Articles

Syzygium aromaticum (L.) Merrill & Perry

Last updated: 15 January 2016

Scientific Name

Syzygium aromaticum (L.) Merrill & Perry

Synonyms

Caryophyllus aromaticus L., Eugenia aromatica (L.), Eugenia caryophyllus. [1]

Vernacular Name

Malaysia Chengkeh, chingkeh [2]
English Clove [2]
Indonesia Cengkeh [2]
Thailand Kanphlu [2]
Laos Do:k chan, ka:nz ph'u: [2]
Myanmar Lay-hnyin [2]
Philippines Klabong pako, clavo de comer [2]
Cambodia Khan phluu, khlam puu [2]
Vietnam Dinh h[uw][ow]ng [2]
France Clou de girofle [2]

Geographical Distributions

Syzygium aromaticum was first cultivated on some islands of the Moluccas, where it occurs wild, as well as in New Guinea. It is found in abundance as a second-storey forest tree on the lower mountain slopes. The crop and its trade have a long and fascinating history going back to the Han Dynasty in the 3rd Century BC. The story of S. aromaticum trade and the spread of the crop are full of intrigue and brutality. Apart from pepper (Piper nigrum L.), no other crop may have played a comparable role in world history. Early in the 17th Century, when the Dutch ousted the Portuguese from the Moluccas, S. aromaticum cultivation had spread to many islands. Under Dutch rule, the crop was forcibly eradicated everywhere but concentrated on Ambon (a southern island of the group) and 3 nearby small islands. This is the wettest part of the Moluccas. From the Moluccas, S. aromaticum was taken to other parts of Asia: early in the 19th Century, the British took plants to Pinang (Malaysia), Sumatra (Indonesia), India and Sri Lanka. In the 20th Century, much material had spread throughout Indonesia. During expeditions in 1753, 1770 and 1772, the French appropriated some offsprings from trees that must have escaped the Dutch axe, and took them from the North Moluccas to Mauritius. These plants gave rise to the clove populations outside Asia, in Zanzibar, Madagascar and recently also in Bahia in Brazil. [2]

Its origin is thought to be Indonesia, but it is presently found throughout Africa and parts of Southeast Asia. [3]

Botanical Description

S. aromaticum is a slender, evergreen tree that can grow up to 20 m tall, and appears conical when young but becoming cylindrical later. In cultivation, it is usually smaller and branched from the base. The roots form an extensive and dense mat close to the surface with some major laterals, from which occasional 'sinker' roots descend. The shoot growth is determinate, appears in flushes and forms a dense canopy of fine twigs. The leaves are arranged opposite, simple and hairless. The petiole is 1-3 cm long, reddish and somewhat thickened at the base. The blade is obovate-oblong to elliptical, measuring 6-13 cm x 3-6 cm, with very acute base, acuminate at apex, coriaceous, shiny and gland-dotted. The inflorescence is terminal, resembling a panicle, measuring about 5 cm long, with 3-20(-40) bisexual flowers and usually borne in groups of 3 cymes. The flower buds are 1-2 cm long and constitute the cloves just before opening. The sepal is tubular, with sub-cylindrical to subquadrangular tube, measuring 1-1.5 cm long, yellowish-green with a red flush and slightly protruding beyond the ovary (hypanthium). The sepal is with 4 ovate-triangular, fleshy lobes which are 2-4 mm long. The 4 petals are coherent, tinged with red, rounded, measuring 6 mm in diametre and shedding as an hemispherical calyptra as the flower opens. The stamens are numerous and measuring up to 7 mm long. The pistil is with a 2-celled ovary, with style 3-4 mm long and with 2-lobed stigma. The fruit (called mother of cloves) is an ellipsoidal-obovoid berry, measuring 2-2.5 cm long, dark red and usually containing only one oblongoid seed 1.5 cm long. [2]

Cultivation

Notions about the ecological requirements of S. aromaticum vary, perhaps because of an underlying dilemma: a climate with a marked dry season promotes flowering, but the tree does not cope well at all with stress. There are two ways out of this dilemma. The first is to choose a climate with a pronounced dry season (Zanzibar, East Java), but to limit stress by going for deep fertile soils, providing water and shade during the early years. The other way is to choose a wet climate with a short dry season (Madagascar, Sumatra, Pinang); The choice is linked with the use of the product. S. aromaticum from wet areas are less suitable for making cigarettes, since the smoke becomes pungent and there is no crackling ('kretek') sound during smoking. [2]

