Fig. 2: Eucalyptol.
Eucalyptus essential oil appears in almost all European national
pharmacopoeias and is traditionally used as a mucolytic, as an
antiseptic and to treat asthma, fever, flu, bronchitis and whooping
cough. EMA indicates its traditional use of this essential oil as a
treatment for the cough associated with a cold. In Germany, 1,8-cineole
is a licensed medicinal product formulated in gut soluble capsules
containing 100 mg/capsule and is indicated for acute and chronic
bronchitis, sinusitis, and respiratory infections.
In vitro studies have underlined the effect of eucalyptol as a
bronchodilator (credo), in enhancing the activity of mucociliary cells
with a corresponding effect on clearance and in decreasing mucus
production (Galan et al., 2020). In vitro investigation has shown
up to a 92% inhibition of the release of pro-inflammatory cytokines
tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1b) by
lipopolysaccharide (LPS)-stimulated monocytes treated with 1.5 μg/ml of
eucalyptol (Juergens et al., 2003). Another study has reported 0.6 mg/μL
eucalyptol extract to significantly inhibit the NF-κB p65 gene promoter
in LPS-stimulated human cell lines resulting in a decrease in
inflammation compared to that of the control (Greiner et al .,
2013). An interesting experiment was conducted analysing human blood of
asthmatic patients and healthy subjects, both pre-treated with 200 mg
eucalyptol thrice daily for 3 days, ex vivo . Up to 40.1%
inhibition of LTB4 and PGE2 from monocytes from asthmatic patients
(n=10) and up to 57.9% inhibition of those from healthy subjects (n=12)
have been reported ex vivo (Juergens et al 1998).
A placebo-controlled clinical trial analysing 242 patients with acute
bronchitis has measured the effect of 200 mg eucalyptol thrice daily for
10 day on the bronchitis endpoint “Bronchitis-Sum-Score” at 4 and 10
days. The group treated with eucalyptol showed a significant reduction
in the score compared to that of the placebo group (3.55 vs 2.91)
on day 4, but no significant differences were reported on day 10
(Fischer et al., 2013).
A double-blind placebo-controlled trial has considered
glucocorticosteroid reduction endpoints for 32 asthmatic patients given
200 mg of eucalyptol, or placebo, thrice daily for twelve weeks. The
results demonstrated a significant reduction of glucocorticosteroid
medication in the treatment group, even when the use of salbutamol was
doubled in this group, compared to the baseline condition, but the score
of dyspnoea was significantly greater in the placebo group (Juergens et
al., 2003).
The same dosage of eucalyptol, but taken for 6 months, has been used as
an adjunctive therapy in a more recent multicentre placebo-controlled
double-blind trial considering 247 asthmatic patients already under
medication. The authors reported a significant improvement in lung
function in the treatment group compared to the placebo group, by
reducing dyspnoea demonstrated by primary end-points, such as forced
expiratory volume 1 second, asthma symptoms and quality of life (Worth
et al., 2012). The same authors conducted a similar trial on 242 smoking
or former smoking patients with moderate/severe chronic obstructive
pulmonary disease (COPD) with concomitant use of standard therapy. The
group treated with eucalyptol showed a significant reduction in the
frequency, duration and severity of COPD exacerbations compared with
those of the control group. Secondary end-points, lung function,
dyspnoea and quality of life, improved without significance (Worth et
al. 2009). Data from a COPD experimental animal model exposed to
cigarette smoke have highlighted normal lung parenchyma and
significantly less leukocyte infiltration by 40-50% in mice treated
with 3 mg/kg and 10 mg/kg eucalyptol compared to placebo. In the same
study, the eucalyptol group showed a significant 60% reduction in
myeloperoxidase activity and 50% and 40% decreases in IL-1β and
interleukin-6 (IL-6) expression, respectively; TNF-α levels were reduced
by 80% in the higher dosage group. In addition to the anti-inflammatory
effect, a predictable disinfectant effect of reduced bacterial colonies
was also measured in this experimental COPD model of mice treated with
260 mg of eucalyptol per day (Yu et al., 2017).
The in vitro antiviral activity of nebulized eucalyptol essential
oil has been explored by Usachev et al. (2013). The authors
analysed the effect of eucalyptus aerosol on two viral model systems of
nebulized influenza virus A strain NWS/G70C (H11N9), simulating
hazardous bioaerosols in indoor and outdoor environments, by a plaque
assay technique.
The results underlined that 99% viral inactivation is achieved after 15
seconds of aerosolization and exposure for 5 minutes. The antiviral
activity was exerted by both the aerosol form and vaporized phase. The
antiviral effect was measured in an in vitro experimental model of
Herpes simplex virus, and 1,8-cineole had an
antiviral IC50 equal to about a quarter of the maximum
non-lethal dose measured in a cytotoxicity assay (Astani et al., 2010).
A small number of both in vivo and in vitro pharmacokinetic studies have
considered oral administration. In a rabbit model given 200 mg/kg of
eucalyptol, a peak plasma concentration was reached after 1 h (Bhowal et
al 2005). The oxidative metabolic pathway of eucalyptol produces
2-hydroxy-1,8-cineole and 3-hydroxy-1,8-cineole, conjugated to
glucuronide products. It has been reported that chronic administration
of 800 mg/day does not imply accumulation (Juergenes et al., 2003). By
extrapolation from data on other monoterpenes with similar chemical
structures, it could be supposed that lung elimination of the unchanged
form of eucalyptol could range from 1 to 10% in the expired air
(Kohlert et al. 2000).
The EMA monograph on eucalyptus essential oil (eucalyptol content of at
least 70%) indicates oral use of up to 200 mg of essential oil for a
maximum of 5 times a day for adults and adolescents, while use in
children under 30 months is contraindicated.