[This corrects the article DOI: 10.3389/fphar.2026.1830217.].

IntroductionHeart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and lacks effective therapies. Key features of HFpEF include endothelial dysfunction, fibrosis, and oxidative stress. Adenosine signaling, regulated by enzymes and receptors, is critical for vascular homeostasis and inflammation, but its role in HFpEF remains poorly understood. Adenosine receptors are abundantly expressed in the heart and kidney, modulating vascular, fibrotic, and tubular processes. Dysregulation of adenosine pathways in either organ may drive hypertension, microvascular dysfunction, and maladaptive cardio-renal crosstalk, highlighting the need to investigate adenosine signaling as a combined multi-organ target.MethodsHFpEF was induced in Dahl salt-sensitive rats by high-salt diet. Cardiac structure, function, fibrosis, oxidative stress, cytokines, renal adenosine receptors and cardiac adenosine pathway components were assessed using echocardiography, histology, proteome profiling and Western blotting. Human cardiac microvascular endothelial cells were treated with endothelin-1 in the presence of selective A2A or A2B agonists, or adenosine deaminase (ADA) inhibition, and profibrotic/oxidative stress genes were analyzed by qPCR.ResultsHypertensive rats exhibited diastolic dysfunction with preserved systolic function, cardiac and renal fibrosis, oxidative/nitrative stress, and elevated pro-inflammatory cytokines. Cardiac expression of CD39, CD73, and ADA enzymes was significantly reduced, indicating impaired adenosine metabolism, while transporters ENT2 and CNT2 were also downregulated, reflecting impairment of both equilibrative and concentrative adenosine transport. Adenosine receptor profiles were altered: A1 expression increased, A2A decreased, and A2B and A3 selectively upregulated in hypertensive, but not HFpEF, animals. In the kidney, A1 and A2A receptor expression showed region-specific, time-dependent changes. In human endothelial cells, A2A activation or ADA inhibition suppressed endothelin-1-induced COL1, COL3, and TGF-β1 expression, whereas A2B had no effect. Both A2A and A2B restored MnSOD expression, while NOX4 was selectively increased by A2B. Only A2A activation induced CAT expression, highlighting its stronger antioxidant role.ConclusionImpaired adenosine metabolism and transport, along with altered receptor signaling contribute to HFpEF progression. Selective A2A activation attenuates endothelial pro-fibrotic profiles and restores antioxidant defenses, supporting its therapeutic potential. Renal receptor changes reinforce maladaptive cardio-renal crosstalk, emphasizing the importance of multi-organ adenosine modulation in HFpEF and encouraging further translational studies.

Background: Although Duchenne muscular dystrophy (DMD) is primarily characterized as a skeletal muscle-wasting disorder, the resulting pathophysiological changes extend to multiple non-muscle tissues and organ systems. Among these, renal and urinary tract dysfunctions have been reported, albeit in relatively few studies, as potential complications in DMD patients, sometimes occurring from an early age. Importantly, as life expectancy improves, the incidence of renal impairment is also expected to increase. This narrative review summarizes the available evidence on kidney involvement in DMD and discusses the associated biomarkers of renal dysfunction within the context of multisystem disease progression. Methods: The review draws on data from both human and animal studies and analyzes published evidence to explore kidney involvement in DMD, with a focus on clinical manifestations, biomarkers of renal dysfunction, and potential pathogenic mechanisms. Results: Available data indicate a close association between cardiac and renal dysfunction, particularly in patients with advanced-stage DMD. The review explores potential underlying mechanisms of renal impairment, including intrinsic dystrophin deficiency in the kidney, secondary effects of cardiovascular complications, and the nephrotoxic impact of drug therapies, highlighting renal function as an active determinant of clinical risk. Conclusions: While cardiac function monitoring is already a cornerstone of multidisciplinary care for this multisystem disease, systematic assessment of renal function should also be implemented, with implications for clinical management and drug safety. Moreover, the risk of drug-induced nephrotoxicity warrants attention in both clinical management and the development of novel therapeutic strategies for DMD.

