Phytomedicine Plus 1 (2021) 100089

Contents lists available at ScienceDirect

Phytomedicine Plus
journal homepage: www.elsevier.com/locate/phyplu

A systematic and comprehensive review on current understanding of the

pharmacological actions, molecular mechanisms, and clinical implications
of the genus Eucalyptus
Nikhil Chandorkar a,1, Srushti Tambe b,1, Purnima Amin b, Chandu Madankar a,∗
a
Institute of Chemical Technology, Department of Oils, Oleochemicals, and Surfactants Technology, Mumbai 400019, India
b
Institute of Chemical Technology, Department of Pharmaceutical Science and Technology, Mumbai 400019, India

a r t i c l e i n f o a b s t r a c t

Keywords: Background: The interest in the use of Eucalyptus genus members, in parallel with preclinical studies has been
Eucalyptus steadily growing over the last few decades in the field of pharmaceuticals, agriculture, cosmetics, food, etc.
Cineole Eucalyptol (1,8-cineole or cineole), the main terpenoid constituent in Eucalyptus species, has been studied in both
Eucalyptol
preclinical and clinical settings for its various pharmacologic activities. Investigations into the pharmacological
Respiratory disorders
activities of the genus Eucalyptus revealed that it manifests astounding potential in the treatment and management
COVID-19
Wound healing of respiratory disorders, COVID-19, pain, oral health, infectious diseases, cancer, etc.
Purpose: This review congregates and discusses the hitherto scattered data on Eucalyptus species morphology,
chemical composition, some of its profusely investigated multifaceted therapeutic applications with insights into
their molecular mechanisms, and clinical studies. The current understanding of the molecular mechanisms arising
from cell lines, animal models, and clinical trials are emphasized. Lattermost, this review sheds light on various
reported Eucalyptus-based formulations and relevant patents. Overall, this review aims to summarize and bridge
the lacunae in the current research and offer a plethora of opportunities for the researchers engaged in the
validation of the traditional claims and development in Eucalyptus utilization for safe and effective treatment of
various diseases
Method: The systematic and comprehensive review was carried out by adhering to the guidelines of the Preferred
Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements. PubMed, Scopus, ScienceDirect,
Google Scholar, and Google patents databases were used to explore literature published till April 2021 by using
relevant keywords.
Results: The systematic search retrieved 306 papers that were potentially relevant and after the selection pro-
cedure, 103 studies were included in this review and discussed. The evidence reviewed herein suggested that
several Eucalyptus species possess anti-inflammatory, anti-microbial, anti-viral, anti-oxidant, anti-nociceptive,
anti-cancer, anti-diabetic, etc., activities.
Conclusion: Preclinical and clinical studies have shown that the Eucalyptus plant and its chemical constituents
have enormous potential for disease prevention and treatment. Eucalyptus, an ancient and underutilized ally with
its diverse therapeutic applications can give rise to a paradigm shift in the treatment regime of several diseases
in this era of modern science.

Abbreviations: 𝛽-TrCP, 𝛽-Transducin Repeat-Containing Protein; 3CL-
pro, 3C-like protease; 3Cpro, 3C protease; 5-HT – Serotonin; AMPK,
5′ adenosine monophosphate-activated protein kinase; AP-1, Activa-
tor protein 1; BALF – bronchoalveolar lavage fluid; Calm – Calmod-
ulin; CAT – catalase; CD 8/ 14, Cluster of differentiation 8/ 14; ChAT,
Choline-acetyltransferase; COX – cyclooxygenase; DAG – diacylglyc-
erol; DNA, Deoxyribonucleic Acid; EAC, Ehrlich ascites carcinoma;
EEO, Eucalyptus essential oil; EGR-1, Early growth response protein
1; EO, Essential oil; ER, Endoplasmic Reticulum; ERK, Extracellular-
signal-regulated kinase; Fc𝜀RI, high-affinity receptor for the Fc re-

∗
Corresponding author at: Institute of Chemical Technology, Department of Oils, Oleochemicals, and Surfactants Technology, Nathalal Parekh Marg, Matunga,
Mumbai, Maharashtra, 400019, India.
E-mail addresses: cs.madankar@ictmumbai.edu.in, chandumadankar@gmail.com (C. Madankar).
1
Nikhil Chandorkar and Srushti Tambe contributed equally to this work as first authors.

