Search Results (404)

Methamphetamine (METH)-induced cardiomyocyte injury is the leading cause of mortality beyond acute intoxication. METH abuse often occurs in crowded, poorly ventilated environments, and even moderately high ambient temperatures exacerbate METH-related cardiovascular emergencies. However, the underlying mechanisms by which environmental factors drive the progression of cardiac diseases remain poorly understood. This study modeled the real-world scenario in vivo by exposing mice to METH under normothermic condition (NC, 22 °C) or subthreshold thermal stress (STS, 28 °C, a mild thermal challenge for mice) conditions, and in vitro by using H9c2 cardiomyocytes exposed to METH at 37 °C or 39 °C. STS significantly potentiated METH-induced cardiac dysfunction, mitochondrial ultrastructural damage, and oxidative stress (p < 0.05). Mechanistically, the co-exposure impaired mitochondrial respiratory chain complex I and led to excessive mitochondrial ROS (mtROS) production, activating the pro-apoptotic protein BAX, causing mitochondrial outer membrane (MOM) permeabilization and the cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA-mediated NLRP3 inflammasome activation subsequently executed cardiomyocyte pyroptosis via caspase-1/Gasdermin D (p < 0.05). Crucially, the mitochondria-targeted antioxidant mitoquinone (MitoQ) substantially attenuated the aggravated cardiotoxicity by scavenging the initial mtROS (p < 0.05), thereby preventing the activation of the downstream BAX/mtDNA/NLRP3 axis. These findings provide evidence for a defined signaling basis for this drug-environment interaction and highlight mitochondrial redox modulation as a potential therapeutic strategy for psychostimulant-associated cardiovascular injury. Full article

The advent of novel Human Epidermal growth factor Receptor 2 (HER2)-targeted therapies and tyrosine kinase inhibitors (TKIs) has significantly improved outcomes in HER2-positive malignancies, particularly breast cancer. However, these agents carry a growing burden of cardiovascular adverse events, representing a critical concern in modern oncology. This narrative review explores the evolving landscape of cardiovascular toxicity associated with these therapeutic classes, integrating mechanistic insights with real-world clinical data. HER2-targeting monoclonal antibodies and antibody–drug conjugates exert off-target effects on cardiomyocytes via HER2 pathway inhibition, leading to reversible or irreversible myocardial dysfunction. In parallel, small-molecule TKIs, especially those targeting multiple kinases, have been associated with hypertension, arrhythmia, QT prolongation, and heart failure, through mechanisms such as mitochondrial dysfunction, endothelial damage, and disruption of cardioprotective signaling. We summarize clinical evidence elucidating the molecular basis of these toxicities and critically review clinical trials and post-marketing data highlighting their incidence and management. The review emphasizes the heterogeneity of cardiotoxicity profiles across different agents, underscoring the need for individualized cardiovascular risk stratification and monitoring. Finally, we address the emerging role of cardio-oncology in bridging oncologic efficacy with cardiac safety, advocating for multidisciplinary approaches, biomarker-guided surveillance, and standardized definitions of cardiotoxicity. As precision oncology advances, a parallel refinement in cardiotoxicity prediction and prevention is imperative to optimize patient outcomes. Full article