Deleterious variants in the CACNA1A gene, encoding the CaV2.1 P/Q-type voltage-gated calcium channel, cause a broad spectrum of neurological disorders, including familial hemiplegic migraine, episodic ataxia, and developmental and epileptic encephalopathy (DEE). Information on genotype-phenotype correlations and on the factors influencing clinical variability is still limited, hindering potential applications in precision medicine. We present three adults (aged 26, 27, and 40 years) from two families with heterozygous CACNA1A deleterious variants and DEE, highlighting striking interindividual and intrafamilial variability in adult-onset presentations. Genetic testing revealed two distinct pathogenic variants [p.(Val1392Met) and p.(Glu1263Lys)], including one instance of germinal/gonosomic mosaicism in unaffected parents. The electroclinical details demonstrated profound differences, notably: a pair of siblings with the same variant showing discordant clinical severity, and an unrelated patient whose complex phenotype, dominated by cerebellar ataxia, required prolonged video-EEG to accurately diagnose a high burden of subtle absence seizures. These cases significantly expand the phenotypic spectrum and highlight the critical role of comprehensive electroclinical characterization in adults with CACNA1A-related DEE for personalized management.

OBJECTIVE:To assess the 12-month clinical impact of cenobamate (CNB) in adults with drug-resistant focal epilepsy in clinical practice, exploring whether outcomes differed according to prior antiseizure medication (ASM) exposure. METHODS:This single-center, retrospective, observational, real-world study included 91 adults stratified by the number of prior ASMs: ≤ 6 prior ASMs (n = 44) and > 6 prior ASMs (n = 47). Outcomes assessed at 3, 6, and 12 months included monthly seizure frequency, seizure freedom, retention rate, CNB dose, concomitant ASM burden, and adverse drug reactions (ADRs). RESULTS:In the overall cohort, mean monthly seizure frequency decreased from 28.77 at baseline to 22.73 (3 months), 19.37 (6 months), and 14.58 (12 months), representing mean reductions of 21%, 33%, and 49%, respectively. Seizure freedom was achieved by 12% (11/91) of patients at 3 months, 13% (11/87) at 6 months, and 19% (16/82) at 12 months. Treatment retention rate was 100% at 3 months, 95.6% at 6 months, and 90.1% at 12 months. Both subgroups showed clinical benefit, but outcomes were more favorable in patients with ≤ 6 prior ASMs, who had a lower baseline seizure burden and higher 12-month seizure freedom than those with > 6 prior ASMs (29% vs. 10%). At 12 months, most patients were receiving CNB doses of 200 mg or higher, and 79% were maintained on ≤ 2 concomitant ASMs. Overall, 38.5% (35/91) of patients reported at least one ADR (most frequently somnolence, vertigo, and asthenia). SIGNIFICANCE:In this real-world cohort of adults with drug-resistant focal epilepsy, CNB was associated with sustained seizure reduction, high 12-month retention rate, and acceptable tolerability, while most patients were maintained on a low concomitant ASM burden during follow-up. Improvement was observed even in highly treatment-experienced patients, although outcomes were more favorable in those with lower prior ASM burden, supporting the hypothesis that earlier CNB positioning may provide greater efficacy.

Selenoprotein N (SelN or SELENON) is a selenium-containing protein of the endoplasmic/sarcoplasmic reticulum (ER/SR), encoded by the SEPN1 gene. In skeletal muscle, SelN is particularly important for regulating SR calcium homeostasis. It acts as a calcium sensor, modulating the activity of the sarcoplasmic reticulum calcium pump (SERCA) through a redox-dependent mechanism. Loss-of-function mutations in the SEPN1 gene give rise to a spectrum of skeletal muscle disorders collectively referred to as SEPN1-related myopathies (SEPN1-RM). Histopathologically, SEPN1-RM is characterized by the presence of minicores, which are localized regions within muscle fibers exhibiting mitochondrial depletion (i.e., cores) and sarcomeric disarray. As no effective therapy is currently available for SEPN1-RM, understanding SelN biology through loss-of-function models remains essential for elucidating disease mechanisms and identifying potential therapeutic targets. This review examines the current knowledge on SelN function and the pathological mechanisms underlying SEPN1 loss-of-function, with a particular focus on the connection between calcium handling, oxidative/ER stress, and muscle dysfunction. It also highlights emerging strategies aimed at restoring SelN activity or mitigating downstream defects, outlining potential therapeutic avenues for SEPN1-RM.

