Frontiers in cardiovascular medicine · 2026
4,4'-DMAR in-vivo acute cardiotoxicity: differences between (±)cis-4,4'-DMAR and its coadministration with the (±)trans-4,4'-DMAR isomer.
СтатьяНазвание и аннотация: Перевод в очереди
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Corli Giorgia, Roda Elisa, Marchetti Beatrice, Tirri Micaela, Bilel Sabrine, Bassi Marta, Benedetti Beatrice, Cavarretta Elena, Frati Giacomo, De Luca Fabrizio, Locatelli Carlo Alessandro, De-Giorgio Fabio, Marti Matteo
Аннотация
BACKGROUNDS/AIMS: Synthetic stimulants represent the largest group of new psychoactive substances and include the aminorex class, which possess anorectic properties and a pharmacological profile similar to that of amphetamine. Among these, 4,4'-dimethylaminorex (4,4'-DMAR) is one of the best-known synthetic stimulants with a chiral structure, which gives rise to two stereoisomers [(±)cis-4,4'-DMAR and (±)trans-4,4'-DMAR] with distinct pharmacological and toxicological characteristics. This substance has been detected in cases of intoxication and deaths among adults and adolescents. Although 4,4'-DMAR can also induce respiratory impairments, tachycardia, and sudden cardiac death/arrest, clinical and preclinical investigations of its cardiorespiratory toxicity remain limited. Thus, this study aimed to investigate the cardiorespiratory effects of (±)cis-4,4'-DMAR (1, 3, and 10 mg/kg) administration and the coadministration of 1 mg/kg (±)cis-4,4'-DMAR and 30 mg/kg (±)trans-4,4'-DMAR in awake CD-1 male mice.
METHODS: We evaluated heart rate, breathing rate, and cardiac (ECG) and respiratory (plethysmography) electrical parameters. The most severe effects were observed after administration of 10 mg/kg (±)cis-4,4'-DMAR and coadministration of 1 mg/kg (±)cis-4,4'-DMAR and 30 mg/kg (±)trans-4,4'-DMAR.
RESULTS: These treatments induced tachycardia and narrow-QRS arrhythmias, characterized by an increase in the corrected QT/QT interval, tachypnea, and a decrease in relaxation time, with varying degrees of intensity, probably due to differences in metabolism. Moreover, immunohistochemical analysis of the heart specimens revealed significant alterations in inflammation/oxidative stress markers in cardiomyocytes and blood vessel walls, accompanied by cytoarchitectural changes.
CONCLUSIONS: These findings provide the first evidence of the severe toxicity of 4,4'-DMAR to the cardiac and respiratory systems, highlighting the importance of dosage and stereoisomer coadministration. This serves as a warning of the complex nature and potential dangers of intoxication.
METHODS: We evaluated heart rate, breathing rate, and cardiac (ECG) and respiratory (plethysmography) electrical parameters. The most severe effects were observed after administration of 10 mg/kg (±)cis-4,4'-DMAR and coadministration of 1 mg/kg (±)cis-4,4'-DMAR and 30 mg/kg (±)trans-4,4'-DMAR.
RESULTS: These treatments induced tachycardia and narrow-QRS arrhythmias, characterized by an increase in the corrected QT/QT interval, tachypnea, and a decrease in relaxation time, with varying degrees of intensity, probably due to differences in metabolism. Moreover, immunohistochemical analysis of the heart specimens revealed significant alterations in inflammation/oxidative stress markers in cardiomyocytes and blood vessel walls, accompanied by cytoarchitectural changes.
CONCLUSIONS: These findings provide the first evidence of the severe toxicity of 4,4'-DMAR to the cardiac and respiratory systems, highlighting the importance of dosage and stereoisomer coadministration. This serves as a warning of the complex nature and potential dangers of intoxication.