PHYTOTHERAPY RESEARCH Phytother. Res. 28: 1125–1136 (2014) Published online 4 February 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5122

REVIEW

Review of Pharmacological Effects of Myrtus communis L. and its Active Constituents Ghazal Alipour,1 Saeedeh Dashti2 and Hossein Hosseinzadeh3* 1

Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, I.R. Iran Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, I.R. Iran 3 Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, I.R. Iran 2

Myrtle (Myrtus communis L., Myrtaceae) is a medicinal herb used worldwide in traditional medicine. A large number of components have been isolated from this herb. Polyphenols, myrtucommulone (MC), semimyrtucommulone (S-MC), 1,8-cineole, α-pinene, myrtenyl acetate, limonene, linalool and α-terpinolene are among the compounds considered to be the main biologically active components. Various parts of this herb such as its berries, leaves and fruits have been used extensively as a folk medicine for several centuries. The herb is used traditionally for the treatment of disorders such as diarrhea, peptic ulcer, hemorrhoid, inflammation, pulmonary and skin diseases, although clinical and experimental studies suggest that it possesses a broader spectrum of pharmacological and therapeutic effects such as antioxidative, anticancer, anti-diabetic, antiviral, antibacterial, antifungal, hepatoprotective and neuroprotective activity. The present review attempts to give an overview on the phytochemical, pharmacological, toxicological and clinical studies of total extracts and the most relevant active ingredients of M. communis. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: Myrtus communis; Myrtle; phytochemical constituents; medicinal uses.

INTRODUCTION

BACKGROUND AND OBJECTIVE

Myrtle (Myrtus communis L., Myrtaceae) is a wellknown medicinal plant that has been used worldwide in traditional medicine. Myrtaceae family includes 100 genera and 3000 species. Myrtus genus belongs to this family of evergreen shrubs or small trees, which grow up to 5-m tall spontaneously (Sumbul et al., 2011). It is native to Southern Europe, North Africa and Western Asia and also distributed in South America, North western Himalaya and Australia.(Males et al., 2006; Nassar et al., 2010; Sumbul et al., 2012). The plant is 2.4–3 m high and branches forming a close full head, thickly covered with leaves (Sumbul et al., 2011). Leaves are small and green and fruits are small and dark (Asif et al., 2011). The evergreen leaves are 2–5 cm long and aromatic after crushing such as in the case of myrrh or eucalyptus. The taste of it is bitter and intensive (Gortzi et al., 2008; Özkan and Güray, 2009) which is mainly due to its astringency (Anonymous, 1998). Flowers are star-like, white or pinkish and very fragrant (Charles, 2013). The round blue-black berry fruit contains several seeds. The pollination is done by insects, and the seeds are dispersed by birds that eat the berries (Satyavati et al., 1976).

Different parts of this herb such as its berries, branches, leaves and fruits have been used extensively as a folk medicine for a long time. The astringent, tonic and antiseptic characteristics of its leaves justify its use for healing wounds or disorders of the digestive and urinary systems. The oil is antiseptic and anti-catarrhal and is therefore used to treat chest ailments (Charles, 2013). The fruit decoction was used to bathe newborns with reddened skin, whereas the decoctions of leaves and fruits were useful in sore washing. The decoction of the leaves is still used in some countries for vaginal lavage, enemas and against respiratory diseases (Akin et al., 2012). Generally speaking, this herb has been used traditionally for the treatment of diarrhea, peptic ulcers, hemorrhoids, inflammation, bleeding, headache, palpitation, leucorrhoea, urethritis, epistaxis, conjunctivitis, excessive perspiration, pulmonary and skin diseases, (Gauthier and Gourai, 1989; Anonymous, 1998; Evans, 2002) although clinical and experimental studies suggest that it possesses a broader spectrum of pharmacological and therapeutic effects as discussed later (Table 1). Myrtle extensive use in traditional medicine and also the entry of its products (such as topical ointments and drops) to the pharmaceutical industry provoke the need for further knowledge of the herb’s different aspects such as phytochemical, pharmacological and toxicological properties. Herein, we attempt to give an overview on the different prospects of this herb and the clinical studies of its extracts and the most relevant active ingredients.

*Correspondence to: Hossein Hosseinzadeh, Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, I.R. Iran. E-mail: [email protected]

Copyright © 2014 John Wiley & Sons, Ltd.

Received 22 July 2013 Revised 26 December 2013 Accepted 4 January 2014

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Table 1. The pharmacological effects of Myrtus communis References (Hosseinzadeh et al., 2011) (Hosseinzadeh et al., 2011) (Ines et al., 2011)

(Tumen et al., 2012) (Mimica-Dukić et al., 2010) (Tretiakova et al., 2008)

(Tuberoso et al., 2010)

(Gholamhoseinian et al., 2009) (Moradi et al., 2011) (Tayoub et al., 2012) (Zaidi et al., 2012) (Ferchichi et al., 2011) (Shariati et al., 2010) (Al-Jeboory et al., 1985) (Jorsaraei et al., 2006) (Bureau et al., 2003) (Babaee et al., 2010)

Proposed possible mechanisms Effect on proliferative phase of inflammation Via opioid receptors or promotion of the release of endogenous opiopeptides Increase in the activity of antioxidant enzyme family and DNA repair enzymes

Anti-oxidant; considerable effects in DPPH, DMPD and FRAP assays Radical scavenging activity Activation of caspase-3, -8 and -9; cleavage of poly PARP; release of nucleosomes into the cytosol; DNA fragmentation Inhibition of the reduction of polyunsaturated fatty acids and cholesterol; inhibition of the increase of their oxidative products Inhibition of alpha-glycosidase enzyme Inhibitory effect on virus before and after entering the cell Acting as a neurotoxin Reducing the gastric juice volume and total acidity; increasing the gastric pH and gastric wall mucus content Antioxidant and free radical scavenging activities Inhibition of aromatase activity; inhibition of 5-alpha reductase; cytochrome-P450 inducer activity Probable presence of an adenosine-like compound Increase in revascularization and amount of fibroblasts Increase in nutritive intake of the hair papilla cells and regulation of the function of sebaceous glands Antibacterial effect or free radical scavenging activity

CONSTITUENTS The plant contains many biologically active compounds. Myrtle essential oil, extracted from its leaves, branches, fruits and flowers through steam distillation, is yellow or greenish yellow with a refreshing odour (Sumbul et al., 2011). The oil has been widely investigated; its composition is quite variable depending on the geographic region of production, the season of harvest and the length of distillation (Tuberoso et al., 2006; Sumbul et al., 2011). However, in most regions, terpenoid compounds (1,8cineole, α-pinene, myrtenyl acetate, limonene, linalool, α-terpinolene) are the major constituents found in the essential oil obtained from the leaves (Bradesi et al., 1997; Aidi Wannes et al., 2010; Hassiotis and Lazari 2010; Ghasemi et al., 2011; Berka-Zougali et al., 2012). Eucalyptol is reported as the major constituent of myrtle leaf essential oil grown in northern Cyprus as well (Akin et al., 2012). The leaves also contain tannins, flavonoids such as quercetin, catechin and myricetin derivatives, coumarins, myrtucommulone (MC) A and B, semimyrtucommulone (S-MC) (which are unique oligomeric, nonprenylated acylphloroglucinol compounds), galloyl-glucosides, Copyright © 2014 John Wiley & Sons, Ltd.