https://doi.org/10.1016/j.phyplu.2021.100089
Received 7 June 2021; Received in revised form 18 June 2021; Accepted 23 June 2021
2667-0313/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
N. Chandorkar, S. Tambe, P. Amin et al.
gion of immunoglobulin E (IgE); FYN, Proto-oncogene tyrosine-protein
kinase; G6PDH, Glucose-6-phosphate dehydrogenase; GABA, Gamma-
amino butyric acid; GADS, Grb2-related adaptor downstream of dock-
ing protein Shc; GLUT5, a fructose transporter expressed on the apical
border of enterocytes in the small intestine; GPX, Glutathione peroxi-
dase; GRB2, Growth factor receptor-bound protein 2; HepG2, a human
liver cancer cell line; HSV, Herpes simplex virus; IgE, Immunoglobulin E;
IKK, I𝜅B kinase; IL-1 𝛽, interleukin-1𝛽; IL-10, Interleukin 10; IP3, Inosi-
tol trisphosphate; I𝜅B𝛼, Nuclear factor of kappa light polypeptide gene
enhancer in B-cells inhibitor, alpha; JNK, c-Jun N-terminal kinase; KC
– Chemokine; LAT, linker for activation of T cells.; LBP, Lipopolysac-
charide binding protein; LPS – lipopolysaccharides; LTB4, leukotriene
B4; LTC4, Leukotriene C4; LYN, Tyrosine-protein kinase; MAPK/ MEK/
p38, Mitogen-activated protein kinases; MCP-1, Monocyte chemoattrac-
tant protein-1; MDA – Malondialdehyde; MDR, Multidrug-resistant; MIA
PaCa-2, Human pancreatic cancer cell line; MIC, Minimum inhibitory
concentration; MKP-1, Mitogen-activated protein kinase; Mpro, Main
protease; MYD88, Myeloid differentiation primary response 88; NE, Nor-
epinephrine; NFAT, Nuclear factor of activated T-cells; NF-𝜅B, Nuclear
factor ‘kappa-light chain enhancer of activated B cells; NK, Natural
Killer; NLRP3, NLR Family Pyrin Domain Containing 3 is a Protein Cod-
ing gene; NOS, Nitric oxide synthase; p50/p65, also known as RELA. It is
a REL-associated protein involved in NF-𝜅B heterodimer formation, nu-
clear translocation and activation; PARP, Poly(ADP-ribose) polymerase;
PGD2, Prostaglandin D2; PGE2, prostaglandin E2; PIP2, Phosphatidyli-
nositol 4,5-bisphosphate; PKC, Protein kinase C; PLA2, Phospholipases
A2; PLC𝛾, Phospholipase C-𝛾; RAF, Rapidly Accelerated Fibrosarcoma;
RAS, Renin-Angiotensin System; ROS, Reactive oxygen species; SLP76,
SH2-domain-containing leukocyte protein of 76 kDa; SOD, Superox-
ide dismutase; SOS, Son of Sevenless; Spp. – Species; SYK, Tyrosine-
protein kinase; TBARS, Thiobarbituric acid reactive substances; TLR4,
Toll-like receptor 4; TNF𝛼, Tumor necrosis factor-𝛼; TREM-1, Triggering
Receptor Expressed On Myeloid Cells 1; TRP, Transient receptor poten-
tial; TRPM8, Transient receptor potential cation channel subfamily M
(melastatin) member 8; TXB2, thromboxane B2
Introduction
The use of extracts from Eucalyptus species leaves for the treatment
of various ailments especially respiratory problems have a rich folkloric
history, especially by the Australian Aborigines (Galan et al., 2020).
The French botanist Charles L’Héritier de Brutelle first described the
genus Eucalyptus in 1788, based on a specimen of Eucalyptus obliqua
from Adventure Bay on Bruny Island, Tasmania (Kantvilas, 1996). The
word Eucalyptus originates from the prefix "Eu," which implies "true,"
and "calyptus," which implies "to cover," and corresponds to the lower
bud made up of united calyx and corolla parts that seal the flower un-
til it blooms (Kantvilas, 1996). Eucalyptus oil is ethnomedicinally im-
portant and popular essential oil (EO) with diverse therapeutic activ-
ities such as analgesic (Silva et al., 2003), antimicrobial (Gilles et al.,
2010), anti-oxidant (Mishra et al., 2010), antibacterial (Bachir and Be-
nali, 2012), antiviral (Elaissi et al., 2012), sedative (Teixeira et al.,
2008), CNS stimulant (Kovar et al., 1987), pulmonary decongestant
(Burrow et al., 1983), antispasmodic (Coelho-de-Souza et al., 2005), etc.
Due to its therapeutic potential, Eucalyptus essential oil (EEO) has found
its application in the treatment of various ailments such as bronchitis
(Lu et al., 2004), sinusitis (Kehrl et al., 2004), asthma (Juergens et al.,
2003), Chronic obstructive pulmonary disease (COPD) (Worth et al.,
2009), pain (Jun, Yang Suk et al., 2013), infections (Schnitzler et al.,
2001; Yadav and Chandra, 2017), wounds (Velmurugan et al., 2014),
cancer (Takasaki et al., 2000), malaria (Nathan, 2007) and last but not
the least COVID-19 (Panikar et al., 2021). Moreover, it is widely used
in perfumery, cosmetics, food, beverages, aromatherapy, phytotherapy,
and soap industries. The EEO has also expanded its application in other
industries as a mosquitocide (Nathan, 2007), insecticide (Kumar et al.,
2012; Maciel et al., 2010), herbicide (Benchaa et al., 2018) over the
2
Phytomedicine Plus 1 (2021) 100089
years. Eucalyptus globulus Labill. (E. globulus) is a widely cultivated
species around the world and well-represented in the international phar-
macopoeia. E. globulus is the world’s leading source of Eucalyptus oil,
where1,8-cineole is the most important monoterpene ether. Although E.
globulus contains a lower proportion of 1,8-cineol than Eucalyptus poly-
bractea R.T. Baker (E. polybractea) and some other species, E. globulus
remains the most important source of cineole in the world. This can be
attributed to the mass utilization of E. globulus in the wood and pulp
industry and as a result, the ‘waste’ leaf is used to produce oil. This and
other commercially generated oils with lower cineole concentrations
than E. polybractea such as Eucalyptus smithii R.T. Baker (E. smithii) and
Eucalyptus radiata Sieber ex DC. (E. radiata) are either fractionated to in-
crease cineole levels to 70–75% or 80–85% as required by International
Organization for Standardization and various national pharmacopoeias,
or marketed for uses where cineole content is not as essential (e.g.,
aromatherapy). Eucalyptus’s medicinal properties are found in its oil
which is extracted from fresh leaves. Other Eucalyptus spp. with medic-
inal properties include E. smithii, Eucalyptus bentahmii Maiden & Cam-
bage (E. bentahmii), E. polybractea, Eucalyptus bicostata Maiden, Blakely
& Simmons (E. bicostata), Eucalyptus sideroxylon A.Cunn. ex Woolls (E.
sideroxylon), Eucalyptus cineria F.Muell. ex Benth. (E. cineria), Eucalyp-
tus leucoxylon F.Muell. (E. leucoxylon), Eucalyptus camaldulensis Dehnh.
(E. camaldulensis), Eucalyptus Tereticornis Sm. (E. Tereticornis), Eucalyp-
tus grandis W.Hill ex Maiden (E. grandis), Eucalyptus radiata Sieber ex DC.
(E. radiata) (Ashour et al., 2019; Döll-Boscardin et al., 2012; Liapi et al.,
2007; Luís et al., 2016; Silva et al., 2003; Soyingbe et al., 2013). In the
light of various potentialities as well as the existing demand for Euca-
lyptus species, this review aims to address the myriad of therapeutic
applications of Eucalyptus spp. including its emerging role in SARS-CoV-
2 treatment with a brief discussion on its morphology and chemistry.
The molecular mechanisms of the pharmacological activities of the Eu-
calyptus spp. derived from the cell lines, in vivo models, and clinical tri-
als are discussed. Lattermost, this review congregates the hitherto scat-
tered reports on Eucalyptus-containing formulations and patents for var-
ious therapeutic applications. Overall, this review emphasizes the sig-
nificance of Eucalyptus spp. in therapeutics as a natural medicine based
on the encouraging evidence that exists in the literature.
Literature search and selection methodology
PubMed, ScienceDirect, Scopus, Google Scholar, and Google patents
databases were used to conduct an extensive literature search to iden-
tify and retrieve scientific studies performed with Eucalyptus spp. and
its therapeutic applications for the treatment, management, and pre-
vention of various diseases. This review was structured and constructed
according to the Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) criteria (Fig. 1) (Liberati et al., 2009). Appro-
priate articles published in peer-reviewed journals till the year 2021 (up
to April) were included. Publications or reports in English were cho-
sen whereas non-English language papers, letters to editors, conference
abstracts, and unpublished data were eliminated. The keywords were
used in numerous permutations for literature searches which included
Eucalyptus, ethnobotany, pharmacological actions, treatment, molecu-
lar mechanism, in vitro cell lines model, in vivo model, health benefits,
patents and formulations. The primary literature bibliography was also
used to discover additional related publications. The studies included
in the review met the predefined eligibility criteria: (1) The search re-
sult was a study on a Eucalyptus species comprising cell lines model, in
vivo model, or involved molecular docking; (2) The search result was a
randomized controlled clinical trial; (3) The search result demonstrated
outcomes pertaining to the respiratory disorders, cancer, tumors, gas-
trointestinal disorders, pain, immunomodulation, diabetes, infectious
diseases, neurological disorders, periodontitis, oral health, wound heal-
ing; (4) The search result featured novel formulations and inventions
containing Eucalyptus for therapeutic application. Based on this, the sys-
tematic search approach retrieved 306 potentially relevant papers and
N. Chandorkar, S. Tambe, P. Amin et al.
Fig. 1. PRISMA flowchart of included articles in this review.
after the exclusion of articles based on the eligibility criteria, 103 stud-
ies were included in this review and discussed below. The inconclusive
studies were discussed between authors to reach a consensus.
Morphological description
Eucalyptus is a genus of the Myrtaceae family, which comprises
900 species and subspecies. This evergreen woody perennial ranges
in height from shrubs to tall trees and grows rapidly to gigantic size
(Coppen, 2002). Eucalyptus is native to Australia and Tasmania and is
known to be the second-largest genus after Acacia (Davis, 2002). Aus-
tralia is a home to almost all 700 known species of Eucalyptus trees.
Among the several Australian Eucalyptus species, E. globulus was intro-
duced extensively thus becoming the most widely cultivated species in
Mediterranean and subtropical regions as well as in Nigeria. The Eu-
calypts have a natural latitude range extending from 7° N to 43 ° 39′
S. Their natural habitat is specifically limited to the east of the hypo-
thetical ‘Wallace’s line’ that divides Indo-Malayan and Austro-Malayan
life forms (Williams and Woinarski, 1997). Eucalyptus species can dra-
matically range in height, anywhere from 30 to 200 feet. The tallest
Eucalyptus tree, the Mountain Ash, can reach over 301 feet. The E. radi-
ata tree is typically about 98 feet tall, sometimes reaching up to 164 feet
(Boland et al., 2006). The leaves and twigs of many Eucalyptus species
are the most important source of Eucalyptus oil for pharmaceuticals, per-
fumes, soaps, and detergents. Most of the Eucalyptus species exhibit leaf
dimorphism and they exist as mature and juvenile leaves. In the juvenile
stage, the leaves are opposite, sessile, oval to roundish, and glaucous.
Leaves in the mature stage are usually petiolate, pendulous, and lance-
olate, often stiff, thick, highly coriaceous, and cutinized. Leaf venations
play a major role in determining the Eucalyptus species and most of-
ten, pinniveined, oblique, or spread form of leaf venations are observed
(Hardel and Laxmidhar, 2011). The bark of the Eucalyptus tree exists
in several types including smooth or rough, deciduous or persistent, or
both. The shedding pattern, length of the fiber, color, thickness, hard-
ness, and the extent of furrowing of the bark of Eucalyptus varies with
the age and species of the plant (Blakely, 1965). Every year, all Euca-
lyptus species add a layer of bark soon after the death of the outermost
layer. Species like Eucalyptus sheathiana Maiden (E. sheathiana), Eucalyp-
3
Phytomedicine Plus 1 (2021) 100089
tus cosmophylla F.Muell. (E. cosmophylla), Eucalyptus cladocalyx F.Muell
(E. cladocalyx), and Eucalyptus diversicolor F.Muell. (E. diversicolor) shed
the dead bark in the form of large slabs, ribbons, or small flakes. Other
species like Eucalyptus leptophleba F.Muell. (E. leptophleba), E. radiata,
and Eucalyptus jensenii Maiden (E. jensenii) retain and accumulate the
dead bark that dries out. Eucalyptus species like Eucalyptus brachycalyx
Blakely (E. brachycalyx), Eucalyptus ochrophloia F.Muell, and Eucalyptus
occidentalis Endl. are called ‘blackbutts’ or ‘half-barks’ as they tend to re-
tain their dead bark in the lower half of the trunks or stems (Khan et al.,
2020). E. globulus appears to be unique as their bark cells can photo-
synthesize in the absence of foliage that increases their capacity to re-
fix internal CO2 following partial defoliation (Eyles et al., 2009). This
ability allows the tree to grow in less-than-ideal climates, additionally
providing them with a better chance of recovery from the damage done
to its leaves in events such as forest fires, insects or leaf fungal pathogen
infestations, grazing, etc. (Saveyn et al., 2010). Eucalyptus plants have
been drawing the attention of several researchers and environmentalists
worldwide because they represent a rapidly growing source of wood and
oil that can be used for several purposes. However, this plant has some
disadvantages. It squeezes the water from the earth, decreases the wa-
ter table, and disturbs the tube well system of the world. Moreover, this
plant needs more water so they tend to compete with other plants in the
area. The root of this plant goes very deep which also affects the plain
land of the farmer (Khan et al., 2020).
Chemical composition
The EO from Eucalyptus is generally obtained from steam distilla-
tion (Moudachirou et al., 1999) or hydro-distillation (Mann et al., 2013;
Vivekanandhan et al., 2020) majorly from the leaves and less commonly
from the fruits, flowers, and stems of the Eucalyptus. Several other ex-
traction techniques such as Soxhlet extraction (Zhao and Zhang, 2014),
supercritical CO2 extraction (Santos et al., 2012; Zhao and Zhang, 2014),
microwave-assisted extraction (Bhuyan et al., 2015; Liu et al., 2016),
and solid-phase microextraction (Zini et al., 2003) are also utilized
to obtain EEO. The EO profile of Eucalyptus is characterized by a
high content of volatile organic compounds. Essential oils are a mix-
ture of natural volatile bioactive compounds, mainly sesquiterpenoids,
N. Chandorkar, S. Tambe, P. Amin et al. Phytomedicine Plus 1 (2021) 100089

Table 1
Important Eucalyptus species with major constituent and total percentage.

Species Major component Total Percentage References

Medicinal Eucalyptus oil

Eucalyptus smithii 1,8-cineole 84.27 (Chalchat et al., 1997)
Eucalyptus globulus 1,8-cineole 83.89 (Maciel et al., 2010)
Eucalyptus maideni 1,8-cineole 83.59 (Sebei et al., 2015)
Eucalyptus bicostata 1,8-cineole 81.29 (Sebei et al., 2015)
Eucalyptus sideroxylon 1,8-cineole 80.75 (Sebei et al., 2015)
Eucalyptus cineria 1,8-cineole 79.18 (Sebei et al., 2015)
Eucalyptus leucoxylon 1,8-cineole 77.76 (Sebei et al., 2015)
Eucalyptus camaldulensis 𝛾-terpinene 72.50 (Mubarak et al., 2015)
Eucalyptus tereticornis 𝛽-pinene 39.00 (Ogunwande et al., 2003)
Eucalyptus grandis 𝛼-pinene 30.40 (Ogunwande et al., 2003)
Industrial Eucalyptus oil
Eucalyptus dives Schauer Piperitone 53.00 (Ebadollahi, 2013)
Eucalyptus elata Dehnh. 𝛼-Phellandrene 35.20 (Ebadollahi, 2013)
Eucalyptus oil for essence/aroma
Eucalyptus citriodora 𝛽-citronellal 71.77 (Maciel et al., 2010)
Eucalyptus gomphocephala A.Cunn. ex DC. Dihydrocarveol acetate 50.82 (El-Mageed et al., 2011)
Eucalyptus macarthurii H.Deane and Maiden Geranyl acetate 50.49 (Chalchat et al., 1997)
Eucalyptus staigeriana F.Muell. ex F.M.Bailey (+) Limonene 28.82 (Maciel et al., 2010)
Eucalyptus aggregata H.Deane & Maiden ß-phenylethyl phenyl acetate 90 (Hellyer, Lassak and McKern, 1966)
Eucalyptus globulus var. bicostata 1,8-cineole 73.09 (Dayal and Ayyar, 1986)
Eucalyptus deglupta Blume p-cymene 7.90 (Dayal and Maheshwari, 1985)