Cardiac safety assessment is an integral part of drug discovery and development. Drug candidates that adversely affect cardiac or hemodynamic function should be discontinued early unless a favorable benefit-risk ratio for patients can be justified. In this hypothesis-generating work, we aimed to develop a conceptual framework for informing early safety risk assessment based on in vitro drug affinities to pharmacological targets. For illustration, we used the drug-induced cardiotoxicity rank (DICTrank) data comprising 1318 drugs with cardiac safety concerns according to FDA labeling. The data was enriched with information on affinity to the most plausible mechanistic targets, clinical drug exposure, and human plasma protein binding. We descriptively identified 18 target classes potentially associated with elevated cardiovascular risk: potassium channels (accounting alone for 20% of the ‘most concern’ safety group); adrenergic, dopamine, serotonin, androgen, sex hormone, and opioid receptors; cyclooxygenase; sodium and calcium channels; muscarinic and glucocorticoid receptors; phosphodiesterase; topoisomerase; angiotensin-converting enzyme; angiotensin II type 1 receptor; monoamine transporters, and acetylcholinesterase. Overall, 80% of the ‘most concern’ drugs compared with only 12% of the ‘no concern’ drugs were associated with these targets in this exploratory descriptive analysis. Concentration–response analyses revealed differences in target potency and free drug exposure that appeared associated with variability in the severity of cardiotoxicity among drugs acting on the same target. This framework demonstrates how in vitro data can be used to benchmark new compounds early in development, enabling the timely discontinuation of candidates associated with substantial risk. Full article

Background/Objectives: Drug-induced hypersensitivity and cardiotoxicity are important yet often underrecognized clinical concerns, and fluoroquinolones are widely used antibiotics with well-documented safety issues. Given the limited systematic evidence and underreporting in pharmacovigilance databases, this study explored a potential association between fluoroquinolones and Kounis syndrome (KS) and the possibility of a class-related effect. Methods: This retrospective descriptive study analyzed individual case safety reports from VigiBase, complemented by published case reports to capture additional cases not recorded in the database. All fluoroquinolones reported as suspected drugs in KS cases were included, and a systematic search of major literature databases was undertaken to identify further case-level evidence. Quantitative data were explored using VigiLyze, while qualitative clinical data were extracted for case characterization. Literature cases underwent Naranjo assessment, and the overall body of evidence was evaluated using a qualitative Bradford Hill framework. Results: A descriptive disproportionality signal for fluoroquinolones was identified in VigiBase (IC₀₂₅ = 1.3). Seventeen cases of fluoroquinolone-associated KS were identified across VigiBase and the published literature, all originating from unsolicited sources. Most cases involved ciprofloxacin and levofloxacin, whereas other fluoroquinolones were only rarely reported. Across cases, a consistent clinical pattern was observed, including a clear temporal relationship between drug exposure, allergic manifestations, and acute coronary events, compatible with hypersensitivity-mediated coronary involvement. Conclusions: KS cases associated with several fluoroquinolones were identified in pharmacovigilance data and the published literature, with the most consistent evidence observed for ciprofloxacin and levofloxacin. Although a class effect was not confirmed, a potential association cannot be excluded. These findings should be interpreted as hypothesis-generating, and further research is required to clarify underlying mechanisms, drug-specific risks, and clinical relevance. Full article

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality worldwide, primarily due to the systemic toxicity and drug resistance associated with conventional doxorubicin (DOX) therapy. To overcome these limitations, we developed and optimized a novel cationic-ionizable lipid nanoparticle platform, QTPlus, for the co-delivery of DOX and siRNA targeting fibroblast growth factor 2 (siFGF2). Methods: The study evaluated the physicochemical properties, cellular uptake, gene regulation, apoptosis induction, and in vivo antitumor efficacy and safety of QTPlus-DOX-siFGF2 in breast cancer models. Results: QTPlus nanoparticles based on the A-066 formulation achieved uniform particle size (~218 nm), low polydispersity (PDI 0.164–0.214), and high encapsulation efficiencies (DOX: 49.56 ± 0.15%; siFGF2: 77.66 ± 1.30%). In vitro release studies revealed a robust pH-responsive profile, characterized by sustained stability at physiological pH (7.4) and rapid burst release at acidic endosomal pH (5.5). In MCF-7 and MDA-MB-231 cells, QTPlus-DOX-siFGF2 significantly enhanced cellular uptake, downregulated FGF2 (0.639-fold) and VIM (0.373-fold), and upregulated CASP3 (3.364-fold in siFGF2 group) and BRCA1 (4.041-fold). Flow cytometry showed markedly increased apoptosis (78.5% vs. 42.65% for QTPlus-DOX alone). In the MDA-MB-231 xenograft model, QTPlus-DOX-siFGF2 achieved 65.87% tumor growth inhibition with stable body weights and favorable trends in cardiotoxic biomarkers. Conclusions: These results demonstrate that QTPlus enables effective co-delivery of DOX and siFGF2, producing synergistic antitumor effects through apoptosis induction and suppression of epithelial–mesenchymal transition while improving the safety profile. QTPlus-DOX-siFGF2 represents a promising nanotherapeutic strategy for breast cancer warranting further clinical development. Full article

Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. GLP-1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3′-5′-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various effects mainly via protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). Cardiac GLP-1R has been reported to induce atrial natriuretic peptide (ANP) secretion via Epac2, while ANP is known to inhibit aldosterone secretion from adrenocortical zona glomerulosa (AZG) cells. Herein, we tested the effects of the GLP-1R agonist liraglutide on ANP secretion in H9c2 cardiomyocytes and on angiotensin II (AngII)-induced aldosterone secretion. We also examined whether phosphodiesterase (PDE)-4 inhibition with roflumilast could potentiate liraglutide’s effects. We found that liraglutide stimulated ANP secretion from H9c2 cardiomyocytes, an effect potentiated by roflumilast but blocked by AC inhibition. Epac inhibition with ESI-09 also significantly reduced liraglutide-dependent ANP secretion in H9c2 cardiomyocytes. Moreover, application of medium from liraglutide-treated H9c2 cardiomyocytes, but not from control cardiomyocytes, led to suppression of AngII-dependent aldosterone secretion from H295R cells. This effect was blocked by cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibition (an effector of ANP) in H295R cells, while direct application of liraglutide to these cells failed to suppress AngII-induced aldosterone secretion. Again, aldosterone suppression was more potent when medium from liraglutide plus roflumilast-treated cardiomyocytes was applied to H295R cells. Taken together, these results suggest that roflumilast enhances the adrenocortical aldosterone suppression induced by GLP-1R agonists via cardiac GLP-1R/cAMP/Epac-dependent ANP secretion. Given the cardio-toxic effects of elevated aldosterone levels in the context of various heart diseases, such as post-myocardial infarction heart failure, combination of a GLP-1R agonist drug with a PDE4 inhibitor drug may be more advantageous than either agent alone in treatment of certain cardiovascular diseases. Full article

Ponatinib, a third-generation BCR::ABL1 inhibitor, has antileukemic activity but is associated with cardiovascular toxicity, for which transcriptome-level responses remain incompletely characterized. Here, we defined a ponatinib-associated transcriptomic signature and examined its mechanistic implications using two public RNA sequencing (RNA-Seq) datasets: GSE186341 (11 cancer cell lines treated with kinase inhibitors) and GSE217421 (induced pluripotent stem cell (iPSC)-derived cardiomyocytes treated with approved drugs). Principal component analysis (PCA) and k-means clustering were used to define expression-based subgroups of vehicle-treated (DMSO) controls. DESeq2, followed by fixed-effect meta-analysis, estimated subgroup-specific treatment effects and pooled effect estimates across subgroups. In GSE186341, we identified 2639 meta-analytic differentially expressed genes (meta-DEGs). Among these, 81 genes were also differentially expressed in GSE217421 after ponatinib treatment, identifying an overlapping gene set across datasets. In contrast, imatinib showed no overlap with these 81 genes under the same cross-dataset analysis framework. Cardiotoxicity-relevant functions were represented by directionally consistent genes linked to cardiac repolarization-associated ion handling (KCNN3), insulin-responsive metabolic regulation (FOXO1, HK2), cyclic adenosine monophosphate (cAMP)-responsive stress signaling (RAPGEF3), and mitochondrial homeostasis and redox regulation (MCL1, GCH1). Collectively, these results define a ponatinib-associated transcriptomic signature and nominate cross-dataset transcript-level candidates for subsequent mechanistic and experimental validation in ponatinib-associated cardiotoxicity. Full article

