4D or not 4D – the emetogenic basis of PDE4 inhibitors uncovered?

Compelling evidence supports the idea that phosphodiesterase (PDE) 4 inhibitors have utility in the treatment of airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). However, most PDE4 inhibitors tested in clinical trials have, so far, exhibited a low therapeutic ratio, and side-effects including nausea and vomiting are common and potentially worrisome. These adverse events result from the inhibition of PDE4 in the gut and brain and, although the therapeutic ratio of second-generation PDE4 inhibitors has been improved by targeting a conformation of PDE4 that is abundant in pro-inflammatory and immune cells, untoward effects still preclude their administration at doses necessary for optimal clinical activity to be realised.