monoterpenoids, phenylpropanoids, etc., containing hundreds of indi-
vidual chemical constituents. The importance of Eucalyptus in medicine
largely depends on the content of one specific constituent namely, 1,8-
cineole (cineole or eucalyptol). The major composition of Eucalyptus oil
is 1,8-cineole and constitutes more than 70% (v/v) of the total oil and
the other major constituents co-occurring with eucalyptol are limonene
and 𝛼-terpineol. Eucalyptus oil for medicinal purposes is commonly ex-
tracted from E. globulus, E. polybractea, or E. smithii as their total eucalyp-
tol content is more than 70% and listed in the pharmacopoeias of many
countries, including the United Kingdom, France, Germany, Belgium,
the Netherlands, the United States, Australia, Japan, and China. Euca-
lyptol accounts for more than 90% in some species like E. polybractea
(Mishra et al., 2010), Eucalyptus bakeri Maiden (Mishra et al., 2010),
Eucalyptus kochii Maiden and Blakely (Barton et al., 1989), Eucalyptus
oblonga A.Cunn. ex DC. (Baker and Smith, 1920), Eucalytpus plenissima
(C.A.Gardner) Brooker (Brooker et al., 1988), and Eucalyptus sturgissiana
L.A.S.Johnson and Blaxell. Except for E. polybractea, few of these are be-
ing exploited as commercial sources of 1,8-cineole. Other constituents
are macrocarpals (phloroglucinol-sesquiterpenes), eucalyptin, monoter-
penes (p-cymene, 𝛼-pinene, d-limonene, 𝛽-pinene), phenols, oleano-
lic acid, flavonoids (8-desmethyl-eucalyptin, 6,8- dimethylkaempferol-
3,7-dimethyl ether), alkaloids, tannins, 2′6′-dihydroxy-3′-methyl-4′-
methoxy-dihydrochalcone, terpenoid phenolaldehydes, and verbenone,
a monoterpene bicyclic ketone (Dhakad et al., 2018). E. globulus is a
Eucalyptus species that has been researched extensively. Phytochemical
analysis has revealed that the monoterpene profile differs among Euca-
lyptus species, indicating the differences in the medicinal properties of
various species. E. camaldulensis EO exhibits a more complex composi-
tion. Approximately fifty-four compounds representing 95% of the total
leaf oil were identified wherein eucalyptol (16.20%) was the most abun-
dant monoterpene, followed by 𝛼-pinene (15.60%) (Gakuubi, 2016).
The phytochemical analysis of E. grandis oil revealed that it consti-
tutes high content of eucalyptol and a total of 22 other chemical com-
ponents accounting for 95.95% of the major components of the EO
(Sewanu, 2012). The common chemical constituents in Eucalyptus are
represented in Fig. 2. Table 1. represents important Eucalyptus species
with their major oil components and total percentage.
Therapeutic applications of Eucalyptusoil
The bark and leaves of various Eucalyptus species have been used as
folk medicines for the treatment of various ailments since ancient times.
1,8-cineole is the major constituent of Eucalyptus spp. that attributes
to the medicinal properties. The following section discusses the mul-
tifaceted therapeutic applications of Eucalyptus spp. for the treatment
of various diseases and disorders with an emphasis on their molecular
mechanisms. Fig 3. represents various therapeutic applications of Euca-
lyptus spp.
Respiratory disorders
Herbal medicines such as cineole capsules and Myrtol® standardized
(GeloMyrtol®, GeloMyrtol forte®) have received tremendous attention
over the past 20 years due to their potential therapeutic benefits in var-
ious respiratory conditions. Several in vivo and ex vivo studies suggest
that Myrtol® standardized has significant secretolytic and secretomo-
toric effects, resulting in increased upper and lower airway patency and,
as a result, rapid relief of patients’ symptoms. The medication has been
used to treat a variety of acute and chronic infections of the upper and
lower airway system, including acute and chronic rhinosinusitis, acute
and chronic bronchitis, and COPD (Rantzsch et al., 2009), due to its
additional antioxidative, anti-inflammatory, and antibacterial proper-
ties. In Germany, small gut soluble capsules namely, SoledumTM con-
taining 100 mg of 1,8 – cineole have been used for the treatment of
acute and chronic bronchitis, sinusitis, and other respiratory infections.
The pharmacological effects of eucalyptol in respiratory diseases can
be attributed to its anti-inflammatory (Yu et al., 2018), anti-spasmodic
(Bastos et al., 2009), and mucus secretion inhibiting (Sudhoff et al.,
2015) actions that result in the downregulation of tumor necrosis factor-
𝛼 (TNF𝛼) and inflammation cytokines such as interleukin-1𝛽 (IL-1 𝛽)
(Juergens et al., 2004). Zhou et al. (Zhou et al., 2007) demonstrated
that the anti-inflammatory action of 1,8-cineole may be attributed to the
1,8-cineole induced blockage of Egr-1 effect by inhibiting the synthesis
of Egr-1 and preventing Egr-1 nuclear internalization. In another study,
Greiner et al. (Greiner et al., 2013) studied 1,8-cineole to enunciate the
molecular mechanism of its anti-inflammatory action using lipopolysac-
charides (LPS). LPS plays a critical role in inflammatory processes by
activating the NF-𝜅B and MAPK signaling pathways (He et al., 2015).
It was observed that cineole reduced NF-𝜅B (nuclear factor ‘kappa-light
chain enhancer of activated B cells), which plays a vital role in regulat-
ing the pathogenesis of inflammatory diseases (Salminen et al., 2008).
After treating with cineole, an increase in the protein amounts of I𝜅B𝛼
was observed which restored interaction between I𝜅B𝛼 and NF-𝜅B p65.
As a result, due to the absence of p65 translocation into the nucleus,