Background: H1-antihistamines are widely used for allergic and upper respiratory conditions; however, several agents included in this class have been associated with cardiac electrophysiological adverse effects, including QT interval prolongation and torsades de pointes (TdP). These effects are largely exposure-dependent and mechanistically linked to inhibition of cardiac ion channels. Chlorpheniramine maleate (CPM), a first-generation H1-antihistamine, has been implicated in arrhythmic events primarily under conditions of increased systemic exposure, prompting interest in whether alternative routes of administration may lower cardiac risk. Methods: This narrative review integrates mechanistic, preclinical, clinical, pharmacokinetic, and regulatory evidence. Information was extracted from PubMed, Google Scholar, and Scielo using search terms such as cardiotoxicity, chlorpheniramine, QT prolongation, intranasal administration, and cardiac arrhythmias, with no language restriction. Results: Comparative pharmacokinetic evidence shows that, on a dose-normalized basis, intranasal and oral chlorpheniramine exhibit comparable bioavailability; however, in a clinical context, intranasal doses (1.12–2.24 mg) are lower than oral daily doses (4–12 mg/day), resulting in a lower systemic exposure (Cmax and AUC) with intranasal administration. Available pharmacovigilance or epidemiological data have not specifically evaluated intranasal chlorpheniramine, and the number of dedicated safety trials remains limited. Conclusions: Preclinical, in vitro, mechanistic studies suggest that intranasal administration of chlorpheniramine should confer superior cardiac safety compared to the oral route. However, clinical data from human studies directly comparing the cardiac safety of intranasal chlorpheniramine versus systemic chlorpheniramine is extremely limited. More data from clinical trials, case–control studies, and regulatory databases are needed to validate these theoretical claims. Full article

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, and its co-occurrence with psychiatric disorders poses significant therapeutic challenges. This narrative review examines the safe use of psychopharmacological agents in patients with HF, focusing on mood stabilizers (particularly lithium) and antipsychotics. We summarize clinically relevant pharmacokinetic and pharmacodynamic interactions between these agents and guideline-directed HF therapies, including ACEIs, ARBs, ARNIs, beta-blockers, MRAs, SGLT2 inhibitors, and diuretics. Lithium is particularly prone to interactions due to its narrow therapeutic index and dependence on renal sodium handling, with RAAS inhibitors, thiazide diuretics, and SGLT2 inhibitors increasing the risk of toxicity. Antipsychotics are associated with QT prolongation, orthostatic hypotension, and electrolyte disturbances, with substantial variability between agents. This review highlights key clinical risks, provides a practical summary of drug interactions, and outlines principles for individualized, multidisciplinary management. Care requires coordinated cardiology–psychiatry collaboration, careful drug selection, and assessment of renal function, electrolytes, drug levels, and ECG parameters. Further studies and improved guideline integration are needed. Full article

Background: Ponatinib (PON), an effective tyrosine kinase inhibitor for leukemias harboring the T315I mutation, is limited by severe cardiotoxicity, including myocardial infarction and heart failure. Here, we investigated the therapeutic potential of Bone Morphogenetic Protein-7 (BMP-7), an anti-inflammatory growth factor, in a murine model of PON-induced cardiotoxicity. Methods: C57BL/6J mice were distributed into experimental groups receiving PON (25 mg/kg cumulative dose) either alone or with BMP-7 (600 μg/kg cumulative dose), along with a corresponding control group. Cardiac analyses included molecular and histological assessments. Results: PON administration induced a marked increase in monocyte infiltration and M1 macrophage polarization. These inflammatory events led to the upregulation of the pyroptotic cascade, leading to activation of the TGF-β1/SMAD2/3 signaling axis. In contrast, BMP-7 significantly attenuated these pathological responses by suppressing inflammation-induced pyroptosis and the TGF-β1/SMAD2/3 signaling axis. Conclusions: These findings identify inflammation-induced pyroptosis as a central driver of the pathological changes in PON-induced cardiotoxicity. Notably, our work highlights BMP-7’s capacity to inhibit these disease-related alterations. Collectively, these results expand on the current knowledge of the mechanistic framework of PON-induced cardiotoxicity, while also emphasizing BMP-7 as a promising therapeutic candidate with potential translational relevance. Full article