Part of plant

Effect

Aerial parts

Antiinflammatory

Aerial parts

Analgesic

Leaves

Berries

Antiproliferative and antigenotoxic (protection of cells from oxidative stress) Neuro-protective

Aerial parts Leaves

Anti-mutagenic Effect on cancer cell lines

Berries

Effect on LDL oxidation

Leaves Leaves

Anti-diabetic Antiviral

Leaves Berries

Insecticidal Treatment of peptic ulcers Anti-hepatic ischemia

Leaves and fruits Leaves Leaves Leaves Essential oil Leaves

Treatment of impotence Negative inotropic effect Positive effects on burn lesions Anti hair loss Treatment of aphtus lesions

ellagitannins, galloyl-quinic acids, caffeic, gallic and ellagic acids (Yoshimura et al., 2008; Sumbul et al., 2011; Asif et al., 2011; Akin et al., 2012). Bazzali et al. (2012) identified four C8–C10 esters in Mediterranean myrtle leaf essential which contributed to the pleasant odour of the oil. Myrtle berries volatile oil contains large amounts of monoterpene hydrocarbons and oxygenated monoterpenes with α-pinene, 1,8-cineole, geranyl acetate and linalool as the main components (Aidi Wannes et al., 2009; Barboni et al., 2010). There were also high percentages of α-terpineol, methyl eugenol, geraniol and myrtenyl acetate present in the extracts of dark blue and white berries of Tunisian myrtle (Messaoud and Boussaid, 2011). Polyphenolic composition of the berries was characterized by high concentrations of flavonol glycosides, flavonols and flavanols. The major fatty acids of berries were reported as linoleic, palmitic, oleic and stearic acids (Aidi Wannes et al., 2009; Barboni et al., 2010). Berries are also reported to contain tannin, resins, citric, malic and caffeic acids, sugar, anthocyanin arabinosides, anthocyanin glucosides, kaempferol, quercetin, myricetin 3-o-glucoside, myricetin 3, 3-di-ogalactoside amongst others (Sumbul et al., 2011; Akin et al., 2012). Phytother. Res. 28: 1125–1136 (2014)

MYRTUS COMMUNIS L. AND ITS ACTIVE CONSTITUENTS

Mersin myrtle fruits contained crude protein, tartaric, malic and citric acids, and they were rich in minerals including Ca, K, Mg and Na (Hacıseferoğulları et al., 2012).

PHARMACOLOGICAL EFFECTS Antiinflammatory effect Several studies have indicated the antiinflammatory properties of the essential oil of M. communis in animal models (Rossi et al., 2009; Hosseinzadeh et al., 2011; Maxia et al., 2011; Amira et al., 2012). Hosseinzadeh et al. (2011) evaluated the antiinflammatory effect of aqueous and ethanolic extracts of the aerial parts of M. communis L. using xylene-induced ear oedema and cotton pellet tests. The extracts showed significant activity against acute inflammation that was dose dependent for the aqueous extract. The ethanolic (0.05 g/kg) and aqueous extracts (0.005, 0.015 and 0.03 g/kg) demonstrated antiinflammatory effects against chronic inflammation. The extract effectively and significantly reduced cotton pellet-induced granuloma. Therefore, this activity may have occurred through the proliferative phase of the inflammation. Furthermore, topical use of the essential oil of M. communis is reported to cause a significant decrease in the ear oedema and cotton pellet-induced granuloma (Maxia et al., 2011). Antiinflammatory and antiproliferative properties of the ethanolic extract of myrtle have shown an important role in the treatment of acne lesions, in vitro. The evaluation of antiinflammatory activity by measuring 6-keto-prostaglandin F1 and [3H]-arachidonic acid metabolite production in keratinocytes stimulated for inflammation revealed that the extract significantly decreased all metabolite production from the cyclooxygenase (p < 0.0001) and lipoxygenase (p < 0.001) pathways. The extracts also inhibited keratinocyte proliferation by 27% and 76% at 1 and 3 μg/mL, respectively (p < 0.001) in HaCat keratinocytes using the BrdU incorporation assay (Fiorini-Puybaret et al., 2011). Rossi et al. (2009) investigated the effects of M. communis in in vivo models of inflammation. MC (0.5, 1.5 and 4.5 mg/kg( when administered intraperitoneally reduced the development of mouse carrageenaninduced paw oedema in a dose-dependent manner. Moreover, MC (4.5 mg/kg i.p. 30 min before and after carrageenan) exerted antiinflammatory effects in the pleurisy model. In particular, 4 h after carrageenan injection in the pleurisy model, MC showed promising and potent antiinflammatory effects in different models of inflammation assay such as histological analysis, myeloperoxidase activity, immunohistochemical localization study, cytokine, leukotrienes and prostaglandins measurement as well as lung peroxidation and immunostaining methods. These data led to the conclusion that myrtle’s potent antiinflammatory effects offer a novel promising approach in treatment of acute inflammation (Rossi et al., 2009). Mechanisms of antiinflammatory activity. MC and S-MC present in the leaves potently suppress the biosynthesis of eicosanoids by directly inhibiting cyclooxygenase-1 and 5-lipoxygenase in vitro and in vivo. Furthermore, they Copyright © 2014 John Wiley & Sons, Ltd.