Cenobamate (CNB) demonstrates high efficacy in drug-resistant focal epilepsy, yet optimal management requires personalized strategies. This exploratory case series describes five patients selected from a cohort of 125 individuals treated with CNB, examining the relationship between pharmacogenetic (PGx) profiles and clinical outcomes. Clinical data and therapeutic drug monitoring (TDM) were integrated with targeted Next-Generation Sequencing of key metabolic genes (UGT2B7, UGT2B4, CYP2E1, CYP2B6, CYP2A6, CYP3A4, CYP2C19) to predict metabolizer phenotypes. Three patients (Cases 1, 3, 4) achieved seizure freedom or ≥50% response at sub-target or target doses (100–200 mg/day) enabling early de-escalation of concomitant sodium channel blockers and valproate. This success was supported by a proactive digital communication protocol and a mandatory 100 mg clinical checkpoint. Case 2—a non-responder at 400 mg/day despite therapeutic plasma levels (28.22 mg/L)—exhibited a predicted “Ultrarapid Metabolizer” (UM) phenotype characterized by UGT2B7 Haplotype 4 and CYP2E1 duplication, suggesting possible pharmacokinetic contribution to non-response. Case 5 experienced dose-limiting toxicity at 100 mg/day; we hypothesized this toxicity could be driven by a drug-drug-gene interaction involving CNB-mediated CYP2C19 inhibition that impairs clearance of N-desmethylclobazam (the active metabolite of clobazam) in a patient with impaired CYP2A6 activity and intermediate UGT2B7 function. As an exploratory case series, these findings require validation in adequately powered prospective studies. Associations between UM phenotype and non-response, and between PM phenotype and dose-limiting toxicity, represent preliminary observations that may reflect pharmacokinetic variability. Nevertheless, our experience is consistent with a personalized, sub-target dose titration strategy that may help minimize adverse events in complex polypharmacy settings.

Variants in neuronal sodium channel genes are responsible for a spectrum of neurological disorders, including developmental and epileptic encephalopathies (DEEs), with considerable genetic and phenotypic heterogeneity and drug resistance. Gene variants can produce loss-, gain-, or mixed-function effects, resulting in complex genotype-phenotype correlations. Current treatments rely mainly on symptomatic polytherapy with antiseizure medications, with sodium channel blockers contraindicated in loss-of-function cases but beneficial in gain-of-function forms. Existing therapies often provide limited benefit or even no seizure control at all and fail to address developmental impairments, highlighting the need for novel approaches. Emerging strategies include antisense oligonucleotides, gene therapy, and selective small-molecule modulators, which have shown antiseizure potential in preclinical models and in initial clinical studies by modulating SCN gene expression and function. Additionally, pharmacological agents such as fenfluramine, stiripentol, and cannabidiol, although not acting directly on sodium channels, represent recognized therapeutic options for SCN1A-related Dravet syndrome. This review summarizes recent advances in approved and investigational treatments for sodium channel-related neurological disorders, highlighting the transition from symptomatic to precision therapies.

