European journal of pharmacology · 2025
Ocular safety evaluation of toplic and systemic antifungal medications: A multi-source pharmacovigilance and genomic study.
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Wang Dangdang, Peng Yang, Zhang Qi, Pu Yanyu, Gao Xi, Zeng Lihong, Lan Yufan, Lei Junqin, Zhu Huiyu, Huo Yujia, Du Shaowen, Wu Ping, Li Hong
Аннотация
BACKGROUND: Antifungal agents, used topically and systemically to treat fungal infections, have been associated with ocular adverse events (AEs), yet their ocular safety profiles remain under-characterized.
METHODS: This study utilized data from the FDA Adverse Event Reporting System (FAERS, 2004-2024), a single-center retrospective study validation, and systems pharmacology analyses to investigate ocular AEs linked to antifungal drugs. Disproportionality analysis identified AE signals, while retrospective clinical data validated key findings. Drug-gene interaction networks, pathway enrichment (GO/KEGG), and summary-data-based Mendelian randomization (SMR) using keratitis GWAS were employed to explore molecular mechanisms.
RESULTS: A total of 71,529 antifungal-related AE reports were identified. Topical agents were mainly linked to surface-level ocular symptoms (e.g., eyelid and periorbital oedema), whereas systemic agents showed stronger associations with vision-threatening events such as macular opacity, color vision disturbances, and toxic optic neuropathy (e.g., ROR >50). Collected clinical data partially supported these trends. Network analysis revealed hub genes (e.g., STAT3, AKT1, SRC) involved in PI3K-Akt and apoptotic signaling pathways. SMR analysis identified CES1 as a gene significantly associated with keratitis risk, suggesting a metabolic role in antifungal-induced toxicity.
CONCLUSION: Systemic antifungals are associated with a broader and more severe spectrum of ocular AEs than topical agents. Integration of pharmacovigilance, clinical data, and genomic analysis highlights PI3K-Akt signaling and CES1 as potential mediators of antifungal-related ocular toxicity. These findings offer new insights for risk assessment and mechanistic understanding, warranting further experimental validation.
METHODS: This study utilized data from the FDA Adverse Event Reporting System (FAERS, 2004-2024), a single-center retrospective study validation, and systems pharmacology analyses to investigate ocular AEs linked to antifungal drugs. Disproportionality analysis identified AE signals, while retrospective clinical data validated key findings. Drug-gene interaction networks, pathway enrichment (GO/KEGG), and summary-data-based Mendelian randomization (SMR) using keratitis GWAS were employed to explore molecular mechanisms.
RESULTS: A total of 71,529 antifungal-related AE reports were identified. Topical agents were mainly linked to surface-level ocular symptoms (e.g., eyelid and periorbital oedema), whereas systemic agents showed stronger associations with vision-threatening events such as macular opacity, color vision disturbances, and toxic optic neuropathy (e.g., ROR >50). Collected clinical data partially supported these trends. Network analysis revealed hub genes (e.g., STAT3, AKT1, SRC) involved in PI3K-Akt and apoptotic signaling pathways. SMR analysis identified CES1 as a gene significantly associated with keratitis risk, suggesting a metabolic role in antifungal-induced toxicity.
CONCLUSION: Systemic antifungals are associated with a broader and more severe spectrum of ocular AEs than topical agents. Integration of pharmacovigilance, clinical data, and genomic analysis highlights PI3K-Akt signaling and CES1 as potential mediators of antifungal-related ocular toxicity. These findings offer new insights for risk assessment and mechanistic understanding, warranting further experimental validation.