# Male mice treated with combined anti-fibrotic therapeutics, IPW5371 and tadalafil, are predisposed to adverse cardiovascular events

## TL;DR

Combining two anti-fibrotic drugs in male mice unexpectedly caused severe cardiovascular issues, highlighting a dangerous drug interaction.

## Contribution

The study reveals a previously unknown adverse interaction between IPW5371 and tadalafil in male mice, independent of radiation effects.

## Key findings

- Combined IPW5371 and tadalafil caused increased male mouse mortality due to aortic rupture.
- Irradiation protected against the drug-induced lesions, showing drug effects independent of radiation.
- Non-irradiated mice had worse outcomes with the drug combination compared to irradiated mice.

## Abstract

Fibrosis is a pathological process with few therapeutic options. Experimental molecules are being developed to counteract the fibrotic effects through TGFβ receptor inhibition. Additionally, phosphodiesterase 5 (PDE5) inhibitors also have anti-fibrotic effects; however, the mechanism of action remains unresolved. IPW5371 is an example of an experimental TGFβ-mediated anti-fibrotic compound, and tadalafil is an example of a PDE5 inhibitor. Irradiation increases the frequency of fibrotic lesions, driven by the activation of the TGFβ pathway. We hypothesized that the TGFβ receptor and PDE5 inhibitor agents would be additive in their ability to prevent fibrosis development in tissues in a sub-lethal whole-body irradiation mouse model. However, the combined use of anti-fibrotic agents, tadalafil and IPW5371, caused increased male mouse mortality associated with ascending and thoracic aortic rupture compared to mice that only received one of the drugs. Following histopathological analysis of the mouse hearts, we also observed that irradiation protected against lesions caused by the combination therapy as non-irradiated male mice had significantly worse outcomes as compared to irradiated male mice, substantiating the drug–drug interaction independent of the radiation effects. This important drug interaction needs further investigation as these agents are developed for anti-fibrosis therapy, and PDE5 inhibitors are commonly prescribed to male patients.