The withdrawal of numerous approved drugs in late development stages, or even from the market, due to safety concerns remains a major challenge, contributing to the high attrition rate in drug discovery and development. Among these concerns, cardiotoxicity is a critical toxicological issue, particularly in oncology, as drugs can induce heart damage by triggering pathological conditions such as arrhythmia, myocardial infarction, and myocardial hypertrophy. Here, we introduce CUPID (Cardiotox Understanding Platform for Intelligent Drug Discovery), an explainable artificial intelligence (XAI) framework designed to predict cardiotoxicity associated with ERG (ether-à-go-go-related gene) potassium, Nav1.5 sodium, and Cav1.2 calcium ion channels. The framework was trained using three carefully curated interspecies experimental datasets from the latest ChEMBL database (release 34) and the CSFP (Core-Substituent Fingerprint), which encodes molecular fragments derived from the decomposition of drug-like small molecules. By leveraging these experimental datasets, highly accurate explainable machine learning models were developed, achieving approximately 80 % accuracy in 5-fold stratified cross-validation analyses. CUPID provides a comprehensive risk assessment of early cardiotoxicity and a key feature is its interpretability: predictions are annotated with clear applicability domain information, while chemical substructures linked to cardiotoxicity risks are highlighted using SHAP (SHapley Additive exPlanations) values. This enhances molecular understanding and facilitates the rational design of safer bioactive compounds. Last but not least, CUPID is freely accessible at https://prometheus.farmacia.uniba.it/cupid.

Growth hormone secretagogues (GHSs) are gaining interest as promising therapeutics for Duchenne muscular dystrophy (DMD) due to their broad activity profile and proven benefits in other muscle-wasting conditions. We previously found that JMV2894 - a pseudopeptide GHS - exerts functional, anti-inflammatory, and antifibrotic benefits in classic BL10-mdx mice, supported by in silico predictions of its interaction with ADAMTS-5 and matrix metalloproteinase 9 (MMP-9), both overactivated in DMD. This led us to test JMV2894 in the D2.B10-Dmdmdx/J (D2-mdx) mouse model, chosen for its hyper-fibrotic and atrophic disease phenotype. JMV2894 was administered subcutaneously at 640 or 1280 µg/kg for six weeks to 4-week-old D2-mdx mice, showing good tolerability. In vivo, the treatment partially improved hind limb plantar flexor torque, ultrasound volume, and reduced gastrocnemius (GC) muscle echodensity. While decreasing the expression of matrix-remodeling genes (i.e., MMP-9, ADAMTS-5, transforming growth factor beta-1, type I collagen α1), JMV2894 only mildly alleviated GC muscle fibrosis histologically. However, JMV2894 - particularly at the lower dose - exerted a remarkable anti-atrophic action, evidenced by increased GC myofiber size and decreased gene expression of Atrogin and Muscle RING Finger 1. Enhanced insulin-like growth factor 1 (IGF-1) transcript and plasma levels, along with increased IGF-1 receptor and downstream signalling proteins, suggest that JMV2894 actions are most likely GH-mediated. These effects occurred despite limited muscle drug exposure, highlighting the need for improved formulations to enhance bioavailability. Overall, our results show that GHSs exert different actions in dystrophic settings, likely related to distinct disease phenotype, reflecting the complexity of translational exercise towards universal therapies in DMD.

Heart failure (HF) is a syndrome characterized by dyspnoea, fatigue and exercise intolerance. Among non-cardiac comorbidities which often accompany HF, skeletal muscle abnormalities impact patients' daily activities and quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promise in improving clinical outcomes and enhancing physical performance in HF patients, although their mechanism of action remains unclear. In this context, altered muscle ions and glucose homeostasis may contribute to HF-related muscle changes and serve as indirect targets for SGLT2i effects. To explore this further, we used Dahl salt-sensitive rats fed with a high-salt diet for five weeks and then randomized to receive dapagliflozin (HS + DAP) or vehicle (HS) for the following six weeks. Control animals received a low-salt diet (LS). We investigated whether variations in indexes of glucose and ions homeostasis occur in extensor digitorum longus muscle of this rodent model of HF with preserved ejection fraction and are counteracted by dapagliflozin treatment. Gene and protein expression analysis revealed altered expression of proteins involved in glucose (SGLT2, GLUT4, GPD1) and Ca2+ and Na + homeostasis (NCX3, Ryr1, NHE1/6, Na+/K+-ATPase, Nav1.4) in HS vs LS animals. Furthermore, HS rats showed an increased CaMKII expression in its active phosphorylated form and a change in plasma pH toward acidification. Dapagliflozin treatment counteracted the altered expression of most of the components under investigation, also promoting an amelioration of atrophy indexes and a recovery of plasma pH. Thus, skeletal muscle appears highly responsive to SGLT2i treatment, supporting the potential of these drugs in mitigating HF-related muscle pathology.