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prevent the mobilization of calcium in polymorphonuclear leukocytes, mediated by G protein signaling pathways, and suppress the formation of reactive oxygen species and the release of elastase which are of relevance for initiation and maintenance of inflammatory processes (Feißt et al., 2005). However, in another study, MC was believed to inhibit cell-free mPGES-1-mediated conversion of prostaglandin H2 (PGH2)to PGE2 in a concentration-dependent manner without significant inhibition of the COX enzymes (Koeberle et al., 2009). In addition, suppression of serum IL-6 and TNF-alpha and consequent reduction of leukocyte migration to the damaged tissue played a serious role in the antiinflammatory properties of the herb (Rossi et al., 2009; Maxia et al., 2011). The selective inhibition of PGE2 formation via interference with microsomal PGE2 synthase (mPGES)-1 could have advantages in the treatment of PGE2-associated diseases, such as inflammation, fever and pain, compared with a general suppression of all prostaglandin biosynthesis, caused by inhibition of COX-1 and 2 (Koeberle et al., 2009). According to these data, myrtle could be considered as an alternative agent for the treatment of chronic inflammation without the typical side effects of Coxibs and non-steroidal antiinflammatory drugs (Gerbeth et al., 2012). Analgesic effect M. communis aerial parts have been used in Arabic traditional medicine as an analgesic agent (Twaij and El-Jalil, 2009). In order to investigate this activity, hot plate and writhing tests were run. Both the aqueous and ethanolic extracts of the aerial parts showed significant antinociceptive activity in the hot plate test and this effect was inhibited by naloxone. As the hot plate test is a specific test for evaluating central antinociceptive activity, this effect may be mediated through the central opioid receptors or be due to the promoted release of endogenous opiopeptides. Furthermore, the extracts exhibited antinociceptive activity against acetic acid in writhing test which was not inhibited by naloxone. These findings led to the assumption that the peripheral effect of the extract is not mediated via the opioid receptors. Other mechanisms of action, such as inhibition of cyclooxygenase or inhibition of the release of prostaglandins, were therefore suggested (Hosseinzadeh et al., 2011). Antioxidative effect Oxidative stress is involved in the pathogenesis of numerous diseases (Romani et al., 2004). Several efforts have focussed on finding natural antioxidants with therapeutic properties. Different methods have been applied to evaluate the antioxidative activity of myrtle extracts. Significant antioxidant capacity of myrtle extracts was observed when measured with 1, 1-diphenyl-2-picrylhydrazyl (DPPH) and ferric-reducing antioxidant power (FRAP) assays (Gardeli et al., 2008, Tuberoso et al., 2010). Myrtle’s ability to protect biological molecules was assessed by means of the cholesterol and LDL oxidation assays. Myrtle berries extracts showed protective effect in assays of thermal (140 °C) cholesterol Phytother. Res. 28: 1125–1136 (2014)

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degradation and Cu2+-mediated LDL oxidation, inhibiting the reduction of polyunsaturated fatty acids and cholesterol. Furthermore, antiradical or antioxidant activities were significantly correlated with the amount of total phenols (Amensour et al., 2009; Tuberoso et al., 2010; Tuberoso et al., 2013). Another study demonstrated that myrtle leaf extract did not affect the basal oxidation of LDL but dose-dependently decreased the oxidation induced by copper ions. Moreover, myrtle extracts reduced the formation of conjugated dienes. The hydroalcoholic extract exhibited a stronger antioxidant effect versus ethylacetate and aqueous residues after liquid–liquid extraction of myrtle leaves. The hydroalcoholic extracts contained high amounts of polyphenols including galloyl-glucosides, ellagitannins, galloyl-quinic acids and flavonol glycosides. Therefore, the potent antioxidant activity observed was suggested to be mainly due to the presence of galloyl derivatives in the extracts (Romani et al., 2004). These effects have also been attributed to the unique oligomeric non-prenylated acylphloroglucinols, S-MC and MC. The compounds mentioned not only had a remarkable protective effect on the reduction of polyunsaturated fatty acids and cholesterol, inhibiting the increase of their oxidative products such as conjugated dienes, fatty acids hydroperoxides, 7beta-hydroxycholesterol and 7-ketocholesterol (Rosa et al., 2008) but also protected linoleic acid from free radical attack in simple in vitro systems, inhibiting its autoxidation and its FeCl3- and EDTA-mediated oxidation. Both chemicals lacked pro-oxidant activity. However, S-MC was more potent than MC-A (Rosa et al., 2003). Ines et al. (2011) evaluated the antioxidative, antiproliferative and antigenotoxic properties of 3, 5-Odi-galloylquinic acid (DGQA) purified from leaves of M. communis. The antioxidant activity was assessed by the ability of the compound to inhibit lipid peroxidation which was induced by H2O2 in the K562 cell line. DGQA remarkably inhibited malondialdehyde (MDA) formation and exhibited an inhibitory effect against H2O2induced genotoxicity, using the comet assay. It also exhibited protective effects when evaluating the gene expression of the chronic myelogenous leukemia cell line (K562), stressed with H2O2. The analysis of cDNAmicroarray containing 82 genes related to cell defence, essentially antioxidant and DNA repair proteins, revealed that DGQA increased the activity of antioxidant and DNA repair enzymes. It was concluded that DGQA was able to protect cells against oxidative stress. Hayder et al. (2008) similarly determined antioxidative activity of myricetin-3-o-galactoside and myricetin3-o-rhamnoside, isolated from the leaves of M. communis by four different methods: the ability of each compound to inhibit lipid peroxidation, xanthine oxidase activity, DPPH scavenging and analysis of gene expression response to an oxidative stress. The 50% inhibitory concentrations (IC50) of lipid peroxidation by myricetin3-o-galactoside and myricetin-3-o-rhamnoside were reported as 160 mg/mL and 220 mg/mL respectively. Both compounds at the concentration of 100 mg/mL showed the most potent inhibitory effect on xanthine oxidase activity by 57% and 59%, respectively. Myricetin-3-orhamnoside was reported to be a very powerful radical scavenger with an IC50 value of 1.4 mg/mL. The analysis of gene expression response to oxidative stress using a cDNA micro-array revealed that myricetin-3-o-galactoside and myricetin-3-o-rhamnoside modulated the expression Copyright © 2014 John Wiley & Sons, Ltd.

patterns of cellular genes involved in oxidative stress, DNA damage repair and apoptosis. Gortzi et al. (2008) demonstrated that myrtle leaf extract at concentrations up to 160 ppm was significantly more potent than α-tocopherol (P < 0.05). Furthermore, the antioxidative activity after encapsulation in liposome appeared to be higher than in its pure form. To sum up, according to the data on in vitro and in vivo alleviation of oxidative stress and in vitro vasodilator activity, myrtle could be a great candidate for the management of related diseases (Tuberoso et al., 2013). The use of myrtle essential oils has proved to be beneficial in preservation of edible oils since it has been reported to improve their oxidative stability and fasten their viscosity, especially in the cases of pomegranate kernel, poppy, grape and linseed oils (İnan et al., 2012). Meanwhile, a study supporting myrtle freeradical scavenging activity showed that the antioxidant effects of myrtle’s berry extracts were preserved during 3 months, warning not to use the extracts after 3 months of their preparation (Montoro et al., 2006). Enhancing retinol tolerability and efficacy for use in antiaging products The topical use of retinoids to improve the signs of photodamage can induce transient intolerance reactions. In a double-blind, placebo-controlled clinical study, water soluble extract of M. communis leaves combined with retinol significantly enhanced retinol-induced expression of specific genes for retinoid activity, such as heparin-binding epidermal growth factor (HB-EGF) or cellular retinoic acid binding protein II (CRABPII) in epidermal cells in the ex vivo model and therefore delivered higher antiwrinkle effects than retinol alone as assessed using skin replica methodology (P < 0.05) (Hornby et al., 2011a; Hornby et al., 2011b). Neuroprotective effect In order to evaluate in vitro neuroprotective effects of myrtle, Tumen et al. (2012) screened the dichloromethane (DCM), acetone, ethyl acetate and methanolic extracts of the leaves and berries against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and tyrosinase (TYRO), all enzymes related to neurodegenerative diseases. Antioxidant activity was determined using DPPH, N,N-dimethyl-p-phenylenediamine (DMPD) scavenging activity, metal chelation capacity, FRAP and PRAP (phosphomolybdenum-reducing antioxidant power) assays. The extracts were reported to exert a moderate AChE and TYRO inhibition. BChE inhibition was almost negligible in the case of leaf extracts, whereas the berry extracts displayed significant inhibition. Furthermore, the polar extracts showed a remarkable effect in DPPH, DMPD and FRAP assays, whilst the DCM extract of the berries had the highest metal chelation capacity. Antimutagenic effect Antimutagenic properties of M. communis have been evaluated against spontaneous and t-BOOH-induced mutagenesis in Escherichia coli oxyR mutant IC202 Phytother. Res. 28: 1125–1136 (2014)

