Synergistic cardiotoxic effects of captagon and azithromycin in rat via oxidative stress, apoptosis and upregulation of the PI3K/AKT/NF-kB pathway

Fenethylline (Captagon) is a blend of amphetamine and theophylline that functions as a stimulant, while azithromycin (AZ) is a commonly prescribed macrolide antibiotic. The co-usage of illicit substances and therapeutic drugs can result in substantial health risk especially cardiotoxicity. This study aimed to assess cardiotoxicity effects of Captagon (Capta) and Azithromycin/Captagon interaction in adult male rats. Forty-two animals were assigned into 6 groups: Group I (Control) and group II (AZ (30 mg/kg/day) starting from the 14th day of the experiment and for 2 weeks. Group III (Capta10 mg/kg/day), group IV (Capta20 mg/kg/day), group V (AZ+Capta10) and group VI (AZ+Capta20) daily 28 days. Electrocardiogram (ECG), cardiac enzymes, oxidative stress markers, inflammatory genes expression, histopathological and immunohistochemical changes were assessed. Administration of AZ and Capta alone or in combination cause cardiotoxicity. This was indicated by elevated LDH and CTNI levels, ECG changes as increased HR, prolonged QT interval and elevated ST segment accompanied by cardiac histopathological changes. There was a significant reduction in antioxidants SOD, GSH, TAC, and catalase, alongside a significant rise in oxidative stress MDA and NO. Significant rise of ERK, TNF-α, NF-ҡB, PI3K/AKT, Il-1β and IL-6, in both the Capta20 and AZ+Capta groups in dose dependent manner. The Coadministration of AZ and Capta20 produced intense immunoexpression of caspase-3 and BAX and wide areas of negative reactivity for Bcl-2. Coadministration of AZ and Capta induced cardiotoxicity through oxidative stress, inflammation, and apoptosis pathways. It is important to educate healthcare providers and patients about the potential harmful interactions.