Lafora disease (LD) is an ultra-rare, autosomal recessive neurodegenerative disorder characterized by the accumulation of Lafora bodies in the brain, leading to drug-resistant epilepsy, myoclonus, progressive dementia, and cerebellar dysfunction. This retrospective study describes the clinical course and management challenges of LD in a cohort of patients from the Apulia region of Southern Italy, where the disease prevalence appears to be higher than in other populations. We retrospectively analyzed clinical, electroencephalographic, and management data from six unrelated families with a confirmed diagnosis of LD, followed at the Neurology Unit of the Scientific Institute Casa Sollievo della Sofferenza Hospital between 2010 and 2024. Demographic information, clinical presentation, treatment history, disease progression, and outcomes were collected. Our analysis identified three distinct electroclinical stages: an initial Presenting Symptoms Stage with the onset of seizures and subsequent development of myoclonus; a Progressive Neurodegeneration Stage characterized by drug-resistant epilepsy, dementia, and ataxia; and a Terminal Stage marked by severe disability, frequent seizure emergencies, and medical complications. Management in the late stages proved particularly challenging, requiring a multidisciplinary approach to address refractory seizures, status epilepticus, and medical complications such as aspiration pneumonia and respiratory failure. Home-based care, with specialized team support, played a crucial role in minimizing hospitalizations. Our findings underscore the importance of early diagnosis and a multidisciplinary approach in the management of LD. The late stages of the disease are characterized by significant clinical challenges necessitating close collaboration among neurologists, epileptologists, and other healthcare professionals, supported by effective home-based care. The apparent higher prevalence in Apulia warrants further investigation into potential genetic or environmental factors. This study highlights the significant clinical burden of LD and emphasizes the importance of multidisciplinary management, particularly in the advanced stages. Home-based care supported by specialized teams and caregivers is essential for optimizing patient well-being. Further research is needed to identify early biomarkers and develop targeted therapies for this devastating condition.

Rapid and detailed post-marketing surveillance of drugs and vaccine is required to enable assessment of their real-world safety and effectiveness. Spontaneous reporting from healthcare professionals and citizens is recognized as the basic method in the passive post-marketing surveillance of drugs and vaccines, allowing the identification of rare adverse drug reactions (ADRs) and adverse events following immunization (AEFIs). According to the current law, online platforms for ADRs and AEFI reporting and related databases are available in every country and at the global level. Recently, the use of electronic health records and the establishment of networks of databases as different sources of real-world data is emerging allowing high-quality, large-scale evaluations and providing real-world evidence on questions of clinical and regulatory interests. Here, we summarize the adverse event pharmacovigilance reporting systems in place at the global, European and in some European countries, and provide examples from recent literature of how the analysis of pharmacovigilance reports can provide evidence for unexpected and novel adverse drug reactions. Furthermore, we discuss the role of real-world data to generate real-world evidence in pharmacovigilance and regulatory activities.

