Objectives Amiodarone remains an important antiarrhythmic drug, but cumulative exposure can cause pulmonary, hepatic, renal, thyroid, and reproductive toxicity. This systematic review critically compares interventions tested to prevent or attenuate amiodarone-induced injury, evaluates evidence strength and replication, and integrates the implicated molecular pathways. Methods PubMed, MEDLINE, Scopus, and Web of Science were searched from inception to July 2025 for English-language in vitro, animal, and human studies of protective interventions against amiodarone toxicity. Animal studies were evaluated using SYRCLE; in vitro studies using an adapted OHAT framework; and the human observational study using the applicable JBI checklist. Because of substantial heterogeneity, findings were synthesized narratively by organ, mechanism, replication, and translational readiness. Database-specific search strategies are reported in Supplementary Table S1. Disagreements were resolved by consensus; agreement was not quantified. Key findings Thirty-five reports were included. The evidence was overwhelmingly preclinical; only one observational human report was identified and no randomized clinical trial was found. Pulmonary models predominated. Vitamin E had the broadest replication, while curcumin, silymarin, l-carnitine, and grape-seed preparations were evaluated in more than one report or complementary model. Protection converged on attenuation of lipid peroxidation and inflammatory signaling, preservation of endogenous antioxidants and mitochondrial function, and suppression of apoptosis or TGF-β/Smad-associated fibrosis. Most studies had unclear risk of selection or performance bias. Conclusion Current evidence establishes biological plausibility but not clinical effectiveness. No protective adjunct can presently be recommended for routine use with amiodarone. Independent replication, clinically relevant exposure schedules, pharmacokinetic-interaction testing, and rigorously designed human studies are required.
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