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which is a bacterial strain deficient in removal of reactive oxygen species (ROS). In the presence of myrtle essential oil, the spontaneous mutagenesis was only slightly (up to 13% at the highest concentration tested) decreased. However, when applying the oxidative mutagen, it expressed a higher diminution of mutagenesis, in a concentration-dependent manner, with statistical significance at the highest concentration tested (28%). Suppression of t-BOOH-induced mutagenesis appeared to be correlated with the DPPH scavenging activity of myrtle (Mimica-Dukić et al., 2010). Myricetin-3-o-galactoside and myricetin-3-o-rhamnoside, isolated from the leaves of M. communis, also induced an inhibitory activity against nifuroxazide, aflatoxine B1 and H2O2-induced mutagenicity. This activity was determined using the SOS chromotest (which is a bacterial, colorimetric assay for detecting genotoxic potential of DNA-damaging agents) and the comet assay (Hayder et al., 2008).

Effect on cancer cell lines MC present in the leaves of M. communis potently induced cell death of different cancer cell lines (EC50 3–8 μM) by means of induction of apoptosis. This effect was mediated by the activation of caspase-3, -8 and -9, cleavage of poly ADP-ribose polymerase (PARP), release of nucleosomes into the cytosol and DNA fragmentation. Interestingly, Jurkat cells that are an immortalized line of human T lymphocyte cells and lack caspase-9 were resistant to MC-induced cell death. This led to this assumption that MC-induced apoptosis in cancer cell lines marginally affects normal non-transformed cells mainly through the mitochondrial cytochrome c/Apaf-1/ caspase-9 pathway (Tretiakova et al., 2008).

Effect on LDL oxidation Oxidative damage of lipid molecules is implicated in the onset of cardiovascular diseases. The ethyl acetate extract of berries of M. communis showed a highly protective effect in assays of thermal (140 °C) cholesterol degradation and Cu2+-induced LDL oxidation, inhibiting the reduction of polyunsaturated fatty acids and cholesterol and also inhibiting the increase of their oxidative products (Tuberoso et al., 2010) such as conjugated dienes fatty acids hydroperoxides, 7beta-hydroxycholesterol and 7ketocholesterol. This effect was attributed to S-MC and MC-A, two unique oligomeric non-prenylated acylphloroglucinols of M. communis (Rosa et al., 2008). The same effect was also exhibited by leaf extracts. The addition of hydroalcoholic and ethylacetate extracts, together with aqueous residues obtained after liquid–liquid extraction of leaves, did not affect the basal oxidation of LDL but dose-dependently decreased the oxidation induced by copper ions. The hydroalcoholic extract, rich in galloyl derivatives including galloyl-glucosides, ellagitannins, galloyl-quinic acids and flavonol glycosides, showed the most potent antioxidant activity (Romani et al., 2004). These data suggest that the natural compounds S-MC and MC-A are dietary antioxidants with potential antiatherogenicity effects and therefore support the widespread culinary use of myrtle leaves (Rosa et al., 2008). Copyright © 2014 John Wiley & Sons, Ltd.

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Anti-diabetic effect Myrtle is used as an anti-diabetic agent in folk medicine (Sepici-Dincel et al., 2004). Some experiments have been conducted to evaluate myrtle’s hypoglycaemic effect and its blood glucose lowering mechanism of action in animal models. Elfellah et al. (1984) examined its hypoglycaemic effects in streptozotocin-induced diabetic mice (150 mg/kg intraperitoneally). Intragastric administration of an ethanol–water extract (2 g/kg) 30 min prior to streptozotocin treatment (150 mg/kg) inhibited initial hyperglycaemia at 2 h after administration of streptozotocin without affecting the second phase (48–72 h after administration of streptozotocin which persisted throughout a 7-day observation period). The administration of myrtle extract prior to streptozotocin and repeated at 24 h and 30 h, delayed hyperglycemia during 48 h and its administration 48 h after streptozotocin significantly decreased the hyperglycemia, and this effect was maintained by repeated administration. The administration of a phenolic fraction (800 mg/animal) from the leaves of M. communis to streptozotocin-induced diabetic rats induced a much greater antihyperglycaemic response than those who received 400 mg (Benkhayal et al., 2009). In another study, the effect of single and multiple doses of the volatile leaf oil was evaluated in normal and alloxan-induced diabetic rabbits. The oil at the dose of 50 mg/kg significantly decreased blood glucose by 51% in diabetic rabbits on the fourth hour after administration (P < 0.001) (Sepici-Dincel et al., 2004). Myrtle extract had no effect on the blood glucose level of normal animals (Elfellah et al., 1984; Sepici-Dincel et al., 2004). In another study, it was also demonstrated that aqueous and methanolic myrtle leaf extracts significantly reduced the postprandial glucose levels in non-diabetic rats (P < 0.0001) (Gholamhoseinian et al., 2009). The mechanism of anti-diabetic effect is not yet clear. However, according to the fact that myrtle volatile leaf oil did not affect serum insulin concentrations in normal and alloxan-induced diabetic rabbits (Sepici-Dincel et al., 2004), it is assumed that myrtle hypoglycaemic activity is not related to insulin secretion. Myrtle volatile leaf oil exerted its hypoglycaemic activity by enhancing glycolysis (higher activity of glucokinase) (Sepici-Dincel et al., 2004), glycogenesis and by decreasing glycogenolysis. Furthermore, the glucose load data strongly suggested that treatment with myrtle leaf oil induced hypoglycemia mainly by reducing intestinal absorption of glucose; therefore, myrtle oil could be an alpha-glycosidase enzyme inhibitor (Sepici-Dincel et al., 2007; Gholamhoseinian et al., 2009). Tareq (2005) suggested that this activity could be due to myrtle berries’ protein compounds with high molecular weight which have insulinlike action or structure. It has been suggested that oxidative stress constitutes the key role in the pathogenesis of different diabetic complications (Mercuri et al., 2000). Protein glycation and glucose autoxidation can generate free radicals that catalyze lipid peroxidation. The increase of free radicals in diabetic condition could be due to the increased lipid peroxidation and may also be a result of damages to antioxidant defense systems (Bugdayci et al., 2006). In this context, the effects of myrtle oil on the antioxidant enzymes such as superoxide dismutase (SOD) and catalase Phytother. Res. 28: 1125–1136 (2014)