Background: Lafora disease (LD) is an ultra-rare and fatal neurodegenerative disorder with limited therapeutic options. Current treatments primarily address symptoms, with modest efficacy in halting disease progression, thus highlighting the urgent need for novel therapeutic approaches. Gene therapy, antisense oligonucleotides, and recombinant enzymes have recently been, and still are, under investigation. Drug repurposing may offer a promising approach to identify new, possibly effective, therapies. Methods: This study aims to investigate the conditions for repurposing empagliflozin, an SGLT2 (sodium/glucose cotransporter-2) inhibitor, as a potential treatment for LD and to establish a clinical protocol. Clinical phase: This 12-month prospective observational study will assess the safety and clinical efficacy of empagliflozin in two patients with early to intermediate LD stage. The primary endpoints will include changes in the severity of epilepsy and cognitive function, while the secondary endpoints will assess motor function, global function, and autonomy. Multiple clinical and instrumental evaluations (including MRI and PET with 18F-fluorodeoxyglucose) will be performed before and during treatment. Safety monitoring will include regular clinical assessments and reports of adverse events. Preclinical phase: In silico studies (using both molecular docking calculations and reverse ligand-based screening) and in vitro cell-based assays will allow us to investigate the effects of empagliflozin (and other gliflozins) on some key targets likely implicated in LD pathogenesis, such as GLUT1, GLUT3, glycogen synthase (hGYS), and glycogen phosphorylase (GP), as suggested in the literature and digital platforms for in silico target fishing. Results: The expected outcome of this study is twofold, i.e., (i) assessing the safety and tolerability of empagliflozin in LD patients and (ii) gathering preliminary data on its potential efficacy in improving clinical and neurologic features. Additionally, the in silico and in vitro studies may provide new insights into the mechanisms through which empagliflozin may exert its therapeutic effects in LD. Conclusion: The findings of this study are expected to provide evidence in support of the repurposing of empagliflozin for the treatment of LD.

Background: It is crucial to distinguish type-1 myocardial infarction (T1MI) from type-2 myocardial infarction (T2MI) at admission and during hospitalization to avoid unnecessary invasive exams and inappropriate admissions to the acute cardiac care unit. Objectives: The purpose of the study was to define a simple profile derived from commonly used biomarkers to differentiate T1MI from T2MI. Methods: We prospectively enrolled in an observational study 213 iconsecutive patients with a provisional diagnosis of non-ST-elevation acute myocardial infarction (NSTEMI) admitted to the Cardiology Department. A final diagnosis of T1MI, T2MI, and non-ischemic acute myocardial injury (NAMI) was given based on clinical and instrumental findings. We assessed high-sensitivity Troponin I (hs-cTnI), Creatine Kinase MB (CK-MB), C-reactive protein (CRP), procalcitonin (PCT), N-Terminal prohormone of brain natriuretic peptide (NTproBNP). Results: A final diagnosis of T1MI was assigned to 77 patients, T2MI to 60 patients, and NAMI to 76 patients; mean age was not significantly different between groups (73 vs. 71 years), female were more prevalent in the T2MI/NAMI group (53 % vs. 34 %, p G 0.01). Hs-cTnI peak/upper limit of normal (ULN) (559 + 770 vs. 286 + 429; p = 0.04), hs-cTnI peak/CRP ratio (114 + 337 vs. 83 + 430; p G 0.001), hs-cTnI peak/PCT ratio (12,592 + 21,467 vs. 4,609 + 17,284; p G 0.001), and hs-cTnI peak/NTproBNP ratio (0.7 + 1.6 vs. 0.3 + 0.6; p G 0.01) differentiated T1MI from T2MI Hs-cTnI peak/ULN (559 + 770 vs. 271 + 412; p G 0.01), hs-cTnI peak/PCT ratio (12,592 + 21,468 vs. 3,570 + 12,469; p G 0.001), hs-cTnI peak/NTproBNP ratio (0.7 + 1.6 vs. 0.3 + 1.3; p G 0.001) and hs-cTnI peak/CRP (114 + 337 vs. 48 + 288; p G 0.001) differentiated T1MI from T2MI + NAMI. HscTnI peak/PCT ratio was a predictor of T1MI, a multivariable logistic regression analysis (OR 1.03, 95 % CI 1.01-1.06, p G 0.05) with an accuracy of 0.704 (95 % CI 0.626-0.782, p G 0.001). No significant differences between T2MI and NAMI were detected. Conclusions: Admission biomarker profile may differentiate T1MI from T2MI in patients admitted for NSTEMI.