Chemical Constituent

The essential oil (1.06%) from S. aromaticum flower buds contained eugenol, acetyleugenol, α- and β- caryophyllene, ylangene, chavicol, alpha-tujene, β-muurolene, β -selinene, cubenene, hexanal, 2-hexanone, 6-methyl-5-heptene-2-one, fenchone, geranial, furaldehyde, 5-methyl furaldehyde, cuminaldehyde, acetophenone, methyl palmitate, methyl stearate, methyl linoleate, benzyl benzoate and y-decalactone and humelene [4] [8] [9].

Ethanolic extract of S. aromaticum flower buds has been found to contain quinone (e.g. isobiflorin and biflorin) [5]. Ethyl acetate extract of S. aromaticum flower buds has been found to contain terpenes (e.g. β-caryophyllene, β-caryophyllene oxide, α-humulene, α-humulene epoxide) [6]. Hexane extract of S. aromaticum flower buds has been found to contain terpenes (e.g. eugenol, caryophyllene oxide, and nootkatin) [7].

Plant Part Used

Flowerbud (Clove) oil [10][11]

Traditional Use

Traditionally used to treat asthma, bleeding gums, dyspepsia, fevers, and morning sickness and also used to suppress toothache and halitosis. [2][14]Clove is one of the most stimulating herbs used in medicine. They are used principally as an adjuvant in any compound medicine in particular with other bitters and vegetative cathartics. [10] 

It has been used effectively to treat cases of flatulance, diarrhoea, nausea and vometing and cholera. [12] It is prescribed as a remedy for hiccough and vomiting as well as to treat fungal infections and various skin infections. [4]

In Malaysia it is also used to treat headache and made used of in compound medicine for the treatment of various forms of pain like lumbago, rheumatism. [11] [13] Clove relives flu, toothaches, sore muscles, arthritis, colds and bronchial congestion. [15]

Preclinical Data

Pharmacology

Clove essential oil was evaluated in seizure-induced mice. The essential oil showed anticonvulsant activity in maximal electroshock-induced seizure, however not in pentylenetetrazole-induced seizure. [16]. Anti-stress properties were exhibited in an animal study [17]. The methanolic extract of the cortex of E. caryophyllata was found to potently inhibit the prostaglandin E2 production in lipopolysaccharide (LPS)-activated mouse macrophage RAW264.7 cells (98.3 % inhibition at the test concentration of 10 µg/mL). Bioassay-guided fractionation of hexane-soluble partition produced eugenol, which exhibited a significant inhibition of PGE2 production (IC50 = 0.37 µM). In addition, eugenol suppressed the cyclooxgenase-2 (COX-2) gene expression in LPS-stimulated mouse macrophage cells. Eugenol also inhibited the proliferation of HT-29 human colon cancer cells and the mRNA expression of COX-2, but not COX-1. Therefore, it is suggested that eugenol might be a plausible lead candidate for further developing a COX-2 inhibitor as an anti-inflammatory or cancer chemopreventive agent. [18] In contrast, clove oil illustrated motor impairment on rotating rods in male mice. [19]

Antimicrobial activity 

Antiviral activity 

The extracts of E. caryophylata had been found effectively inhibit a number of virus including human cytomegalovirus, murine cytomegalocvirus, herpes simplex virus and hepatitis C virus. [20] 

An earlier study on the anitviral activity of E. caryophylata extract showed inhibition of replication of human cytomegalovirus and murine cytomegalovirus. The antiviral activity was reported that there was significant suppression of MCMV yields in lungs of immunosuppressed mice. [20][21] Kurokawa et. al found that when extracts of E. caryophylata was combined with acyclovir there was a significant limitation of development of skin lesion due to HSV-1 infection and prolonged mean survival times of infected mice as compared to individual acyclovir or clove extract. The combination were found to also reduced yields in brain and skin more strongly with those of the brain more than the skin. [22] In subsequent studies A study was conducted in isolating and characterising the essential element responsible for the anti-herpesvirus activity. Eugenin was found to inhibit the growth of acyclovir-phosphonoacetic acid resistant HSV-1, thymidine kinase-deficient HSV-1 and wild HSV type 2. This effect is due to its ability to inhibit viral DNA and late viral protein syntheses in their infected Vero cells. [23] This is further supported by another study where E. caryophyllus oil and eugenol as extracted from the oil were tested against multiple isolates of HSV. The total virus yield was reduced and some could not replicate when the eugenol was added to the challenge. [24][25] In a screening test for antiviral activities against Hepatitis C virus, it was reported that extracts of E. caryophylata has amongst the most potent activity. [24] 