Cancer remains a primary global health challenge, accounting for millions of new cases and significant mortality annually. Although doxorubicin (DOX) is a fundamental anthracycline used for various malignancies, its therapeutic index is severely limited by poor selectivity, systemic toxicity, and dose-dependent cardiotoxicity. To address these issues, Janus nanoparticles (JNPs) have emerged as a promising bifunctional platform characterized by a structural asymmetry that allows for the independent functionalization of each hemisphere. This review examines primary fabrication routes—such as masking, microfluidics, self-assembly, and phase separation—and their specific applications in DOX delivery. The anisotropic architecture of JNPs enables a “separate rooms” concept, allowing for the co-delivery of incompatible drugs while facilitating multi-stimuli-responsive release mechanisms triggered by pH, enzymes, or NIR light. Furthermore, JNPs have demonstrated enhanced tumor accumulation and reduced systemic toxicity compared to conventional isotropic carriers. Recent developments even highlight the use of autonomous nanomotors to improve therapeutic delivery while minimizing premature leakage. However, clinical translation is currently hindered by manufacturing complexity, high equipment costs, scalability issues, and a lack of standardized reporting in the literature. Ultimately, JNPs represent a sophisticated frontier in precision oncology, though robust manufacturing processes and characterization protocols are required for future medical adoption. Full article

Background/Objectives: While doxorubicin (DOX) and trastuzumab (TRZ) improve overall survival in women with breast cancer, these two anti-cancer drugs increase the risk of developing heart failure. As a novel and largely unexplored approach, our aim was to evaluate whether the prophylactic use of the sodium-glucose co-transporter 2 inhibitor empagliflozin (EMPA), with and without the angiotensin converting enzyme inhibitor perindopril (PER), is cardioprotective in preventing DOX + TRZ-mediated cardiotoxicity. Methods: In a chronic in vivo murine model, female mice received prophylactic treatment with PER (3 mg/kg), EMPA (10 mg/kg), or EMPA + PER via oral gavage for a total of 3 weeks as a run-in period prior to weekly administration of DOX + TRZ (8 mg/kg and 3 mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Results: In mice treated with DOX + TRZ, the left ventricular ejection fraction (LVEF) decreased from 75 ± 2% at baseline to 40 ± 4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 58 ± 3%, 66 ± 3%, and 67 ± 4% at week 6, respectively (p < 0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX + TRZ-treated mice. Prophylactic administration with PER, EMPA, or EMPA + PER, however, improved myofibril integrity at week 6 in mice receiving DOX + TRZ. Finally, although the Bax/Bcl-xL ratio was significantly elevated by 1.5-fold in mice treated with DOX + TRZ, this marker of apoptosis was attenuated by prophylactic treatment with either PER, EMPA, or EMPA + PER. Conclusions: Prophylactic administration of EMPA mitigated adverse cardiovascular remodeling in a chronic in vivo model of DOX + TRZ-mediated cardiotoxicity. Full article

