A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation.

Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1ß and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.

COVID-19 Acute Respiratory Distress Syndrome and Pulmonary Embolism: A Case Report of Nebulized Nitroglycerin and Systemic Thrombolysis For Right Ventricular Failure.

BACKGROUND: Acute respiratory compromise caused by complications of COVID-19, such as acute respiratory distress syndrome (ARDS) or thromboembolic disease, is a complex syndrome with unique challenges in treatment. Management often requires time and intensive care through a multiprofessional, multispecialty approach. Initial management is particularly challenging within the limited-resource environment of the emergency department (ED). The emergency physician's toolbox of treatments with reasonably rapid onset remains limited to respiratory support, prone positioning, steroids, and anticoagulation. CASE REPORT: We present a case of a patient with COVID-19 complicated by ARDS and bilateral pulmonary emboli with severe right ventricular dysfunction and systemic hypotension treated with nebulized nitroglycerin and systemic thrombolytic therapy in the ED. Serial evaluation of right ventricular function using point of care ultrasound over the next 2 h showed improvement of function with both agents as well as improvement in the patient's respiratory rate and work of breathing. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case describes a novel use of a widely available medication for patients with COVID-19-induced right ventricular dysfunction. Nebulized nitroglycerin may be an option to improve right ventricular function when other inhaled pulmonary vasodilators are not available in the initial ED setting. © 2021 Elsevier Inc.