4
N. Chandorkar, S. Tambe, P. Amin et al.
binding to B-sites was substantially reduced, and expression levels of
NF-𝜅B target genes were significantly decreased. I𝜅B𝛼 and JNK were
identified as potential targets of 1,8-cineol by the authors, assuming
that JNK acts directly on NF-𝜅B target gene expression via AP-1. Lack
of I𝜅B𝛼-degradation appears to be phosphorylation-independent, imply-
ing that altered kinetics may be involved in an IKK-independent manner.
The overview of the potential mode of action of 1,8-cineol in an animal
model with LPS-induced pulmonary inflammation is shown in Fig. 4.
(Zhao et al., 2014). Not only an increase in the anti-inflammatory cy-
tokine IL-10 was observed in the lung tissues but inhibition of TNF𝛼,
IL-1𝛽 and decreased expression of p65, which is a subunit of NF-kB was
also seen. Caceres et al. (Caceres et al., 2017) explained that the high
potency of eucalyptol in humans can be attributed to its superior sensi-
tivity to Human TRPM8 channels than rodents. The author also reported
that the metabolite of eucalyptol, 2‐hydroxy‐1,8‐cineol, also possesses
anti-inflammatory effects. It can be concluded that 1,8-cineol can be ex-
tremely beneficial in the treatment of several anti-inflammatory diseases
such as sinusitis, bronchitis, asthma, and COPD. Table 2. represents the
efficacy of Eucalyptus extracts in clinical trials for the treatment of res-
piratory disorders.
Sinusitis
Sinusitis can be broadly defined as inflammation of one or more
of the paranasal sinuses which in turn impair the function of the mu-
cociliary transport due to the accumulation of excessive secretion of
abnormally viscous mucus and inflammatory mediators (Leung and Ka-
tial, 2008). For the treatment of sinusitis, 85–98% of patients have been
generally prescribed antibiotics that target the most common bacte-
rial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae,
Staphylococcus aureus, and Moraxella catarrhalis when culture results are
unavailable (Leung and Katial, 2008). Multidrug resistance (MDR) of
these common pathogens is a major and rapidly growing public health
concern. As a result, alternative antimicrobial agents for the treatment
5
Phytomedicine Plus 1 (2021) 100089
Fig. 2. Chemical structures of some common constituents
present in commercial Eucalyptus oils.
of resistant pathogenic micro-organisms are urgently required. Pinheiro
and co-workers (Pinheiro et al., 2020) investigated the antimicrobial
activity of E. citriodora EO against some of the important MDR bacte-
rial species such as S. aureus and 𝛽-lactamase-producing strains. The
studies revealed that showed E. citriodora EO effectively inhibited re-
sistant strains, presenting itself as a possible alternative for the use of
these drugs at concentrations lower than those indicated against resis-
tant strains. In another study, Cermelli et al. (Cermelli et al., 2008) inves-
tigated the activity of E. globulus EO on various respiratory bacteria and
viruses. In the study, the EEO was found effective against H. influenzae,
Haemophilus parainfluenzae, and Stenotrophomonas maltophilia whereas
S. pneumoniae, Streptococcus agalactiae, and Klebsiella pneumoniae did not
show susceptibility to Eucalyptus oil. Based on the evidence, it can be
concluded that EEO can be used as adjuvant therapy for the treatment
of sinusitis to minimize the risk of MDR. Sudhoff et al. (Sudhoff et al.,
2015) demonstrated that eucalyptol reduces the bacteria-induced mu-
cus hypersecretion in sinusitis by reducing mucin-filled goblet cells and
MUC2-gene expression associated with suppressed NF-𝜅B-activity in hu-
man nasal slice cultures. The authors concluded that therapy with eu-
calyptol in sinusitis can be highly effective.
Bronchitis
Bronchitis is a common inflammation of the lining of the tubes
(bronchi) that carries air to and from the lungs. The inflammation usu-
ally develops due to viral infection, but often antibiotics are prescribed
unnecessarily (Singh et al., 2017). The major constituent of EEO, 1,8-
cineole has been traditionally used for the treatment of bronchitis from
ancient times. Cineole acts by accelerating the beat frequency of the cil-
ias in the mucous membrane. It also acts as a bronchodilating and anti-
inflammatory agent (Fischer and Dethlefsen, 2013). Lu et al. (Lu et al.,
2004) studied the effects of Eucalyptus globulus oil on bronchiolitis and
mucin hypersecretion in chronic bronchitis induced by LPS in rats. The
authors reported that there was a significant decrease of mucin content
N. Chandorkar, S. Tambe, P. Amin et al.
Fig. 3. Various therapeutic applications of the genus Eucalyptus.
in BALF (bronchoalveolar lavage fluid) and MUC5ac expression in the
trachea and bronchiole epithelium indicating the therapeutic potential
of E. globulus EO in bronchitis.
Asthma and COPD
Asthma is characterized by an inflammatory process that causes
bronchial hyper-responsiveness and normally reversible airway ob-
struction. Juergens et al. (Juergens et al., 1998a) studied the ef-
fects of eucalyptol in patients with bronchial asthma by isolating
human blood monocytes. The authors reported that eucalyptol ex-
erts anti-inflammatory effects by inhibiting both the pathways of
arachidonic acid metabolism, namely LTB4 (leukotriene B4 ) and PGE2
(prostaglandin E2 ). This was the first evidence of the anti-inflammatory
action of 1,8-cineole which spiked the tremendous interest of sev-
eral researchers. The same group of researchers expanded the study
and demonstrated a dose-dependent and highly significant inhibition
of production of TNF𝛼, IL-1𝛽, LTB4, and thromboxane B2 (TXB2 )
(Juergens, Stöber and Vetter, 1998b). The potential of 1,8-cineole
to inhibit polyclonal stimulated cytokine production by human uns-
elected lymphocytes and LPS-stimulated monocytes was investigated
(Juergens et al., 2004). The study revealed that 1,8-cineol significantly
suppressed cytokine production in lymphocytes (TNF𝛼, IL-1𝛽, IL-4, IL-
5) and monocytes (TNF𝛼, IL1𝛽, IL6, IL8). Very recently, Hosoki et al.
(Hosoki et al., 2015) reported that neutrophils and IL-8 are the only in-
6
Phytomedicine Plus 1 (2021) 100089
flammatory components in BALF. Inhaled 1,8-cineole, in a recent report,
exhibited a significant reduction in the number of eosinophils in BALF
as well as IL-4, IL-13, and IL-17A in an HDM-induced murine asthma
model (Lee et al., 2016).
Chronic obstructive pulmonary disease is characterized by chronic
inflammation and irreversible airflow obstruction, which is primar-
ily caused by cigarette smoking (Dennis et al., 1996), genetic factors,
and noxious stimuli including infection, environmental pollutants, etc.
(Rabe et al., 2007). Eucalyptol, owing to its expectorant properties in
dyscrinemic mucus, the German Guideline for COPD recommends its ad-
dition to other mucolytics (Vogelmeier et al., 2018). The guideline also
suggests that antioxidant and anti-inflammatory agents can be used to
minimize exacerbations in COPD patients who have recurrent exacer-
bations. It has been proven that eucalyptol can substantially reduce ex-
acerbations in COPD patients who have frequent exacerbations. Feitosa
et al. (Kennedy-Feitosa et al., 2016) attempted to investigate the effects
of eucalyptol in COPD in a mouse model with cigarette smoke-induced
inflammation and oxidative stress in the lungs. It was observed that eu-
calyptol reduced cytokine levels (IL-1𝛽, IL-6, and KC), NF-kappa B p65
subunit, and oxidative stress [reactive oxygen species (ROS), superoxide
dismutase (SOD), catalase, and malondialdehyde (MDA)] at 3 mg/mL
and 10 mg/mL concentrations indicating its potential in the treatment
of COPD. Wang et al. (Wang et al., 2017) studied the protective effects of
EEO in LPS and K. pneumoniae-induced COPD. On treatment with EEO,
a significant reduction in the infiltration of leucocyte cells in BALF, em-
N. Chandorkar, S. Tambe, P. Amin et al.
Fig. 4. Molecular anti-inflammatory mechanism of 1,8-cineole showing inhibition of nuclear translocation of NF-𝜅B p65 and NF-𝜅B target gene expression in a I𝜅B𝛼-
and JNK-dependent manner.
physematous damage, bronchiolitis around the bronchioles, number of
AB-PAS positive goblet cells in bronchioles was observed. Furthermore,
a significant reduction in the production of pro-inflammatory cytokines
(TNF-𝛼 and IL-1𝛽) and MDA formation was seen with an increase in the
SOD activity. The authors concluded that eucalyptol can be beneficial
as a concomitant therapy for the treatment and management of COPD.
SARS-CoV-2 (COVID-19)
The COVID-19 pandemic is widely regarded as the most serious
global health disaster of the century and the greatest threat to human-
ity since World War II. SARS-CoV-2 (severe acute respiratory syndrome
coronavirus 2), a new type of corona virus, has been identified as the
cause of this disease (Chakraborty and Maity, 2020). Coronavirus (CoV)
replication occurs when a polypeptide is converted into a functional pro-
tein, which is accomplished by the key enzyme Main protease (Mpro ).
Mpro is a ~306 aa long main enzyme that aids coronavirus duplica-
tion by removing functional proteins from the viral polypeptide. Mpro
is also known as 3C-like protease (3CLpro) because it shares the same
restriction-site specificity as picornavirus 3C protease (3Cpro). COVID-
19′s main protease (Mpro ) was previously identified as a latent and im-
portant target for blocking CoV replication. In a recent study, Panikar
et al. (Panikar et al., 2021) carried out an in-silico study to investigate
the effects of E. globulus biocompounds on Mpro by molecular docking.
The authors reported that Eucalyptol showed the least binding energy
to Mpro without toxicity which indicated that eucalyptol can be uti-
lized as a potential inhibitor against COVID-19 and also it can be used
in its treatment. Based on this evidence as well as previously demon-
strated anti-inflammatory (Merad and Martin, 2020; Sadlon and Lam-
son, 2010), antiviral (Usachev et al., 2013), mucolytic, and bronchodila-
tory (Juergens et al., 2020) effects of Eucalyptus, further studies are ur-
gently warranted in this regard.
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Gastrointestinal disorders
One of the leading causes of gastrointestinal (GIT) disorders such as
peptic ulcers is a spiral-shaped microaerophillic gram-negative bacillus,
Helicobacter pylori (H. pylori). Approximately 95% of duodenal ulcers
and up to 75% of gastric ulcers are caused by this bacterium and af-
fect nearly 10% of the world’s population (Malfertheiner et al., 2009).
It has been reported that Eucalyptus species, E. camaldulensis and Eu-
calyptus torelliana F. Muell are used to treat GIT disorders in Nigeria
(Gill, 1992). The leaves extract of E. torelliana and E. camaldulensis have
demonstrated a significant reduction in gastric acid intake in an animal
model, making them greatly beneficial for the treatment of gastric ul-
cers (Adeniyi, Odufowoke and Olaleye, 2006). Based on the evidence,
Adeniyi et al. (Adeniyi et al., 2009) studied the in vitro susceptibility
of six H. pylori strains to E. camaldulensis and E. torelliana extracts. The
authors reported good anti-H. pyroli properties of the two extracts with
MIC (minimum inhibitory concentration) range between 12.5 to 400
μg/mL. The presence of tannins and saponins, which are known to have
antimicrobial properties and offer protection against ulcers, may be re-
sponsible for the anti-H. pylori properties of these Eucalyptus species. The
ulcer healing properties of E. camaldulensis and E. torelliana methanolic
extracts were also studied in a rat model with acetic acid induced-ulcer.
The authors demonstrated that E. camaldulensis and E. torelliana extracts
significantly reduced the size of the ulcers to half of their original size
as compared to the controlled group (distilled water and ranitidine).
The authors concluded that the studied Eucalyptus species can be used
for treating existing peptic ulcers effectively (Lawal, Adeniyi and Olal-
eye, 2014). In another study, Jucá et al. (Matthews Jucá et al., 2011)
reported that EO extracted from E. torelliana accelerates GIT transit by
the contrasting effects induced by 𝛼- and 𝛽-pinene on gastrointestinal
smooth muscle which can be attributed to the ability of the monoter-
N. Chandorkar, S. Tambe, P. Amin et al. Phytomedicine Plus 1 (2021) 100089

Table 2
Summary of clinical trials data demonstrating the efficacy of Eucalyptus for the treatment of respiratory disorders.

Disease/Disorder Model Dose Clinical outcome Ref

Sinusitis 331 patients with acute - Myrtol® was proven to be an effective (Federspil, Wulkow and
sinusitis treatment in acute, uncomplicated sinusitis Zimmermann, 1997)
instead of antibiotics as the first choice.
Sinusitis 150 people with acute sinusitis Oral administration of The study revealed that patients on the (Kehrl et al., 2004)
eucalyptol 200 mg, 3 times treatment of eucalyptol recovered
significantly faster than those given a
placebo confirming that eucalyptol thins
and drains secretion and reduces
inflammation as well as secretion in
comparison to placebo.
Acute Bronchitis 676 male and female Oral administration of 300 mg Myrtol® demonstrated superior efficacy and (Matthys et al., 2000)
outpatients with acute Myrtol®, 4 times a day for more rapid and complete recovery in
bronchitis 14 days patients with acute bronchitis. The efficacy
was comparable to ambroxol and
cefuroxime, making it a great substitute
for antibiotic treatment, particularly in
patients who do not have other respiratory
illnesses and whose bacterial infection is
unknown.
Acute Bronchitis 413 patients with acute Oral administration of 300 mg, It was observed that there were significantly (Gillissen et al., 2013)
bronchitis 4 times a day for 14 days fewer daytime coughing fits, less difficulty
in coughing up, fewer sleep disturbances
due to night-time coughing. Treatment
with Myrtol® was found to be
significantly superior to placebo in
treating acute bronchitis.
Acute Bronchitis 242 patients with confirmed 200 mg cineole for three days The authors reported a significant (Fischer and Dethlefsen, 2013)
acute bronchitis improvement in the bronchitis-sum-score
than the placebo group. The study
suggested that the anti-tussive effects with
oral cineole were due to the amelioration
of inflammation and mucociliary clearance
in patients.
Chronic Bronchitis 246 patients with chronic Oral administration of 300 mg The authors reported that long-term (Meister et al., 1999)
bronchitis of cineole 3 times a day for treatment with cineole showed superior
over a period of 6 months efficacy in terms of protecting against
acute exacerbations in patients with
chronic bronchitis. Also, a reduction in the
frequency and intensity of acute
exacerbations were observed along with
reduced health impairment by cough and
expectoration and the need for antibiotics
for treatment.
Bronchial asthma 32 patients with Oral 200 mg 1.8-cineol, 3 times A significant reduction (36%) of prednisolone (Juergens et al., 2003)
steroid-dependent bronchial a day dosage was observed as compared to the
asthma control group (7%) indicating
steroid-saving effect in steroid-dependant
asthma.
Asthma/COPD 247 patients with confirmed 200 mg of cineole 3 times a Authors reported cineole having mucolytic, (Worth and Dethlefsen, 2012)
asthma day for over a period of 6 bronchodilating, and anti-inflammatory
months. effects of cineole that reduced the
exacerbation rate in patients suffering
from COPD. They also found that using
cineole in conjunction with other
medications improved lung function and
health condition, along with reduced
dyspnea in asthma patients.
COPD 242 patients with stable COPD Eucalyptol 200 mg 3 times as Eucalyptol decreased the frequency, severity, (Worth et al., 2009)
concomitant and duration of exacerbations in lung
therapy for 6 months function.

