Repurposing of NKA inhibitors ('cardiac glycosides'): a critical analysis

As Na⁺-K⁺-ATPase (NKA) inhibitors ('cardiac glycosides') have declining rates of prescriptions because of their narrow therapeutic window, high toxicity and questionable clinical efficacy in cardiological indications, the question arises what the future of these drugs entails. In this paper, we researched and analysed newer uses of these drugs outside of their traditional indications, also referred to as repurposing. On ClinicalTrials.gov, we analysed the trials on NKA inhibitors including the scientific value of published trials. Of 306 trials to be analysed, only 40 were for repurposed use, of which 17 had a publication. Malignant diseases and foetal demise for late abortion are the most prominent indications. However, the quality of the clinical studies analysed was far from satisfying. Not a single study provided compelling evidence for a new clinical indication of NKA inhibitors at clinically relevant drug doses. NKA inhibitors could still have a future, specifically as part of oncological treatments. Different molecular mechanisms of action beyond NKA inhibition may be relevant for this use. However, further research is still required to see if in vitro effects can be translated to in vivo as well, which is the major bottleneck in repurposing NKA inhibitors in their narrow therapeutic window and high toxicity, unless specifically exploited in foetal demise.