Antibacterial activity 

The use of clove as an analgesic and a breath fresherners had directed researchers to see its effects on the populations of oral pathogens. a crude methanol extract of E. caryophylata exhibited preferential growth-inhibitory activity against Gram-negative anaerobic periodontal oral pathogens, including Porphyromonas gingivaslis and Prevotella intermedia. Amongst the compounds isolated from the extract, they found the flavones, kaempferol and myricetin had the most potent growth inhibitory against these pathogens. [26] The feeding rats with clove oil could significantly reduce bacterial colonization of Klebsiella pneumoniae and thus could protect against bacterial colonization of the lungs. [27]

Multi-drug resistant (MDR) strains of bacteria and fungi pose a great challenge to doctor to treat in clinical practice today. The effects of crude ethanolic extracts of five plants against MDR stains of Escherichia coli, Klebsiella pneumoniae and Candida albicans. ATCC strains of Streptococcus mutans, Staphylococcus aureus, Enterococcus faecalis, Streptococcus bovis, Pseudimonas aeruginosa, Salmonella typhimurium, Escherichia coli, Klebsiella pneumoniae and Candida albicans were tested. It was reported that the MDR strains were sensitive to the antimicrobial activity of E. caryophylata and it could be used against MDR microbes causing nosocomial and community acquired infections. [28] The essential oil of E. caryophylata show quorum sensing inhibitory activity which could explain its usefulness in the treatment of MDR microbial strains. [28]

Antifungal activity 

The essential oil of E. caryophylata was used traditionally to treat many form of fungal dermatoses including the commonly occurring tinea versicolor and ringworm. The major component of this essential oil had been found to be eugenol. Determination of the effectiveness of the essential oil as an antifungal reported that it not only inhibit the growth of Apergillus, Candida and dermatophyte clinical and American type culture collection strains but also the fluconazole-resistant strains. [29]

The main constituent of E. caryophyllus, eugenol, has strong antifungal effects against Candida albicans, the most causative fungus in candidiasis. [30] Additional research demonstrated that the oil had positive results against other strains of Candida as well. [31] The oil also demonstrated strong antifungal action on fungal strains isolated from onychomycosis. [32]

Antiparasites activity 

Petroleum ether extracts of E. caryophylata had been found to be effective in the control of house-dust mites (Dermatophagoides farinae) and renders it useful as an additive is bio-degradable insecticide. [33] The effect of E. caryophylata oil on head lice and their eggs was studied and reported that the oil in a vapour form was effective in killing female lice and deactivating the eggs. [8] The essential oil of E. caryophylata was found to have inhibitory effects on Gardia lamblia. [34]

Antiplatelet activity 

Two components of the essential oil of E. caryophylata had been found to have antiplatelet activity which are eugenol and acetyleugenol. The compounds inhibit arachidonate-, adrenaline- and collagen-induced platelet aggregation, and are more potent in inhibiting the first two agonist. Their antiaggregatory activity is due to inhibition of platelet thromboxane formation, and increased formation of 12-lipoxygenase products. The inhibitory effect was reversible and the presence of plasma proteins was seen to reduce the effective concentrantion of these susbstances due to binding. This is probably due to the fact that the increase in formation of 12-lipocygenase products facilitated by albumin acts as a conduit to divert frees arachidonic acid from the platelet cyclo-oxygenase to the lipoxygenase pathway. Both eugenol and acetyl eugenol were found to be more potent than aspirin and when used in combination was found to be more effective than when alone and also produced additive effect. [35][36]