penes to affect the existing balance between the stomach and duode-
num, thereby accelerating the gastric emptying rate. Despite the fact
that Eucalyptus has demonstrated its potential in the treatment of GIT
disorders including duodenal and gastric ulcers associated with H.pyroli
infection, clinical trials are yet to be approved.
Wound healing
In traditional Aboriginal medicine, topical ointments containing Eu-
calyptus oil have been used for thousands of years to support wound heal-
ing. To relieve joint pain and speed the healing of cuts, skin conditions,
wounds, and infections, Aborigines would make a poultice out of leaves
and apply it to the affected area (Darwin, 1993). To validate the wound
healing activity of Eucalyptus, Velmurugan et al. (Velmurugan et al.,
2014) investigated the wound healing activity of ethyl acetate and
ethanolic extracts of E. citriodora in Wister albino rats. The authors re-
ported that an increase in wound contraction decreased epithelization
in the scarred area. The treated group of wounds [ointment with ex-
tracts 10% (w/w)] showed complete healing of wounds with the al-
most normal architecture of the collagen and reticulin. Furthermore,
a significant increase in skin breaking strength was observed due to
the increased collagen levels owing to the increased cross-linking of
collagen fibers. An increase in the dry granulation tissue weight was
also observed which can be attributed to the higher protein content.

