Evaluation of the cardiopulmonary effects of repurposed COVID-19 therapeutics in healthy rats

Hydroxychloroquine (HCLQ), favipiravir (FAVI), molnupiravir (MOL) and dexamethasone (DEX) are recently used drugs, some of which are currently used in the treatment of Coronavirus Disease (COVID-19). We aimed to investigate the cardiovascular and pulmonary effects of MOL, HCLQ, FAVI and DEX-drugs repurposed or used in COVID-19 treatment-independently of SARS-CoV-2 infection, using a healthy rat model. Wistar albino rats were divided into seven groups by simple randomization. (1) Control, (2) HCLQ, (3) FAVI, (4) MOL, (5) HCLQ + FAVI, (6) MOL + DEX, (7) HCLQ + FAVI + DEX. The doses of drugs to be administered to the experimental groups were adapted to rat doses with reference to the clinical treatment protocol. At the end of the experimental period, hemodynamic parameters of the rats were measured invasively. After that, the heart, lung and thoracic aortic tissues of the rats were removed and evaluated biochemically, histopathologically and immunohistochemically. When the hemodynamic parameters of the rats were compared, a statistically significant difference was found between the groups only in the PR interval (p < 0.001). Compared to the control group, the histopathologic changes observed in the HCLQ + FAVI + DEX group were significantly higher (p < 0.05), while all other groups had a normal histologic appearance similar to the control group. Vimentin immunoreactivity was significantly higher in MOL, HCLQ + FAVI and MOL + DEX groups compared to the other groups (p < 0.05). Receptor interacting protein kinase 3 immunoreactivity observed in the cytoplasm of cardiomyocytes was significantly higher in the HCLQ + FAVI group compared to all other groups except the FAVI group (p < 0.05). In contrast, caspase-3 immunoreactivity was found to be significantly higher in the FAVI group compared to the control group (p < 0.05). Drugs used alone or in combination in the treatment of COVID-19 show immunoreactions using different pathways related to apoptosis and necroptosis. Further studies are needed to elucidate the effects of these drugs.