The antithrombotic activities in two polysaccharides isolated from E. caryophylata was studied. One is relatively high molecular weight while the other was low molecular weight polysaccharides. The LMW polysaccharide was mainly composed of Rha, Gal, GalA and Ara (molar %: 24.1, 18.9, 18.0 and 17.9, respectively) with 10.8% of sulfate and 18.2% of protein. The HMW fraction consisted of Ara, Gal, Glc and Rha (molar %: 26.0, 23.7, 17.5 and 12.4, respectively) with 15.4% of sulfate and 8.0% of protein. Both polysaccharides had the backbone of type I rhamnogalacturonan and the side chain of arabinan. Comparatively, the LMW polysaccharide displayed a slightly lower activity and did not show acute toxicity, while the acute LD50 of the HMW fraction was approximately 2-fold lower than that of heparin. [37] 

Local anaesthetic activity 

β-caryophyllene is one of the main components of clove oil obtained from dried flower-buds of E. caryophylata. Studies on the local anaesthetic acitivity of this compound and found that the local anaesthetic activity of β-caryophyllene is dose dependent and is strictly dependent on its chemical structure. [38]

Gastrointestinal activity 

E. caryophylata had been used traditionally to treat constipation. The possible effects of E. caryophylata extract on the intestinal propulsion as well as its suspected gastrointestinal protective properties was studied and reported that the extract was able to increase gut muscle propulsion via cholinergic mechanism. A decoction of clove was found to reduce the number of ulcer and ulcer area in ethanol induced ulcers in rats. [39] 

Transderma permeability enhancement activity 

Evaluation of the skin permeation ehnhancement effects of essential oil of E. caryophylata and reported that it significantly enhances permeation. The eugenol and acetyleugenol were the main component of the oil that might contribute to this effect both in vitro and in vivo. [40]

COX-2 inhibition activity 

Inducible cyclo-oxygenase (COX-2) had been implicated in the processes of inflammation and carcinogenesis. Thus, COX-2 inhibitors would have anti-inflammatory and cancer chemoprotective propertiesStudies on 170 methanolic extracts of natural products including Korean herbal medicines for the inhibition of prostaglandin e(2) production and nitric oxide formation in lipopolysaccharide-induced mouse macrophages RAW264.7 cells. In this sutdy they found that amongst other the extract of E. caryophylata prove to have significant inhinbitory activity. [41]

Further studies on the COX-2 inhibitory activity in methanolic extract of the bark of E. caryophylata reported to inhibit the prostaglandin E(2) production in lipopolysaccharide-activated mouse macrophages RAW264.7 cells. It was further found that the hexane soluble layer was the most active portion. The main component of this fraction was found to be eugenol. It not only inhibit PGE(2) production but it also suppressed the cyclo-oxygenase-2 gene expression in LPS-stimulated mouse macrophage cells. The eugenol was also able to inhibit proliferation of HT-29 cells (human colon cancer cells) and the mRNA expression of COX-2, but not COX-1. [18] 

Immunomodulatory activity 

E. caryophylata aqueous extract was found to have inhibitive effects on local immunoglobulin E (IgE)-mediated passive cutaneous anaphylactic reaction. Pretreatment with the aqueous extract reduced the serum histamine levels in a dose-dependent manner. The result indicates that the extract inhibits immediate hypersensitivity by inhibition of histamine release from the mast cells both in vivo and in vitro.[42]

Essential oil of E. caryophylata was reported to increase the total white cell count and enhance the delayed-type hypersensitivity response in mice. It was able to restore the cellular and humoral immune responses in in immunosuppressed mice. The immunostimulatory activity of essential oil of E. caryophylata found in mice was due to improvement in humour- and cell-mediated immune response mechanism. [43]  

Chemoprotective and chemopreventive activity 

Antimutagenic activity was seen in various extracts of E. caryophylata as shown in their ability to suppressed furylfuramide-induced SOS response in umu test. The following compounds responsible includes trans-eugenol, eugenol, dihydrodieugenol and trans-coniferyl aldehyde.[44][45]

The chemoprotective and chemopreventive activity of aqueous extracts of E. caryophylata had been reported as it was seen in mice when on administration of the extract there was a delay in the formation of papiloma and a reduction of the incidence of the same. [46] The E. caryophylata infusion was found to have chemopreventive potential in view of its apoptogenic and antiploriferative activities. [47] E. caryophylata oil was found to be highly cytotoxic at concentration as low as 0.03 % with 73% of the activity attributable to eugenol. [48] 

