Phosphodiesterase-4 inhibition for treatment of COPD: Roflumilast

Phosphodiesterase-4 inhibition in COPD is mediated through a family of 11 enzymes that inactivate intracellular 2nd messengers cAMP and cGMP. Antagonists of specific PDE isoenzymes were studied in a wide range of diseases, and are used with a notable success in erectile dysfunction.

Different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could help

From 2 recent clinical trials published in The Lancet:

Phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain COPD patients - Adverse events were more common with roflumilast (67%) than with placebo (62%); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. The difference in weight change during the study between the roflumilast and placebo groups was −2·17 kg. The most likely cause of weight loss is the nausea and vomiting experienced by the patients. Some of the patients with emphysema, described as "pink puffers" in the classic medical textbooks, are already underweight.

Roflumilast improved lung function in patients with COPD treated with salmeterol or tiotropium - However, nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal.

There have been more than 15 trials with roflumilast (Daxas). The incidence of side effects was lower with the lower dose (250 mcg po daily) but also the medication was less effective. The recent studies reported in The Lancet used the higher dose of 500 mcg po daily, which was more effective, but was also associated with more side effects.

Newer, second generation, more selective PDE-4 are currently in development that will have a lower incidence of the known class side effects such as nausea and vomiting.


Roflumilast (Daliresp) for asthma - not FDA-approved and not recommended at this time - AAAAI Ask the Expert, 2011. Update: Roflumilast has been approved.
Roflumilast decreases allergen-induced inflammation in mild asthma - this is is similar to other PDE4 inhibitors
Image source: Wikipedia, public domain.

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