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(CAT), the levels of MDA in liver tissues as an index of lipid peroxidation and nitrite–nitrate levels were measured in normoglycaemic and alloxan-induced diabetic and myrtle oil-treated rabbits in vivo (Sepici-Dincel et al., 2007). SOD as the most important antioxidant enzyme catalyzes the removal of superoxide free radicals in all aerobic and anaerobic organisms. CAT, in vivo, plays an important role in the removal of damaging effects caused by ROS in living systems. The generation of ROS plays an important role in the etiology of diabetic complications. Under diabetic conditions, ROS are produced via glucose auto-oxidation (Wolff and Dean, 1987). Sepici-Dincel et al. (2007) reported that SOD and CAT enzyme activities did not change during acute studies in diabetes animals which received myrtle oil (50 mg/kg). However, after 21 days of treatment, there was a significant increase in SOD enzyme activity in liver homogenates and in CAT enzyme activity in diabetic animals treated with the oil compared to the non treated animals group (p = 0.001). A significant decrease was also observed in MDA levels after 21 days of treatment when compared to the diabetic group of animals (p = 0.001). Nitrite–nitrate levels were significantly decreased after 21 days of treatment and during the acute study (p = 0.004 and 0.02, respectively). In addition to producing a significant reduction in glucose concentration in diabetic animals, the oil also induced a significant decrease in triglyceride level during the acute study (14.3%) and after 21 days of administration (24.7%) (p = 0.001). These data suggest that M. communis has antidiabetic activity, although further studies are needed to determine its potential indication and accurate effective dose for treatment of patients with diabetes mellitus. Antimicrobial effects Antibacterial effect. The antibacterial activity of a methanolic crude extract of M. communis on six Grampositive (Staphylococcus aureus, Micrococcus luteus, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Listeria monocytogenes) and four Gram-negative bacteria (E. coli, Proteus vulgaris, Pseudomonas aeruginosa and Campylobacter jejuni) was evaluated; the crude extract inhibited the growth of all mentioned bacteria except C. jejuni (Mansouri et al., 2001). Myrtle oil has shown activity towards clinical strains of Mycobacterium tuberculosis but not Mycobacterium paratuberculosis. The minimum inhibitory concentration (MIC) of the oil against the former was determined as 0.17% (v/v) compared to a MIC of 2% (v/v) observed for the latter (Zanetti et al., 2010). In another study, the minimum bactericidal concentration (MBC) of myrtle against different microorganisms that are pathogenic to man was measured using agar dilution methods. The data obtained showed that myrtle MBC for most of the microorganisms tested was similar to that of MIC as reported 0.5 mg/mL for S. aureus, 2.5 mg/mL for Proteus mirabilis and Proteus vulgaris, 15 mg/mL for Klebsiella spp. and Salmonella typhi, 20 mg/mL for P. aeruginosa. The MBC of myrtle for the two relatively least sensitive species, Shigella sp. and E. coli was 40 mg/mL and 45 mg/mL of media, respectively. These data reflected the strong antibacterial activity of this herb (Alem et al., 2008). Copyright © 2014 John Wiley & Sons, Ltd.

Myrtle antibacterial activity against P. aeruginosa (Al-Saimary, 2002; Owlia et al., 2010; Hashemi et al., 2011; Hasan et al., 2011), Moraxella catarrhalis (Yazdi Mohammad et al., 2008), Helicobacter pylori (Deriu et al., 2007), L. monocytogenes, Enterococcus durans, S. typhi, Bacillus subtilis (Akin et al., 2012), Vibrio cholera serotype Ogawa (Taheri et al., 2013), Bacillus megaterium (Alemohammad et al., 2011), E. coli and S. aureus (Yadegarinia et al., 2006; Hasan et al., 2011) has also been determined. However, the myrtle methanolic leaf extract effect against E. coli was not significant when Amensour et al. (2010) evaluated its activity on viable counts of bacteria using the bacterial cell-death time method. In another study myrtle also demonstrated antibacterial activity against Bordetella bronchiseptica M. luteus and Klebsiella pneumonia while it had no significant activity against Serratia marcescens (Bonjar, 2004). Gortzi et al. (2008) evaluated myrtle extract antimicrobial and antioxidant activity before and after encapsulation. After encapsulation, the antimicrobial activities appeared to be stronger (P < 0.05). In general, Grampositive bacteria were the least resistant while L. monocytogenes and Candida albicans exhibited the higher resistance. As liposomes promoted myrtle’s both antimicrobial and antioxidant effects, these constructions could be considered as antioxidant and antimicrobial food preservative and conservative agents that could be potentially used in food, cosmetics and medical preparations industry. Gündüz et al. (2009) showed that myrtle leaf oil exhibited inhibitory activity against the nalidixic acid resistant strain of Salmonella typhimurium and suggested it could therefore be used as an alternative to the chlorine or other synthetic disinfectants for fruits and vegetables, especially for organic products. Myrtle has also shown growth-inhibitory effect against Paenibacillus larvae in vitro. P. larvae is the causal agent of American Foulbrood Disease of honey bees (AFB). As it exerts low toxicity to adult honey bees and because of its commercial availability, it has been suggested as a low cost and consumer-acceptable agent for the control of AFB (Flesar et al., 2010). Mechanisms of antibacterial activity. The high content of monoterpene hydrocarbons such as α-pinene (Owlia et al., 2010; Djenane et al., 2011), limonene (Djenane et al., 2011), eucalyptol, linalool and terpineol seemed to contribute to the strong antimicrobial activity of M. communis (Akin et al., 2012). Appendino et al. (2006) investigated a polar glycosidic fraction obtained from the leaves of myrtle for its antibacterial activity and the positive results obtained seemed to be due to the presence of gallomyrtucommulone. Furthermore, an important characteristic of myrtle essential oil and its components was reported to be their hydrophobic nature which could enable them to permeate within the lipids of the bacterial cell membrane and disturb the cell (Owlia et al., 2010). New antimicrobial agents especially those effective against multi drug resistant strains are nowadays desired (Owlia et al., 2010). According to these data, M. communis could therefore be an interesting lead for further investigation as a potential alternative agent in the treatment of infections. Phytother. Res. 28: 1125–1136 (2014)