Eugenol isolated from Clove oil was shown to induce apoptosis in human promyeloctic leukemia cells. [49]

Aphrodisiac activity 

E. caryophylata had been advocated in the treatment of various sexual disorders from impotency to sexual stimulants (aphrodisiacs). Studies on the effects of hexane extracts of E. caryophylata on the testicular function and found that the treatment did not induce toxicity at the doses tested. It was also found that at the lower dose of 15 mg of the extracts increased the activities of Delta(5) 3 β-HSD and 17 β-HSD, and serum level of testosterone. At higher doses it ihibited these parameters and induced non-uniform degenerative changes in the seminiferous tubules associated with decrease in daily sperm production and depletion of 1C (round and elongated spermatids) population. 50% ethanolic extract of E. caryophylata extract significantly increased the Mounting Frequency, Intromission Frequency; Intromission Latency, Erections; Quick Flips, Long Flips as well as aggregate of penile reflexes and caused significant reduction in the Mounting Latency and Post Ejaculatory Interval. It was devoid of any conspicous general short term toxicity. [50][51]

Antidiabetic activity 

E. caryophylata extract acts like insulin in hepatocytes and hepatoma cells by reducing phosphoenolpyruvate carboxykinase and glucose-6-phosphatase gene expression. This suppression is reversed by PI3K inhibitors and N-acetylcysteine. [52]

Antioxidant activity

Pre-clinical and laboratory analysis have supported the antioxidant properties of clove oil. [31][53]

Toxicity

No documentation

Clinical Data

Clinical findings

No documentation

Precautions

When used in its pure form and on large areas of the skin, this essential oil is strongly dermocaustic.

It may be assumed that the eugenol content may indicate that the essential oil of E. Caryophyllus is hepatotoxic. [54]

Side effects

Cloves can cause local skin irritation, pulmonary edema, mouth sensitivity, and sudden lower airway closure. In addition, smoking clove cigarettes can damage soft tissues and injure the airway linings. [55] 

Pregnancy/Breast Feeding

Cloves stimulatory effect on menstrual flow can possibly induce abortion too. It use during pregnancy should be with great caution. [11] 

Age limitation

Use with caution in children because of the rapid absorbability and the toxicity to the brain as cited below. [56]

Adverse reaction

It is a dermal and mucous membrane irritant in high concentrations and it is not advisable to apply any of the clove oils neat because of the high content of eugenol. There have been cases reported of permanent local anaesthesia and anhidrosis after accidental neat spillage on the skin. [56]  

Inhaling clove cigarette smoke has been associated with severe lung injury in a few susceptible individuals with prodromal respiratory infection. Some individuals with normal respiratory tracts have apparently suffered aspiration pneumonitis as the result of a diminished gag reflex induced by a local anesthetic action of eugenol (the active component of cloves), which is volatilized into the smoke. [57] These conditions had been cited in the United States of America amongst the caucasian population. However, no such reports had been recorded to happen amongst keretek smokers in Malaysia and Indonesia. [57]

Interaction & Depletion

No documentation

Interaction with drug

Caution should be exercised when taking clove extracts with anti-diabetic drugs as its insulino-mimetic activity can further supress blood sugar levels. [52]

Due to the eugenol content, clove oil should not be used by those taking anticoagulant drugs. [54]

Interaction with other Herbs

No documentation

Contraindications

No documentation

Case Report

A number of cases of adverse reaction due to exposure to Clove oil had been reported in various journals since 1983: 

A case of a 24-year-old woman reports permanent local anesthesia and anhidrosis following clove oil spillage into the facial area [56]

A 7 month old child developed Central nervous system depression, urinary abnormalities and a large anion-gap acidosis following accidental administration of clove oil. The patient fully recovered following gastric lavage and supportive care. [58]   

A 2-year old child developed disseminated intravascular coagulopathy with hepatocellular necrosis following ingestion of clove oil. Rapid treatment with heparin and fresh frozen plasma followed by specific haemostasis assay and administration of appropriate coagulation factor and inhibitor concentrates were successful in saving the child. [59]

Dosage

No documentation

Poisonous Management

No documentation

Line drawing

No documentation

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