8
N. Chandorkar, S. Tambe, P. Amin et al.
The authors concluded that EEO exhibits would healing activity via
mechanisms: angiogenesis, collagen deposition, granulation tissue for-
mation, epithelization, and wound contraction at the proliferative stage.
In another recent study, Kadhim and Amer (Kadhim and Amer, 2018)
investigated the therapeutic potential of EEO on rats and evaluation
was done based on histopathological data and laser Doppler flowmetry.
The wound size in the Eucalyptus-treated rats was significantly smaller
than in the control rats, according to the findings. When compared to
the controls, blood perfusion was significantly higher in the Eucalyptus
group. Moreover, accelerated epithelialization and a significant reduc-
tion in an inflammatory reaction in the Eucalyptus group were seen as
compared to the control group. Wound healing is a complicated pro-
cess that can be slowed by a variety of factors. Wound infection is one
of the leading causes of wound chronicity (Robson, 1997). Before the
tissue invasion, bacteria have been shown to delay wound healing at
lower levels either by secreting toxins from viable cells (exotoxins) or
as a result of cell lysis (endotoxins). These toxins cause local necrosis
and disturb the sensitive balance of crucial mediators such as proteases
and cytokines, which are essential for wound healing. As a result, toxin
control or absorption could be a useful complement to any infection-
control strategy (Robson, 1997). Several researchers have reported the
anti-microbial activity of Eucalyptus species EOs against a wide range of
microorganisms. The antibacterial activity of EEO is majorly attributed
to its chemical components such as 1,8-cineole, citronellol, citronellal,
p-cymene, citronellyl acetate eucamalol, linalool, 𝛼-terpinol, 𝛽-pinene,
limonene, 𝛾-terpinene, aromadendrene, and alloocimene (Nezhad et al.,
2009). The antibacterial actions can also be linked to the increased
cell permeability owing to the hydrophobic nature of the oil thereby
causing the cell constituents to leak out (Dorman and Deans, 2000;
Helander et al., 1998; Lambert et al., 2001). Also, EOs have multiple
target sites on bacterial cells, but they all appear to be linked to their
principal mode of action on bacterial envelopes, either directly or in-
directly i.e., by disturbing cell wall and cell membrane (Lambert et al.,
2001; Oussalah et al., 2007), which further results in significant loss
of intracellular ATP (Oussalah et al., 2007; Turgis et al., 2009), induc-
tion of the heat shock proteins synthesis, disturbance in the pH levels
(Burt et al., 2014; Oussalah et al., 2007), and intracytoplasmic changes
(e.g., periplasmic space enlargement, coagulation) (Burt, 2004). How-
ever, the exact mechanism is still unknown. The overview of the antimi-
crobial activity of Eucalyptus is shown in Fig. 5. The anti-bacterial activ-
ity of EEO was investigated by Bachir et al. (Bachir and Benali, 2012)
against two pathogens, S. aureus and Escherichia coli, the former being
responsible for toxic shock syndrome, post-operative wound infection,
food poisoning, and the latter being responsible for urinary tract infec-
tions. In the study, EEO exhibited a dose-dependent inhibition of both
bacterial strains. This antibacterial action of Eucalyptus can serve as an
effective treatment for minor cuts and wounds. Based on the evidence,
the inclusion of EEO in wound management appears promising, espe-
cially in chronic wounds, where treating infection and inflammation are
still important issues.
Oral health
Biofilms of cariogenic and periodontopathic bacteria can be found in
dental plaque. Plaque bacteria such as Streptococcus mutans and Strep-
tococcus sobrinus are known to colonize the tooth surface and cause a
disease called dental caries (Hamada and Slade, 1980; Loesche, 1986).
Other gram-negative bacterial strains such as Porphyromonas gingivalis,
Actinobacillus actinomycetemcomitans, and Fusobacterium nucleatum have
also shown to play a role in the onset and progression of periodontal dis-
eases (Signat et al., 2011; Slots et al., 1986; Slots and Listgarten, 1988).
The herbal medicaments have several benefits, including lower tox-
icity, lack of microbial resistance, availability, and cost-effectiveness
(Sinha and Sinha, 2014). The antimicrobial effects of EEO have long
been recognized and used against a wide range of bacteria and fungi,
including oral pathogens. Rasooli et al. (Rasooli et al., 2009) studied E.
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Phytomedicine Plus 1 (2021) 100089
camaldulensis EO for its in vivo and in vitro antimicrobial activity against
oral pathogens along with its ability to prevent biofilm formation. It
was observed that all concentrations of Eucalyptus oil were found to
have substantially higher antibacterial and in vivo biofilm preventive
efficacies than chlorhexidine. The results suggest that EEO can be ef-
fectively used in the treatment of dental caries. In another study, Gold-
beck et al. (Goldbeck et al., 2014) investigated two Eucalyptus species,
namely, E. globulus and Eucalyptus urograndis W. Hill ex Maiden (E. uro-
grandis) for their antimicrobial activity against planktonic and biofilm
cells of Streptococcus mutans. The authors reported that the best results
came from E. globulus oil, which needed just 15 minutes of contact to
kill bacteria whereas, E. urograndis oil required 50 minutes to achieve
the same bactericidal impact. This difference in the antimicrobial ac-
tivity of the two species is attributable to the higher 1,8-cineole con-
tent in E. globulus as compared to E. urograndis. Moreover, in the pres-
ence of the EEOs, biofilm formation by S. mutans was also inhibited
with more successful results than 0.1 percent commercial NaF (sodium
fluoride). Based on the results, it can be concluded that EEO can be
successfully used as an adjuvant therapy to treat periodontal diseases.
Another species of Eucalyptus, named E. galbie was proven to possess
antimicrobial activity against Enterococcus faecalis, the bacteria that is
responsible to cause infection in the root canal. The authors reported
that E. galbie eliminated more than 90% of the bacterial cells from the
root canal via flushing action and hence appears promising in the field
of endodontics (Nourzadeh et al., 2017). The clinical effectiveness of
Eucalyptus‐extract chewing gum was also studied to reduce oral mal-
odor (Tanaka et al., 2010). In this study, at the baseline and 4, 8, 12,
and 14 weeks, tongue‐coating score, organoleptic score, and lastly the
level of volatile sulfur compounds (VSCs) were measured and it was ob-
served that Eucalyptus‐extract chewing gum had long‐term effects on the
tongue‐coating score, olganoleptic score, and the levels of VSCs. Euca-
lyptus extracts functioned as an antiseptic and effectively inhibited the
growth of periodontopathic bacteria and virulence factors of Porphy-
romonas gingivalis which aided in the reduction of oral malodor. In a
similar study, Eucalyptus‐extract chewing gum was investigated for its
efficacy in periodontal diseases by measuring gingival index (GI), peri-
odontal probing depth (PD), plaque accumulation (PLA), clinical attach-
ment level (CAL), and bleeding on probing (BOP) at weeks 0, 4, 8, 12,
and 14 (Nagata et al., 2008). A significant improvement was observed
with respect to PLA, GI, BOP, PD as compared to the control group.
These findings suggest that the daily use of Eucalyptus extract chewing
gum can act as a new functional food for periodontal health distinct from
toothpaste and mouthwash. Currently, deeper knowledge with regards
to the applicability of Eucalyptus and other potential herbal species as
antimicrobial agents against dental caries and periodontal pathogens is
a call for demand. Exploiting research in this field would support the
advancement of a new and groundbreaking strategy, which, apart from
reducing drug resistance, can also simultaneously inhibit the two most
common dental disorders in humans.
Pain management
Patients with serious, chronic pain await the advent of new drugs
with little or no side effects while depending on a variety of alternative
medicines meanwhile. Several studies have demonstrated the analgesic
and anti-inflammatory activities of EEO (Gbenou et al., 2013; Lee et al.,
2019; Mondal et al., 2021; Mworia et al., 2020; Sahouo et al., 2003;
Shuping and Weiming, 1996; Silva et al., 2003). Very recently, Owemidu
et al. (Owemidu et al., 2020) investigated the anti-nociceptive activity of
E. globulus EO and the probable mechanism using thermal and chemical
models of nociception. The authors reported that E. globulus significantly
reduced pain perception in the male Swiss albino mice model which in-
dicated the involvement of peripheral and central systems to achieve
analgesia. An increase in the withdrawal latency was seen which is an
indication of the activation of the periaqueductal gray matter to produce
endogenous peptides that goes to the spinal cord to prevent transmis-
N. Chandorkar, S. Tambe, P. Amin et al.
Fig. 5. Antimicrobial activity of Eucalyptus constituents.
sion of pain impulses in the dorsal horn, thereby preventing nociceptor
activation. The authors concluded that the mechanism of action of anti-
nociception of E. globulus may not be due to the adrenergic system, ATP
sensitive K+ channel but the L-Type voltage-gated calcium channel. In
another study, Mondal et al. (Mondal et al., 2021) studied the analgesic
and anti-inflammatory potentials of EO of E. camaldulensis leaf. Herein,
the authors showed that the anti-nociceptive activity of E. camaldulen-
sis may be due to its affinity towards various anti-inflammatory recep-
tors (COX-2, TNF𝛼, and IL-1𝛽 convertase). Additionally, the authors sug-
gested that that the central analgesic effect of E. camaldulensis EO can be
due to the interactions with 𝜇 opioid receptors based on the results of the
thermal nociception tail immersion method. Lee et al. (Lee et al., 2019)
also reported that the involvement of EEO in the 𝜇-opioid pathway
may attribute to the analgesic and anti-inflammatory properties of EEO.
There is further evidence that shows analgesic and anti-inflammatory ac-
tivity of eucalyptol by stimulating the cool temperature-detecting, ther-
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Phytomedicine Plus 1 (2021) 100089
mosensitive transient receptor (TRP) cation channels (TRPM8). It was
also revealed that eucalyptol acts by inhibiting a known sensor of nox-
ious cold, called the human transient receptor potential cation channel,
belonging to subfamily A, member 1 (TRPA1) (Takaishi et al., 2012).
In contrast, Santos et al. (Santos and Rao, 2000) revealed that the anti-
inflammatory and antinociceptive action of eucalyptol may involve a
non-opioid mechanism. The clinical efficacy of EEO was demonstrated
by Jun et al. (Jun, Y. S. et al., 2013) on patients who had undergone
total knee replacement surgery. The treatment involved inhalation of
Eucalyptus oil for 30 minutes for three consecutive days. It was observed
that inhalation of Eucalyptus oil was effective in decreasing the patient’s
pain and blood pressure following the surgery, suggesting that Eucalyp-
tus oil inhalation may be a nursing intervention for pain management
after total knee replacement surgery. Hong and Shellock (Hong and Shel-
lock, 1991) also made an attempt to demonstrate the clinical efficacy of
Eucalyptus-based ointment (Eucalyptamint) in 10 patients by measuring
N. Chandorkar, S. Tambe, P. Amin et al.
cutaneous circulation and skin and muscle temperatures. An increase in
circulation was observed when the formulation was applied to the fore-
arms of participants. This suggested that Eucalyptus may temporarily
ease minor muscle soreness when applied topically. The authors con-
cluded that based on the significant physiologic responses produced by
Eucalyptus ointment, Eucalyptus can be effective for pain relief and/or
useful to athletes as a passive form of warm-up. These findings suggest
that EEOs can be extremely beneficial in reducing the dose of analgesics
endowed with serious side effects such as opioids. Nonetheless, clinical
translations, extensive research, and standardization of in vivo preclini-
cal studies are the need of the hour in the field of pain research to allow
coherent research in order to elucidate the underlying mechanisms of
EEO analgesic activity.
Cancer
Cancer is a general term that encompasses over 277 different
forms of cancer disease and a second major cause of death worldwide
(Hassanpour and Dehghani, 2017). Traditional medicinal herbs have
been used in East Asia for centuries for pharmaceutical and dietary
therapy, including China, Japan, India, and Thailand. They are com-
monly used in cancer therapy owing to their great structural diversity of
phytochemicals which is attributable to their antioxidant, anticarcino-
genic, antimutagenic, and antiproliferative activity (Cai et al., 2004).
In a study, Takasaki and co-workers (Takasaki et al., 2000) investi-
gated the effects of euglobal-G1 from leaves of E. grandis on two-stage
skin carcinogenesis in a mouse model. The researchers reported that
euglobal-G1 inhibited the promotion stages on two-stage carcinogene-
sis as well as pulmonary tumorigenesis. In another study, Taheri et al.
(Taheri et al., 2020) investigated the anticancer and antioxidant activ-
ity of E. camaldulensis EO on colorectal cancer cell line Caco-2. It was
observed that cell line Caco-2 treated with E. camaldulensis EO showed
dose and time-dependent antioxidant and anticancer activity which may
be due to the induction of apoptosis process as well as reduction of
free radicals in colorectal cancer cells. The mechanism of action of anti-
oxidant activity for chemoprevention is shown in Fig. 6. Vuong et al.
(Vuong et al., 2015) studied the anti-cancer and anti-proliferative activ-
ity of Eucalyptus robusta Sm. leaf against various cancer cell lines (colon,
lung, neuroblastoma, glioblastoma, and ovarian) and was proven effec-
tive in inhibiting cancer cells in all cell lines, especially in pancreatic
cancer cell lines derived from both primary and metastatic sites. A simi-
lar study was performed by Bhuyan et al. (Bhuyan et al., 2017) assessing
the anti-cancer activity of Eucalytpus microcorys F.Muell. (E. microcorys)
against pancreatic cancer which showed inhibition of cancer cells by
Caspase 3/7-mediated apoptosis and morphological changes of the cell
(shrinkage, rounding, and membrane blebbing). Deeper insights into the
mechanism of action of E. microcorys against pancreatic cells were fur-
ther given by the same group of researchers (Bhuyan et al., 2018). Au-
thors proposed that the anti-cancer and anti-proliferative activity of E.
microcorys is attributed to the initiation of apoptosis pathway by reg-
ulating key apoptotic proteins namely Bak, Bcl-2, Bax, procaspase-3,
cleaved PARP, and cleaved caspase-3 in MIA PaCa-2 cells, suggesting
the involvement of intrinsic mitochondrial apoptotic pathway and ar-
rested cells at G2/M phase. E. citriodora species was studied in seven hu-
man cancer cell lines from seven different tissues, such as colon, lungs,
prostate, ovaries, cervix, neuroblastoma, and lastly liver by Bhagat et al
(Bhagat, Sharma and Saxena, 2012). It was observed that ethyl acetate
extract of E. citriodora exhibited antiproliferative effects by significantly
inhibiting growth (71-92%) at the concentration level of 100 μg/ml.
Moreover, anti-tumor effects were also demonstrated on EAC (ehrlich
ascites carcinoma) and sarcoma (solid) tumor models that showed sig-
nificant tumor growth inhibition in 9 days. E. globulus EO was also inves-
tigated for its anticancer, antiproliferative effects against colon cancer
cell lines. The authors demonstrated that E. globulus EO successfully in-
hibited the proliferation of colon cancer cells by inducing apoptosis and
hence might be an excellent candidate as adjuvant therapy for colon
11
Phytomedicine Plus 1 (2021) 100089
cancer (Khazraei et al., 2021). Eucalyptus benthamii Maiden & Cambage
EO has also demonstrated antitumor and cytotoxic effects via apoptosis
mechanism (Döll-Boscardin et al., 2012). Furthermore, EOs extracted
from the leaves of Eucalyptus torquata Luehm. and E. sideroxylon has
also been reported to possess cytotoxic effects against the human breast
adenocarcinoma cell line (Ashour, 2008). In the light of these research
findings, assessment of the safety and efficacy of Eucalyptus for the treat-
ment of various forms of cancer is encouraged by performing preclinical
and clinical studies. Moreover, photodynamic therapy has emerged as a
promising light-based therapy that combines the use of photosensitizers
(aloe-emodin, berberine, hypericin, curcumin, etc.), light, and molecu-
lar oxygen for treating cancer. This treatment approach leads to the pro-
duction of ROS within malignant cells through photochemical reactions
which consequently result in cell death (Foresto et al., 2021). Eucalyptus
in combination with photodynamic therapy has the potential to greatly
minimize the side effects and improve the anti-cancer efficacy as well
as selectivity in the treatment of cancer. Further in-depth research in
this field such as computational simulations, in vitro tests, in vivo pre-
clinical studies, and clinical trials are warranted that can significantly
contribute to effective cancer treatment.
Immunomodulation
The key cellular effectors of the immune response are the mono-
cytic/granulocytic system as well as differentiated macrophages, which
play a critical role in the identification and removal of foreign bodies
such as pathogenic microorganisms. Foreign microorganisms are rec-
ognized by these cells, which leads to phagocytosis and the subsequent
destruction of pathogens by lysosomal enzymes (Stafford, Neumann and
Belosevic, 2002). In a study, Yadav and Chandra (Yadav and Chan-
dra, 2017) reported that EEO not only inhabited inflammatory medi-
ators but also stimulated phagocytosis and pathogen clearance of my-
cobacteria in lung macrophages. It was observed that MKP-1 and TREM-
1 mRNA levels were significantly reduced. Additionally, there was a sig-
nificant increase in phosphorylated ERKs (ERK1/2) and a notable reduc-
tion in phosphorylated p38 and phosphorylated forms of JNK1/2. LPS
activates the NLRP3 inflammasome, which is essential for IL-1 secretion
as well as the inflammatory response, and EEO was found to reduce
the NLRP3 significantly. Based on these results, Shao et al. (Shao et al.,
2020) expanded the study using a rat model to achieve deeper insights
into the mechanism of Eucalyptus in respiratory immunomodulation. A
significant decrease in the proportion of natural killer (NK) cells and
B cells/ B lymphocytes in the blood was observed. Moreover, the au-
thors reported that 30 mg/kg and 100 mg/ kg doses of Eucalyptus ex-
tract had an up-regulation effect on CD8, which may help the body fight
inflammation. During primary respiratory virus infections, CD8 T cells
play a very crucial role in immune memory (Retamal-Díaz et al., 2019;
Zhang and Bevan, 2011). The fact that CD8 was stimulated at a low EO
dose provided sufficient evidence that eucalyptol could help improve
immune cell memory, however, a high dose (~ 300 mg/kg) had an in-
hibitory effect on CD8, potentially lowering body immunity. Also, on
the administration of a high dose, significant inhibition of phagocyto-
sis of rat alveolar lavage fluid macrophages was observed whereas a
medium and a low dose i.e., 100 mg/kg and 30 mg/kg respectively,
showed no significant effect on macrophage phagocytosis. These find-
ings correlated well with the in vitro study demonstrated by Serafino
et al. (Serafino et al., 2008) which revealed that the stimulated cytokine
generation was efficiently inhibited by EEO from human monocytes and
lymphocytes. Furthermore, after oral administration of EEO, a signifi-
cant increase in monocytes, as well as an elevation in the CD 25 and CD
44 monocyte surface markers, was observed after 15 days. However, no
changes were seen in lymphocytes or granulocytes. In another study,
Nakamura et al. (Nakamura et al., 2020) demonstrated the ability of
EEO in reducing allergic reactions and suppressing mast cell degranu-
lation by downregulating IgE-Fc𝜀RI signaling. It was observed that EEO
not only suppressed the degranulation of mast cells but also suppressed
N. Chandorkar, S. Tambe, P. Amin et al.
cytokines such as IL-4 and IL-13, and the production of lipid media-
tors such as prostaglandin D2 and leukotriene C4. The authors also re-
ported a reduction in the intracellular Ca2+ concentration due to the
suppression of PLC𝛾 and p38 which can be attributed to the presence of
1,8-cineole in EEO. Also, 1,8-cineole dependent inhibition of PGD2 and
LTC4 production by pathways other than inhibition of PLA2 phospho-
rylation was reported. Based on these findings, the authors confirmed
that Eucalyptus oil can be extremely beneficial in the treatment of aller-
gic dermatitis. The overview of the role of Eucalyptus and 1,8-cineole in
the inhibition of mast cell degranulation is shown in Fig. 7.
Diabetes mellitus
Diabetes mellitus is a category of metabolic disorders marked by
hyperglycemia caused by insulin resistance, insufficient insulin secre-
tion, or excessive glucagon secretion (Blair, 2016). Eucalyptus has also
been used as a traditional medicine for the management of diabetes
mellitus in South America, Africa, and Iran. In a study, E. globulus was
studied against alloxan-induced oxidative stress in rats by Ahlem et al.
(Ahlem et al., 2009). Alloxan’s diabetogenic effect is caused by an ac-
cumulation of ROS, which causes toxicity in pancreatic cells, reduc-
ing insulin synthesis and release (Sakurai et al., 2001). It was found
that eucalyptol was able to restore the blood glucose to a normal level,
which was comparable with the insulin-treated group. Furthermore, a
significant reduction in the liver proteins content, TBARS (thiobarbi-
turic acid reactive substances) level, an index of lipids peroxidation,
and the antioxidant activity of SOD, CAT, and GPX were observed.
Sugimoto et al. (Sugimoto et al., 2005) demonstrated that E. globulus
leaf extract not only suppressed adiposity but also inhibited intestinal
fructose absorption in rats which was induced by high sucrose diet. A
decrease in the plasma and hepatic triacylglycerol concentrations was
12
Phytomedicine Plus 1 (2021) 100089
Fig. 6. Antioxidant activity of Eucalyptus for chemoprevention.
also observed in a dose-dependent manner. The authors suggested that
the specific transporter GLUT5 transports fructose across the intestinal
brush boundary membrane and inhibits intestinal fructose absorption
thereby preventing adiposity in subjects who consume significant quan-
tities of sucrose and fructose. Fructokinase metabolizes fructose in the
liver, which is then split by aldolase B into glyceraldehydes and dihy-
droxyacetone phosphate, which are glycolytic intermediates. Fructose is
more lipogenic than glucose and can supply carbon atoms for both the
glycerol and acyl parts of triglyceride molecules. The activities of fruc-
tokinase and G6PDH are inhibited by E. globulus, preventing the activa-
tion of fructose metabolism and fatty acid synthesis caused by dietary
sucrose. In another study, E. tereticornis extracts increased glucose up-
take in insulin-resistant C2C12 cells and inhibited glucose production in
insulin-resistant HepG2 cells, according to Guillén et al (Guillén et al.,
2015). Also, E. tereticornis extracts exhibited a significant decrease in
fasting glucose levels as well as a notable increase in glucose toler-
ance in a nutritional mice model which can be due to its role in the
liver activating routes that favor the inhibition of glucose production,
as an insulin pathway, or activating proteins such as AMPK (5′ adenosine
monophosphate-activated protein kinase) that inhibits the expression of
key genes of gluconeogenesis as in the case of G6Pase. It was also ob-
served that E. tereticornis reduced the mRNA levels of all the cytokines
(MCP-1, TNF-𝛼, IL-1, and IL-6) and decreased the proinflammatory con-
dition of adipose tissue in diabetic mice. Similar results with E. globulus
were obtained by Gray et al. (Gray and Flatt, 1998). The author pro-
posed that stimulation of insulin secretion and enhancement of muscle
glucose uptake and metabolism may be attributed to the antidiabetic ac-
tivity of the Eucalyptus species. Another species of Eucalyptus, E. camal-
dulensis has proven its anti-diabetic activity by inhibiting 𝛼-glucosidase
and 𝛼-amylase via non-competitive inhibition (Sahin Basak and Can-
dan, 2010). 𝛼-glucosidase and 𝛼-amylase, carbohydrate hydrolysis en-
N. Chandorkar, S. Tambe, P. Amin et al. Phytomedicine Plus 1 (2021) 100089