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Antifungal effect. M. communis has been reported to have antifungal activity against many species such as C. albicans (Najib Zadeh et al., 2011; Bidarigh et al., 2009; Hasan et al., 2011), Aspergillus flavus (Hasan et al., 2011), Aspergillus fumigatus, Paecilomyces variotii (Gumus et al., 2010), Aspergillus niger, Penicillium sp, anthropophilic and geophilic dermatophytes Trichophyton mentagrophytes (Ayatollahi et al., 2007), Epidermophyton floccosume (Azad et al., 2010) and phytopathogenic fungi Rhizoctonia solani Kuhn (Curini et al., 2003). These data support its traditional claim of antifungal activity. The antifungal activity of myrtle leaf essential oil was studied against Aspergillus spp. by broth microdilution method and was found effective against all clinical isolates tested (Mohammadi et al., 2008). The antifungal effect of M. communis leaf essential oil on oral candidiasis was evaluated in immunosuppressed rats (Najib Zadeh et al., 2011). The MIC was reported as 2 mg/mL against C. albicans (Mahboubi and Ghazian Bidgoli, 2010; Najib Zadeh et al., 2011). Microbiological and histopathological evaluations also indicated that the essential oil had significant activity against this pathogen (p < 0.01). Although the area infected by oral candidiasis was reduced significantly, in some region of mucosa in the back of tongues it persisted suggesting it could lead to future recrudescence of the infection (Najib Zadeh et al., 2011). The MIC of M. communis alcoholic extract and nystatin on clinical isolates and standard strains of vulvovaginal candidiasis was compared in an in vitro study. The highest MIC of myrtle extract was reported as 25 mg/mL and 2.5 mg/mL, respectively, whereas the highest MIC of nystatin on clinical isolates and type strain of C. albicans was 36 mg/mL (Bidarigh et al., 2009). In another study, the effect of various dilutions (30–600 mg/mL and 0.5–4 mg/mL) of a leaf extract on saprophyte and dermatophyte fungi was examined. The hydroalcoholic extract was effective against T. mentagrophytes, E. floccosume and Microsporum canis, with the MIC determined as 1.5 mg/mL, 1 mg/mL and 1 mg/mL respectively (Azad et al., 2010). The essential oil exerted a 60% growth inhibition against phytopathogenic fungi R. solani Kuhn at a dose of 1600 ppm. The microscopic observation revealed that the essential oil caused morphological alterations of hyphae of the fungi at 1600 ppm (Curini et al., 2003). Heat-resistant molds A. fumigatus and P. variotii isolated from margarine have been demonstrated to be sensitive to the essential oil of M. communis. However, P. variotii was more resistant than A. fumigatus. This data indicated myrtle’s potential usage as a natural food preservative (Gumus et al., 2010). Antiviral effect. Herpes simplex virus can cause various infections such as cold sores, encephalitis and keratoconjunctivitis amongst others. In some cases, these diseases may even result in patient’s death. Moradi et al. (2011) determined the effect of hydroalchoholic extract of myrtle on herpes simplex virus-1 (HSV-1) in vitro. The Probit analysis revealed that 50% cytotoxic concentration (CC50%) of the hydroalchoholic extract of myrtle leaves on HSV-1 was equal to 4.96 mg/mL. A significant relationship was found between the concentration of the extract and the cell death (P < 0.01). The IC50s of the extract on the virus before cellular Copyright © 2014 John Wiley & Sons, Ltd.

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attachment and after entering the cells were 3.1 mg/mL and 1.11 mg/mL, respectively (Moradi et al., 2011). Also, another study conducted by Oulia et al. (2007) led to the conclusion that M. communis essential oil could be used as a treatment of herpes simplex infections. Furthermore, myrtle oil has been demonstrated to be effective in treatment of wounds in Foot and Mouth Disease as it causes faster improvement of mouth ulcers and reduces purulent discharge (Najafi et al., 2011). Anti-parasitic effects Anti malaria effect. The essential oil of M. communis aerial parts was reported to inhibit in vitro the growth of chloroquine-resistant and chloroquine-sensitive strains of Plasmodium falciparum in a dose-dependent manner (Dell’agli et al., 2012). Anti-Leishmanial effect. M. communis extract inhibited the growth of promastigote forms of Leishmania major in vitro after 72 h of incubation showing an IC50 of 5.8 μg/mL. Although tartar emetic was more effective, the extract exhibited profound effect on promastigotes of L. major (Barati et al., 2010). Antiprotozoal activity against Trichomonas vaginalis. The effect of methanolic extract of M. communis leaves and its essential oil on growth of T. vaginalis within 72 h of inoculation was investigated. The extract at concentrations of 0.1 and 0.01 mg/mL was effective at the beginning of the inoculation, while the essential oils even at concentrations of 0.1, 0.01, 0.001 and 0.0004 mg/mL were effective at the beginning of the inoculation. At the concentrations of 0.0002 and 0.0001 mg/mL, the essential oil exhibited inhibitory effect after 2 and 4 h, respectively (Azadbakht et al., 2003). Furthermore, myrtle leaf extract is reported to have caused death of T. vaginalis at pH of 4.65 but has failed to do so at pH of 6 (Mahdi et al., 2006). Insecticidal effect The essential oil of M. communis has been reported to have fumigant toxicity against khapra beetle Trogoderma granarium Everts (Tayoub et al., 2012), adult Mediterranean flour moths Ephestia kuehniella Zeller (Lepidoptera: Pyralidae), Indian meal moth Plodia interpunctella Hübner (Lepidoptera: Pyralidae), bean weevil Acanthoscelides obtectus Say (Coleoptera: Bruchidae) (Ayvaz et al., 2010), mosquito Culex pipiens molestus Forskal (Traboulsi et al., 2002) and Phlebotomus papatasi Scopoli. (YaghoobiErshadi et al., 2006) Khapra beetle is one of the most serious pests in stored products throughout the world and is a major threat to stored wheat. It has been regarded as one of the 100 most invasive pests in the world (Lowe et al., 2000). The essential oil obtained from leaves of M. communis was reported to be active against different life stages of khapra beetle T. granarium; the adult stage was the most sensitive of all developmental stages to essential oil vapours. Whereas larvae were the most tolerant with 94% and 100% mortality observed after exposure of larvae to 562.5 μL/l air during 24 and 48 h, respectively. At a 48 h exposure period, LC50 and Phytother. Res. 28: 1125–1136 (2014)

