circulation. The oleander simulation case involved the management of a three-year-old male who presented to the emergency department with nausea, vomiting, and tachycardia after ingesting parts of an unknown plant. As that case progresses, the child becomes increasingly unstable, eventually experiencing atrial fibrillation, bradycardia, and degenerating into pulseless electrical activity and cardiac arrest requiring appropriate resuscitation to achieve the return of spontaneous circulation. Both series of simulation cases were modifiable based on trainee level and had the ability to include ancillary emergency department staff. Results: Each simulation case was performed six times at our simulation center, with a total of 22 learners for the hydroxychloroquine case, and 14 for the oleander case. Through pre- and post-simulation confidence assessments, learners demonstrated increases in knowledge of toxidromes, evaluating pediatric overdoses, treating cardiac dysrhythmias, performing pediatric advanced life support, and managing post-arrest care. Learners also demonstrated improvements in recognizing the unique treatment of hydroxychloroquine and oleander toxicity, the toxic dose of both substances in a child, and the most common electrolyte anomaly seen in each toxicity. Discussion: Simulation training enables learners to manage rare and complex disease processes. These cases were designed to educate trainees in recognizing and treating rare overdoses of emerging "therapeutics" that were touted early in the COVID-19 pandemic.
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    Synthesis and Biological Evaluation of Cardiac Glycosides for Cancer Therapy by Targeting the DNA Damage Response
    (Wiley, 2022) Ainembabazi, Diana; Geng, Xinran; Gavande, Navnath S.; Turchi, John J.; Zhang, Youwei; Medicine, School of Medicine
    Cardiac glycosides (CGs) are bioactive compounds originally used to treat heart diseases, but recent studies have demonstrated their anticancer activity. We previously demonstrated that Antiaris toxicaria 2 (AT2) possesses anticancer activity in KRAS mutated lung cancers via impinging on the DNA damage response (DDR) pathway. Toward developing this class of molecules for cancer therapy, herein we report a multistep synthetic route utilizing k-strophanthidin as the initial building block for determination of structure-activity relationships (SARs). A systematic structural design approach was applied that included modifications of the sugar moiety, the glycoside linker, stereochemistry, and lactone ring substitutions to generate a library of O-glycosides and MeON-neoglycosides derivatives. These molecules were screened for their anticancer activities and their impact on DDR signaling in KRAS mutant lung cancer cells. These results demonstrate the ability to chemically synthesize CG derivatives and define the SARs to optimize AT2 as a cancer therapeutic.