Fig. 7. Overview of the Eucalyptus and 1,8-cineole in the inhibition of mast cell degranulation.

Fig. 8. The overview of anti-Alzheimer activity of Eucalyptus (1,8-cineole).

13
N. Chandorkar, S. Tambe, P. Amin et al. Phytomedicine Plus 1 (2021) 100089

Table 3
Current progress in the development of Eucalyptus containing formulations.

Carrier system Dosage form Results/Clinical outcomes Indication References

Liposomes Gel The results showed that the minimum Antifungal (Moghimipour et al., 2012)
inhibitory volume of the EO was 0.125
ml and 95 ± 0.57% on dermatophytes
Microemulsion Intranasal spray The human volunteers confirmed the Migraine (Tiwari and Bajaj, 2007)
soothing and calming effect of
Eucalyptus oil intranasal formulations
as compared to the blank.
Microemulsion Topical The emulsion system exhibited superior Antimicrobial (Nirmala, Rakesh and
antimicrobial properties against S. Nagarajan, 2018)
aureus.
Nanoemulsion Topical Nanoemulsion was proven to be an Antimicrobial – Wound healing (Sugumar et al., 2014)
effective antibacterial agent with
improved wound healing properties
that can be attributed to the
penetration enhancing property of
eucalyptol.
Nanoemulsion Transdermal The developed NE demonstrated better Analgesic (Aziz et al., 2019)
analgesic activity of Eucalyptus globulus
EO by prolonging the pain responses of
rats towards thermal stimulus after
being put on top of a hot plate.
Nanoliposomes - The developed nanoliposomes Antimicrobial (Lin et al., 2015)
demonstrated excellent antimicrobial
activity against S. aureus.
Lipid nanocapsules Topical The authors reported that the Antifungal (Hussein et al., 2020)
encapsulation into lipid nanocapsules
enhanced the antifungal effects and
Eucalyptus oil had a significantly higher
antifungal activity compared to the
orange oil.
Composite sponges Topical The developed formulation exhibited Antimicrobial (Tang and Ge, 2017)
more rapid and efficient microbicidal
effects against S. aureus, P. aeruginosa,
and C. albicans than pure chitosan
sponges.
Silver nanoparticles - The developed Eucalyptus containing Anti-bacterial, anti-oxidant, (Kiran et al., 2020)
silver nanoparticles exhibited anti-cancer
antibacterial, antioxidant, and
anti-cancer activities.
Colloidal silver - The developed nanoparticles showed Anti-cancer (colon cancer) (Zein et al., 2020)
nanoparticles dose-dependent cytotoxicity against
Caco-2 cell lines. High toxicity effects
were seen at a low concentration of 5
μg/mL.
Nanoemulsion Topical The developed nanoemulsion was Anti-fungal (da Silva Gündel et al., 2020)
revealed superior efficacy than
miconazole for treating vulvovaginal
candidiasis in a murine model.
Nickel oxide Topical Antibacterial and anti-biofilm activity of Anti-bacterial (Saleem et al., 2017)
nanoparticles nickel oxide nanoparticles was
observed.

zymes, are the current focus to develop new anti-diabetic agents as they
can lower the postprandial blood sugar by delaying the absorption of
glucose (Bashary et al., 2020; Kumar et al., 2011). Based on the evi-
dence, it can be concluded that Eucalyptus species are very promising
in the treatment of diabetes. The meticulous and detailed studies are
further required to ensure its safety and antidiabetic potential before
entering into clinical use.
Miscellaneous
Insoluble amyloid beta deposits and neurofibrillary tangles provide
clear stimuli for inflammation, which plays a key role in the pathogen-
esis of Alzheimer’s disease. Neuroinflammation is now recognized as a
key aspect of Alzheimer’s pathology and based on the established anti-
inflammatory activity of Eucalyptus, Khan et al. (Khan et al., 2014) stud-
ied the effects of 1,8-cineole in differentiated PC12 cells with induced
inflammation by A𝛽 25-35 . In this study, pretreatment with cineole caused
attenuation of raised levels of ROS and NO due to inflammation. It was
also observed that cineole not only caused significant suppression of
TNF𝛼 at higher doses but also decreased IL-1b and IL-6 levels in a dose-
dependent manner. In addition, a reduction in the expressions of COX-2,
NOS-2, NF𝜅B, and ChAT was seen. The overview of the anti-Alzheimer
activity of Eucalyptus is shown in Fig. 8. Eucalyptus has also been found
to be beneficial in the treatment of anxiety. Anxiety is described as a
state of mind that is concerned about the future and is associated with
preparation for potential, unfavorable events. One of the major causes
of anxiety disorders is a low level of Gamma-amino butyric acid (GABA)
in the CNS. Serotonin (5-HT), Nor-epinephrine (NE), and dopamine, in
addition to GABA, play important roles in the pathophysiology of anx-
iety disorders. Anxiety disorders can be caused by damage to neuro-
transmitter systems due to ROS (Craske et al., 2009). Manikkoth et al.
(Manikkoth et al., 2017) investigated the effects of E. tereticornis for the
treatment of anxiety in a rat model. Authors reported that E. tereticornis
exhibited anti-anxiolytic activity due to its GABA agonistic activity or

14
N. Chandorkar, S. Tambe, P. Amin et al. Phytomedicine Plus 1 (2021) 100089

Table 4
Patents granted for Eucalyptus-based formulations.

