Clinically Significant Bradycardia and Hypotension Following Consumption of Betel Leaf in a Patient Treated for Chronic Atrial Fibrillation.

Purpose: A case of new onset bradycardia and hypotension following betel leaf consumption in combination with verapamil and metoprolol in an atrial fibrillation (AF) patient. Summary: A 66-year-old Nigerian woman presented to the emergency department for evaluation of multiple near syncope episodes with underlying AF and slow ventricular response. After initial evaluation, the patient disclosed she had ingested several betel leaves that morning. She was admitted for observation of severe, progressive hypotension and symptomatic bradycardia. Her past medical history included AF, type 2 diabetes, asthma, obesity, hypertension and hypothyroidism. Her home medications consisted of spironolactone, metoprolol succinate, and verapamil ER. Upon admission, her home medications were held. She received IV fluids and atropine .4 mg IV as needed for symptomatic bradycardia. Approximately 18 h following admission, her vital signs stabilized and her labs returned to baseline. She remained stable and was discharged with a recommendation to continue her home medications at prescribed doses with reduced doses of verapamil and metoprolol and to follow-up with her primary care provider. Conclusion: A patient with a history of AF developed significant hypotension and symptomatic bradycardia after betel leaf consumption resulting in an overnight critical care unit admission. The use of betel leaf is not common in the United States; however, practitioners should be cognizant of the use of complementary and alternative medications like betel leaf and incorporate this knowledge in patient evaluation. Patients consuming betel leaf or betel nut should be evaluated for cardiovascular effects as well as laboratory evaluation for organ damage.

Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro).

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.