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LC90 were 221 μL/l air and 487 μL/l air, respectively. The toxic effect is almost certainly due to monoterpene components that could act against insects as neurotoxins. This data suggested the use of the essential oil of myrtle as an effective bio-insecticide agent in grain storage which is considered to be less toxic and harmful to humans and environment than conventional insecticides (Tayoub et al., 2012). It is suggested that myrtle essential oil could be used in insect pest management strategies such as the Sterile Insect Technique. The Mediterranean fruit fly Ceratitis capitata (Wiedmann) is an important agricultural insect pest and has a far-reaching range of host plants especially citrus trees. Medfly males are strongly attracted to plant semiochemicals which increase their mating success. Most of the major components of myrtle oil including monoterpenes such as 1,8-cineole, alpha-pinene, linalool and limonene are similarly found in citrus flavedo and orange essential oil. Therefore, a similar effect was expected from male exposure to myrtle essential oil. Laboratory trials revealed that male exposure to myrtle essential oil significantly improved the medfly mating behavior and therefore contributed to enhanced mating competitiveness and significant decrease in medfly populations in fruit orchards (Elfekih and Abderrabba, 2008). In another study, insecticidal activity of the essential oil extracted from leaves and flowers of M. communis against fourth-instar larvae of the mosquito C. pipiens molestus Forskal (Diptera: Culicidae) was reported with LC50 value of 16 mg/L (Traboulsi et al., 2002). Furthermore, the crude water extract and a flavonoid fraction of M. communis induced molluscicidal effect against the aquatic snail Biomphalaria glabrata which contributes to the transmission of schistosomiasis (Deruaz et al., 1993). Leishmaniasis and Malaria are two significant parasitic diseases endemic to the Middle East. Over the past decades, there has been an interest in botanical repellents because of their safety to humans (Tavassoli et al., 2011). In this context, M. communis leaf essential oil was found to have repellent effects against 3–7-dayold unfed females of the sandfly (P. papatasi Scopoli), the zoonotic cutaneous leishmaniasis vector showing a median effective dose (ED50) of 0.1140 on white rabbits (Yaghoobi-Ershadi et al., 2006). Myrtle is also believed to have moderate repellence effects against Anopheles stephensi which is one of the vectors of malaria. The ED50 value of essential oil was reported as 0.1105 mg/cm2 (Tavassoli et al., 2011). These results suggest that the use of repellents such as myrtle essential oil could be of interest in personal protection against such diseases. Gastrointestinal effects Effect on peptic ulcers. H. pylori infection plays a crucial role in the pathogenesis of gastritis, peptic ulcer and gastric cancer (Zaidi et al., 2009; Zaidi et al., 2012).The current proton pump inhibitor (PPI)-based triple regimens used for eradication of H. pylori (which includes prescribing a PPI plus two antimicrobial agents) have confronted uprising resistance problem. Traditional medicinal plants such as M. communis are commonly utilized to treat gastrointestinal disorders (Zaidi et al., Copyright © 2014 John Wiley & Sons, Ltd.

2009) and several studies have been carried out to determine protective effect of M. communis against gastric ulcers (Sumbul et al., 2010; Hosseininejad et al., 2011; Zaidi et al., 2012). In order to investigate the protective effects of dried berries of M. communis on gastric ulcer against ethanol, indomethacin and pyloric ligation-induced models in Wistar rats, aqueous (105 and 175 mg/kg) and methanolic (93 and 154 mg/kg) extracts were administered orally to animals prior to exposure of the ulcerogenic agents. The parameters measuring anti-ulcer activity were ulcer index, gastric juice volume, gastric pH, total acidity, gastric wall mucus and histopathological studies. The oral administration of both doses of aqueous extracts significantly reduced the ulcer index in all models of ulcers. The low dose of the aqueous extract and the high dose of the methanolic extract exhibited more significant effects compared with omeprazole (standard drug) in the ethanol-induced ulcer model. Both aqueous and methanolic extracts reduced the gastric juice volume and total acidity and also increased the gastric pH and gastric wall mucus content in all the models of ulcers used in the study. Histopathological examinations of gastric tissues of rats treated with the aqueous and methanolic extracts in indomethacin-induced ulcer exhibited a significant ulcer-protective effect at both dose levels (Sumbul et al., 2010). Furthermore, Zaidi et al. (2012) determined anti-helicobacter activity and cytotoxic effects of myrtle fruit extract by serial dilution method and DNA fragmentation assay respectively. M. communis was found to markedly inhibit IL-8 secretion. The results of these studies suggest antiinflammatory and cytoprotective effects of the plant, which could validate the traditional use of it in gastrointestinal disorders particularly ones associated with H. pylori. Antihepatic ischemia effect. The effect of myrtle on a model of hepatic ischemia-reperfusion in Wistar rats has been studied. The myrtle extract was injected after inducing ischemia, 15 min before reperfusion. To evaluate the effect of myrtle leaf and fruit extracts on ischemia-reperfusion, the levels of transaminases and the concentration of monoethylglycinexylidide (for assessing the metabolic capacity of the liver) and MDA were determined after a single administration of 1 mg/kg lidocaine. Results showed that myrtle provided protection against the damage of ischemiareperfusion and this effect was variable, depending on the origin and type of myrtle’s fruit (black or white) (Ferchichi et al., 2011). Effects on impotence Since M. communis is used traditionally as a treatment of sexual impotence, a study was performed to evaluate the effect of the hydroalcoholic extract of the leaves on pituitary–gonad axis in adult male rats. In the study, doses of 0.75, 1.5 and 3 mg leaf extract/kg body weight were administrated orally. The analysis of the concentrations of FSH, LH and testosterone by radio immunoassay indicated that administration of M. communis at 1.5 and 3 mg/kg doses led to a significant increase in the level of testosterone (p < 0.05), whereas no significant difference was observed in the concentration of LH or FSH hormones. The mechanism of action by which M. Phytother. Res. 28: 1125–1136 (2014)