The development of novel antiepileptic agents requires early identification of pharmacokinetic limitations to mitigate risks at later stages. This study aimed to perform in silico profiling of a library containing 448 novel 2H,5H-chromeno[4’,3’:4,5]thiopyrano[2,3-d]thiazol-2-one derivatives to select lead compounds with an optimal balance of safety and efficacy. The study was conducted using the ADMET-AI platform, based on a graph neural network, to predict physicochemical, pharmacokinetic, and toxicological properties. The methodology involved calculating drug-likeness descriptors for primary screening and a comparative statistical analysis of the top 20 selected structures against 16 approved antiepileptic drugs and four reference compounds. Based on drug-likeness descriptors and predicted ADMET (absorption, distribution, metabolism, excretion, toxicity) related parameters, 20 structures were prioritized for further analysis. Their predicted profiles suggested high intestinal absorption and blood–brain barrier (BBB) permeability, which may be relevant for central nervous system (CNS) directed agents. In comparison with the reference thiazolidinones, the prioritized compounds showed comparatively more favorable predicted mutagenicity and carcinogenicity profiles. Elevated predicted risks of hepatotoxicity and cardiotoxicity were observed for several structures, indicating the need for further structural optimization. The results suggest that the thiopyranothiazolidinone scaffold merits further anticonvulsant-oriented investigation at the stage of early compound prioritization. Experimental validation will be required to confirm the actual pharmacokinetic, toxicological, and anticonvulsant properties of the prioritized compounds. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to reduce morbidity and mortality associated with type II diabetes mellitus, and/or obesity, and/or cardiovascular disease in multiple clinical trials. Their efficacy in reversing cardiovascular disease and mitigating the risk of major adverse cardiac and vascular events has been well studied, with outcome trials consistently demonstrating benefits such as reduced systemic inflammation, improved endothelial function, and favorable metabolic effects. These pleiotropic actions have nearly innumerable potential applications, with a progressively growing interest in using GLP-1 RAs to mitigate increased cardiovascular disease risk secondary to other off-target pharmacologic agents. Given these effects, the potential to utilize GLP-1 RAs for prophylactic cardioprotection before, during, and/or after chemotherapy regimens is of great interest. These effects are thought to be mediated in part through anti-inflammatory and antioxidant mechanisms that counter inflammation and reactive oxygen species-driven myocardial injury central to anthracycline-induced cardiotoxicity (AIC). Anthracyclines, a widely used class of chemotherapeutics for various malignancies, are frequently associated with dose-dependent and often irreversible cardiotoxicity, leading to heart failure, reduced quality of life, and adverse long-term outcomes. For the past three decades, dexrazoxane has been the sole Food and Drug Administration-approved agent for cardioprotection in this setting. However, in the current era of novel therapies with multi-system benefits—such as GLP-1 RAs—we propose a theoretical framework exploring their potential role in mitigating AIC and underscore the need for further clinical investigation in this new arena in the field of cardio-oncology. Full article

Proliferating cell nuclear antigen (PCNA) is a critical regulator of DNA replication and repair, and its cancer-associated isoforms represent promising therapeutic targets. The small molecule AOH1996 has been previously reported as a PCNA inhibitor with potent antiproliferative activity. Here, a series of novel AOH1996-based structural analogs were synthesized using structure–activity relationship (SAR) and scaffold-hopping strategies, including 1,2,3-triazole, glycine, and amide derivatives with diverse aromatic and polar substituents. The antiproliferative activity of these compounds was evaluated in MCF-7 (breast cancer) and U87 (glioblastoma) cell lines using the MTT assay. The parent compound AOH1996 exhibited the strongest cytotoxicity, reducing cell viability below 30% at 10 μM. Among the analogs, compounds 1f, 2b, 3b, 3c, and 3d demonstrated significant activity, reducing MCF-7 viability by 60–70% and U87 viability to 30–40% at 10 μM. SAR analysis revealed that electron-withdrawing or moderately lipophilic substituents on the amide side chain and aromatic extensions on the triazole ring enhanced potency, while bulky or strongly electron-donating groups diminished activity. ADMET predictions indicated that most derivatives possessed favorable drug likeness and absorption potential, but high plasma protein binding, short predicted half-lives, and potential cardiotoxicity represent limitations that will require further optimization. Several active compounds were predicted to inhibit P-glycoprotein, suggesting their potential to overcome multidrug resistance. Overall, compounds 2b and 3b showed relatively favorable predicted profiles and can serve as useful lead scaffolds for further optimization and experimental validation. Full article