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).