Therapeutics, Volume 2, Issue 2 (June 2025) – 4 articles

Background: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are chronic conditions often accompanied by a prothrombotic state. Antifibrotic therapies, including nintedanib and pirfenidone, have demonstrated efficacy in slowing disease progression. Despite the known interactions between coagulation pathways and fibrotic processes, there is a lack of data in the literature on the safety of the concomitant use of anticoagulants and antifibrotics. Objectives: This study aimed to evaluate the safety and clinical impact of combining antifibrotics and anticoagulants in patients with IPF or PPF. A single-center, retrospective study was conducted on 137 patients diagnosed with IPF or PPF, 25 of whom were on concurrent anticoagulant therapy (AC+). Baseline demographics, pulmonary function tests (PFTs), bleeding risk scores (HAS-BLED, RIETE), and clinical outcomes were analyzed over a 12-month follow-up period. Methods: Statistical analyses included t-tests, χ² tests, Kaplan–Meier survival analysis, and multivariate logistic regression. Results: Two clinically relevant bleeding events were observed, with one in the AC+ group. No major bleeding episodes occurred in either group. Baseline forced vital capacity (FVC) was lower in the AC+ group (73.4 ± 16.9% vs. 83.0 ± 21.9%; p = 0.04), but no significant differences were observed in FVC, forced expiratory volume (FEV1), or diffusing capacity for carbon monoxide (DLCO) at 6 and 12 months. Survival rates and radiological progression were comparable between groups. Multivariate analysis revealed that DLCO was an independent predictor of mortality (HR 0.84; p = 0.005), while anticoagulant use was not. Conclusions: The concomitant use of antifibrotics and anticoagulants appears safe, with no significant increase in bleeding risk or adverse effects on disease progression. Future prospective studies are required to confirm these findings and explore the long-term impact of this therapeutic combination. Full article

Venous thromboembolic events (VTEs), especially in the form of portal vein thrombosis (PVT), are common complications of cirrhosis and are associated with significant morbidity. These patients can also be easily tipped toward bleeding because of deficiencies in procoagulant factors and pharmacokinetic and pharmacodynamic changes that occur during disease progression. Therefore, the understanding of how to use pharmacotherapy to treat VTE is a key to success in achieving VTE resolution without potentiating adverse bleeding events (AEs). Based on a review of the literature and the authors’ clinical experience, it was determined that unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux, argatroban, warfarin, and direct oral anticoagulants all have evidence of use in patients with cirrhosis and VTE. However, the available literature is mostly limited to retrospective studies and case reports. There appears to be a paucity of prospective, randomized trials that compare the available pharmacotherapy at typical and adjusted doses. Overall, the decision as to the choice of agent and dose prescribed for anticoagulant therapy should include assessment on clot burden, bleeding risk, drug-drug/disease interactions, and the risk of presence of AEs. Full article

Background: In metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation, osimertinib is the cornerstone treatment able to prolong overall survival (OS). Evidence around osimertinib being effective in leptomeningeal metastasis (LM) is scarce. Methods: We conducted a retrospective cohort study of patients with metastatic NSCLC-EGFR mutation treated with osimertinib at Sunnybrook Hospital. Results: We identified a total of 56 patients. Of these, 45 (79.4%) were never smokers, 53 (94.6%) had adenocarcinoma histology, and 26 (46.42%) had either the EGFR exon 21-L858R mutation or exon 19 deletion. The estimated median OS was 51 months (43.5–58.5). All eight patients with LM died during the study period. From the time of NSCLC diagnosis, the OS of patients without LM was 53 months (95% CI 47.2–58.7), and with LM was 21 months (95% CI 3.0–39), p = 0.001. However, the median OS from LM diagnosis was 2 months (95% CI, 1.0–26). Conclusions: In our population of patients with metastatic NSCLC-EGFR mutation who received osimertinib, there was a significant reduction in life expectancy in the group with LM. Patients who had advanced stage at diagnosis and were more likely to develop LM exhibited poorer survival compared to those who had early-stage cancer at diagnosis and developed metastases later on. Full article

Background/Objectives: The epigenetic drug 5-azacytidine (AzaC) is being used for the treatment of myeloproliferative diseases. It has multiple immunomodulating activities: it enhances the activity of Treg cells and suppresses effector T cell proliferation and function. Our aim was to repurpose AzaC for the treatment of multiple sclerosis (MS). AzaC treatment of myelodysplastic syndrome often improves the autoimmune disorders accompanying it. Another epigenetic drug, decytabin, was effective in EAE, suggesting that AzaC might behave similarly. Earlier, we found that AzaC improves aggrecan-induced arthritis in mice, further supporting our hypothesis. Methods: AzaC was tested in an animal model of MS: MOG_35–55-induced experimental allergic encephalomyelitis (EAE) in B6 mice. In addition to AzaC, its ester, prodrug triacetyl-5-azacytidine (TAC), reported earlier to exhibit improved stability and oral bioavailability, was also tested. Results: In our proof-of-concept experiment, i.p. administered AzaC ameliorated EAE. Then, we demonstrated that oral TAC is as effective as the positive comparator fingolimod. Next, we demonstrated that sub-optimal doses of oral TAC and fingolimod positively synergize. Importantly, the myelosuppression induced by TAC was not worse than that of the gold-standard fingolimod. Conclusions: Ours is the first study reporting the therapeutic activity of oral TAC. Both AzaC and TAC were effective in EAE; therefore, they can be proposed for the treatment of remitting–relapsing MS and possibly other autoimmune diseases. In addition, combination treatment with TAC and fingolimod might allow for lower individual drug doses, thus offering an alternative when side effects limit the use of current multiple sclerosis drugs. Full article