7. Adverse effects and safety of Roflumilast
Roflumilast can be safely administered as it is not associated with the parlous induction of adverse effects involving seizures and cardiac arrhythmias; in addition, its elimination is not significantly altered by several drug classes or even by food and tobacco smoking (Gupta and O’Mahony, 2008).
Results from clinical trials demonstrated that the only use limitations reported for roflumilast were nausea, vomiting, diarrhea, weight loss and headache (Baye, 2012). These effects were appeared to be dose dependent and transient which in turn did not need treatment discontinuation (van Schalkwyk et al., 2005).
Great efforts have been made to limit the gastrointestinal adverse reactions and to provide a better benefit (Li et al., 2018). Thus, for improving patient tolerability, a study in the allergen-challenged Brown Norway rats, has been performed to evaluate the efficacy of inhaled roflumilast given either intratracheally or by nasal inhalation. As concluded, the inhaled form showed a powerful effect on improving the lung function (Chapman et al., 2007), supporting the therapeutic importance of using inhaled PDE4i against inflammatory lung diseases, which may be then more efficacious and less adverse effects than its oral forms, however it is still under clinical trial (Rhee and Kim, 2020).
8. Roflumilast in aging and diabetic comorbidities
During physiological aging process, a low-grade chronic systemic inflammation, called inflammaging, develops and impairs the maintenance of immunological homeostasis, in which there are high levels of C-reactive protein (CRP), proinflammatory cytokines as IL-6, in addition to low level of anti-inflammatory cytokines as IL-10 (Franceschi et al., 2018). PDE4 enzymes play a major role against inflammaging by increasing cAMP which in turn stimulates AMP-activated Protein Kinase (AMPK), exerting an anti-inflammatory effect. Since PDE4 enzyme activity in elderly individuals is greater than their youngers, using roflumilast, can experience a relatively more increase in cAMP level and as a consequence, potentiate its anti-inflammatory action in old age people (Muo et al., 2019).
Given the essential role of PDE4 in glucose and fat metabolism, roflumilast, through PDE4 inhibition, could prevent the disease progression in diabetes mellitus (DM) type 2 patients via improving the glycemic index. Roflumilast could encourage the secretion of intestinal glucagon like peptide-1 (GLP-1), which is a main incretin and potent insulinotropic agent for stimulating insulin secretion from the β-cells of pancreas (Wouters et al., 2012). In addition, it was documented that a deficiency in PDE4B could attenuate high-fat diet-induced adiposity and adipose tissue inflammation in mice (Vollert et al., 2012), referring to the role of roflumilast in reducing weight and improving insulin sensitivity in adults with prediabetes and/or obesity (Muo et al., 2019).