New Perspectives for Mucolytic, Anti-inflammatory and Adjunctive Therapy with 1,8-Cineole in COPD and Asthma: Review on the New Therapeutic Approach

Abstract

The mucolytic monoterpene 1,8-cineole (eucalyptol), the major constituent of eucalyptus species, is well known for its anti-inflammatory, antioxidant, bronchodilatory, antiviral and antimicrobial effects. The main protective antiviral, anti-inflammatory and mucolytic mechanisms of 1,8-cineole are the induction of interferon regulatory factor 3 (IRF3), the control of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) along with decreasing mucin genes (MUC2, MUC19). In normal human monocytes direct inhibition was shown of reactive oxygen species (ROS)-mediated mucus hypersecretion and of steroid resistence inducing superoxides (O₂^·-) and pro-inflammatory hydrogen peroxides (H₂O₂) with partial control of superoxide dismutase (SOD), which enzymatically metabolizes O₂^·- into H₂O₂. By inhibition of NF-κB, 1,8-cineole, at relevant plasma concentrations (1.5 µg/ml), strongly and significantly inhibited in normal human monocyte lipopolysaccharide (LPS)-stimulated cytokines relevant for exacerbation (tumour necrosis factor alpha (TNFα), interleukin (IL)-1β and systemic inflammation (IL-6, IL-8). Infectious agents and environmental noxa have access via TNFα and IL-1β to the immune system with induction of bronchitis complaints and exacerbations of chronic obstructive pulmonary disease (COPD), asthma and asthma-COPD overlap. In lymphocytes from healthy human donors 1,8-cineole inhibited TNFα, IL-1β, IL-4 and IL-5 and demonstrated for the first time control of Th1/2-type inflammation. 1,8-Cineole at relevant plasma levels increased additively in vitro the efficacy of inhaled guideline medications of budesonide (BUD) and budesonide + formoterol ,and preliminary data also showed increased efficacy of long-acting muscarinic receptor antagonist (LAMA)-mediated cytokine inhibition in vitro. On the basis of the preclinical data, earlier randomised controlled studies with adjunctive therapy of 1,8-cineole (3 × 200 mg/day) for 6 months showed improvement of uncontrolled asthma by significant improvement of lung function, nocturnal asthma and quality of life scores and in COPD decrease of exacerbations (- 38.5%) (during wintertime). This review reports an update with reference to the literature of 1,8-cineole, also as adjunctive therapy, as a therapeutic agent for the protection and control of inflammatory airway diseases.

Keywords: 1,8-Cineole; Asthma; Chronic obstructive pulmonary disease (COPD); Mucolytics; Sinusitis.

Fig. 1

Various inhalable pollutants as well as viruses and bacteria induce or intensify pre-existing airway inflammation. The result is the release of oxygen radicals and inflammatory mediators, which cause bronchitis with hypersecretion and acute respiratory distress, depending on the type of inflammation and genetic determinism. As a result of the at least bifunctional anti-inflammatory and antioxidant efficacy profile of 1,8-cineole, this is not only a symptomatic but also a causative therapy for the treatment of bronchial complaints. Through this approach, mucus hypersecretion and recurrent exacerbations are directly controlled with the aim to reduce the progression of chronic respiratory diseases

Fig. 2

Cigarette smoke is rich in oxygen radicals that induce bronchial hypersecretion and, among other activities, steroid resistance. Oxygen radicals (O₂^·−) are degraded via the activity of superoxide dismutases (SOD) to hydrogen peroxide (H₂O₂), which induces bronchial inflammation. In vitro studies of foetal calf serum-stimulated human monocytes showed modulating antioxidant effects of therapeutically relevant concentrations of 1,8-cineole with approximately 50% inhibition of O₂^·− and H₂O₂ and a partial inhibition in this approach of SOD [52]

Fig. 3

Previous randomized trials in COPD found a decrease in exacerbation frequency for LABA + ICS in the range of 24%, regardless of the amount of ICS used [–88], with only a slight difference to ICS alone (20%) [89]. Studies with monotherapy of a LAMA [90, 91] or PDE-IV inhibitor [92] showed comparable reductions (14−18%) of exacerbations such as ICS alone. In recent studies with LAMA + LABA, however, there a nearly twofold decrease in exacerbations in the range of 50% has been detected [93, 94]. For the first time, the effect of adjunctive therapy with the monoterpene 1,8-cineole showed a 38% decrease in exacerbations

Fig. 4

In an in vitro model (10⁵/ml, 2 Expt., n = 6) of human monocytes from healthy volunteers (expressing M₁–M₅ receptors), the effects of respiratory-relevant concentrations (2 × 10⁻⁶ M) and a relevant plasma concentration (4 × 10⁻⁶ M) of 1,8-cineole (C), tiotropium 15 pg/ml (TIO) alone and of TIO + C after incubation for 20 h were investigated for IL-8 in the presence of LPS (10 μg/ml) (Sigma-Aldrich, Germany). Stimulated IL-8 production was inhibited (p < 0.0001 compared to the LPS control) in a dose-dependent manner, even comparable to tiotropium (TIO) (15 pg/ml) at a small exhaled and therefore respiratory-relevant concentration of C (2 × 10⁻⁶ M). This inhibitory effect of TIO on IL-8 production increased significantly after co-incubation with the investigated breath-relevant concentration of C, and further dose-dependently, at an increasing, small systemically relevant concentration (4 × 10⁻⁶ M)