Lafora disease (LD) is an ultra-rare and still incurable neurodegenerative condition. Although several therapeutic strategies are being explored, including gene therapy, there are currently no treatments that can alleviate the course of the disease and slow its progression. Recently, gliflozins, a series of SGLT2 transporter inhibitors approved for use in type 2 diabetes mellitus, heart failure and chronic kidney disease, have been proposed as possible repositioning drugs for the treatment of LD. With this in mind, we tested dapagliflozin (50 µM), canagliflozin (2.5 µM) and empagliflozin (200 µM) in our epm2a−/− zebrafish model, investigating their effects on pathological behaviour. In the case of dapagliflozin, we also investigated the possible mechanisms of action. Overall, the gliflozins reduced or rescued neuronal hyperexcitability and locomotor impairment. Dapagliflozin also reduced spontaneous seizure-like events in epm2a−/− larvae. At the biochemical and molecular level, dapagliflozin was found to slightly reduce glycogen content, and suppress inflammation and oxidative stress. It also ameliorates autophagic homeostasis and improves lysosomal markers. In conclusion, our preclinical study showed that dapagliflozin was able to ameliorate part of the pathological phenotype of epm2a-/- zebrafish larvae and could potentially be a suitable drug for repurposing in LD. However, since our model does not present Lafora bodies (LBs), at this early disease stage at least, it would be important to use mouse models in order to ascertain whether it is able to prevent or reduce LB formation.

Background/Objectives: People affected by COVID-19 are exposed to abnormal clotting and endothelial dysfunction, which may trigger thromboembolic events. This study aimed at retrospectively investigating whether oral anticoagulant therapy (OAT), encompassing either direct oral anticoagulants (DOACs), mainly apixaban, or the vitamin K antagonist (VKA) warfarin, could have impacted medium-term mortality in a cohort of SARS-CoV-2 patients. Methods: Among 1238 COVID-19 patients, hospitalized from 17 March 2020 to 15 June 2021, 247 survivors and 247 deceased within 90 days from hospitalization were matched 1:1 based on age, sex, and intensive care unit (ICU) admission within three days. Conditional logistic regression was used to estimate associations by means of odds ratio (OR) with a 95% confidence interval (CI). Results: A univariate regression analysis suggested that OAT, no differently from subcutaneous low-molecular-weight heparins (LMWHs) during hospitalization, has no significant impact (p value > 0.05) on medium-term mortality. A multivariate analysis, limited to baseline variables (i.e., comorbidities and pharmacotherapies at hospital admission) showing significant association (p < 0.05) to mortality in a univariate analysis, revealed that, compared to patients living at 90 days from hospitalization, deceased patients had cancer histories (OR 1.75, CI 1.06–2.90, p = 0.029) or suffered from asthma (OR 2.25, CI 1.13–4.47, p = 0.021). In contrast, heart failure (HF), atrial fibrillation (AF), arteriopathy, chronic obstructive pulmonary disease (COPD), and kidney failure (KF), which, in a univariate analysis, were found to be associated with the endpoint (p < 0.05), lost significance in a multivariate analysis. Therapy at admission with aldosterone antagonists also appeared to be associated with medium-term mortality (OR 2.49, CI 1.52–4.08, p < 0.001); whereas, vitamin D supplementation during hospitalization appeared to be beneficial. Although not conclusive, a search into the Eudravigilance database, combined with consulting a digital predictive platform (PLATO, polypharmacology platform prediction), suggested potential off-target activities, which might contribute to increasing the severity of SARS-CoV-2 infection. Conclusions: This retrospective clinical study furnished evidences of the impact of OAT, comorbidities and other pharmacological treatments on COVID-19 clinical course.