Antithrombotic potential of lornoxicam and possible mechanistic pathways.

Abstract

Lornoxicam is traditionally used as an anti-inflammatory and analgesic drug. Recent studies suggest that nonsteroidal anti-inflammatory drugs can influence platelet and coagulation pathways. However, the antithrombotic and cardiopulmonary protective potential of lornoxicam remains unexplored. This study addressed this gap by evaluating lornoxicam's effects on thrombosis, myocardial infarction (MI), and pulmonary embolism (PE) using in silico, in vitro, and in vivo models. Docking analysis with 16 target proteins revealed novel interactions with lornoxicam, suggesting potential antithrombotic and cardiopulmonary benefits of beyond its cyclooxygenase (COX)-mediated actions. AutoDock (version 4.2.6) was used with default parameters and empirical force field (Exhaustiveness: 8). High binding affinities (E-value > -9.0 kcal/mol) were observed for COX-1, glycoprotein IIb/IIIa, antithrombin III, COX-2, and nuclear factor kappa light chain enhancer of activated B cells (NFκB), and molecular dynamics simulations confirmed stable ligand-protein complexes. In arachidonic acid-induced platelet aggregation, lornoxicam showed concentration-dependent inhibition (77.8% at 10 μM, IC₅₀ = 0.61 μM) compared with 94.81% inhibition by aspirin (10 μM). In ADP-induced aggregation assays, inhibition was less pronounced (23.21% at 10 μM, IC₅₀ = 20.6 μM). Lornoxicam significantly prolonged prothrombin time, activated partial thromboplastin time, thrombin time, and clot lysis at 1, 3, and 10 μM concentrations (P < .001 vs saline). The cardioprotective potential of lornoxicam was confirmed via an isoprenaline (ISO)-induced MI model in rats, while its protective effect on PE was assessed using a self-embolus-induced PE rat model. Lornoxicam protected the heart and lung tissues of rats against histological damage and infarction by decreasing oxidative stress and inflammatory responses. This effect was due to reduced expression of NFκB, tumor necrosis factor alpha, COX-2, NOD-like receptor family, pyrin domain containing 3, and platelet-derived growth factor beta (in the lungs), as confirmed via immunohistochemical analysis, ELISA, and reverse-transcription polymerase chain reaction. This study opens a new avenue for the repurposing and prophylactic use of lornoxicam in patients more prone to thrombotic disorders. SIGNIFICANCE STATEMENT: The in silico, in vitro, and in vivo experiments in this study revealed the excellent antithrombotic potential and protective effect of lornoxicam on myocardial infarction and pulmonary embolism, even at lower doses. This study proposes that lornoxicam treatment, just like aspirin, at lower doses could be an appropriate prophylactic option in patients who are more prone to myocardial infarction and pulmonary embolism.