Patent number Patent Title References

US7048953B2 Methods and apparatus to prevent, treat and cure infections of the human (Vail, W. and Vail, 2006)
respiratory system by pathogens causing severe acute respiratory
syndrome (SARS)
US5976547A Analgesic and antiphlogistic compositions and therapeutic wrap for (Archer and Pettit, 1999)
topical delivery
CN101391108B Sympathetic nerve-stimulating fragrant compositions (Haze et al., 2005)
US6019963A Deodorizing composition containing tea tree and Eucalyptus oils (Kling and Kling, 2000)
WO2008011699A1 Eucalyptus oil based fungicid (Tessmann, 2008)
US6352727B1 Bactericide (Takahashi, 2009)
US6413555B1 Composition and method of treating nail infections (Lee, 2002)
US5998335A Herbicidal composition and method (Selga and Kiely, 1999)
US6086853A Medicated vapor candle (Michaels, 2000)
US005620695A Method and composition for treating minor skin irritations (Elliott, 1997)
US6287567B1 Method of making an herbal drink (Blount, 2001)
EP0772434B1 Method of preparing natural-oil-containing emulsions and microcapsules (Magdassi, Mumcuoglu and Bach, 1996)
and its uses
US7150888B1 Methods and apparatus to prevent colds, flus, and infections of the human (Vail, W. and Vail, 2002)
respiratory system
US6444238B1 Pain relief composition and method of relieving pain (Weise, 2002)
US5686074A Poison ivy treatment composition and method of use (Stewart, 1997)
US6159473A Sore throat spray (Watkins and Coyne, 2000)
US5970212A Waterless vaporizer (Freidel, 1999)
US20070054000A1 Anti-obestic composition (Hayashi, Nakagawa and Sugimoto, 2010)
US20030049337A1 Composition for preventing fructose absorption (Sugimoto et al., 2003)
US20030077319A1 Double-headed, closed-mouth cough suppressant and cold relief device (Huntley, 2005)
US6626673B2 Root canal filling material remover (Abiru, Sato and Takeshita, 2003)
US6582736B2 Therapeutic oil composition (Quezada, 2003)

antioxidant property. Furthermore, the effect of inhalation of Eucalyptus
oil and its constituents on patients with preoperative anxiety was stud-
ied by Kim et al. (Kim et al., 2014). It was observed that not only systolic
blood pressure significantly lowered after the inhalation but a decrease
in anxiety was also observed in patients inhaling 1,8-cineole as com-
pared to the control group. The authors concluded that Eucalyptus oil can
be used to relieve anxiety. In another study, 1,8-cineole demonstrated
the ability to lower aortic pressure and minimize Ca2+ influx through
calcium channels in cardiac muscle in a rat model (Lahlou et al., 2002;
Soares et al., 2005). Based on these findings, Moon et al. (Moon et al.,
2013) further investigated the effects of cineole on systolic blood pres-
sure (SBP), nitrite concentrations, corticosterone, Angiotensin II concen-
trations, and oxidative stress in rats chronically exposed to nicotine. The
authors reported that cineole inhibited lipid peroxidation, reduced cell
damage and corticosterone levels, and elevated nitric acid concentra-
tions. The authors suggested that cineole may also reduce Angiotensin
II concentrations. For decades, Eucalyptus extracts have been used to
treat a variety of infectious diseases. Okba et al. (Okba et al., 2017) in-
vestigated the anti-HSV-II (herpes simplex virus 2) activity of E. siderox-
ylon leaves and revealed its antiviral potential which can be attributed
to the presence of phloroglucinols, cypellocarpines, and flavonoids. The
mechanism of action involved reduction in the viral replication and at-
tachment on Vero cells rather than virucidal effect. In another study,
the antiviral activity of E. camaldulensis was demonstrated on HSV-1,
HSV-2, and VZV (Varicella-Zoster Virus) by Jafar and Huleihel (Abu-
Jafar and Huleihel, 2017). It was observed that E. camaldulensis inhib-
ited all the three tested viruses by interfering with different stages of the
viral infection such as inhibiting the early stages of the infection (viral
adsorption/ penetration into the host cells) and probably blocking one
or more steps during the virus replication inside the host cells after their
penetration.Brezáni et al. (Brezáni et al., 2008) studied another species
of Eucalyptus, E. globulus for its antiviral activity against HSV. Twelve
pure compounds were isolated from E. globulus and it was found that
Tereticornate A, one of the isolated compounds showed the strongest
antiviral activity against HSV – I, even stronger than acyclovir. Another
isolated compound, Cypellocarpin C showed the highest activity against
HSV – II, greater than acyclovir as well.
Eucalyptus-based formulations and patents
Formulations containing Eucalyptus for therapeutic application
Terpenes, like eucalyptol, are lipophilic molecules that increase the
fluidity of stratum corneum (SC) lipids by acting on the intercellu-
lar lipid structure between corneocytes and improve drug penetration
(Furuishi et al., 2013). The overall size and degree of long-chain alkyl
functionality may be linked to the extent of SC lipid disruption caused by
terpenes (Moghadam et al., 2013). It has been reported that the boiling
points of terpenes play an important role in determining the efficiency of
penetration enhancement (Narishetty and Panchagnula, 2004). Higher
penetration enhancement efficacy appears to be associated with ter-
penes having lower boiling points. When it comes to sesquiterpenes,
oxygenated sesquiterpenes outperform hydrocarbons in terms of drug
permeation (Moghadam et al., 2013). In addition, combining terpenes
can boost the permeation enhancement effect (Prasad et al., 2007). EOs
are assumed to transport drugs across the skin via various mechanisms:
(1) Creating a permeable layer for the transportation of the drugs by
disrupting the highly ordered intercellular lipid structure between cor-
neocytes in SC; (2) interacting with the intercellular domain of the
protein, which results in some conformational modifications, making
SC more permeable; (3) partitioning promotion – many solvents alter
the properties of the SC, resulting in increased drug partitioning and;
(4) increasing desmosomal connections between corneocytes or altering
metabolic activity within the skin (Williams and Barry, 2012). Eucalyp-
tus has been used as a penetration enhancer to improve skin penetra-
tion of the drugs such as Chlorhexidine (Karpanen et al., 2010), tetram-
ethylpyrazine (Shen et al., 2013), 5-fluorouracil (Abdullah, Ping and
Liu, 1996; Williams and Barry, 1989), and ketoconazole (Rajan and Va-
sudevan, 2012). Table 3. Represents the current progress in the develop-
ment of Eucalyptus-containing formulations for the treatment of various
diseases.
Patents on Eucalyptus-based inventions
Several studies are being carried out on the Eucalyptus genus for var-
ious therapeutic applications. Patents granted for novel therapeutic ap-
plications and delivery systems of Eucalyptus species are represented in
Table 4.

15
N. Chandorkar, S. Tambe, P. Amin et al.
Conclusion and future perspectives
Eucalyptus species have demonstrated their incredible health benefits
from ancient times till the present. 1,8-cineole is the main component
of EEO that is responsible for its medicinal value and biological effects
such as antibacterial, antiseptic, antioxidant, anti-inflammatory, anti-
cancer, and several other biological activities. 1,8-cineole has demon-
strated anti-inflammatory and antioxidant activity by regulating NF-𝜅B
and MAPK signaling pathways. Caspase, ROS, Erk, p38, μ opioid recep-
tors, TRP channels, etc. have also been identified as 1,8-cineole targets.
The plethora of health benefits offered by the Eucalyptus genus can act
as a revolutionary breakthrough in the future of healthcare majorly re-
solving issues linked with multi-drug resistance, pain management, and
treatment of several serious diseases including COVID-19, cancer, di-
abetes, Alzheimer’s, hypertension, etc. This review has critically ana-
lyzed and comprehensively summarized the current state-of-art of the
Eucalyptus genus in the field of health sciences with insights into their
molecular mechanisms. The preclinical and clinical studies reported in
the present review also confirm the therapeutic value of the genus Euca-
lyptus. In addition, this review has taken into consideration the various
Eucalyptus-containing drug delivery systems and patents developed to
achieve enhanced targeting, stability, and solubility of the oil and its
active constituents.
Despite its remarkable applications which can serve as a major break-
through in the arena of healthcare, the clinical translation is still in
its initiation phase and has a number of complications and drawbacks
linked to it. Some advanced research is required to close the existing
gaps and elucidate the benefits of Eucalyptus beyond its traditional uses
and extend its therapeutic potential for treating a wide spectrum of
ailments. The phenolic and terpenoid compounds found in Eucalyptus
species are potentially toxic. In humans, excessive consumption of Euca-
lyptus oil can cause GIT irritation, stomach discomfort, nausea, seizures,
decreased respiration, CNS suppression, and may also lead to death. As
a result, a more thorough risk assessment of EEO toxicity is required in
terms of safety. However, establishing the level and extent of toxicity
caused by the components of Eucalyptus is difficult because the level of
content and the type of chemical constituent present in the Eucalyptus
varies significantly with the age of the plant, species, method of extrac-
tion or drying, etc. A few pilot-scale clinical studies have confirmed the
safety of some Eucalyptus species. However, further well-designed multi-
centric clinical trials on larger populations, such as children, the elderly,
and patients with co-morbid conditions are necessary. Improved pre-
clinical study designs may also enhance clinical translation. Moreover,
the research on the development of drug delivery systems containing
Eucalyptus extracts is still nascent, particularly the development of pul-
monary drug delivery formulations for the treatment of respiratory dis-
eases which is currently the need of the hour. There are few limitations
to this review, as well as the studies analyzed that deserve a mention.
The research findings discussed in this review are based on a limited
database search that only includes English articles. Furthermore, one
of the studies demonstrated the antiviral activity of Eucalyptus species
against SARS-CoV-2 based on molecular docking studies. However, fur-
ther validation of the findings is warranted to investigate its potential
use for COVID-19 treatment under preclinical and clinical settings. Con-
sidering all of these factors, as well as the fact that several species of
Eucalyptus remain unexplored in terms of EO content and composition,
we anticipate that research in this area will continue in the future.
The knowledge derived from the research studies on the Eucalyp-
tus genus to date discussed in this review can be optimally used to
bridge the existing gaps in the understanding of exact mechanisms of
the pharmacological activities and safety aspects of Eucalyptus species.
An integrated approach to determine and reduce side-effects of Euca-
lyptus constituents, development of novel, safe, and efficacious formu-
lations, better clinical understanding, and the evaluation of economic
and production aspects are necessary. In foreseeable future, there is a
possibility that Eucalyptus-containing formulations including micro- and
16
Phytomedicine Plus 1 (2021) 100089
nano-formulations will advance beyond infancy for treating several ail-
ments, and the future developments and applications are assured to be
astounding. Also, activity enhancement in combination with other avail-
able agents offers a promising strategy that may ultimately improve clin-
ical outcomes. The context provided in this review serves as a strong
base for the future development and utilization of Eucalyptus species to
its full potential in the field of health sciences which will encourage
researchers to continue making major contributions that will yield in-
teresting results in the coming years.
Declaration of Competing Interest
The authors declare that there are no conflicts of interest.
Author contribution
N.C. and C.M. conceptualized the idea. N.C. and S.T. performed the
literature search. N.C. and S.T. wrote the first draft of the manuscript.
N.C. and S.T. reviewed and revised the manuscript. C.M. and P.A. criti-
cally reviewed the manuscript. All the authors have read and approved
the final version of the manuscript. All authors agree to be accountable
for all aspects of work ensuring integrity and accuracy.
Acknowledgments
None.
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