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communis leaf extract causes an increase in testosterone hormone level is not yet clear but it could be related to the presence of compounds such as flavonoid, ascorbic acid and myricetin (inhibition of aromatase activity), linoleic, oleic and palmitic acids (inhibition of 5-alpha reductase activity). 1,8-Cineole and delta-cadinene (the cytochrome-P450 Inducer) could also be involved in the activity described (Shariati et al., 2010). Cardiovascular effect The aqueous leaf extract of M. communis showed a negative inotropic effect on isolated guinea pig atria; this effect was not reversed by atropine. Besides, the total extract induced concentration-dependent depressive effect in anaesthetized rabbit which was not attenuated by propranolol, cimetidine and atropine but blocked by theophyline. These effects could be due to the presence of an adenosine-like compound in this extract as studied by Al-Jeboory et al. (1985). Dermatological effects Effect on burn lesions. Application of topical myrtle oil once a day on second degree burn wounds enhanced the healing process (Hasanzadeh et al., 2003). The methanolic extract of M. communis also showed a higher healing potential on second-degree burn wounds than silver sulfadiazine, as a histopathological study indicated an increase in revascularization (p < 0.001) and a higher number of fibroblasts (p < 0.001) in the group of rats receiving the extract versus silver sulphadiazin. A faster healing process, less complications and availability of myrtle are the reasons supporting its traditional use in the treatment of burn wounds (Jorsaraei et al., 2006). Furthermore, topical myrtle oil, unlike silver sulfadiazine, caused a reduction in scar tissues after healing (Hasanzadeh et al., 2003). Treatment of acne lesions. The ethanolic extract of myrtle was found to be effective in treatment of acne lesions. This effect was due to its antiinflammatory, anti-proliferative and antibacterial properties. The first two effects have already been described in the antiinflammatory section of the present review. The inhibitory and bactericidal activity of the herb against Propionibacterium acnes strains was determined by measuring the MIC and D value. The extracts inhibited erythromycin-sensible and resistant P. acnes strains growth with MICs of 4.9 μg/mL and 2.4 μg/mL, respectively. MC-B and MC-A displayed a strong inhibitory activity against both strains as well (MICs of 1.2 μg/mL and about 0.5 μg/mL, for both strains respectively). The extract also exhibited a concentration-dependent antilipase activity at 100 μg/mL and 1 mg/mL, as they decreased lipase activity by 53% and 100% (p < 0.01 for both), respectively. This effect, together with the previously mentioned activities, suggests that myrtle could provide an effective treatment for acne lesions (Fiorini-Puybaret et al., 2011). Effect on hair growth. The essential oil of M. communis has been used as a hair tonic agent in French and Persian folk medicine. In a study conducted by Bureau et al. (2003), the effect of the application of a blend of 100% essential plant oils combined with low Copyright © 2014 John Wiley & Sons, Ltd.

electromagnetic pulses on hair growth in treatment of androgenetic alopecia was assessed. The solution contained M. communis as well as other plant essential oils. Using the oils alone prevented hair loss and occasionally induced light hair growth by two mechanisms: first, favouring nutritive intake of the hair papilla cells due to the stimulation of the microcirculation and second, regulating the function of sebaceous glands. However, the association of a complementary technique and using electromagnetic pulses stimulated the cells. Thus, the treatment described did not only stop hair loss but also stimulated its growth. Results showed that as well as an increase in hair density and total hair ratio, there was an increase in the proliferation index, which was observed in immunohistochemical examination. Furthermore, the expression of Ki67 which is a cell proliferation marker was increased. Effect on aphthous lesions. Myrtle is used as a treatment of mouth ulcers in folk medicine. Some studies have been conducted to evaluate myrtle activity against recurrent aphthous stomatitis (RAS) (Chamani et al., 2005; Rad et al., 2010; Babaee et al., 2010; Eslami Raveshty and Eslami Raveshty, 2011). In a randomized, double-blind, controlled before–after clinical trial, five parameters including size change, pain scale, erythema and exudation level, oral health impact profile and patient overall assessment of their treatment were studied. Statistically significant reduction of ulcer size (p < 0.001), pain severity (p < 0.05), erythema and exudation level (p < 0.001) was observed in the group of patients who had applied myrtle leaf oral paste four times a day for 6 days. The Oral Health Impact Profile improved significantly in the treated group (p < 0.001). Patient overall assessment of their treatment had also improved (p < 0.05). The mechanism of action could be either due to myrtle’s antibacterial effect or to its free radical scavenging activity (Babaee et al., 2010). In another double-blind randomized clinical trial, the effect of mucoadhesive paste containing myrtle leaf essential oil on RAS was assessed. Mucoadhesive paste is a dosage form that can hold the drug for a long time on a specific location. The reduced time of burning sensation and the significant (P < 0.001) reduction in the size of lesions in the group that had received mucoadhesive paste containing myrtle essential oil compared to the group that had received mucoadhesive paste without any drug as a placebo, led to the conclusion that the mucoadhesive paste containing myrtle essential oil is a suitable formulation for treatment of RAS (Chamani et al., 2005).

SIDE EFFECTS AND TOXICITY Systemic administration of the drug should be avoided in case of inflammatory illness of the gastrointestinal area, bile ducts and severe liver disease. No health hazards or side effects are reported as a result of the proper administration of designated therapeutic dosages. However, in rare cases, systemic administration of myrtle oil as a drug may lead to nausea, vomiting and diarrhea. Because of the possibility of triggering glottal spasm, asthma like attacks or even respiratory failure, preparations containing volatile oil should not be applied to infants or young children. Overdoses of myrtle oil (more Phytother. Res. 28: 1125–1136 (2014)

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than 10 g) can cause life-threatening poisoning, due to the high amount of cineole. Symptoms include drop in blood pressure, circulatory disorders, collapse and respiratory failure (Anonymous, 2004). In a study performed to investigate the toxicity of the myrtle oil on liver size and hepatic cytochromes in rats, doses above 3 mL/kg of myrtle oil produced the following consecutive symptoms within 1–2 h: increased motility, frequent licking of the paws, loss of coordination, fur erection, tremor, paralysis of the hind legs, short clonic convulsions (an involuntary rhythmic alternation between contraction and relaxation of skeletal muscles, also called a clonic spasm), cyanosis, dyspnoea, loss of righting reflexes and narcosis. During determination of the toxicity, reducing toxicity was observed during continuous daily oral application of the essential oil which was mediated through adaptive liver stimulation. Results showed that the typical stimulation of the liver (liver enlargement, hypertrophy of endoplasmic reticulum, increase of cytochrome concentrations) with the known increase of total hepatic capacity for drug metabolism can explain the decrease in oral toxicity of the essential oil. The hepatic parameters estimated (liver size, endoplasmic reticulum and cytochromes) increased as a result of the oral dose of 0.2 mL/kg. Thus, in people receiving therapeutic

doses of this essential oil (1–2 mL/day), the appearance of adverse effects on liver is unlikely to happen (Uehleke and Brinkschulte-Freitas, 1979).

CONCLUSION Myrtle is used throughout the world as a traditional herbal remedy. According to the data on in vitro and in vivo studies, myrtle has the potential for being used in pharmaceutical development as a medicine. Many of the traditional uses of this herb have been validated from a scientific point of view. In recent years, there has been an emphasis on the use of the traditional medicines with long and proven histories in the treatment of various ailments. In this regard, it is suggested that further studies should be carried out in order to uncover the potential roles of myrtle as an alternative in the treatment of microbial, cardiovascular, gastrointestinal, dermatological and neurological diseases amongst others.

Conflict of Interest The authors have declared that there is no conflict of interest.

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