Plant active components – a resourcefor antiparasitic agents?Jean-Paul Anthony1, Lorna Fyfe1 and Huw Smith2

1Department of Dietetics, Nutrition and Biological Sciences, Queen Margaret University College, Clerwood Terrace,

Edinburgh, UK, EH12 8TS2Scottish Parasite Diagnostic Laboratory, Stobhill Hospital, Glasgow, UK, G21 3UW

Plant essential oils (and/or active components) can be

used as alternatives or adjuncts to current antiparasitic

therapies. Garlic oil has broad-spectrum activity against

Trypanosoma, Plasmodium, Giardia and Leishmania,

and Cochlospermumplanchonii and Croton cajucara oils

specifically inhibit Plasmodium falciparum and Leish-

mania amazonensis, respectively. Some plant oils have

immunomodulatory effects that could modify host–

parasite immunobiology, and the lipid solubility of

plant oils might offer alternative, transcutaneous delivery

routes. The emergence of parasites resistant to current

chemotherapies highlights the importance of plant

essential oils as novel antiparasitic agents.

Pharmacological potential of plants

Plants and their extracts have been used for manycenturies as treatments for ailments from headaches toparasite infections [1], yet only in the past 20–30 yearshave scientists seriously begun to determine whetherplant-derived traditional remedies are effective, and, if so,their mode of action. Less than 10% of w250 000 of theworld’s flowering plant species have been investigatedscientifically for their pharmacological properties [2] butalmost 25% of active medical compounds currentlyprescribed in the USA and UK were isolated from higherplants. This source offers a vast, untapped reservoir ofpotential new antiparasitic drugs for study.

Historical aspects

Most knowledge of the therapeutic use of plants isacquired through folklore, handed down by word ofmouth. Plants are an important source for drug discovery– particularly for parasites because of the long associationbetween the coexistence of parasites, humans and herbalremedies. Increased availability of chemotherapy forparasitic infection, coupled with the high cost of treatmentcompliance in endemic regions, increased travel toendemic areas and its attendant requirement for effectiveprophylaxis, and increased resistance to conventionaldrugs are major drivers of drug discovery. In addition,the increased understanding of the modes of action ofplant medicinal extracts, together with the availability ofvarious complete and partial parasite genome sequences,

Corresponding author: Smith, H. (huw.smith@northglasgow.scot.nhs.uk).Available online 15 August 2005

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further drive the search for novel antiparasitic drugs.Plasmodium falciparum (for review, see Ref. [3]) andLeishmania donovani (for review, see Ref. [4]) arebecoming increasingly resistant to conventional drugs;therefore, new drugs, or combinations of new and existingdrugs, are required.

Most research effort into the effects of plants on para-site infections has been undertaken using aqueous oralcoholic extractions, yet purified plant essential oils couldalso be efficacious in treating or preventing parasiticdiseases. Properties such as low density (around 0.94 g/m)and rapid diffusion across cell membranes (owing to theirlipid solubility) can enhance the targeting of active com-ponents within an oil to intracellular parasites [5]. Plantessential oils can be extracted from fruits, leaves, stem orroots by crushing or by distillation in a heated aqueous oralcoholic solvent, and their active components can beisolated and characterized by HPLC and gas–liquidchromatography. Many oils and their components havebeen characterized by HPLC, and suppliers have goodquality control regarding consistency of composition andpurity as a result of food and aromatherapy industryrequirements [6]. An advantage of using commerciallysourced oils is that sufficient stock and quality assuranceand control are available so that an effective ‘batch’ can bereordered.

Plant essential oils and parasitic infections

Two separate modes of action can be attributed to theefficacy of plant essential oils for treating parasiticinfections: their immunomodulatory properties and theirantiparasitic effects.

Properties of plant essential oils on macrophages

Some plant oils have immunomodulatory effects that areuseful for treating infectious diseases, particularly incases where the oil has no direct adverse effect on the host.Clove [7], turmeric [8] and garlic [9] oils inhibit nitricoxide (NO) production in macrophages. NO is a potentintracellular parasite-killing mechanism in macrophages(for review, see Ref. [10]), and macrophages are pivotal inthe innate immune response. An ethanol extract of cloveoil inhibits prostaglandin E2 (PGE2) production in acti-vated murine macrophages [11], and 1,8-cineol, a productfrom eucalyptus oil, inhibits cytokine production [12].Further anti-inflammatory effects of oils are described in

Review TRENDS in Parasitology Vol.21 No.10 October 2005

. doi:10.1016/j.pt.2005.08.004

Review TRENDS in Parasitology Vol.21 No.10 October 2005 463

Box 1. These inhibitory effects assist in providing anenvironment conducive to intracellular parasite multi-plication; however, the inhibition of one killingmechanism can cause the upregulation of secondarymechanisms which the parasite cannot protect itselfagainst. The inhibition of NO production causes anincrease in tryptophan degradation through indola-mine deoxygenase induction in human peritonealmacrophages [13]; this starves the coccidian parasiteToxoplasma gondii of an essential amino acid, leadingto its death.

Basil and clove oils contain eugenol, which hasantiphagocytic properties.Basil oil inhibits thephagocytosisof opsonized sheep erythrocytes by murine peritoneal cells[14], and eugenol from clove oil impairs macrophageadherence to glass, NO production in response to interferon,and phagocytosis of Listeria monocytogenes in murinemacrophages, although it does not influence interleukin 12(IL-12) responses to L. monocytogenes [7].

Sacaca (Croton cajucara) oil might enhance intracellularparasite killing. Its linalool component can increasemacrophage NO production [15].

Box 2. Mode of action of some plant oils on parasites

The mode of action of allicin and its condensation product ajoene is

through interaction with important thiol-containing enzymes [19].

Complement modulation

Plant oils can adversely affect the complement cascade.Rosmarinic acid from lemon balm (Melissa officinalis)inhibits the classical complement lysis pathway byblocking both C5 convertase [16] and C3 convertase [17]activity, whereas an acidic polysaccharide from a hot-water extract of thyme leaves potently inhibits both theclassical and alternative complement cascades [18].Complement inhibition can lead to reduced antibody-dependent and -independent complement-mediated opso-nization and pathogen killing.

Box 1. Protective and anti-inflammatory effects of plant oils

† The oil from black seed (cumin) is known to have anti-

inflammatory properties and has been found to be hepatoprotective

when liver injury is induced in mice by carbon tetrachloride [62]. It

has also been shown to help to protect against chromosomal

aberrations induced as a result of S. mansoni infection. In addition,

oil from cumin might also afford protection in schistosomiasis by

modulating the immune response and reducing inflammation [37].

† Tea tree oil reduces histamine-induced skin inflammation in

humans [61] and mice [64]. PGE2 production in activated murine

macrophages is inhibited by eugenol derived from an ethanol

extract from cloves through inhibition of cyclooxygenase-2 mRNA

expression [11]. In rats, the fixed oil of basil inhibits both the

cyclooxygenase and lipoxygenase pathways of arachidonic acid

metabolism [65]. Eucalyptus oil can inhibit arachidonic acid

metabolism in human monocytes, with a significant steroid-saving

effect in steroid-dependent asthma [12].

† Oil from sacaca has opposing effects on PGE2 production,

depending upon the cell target. In mice, cyclooxygenase is inhibited

[66], and PGE2 production and release from glandular cells

promoted [67]. Two components of this oil (cajucarinolide and

isocajucarinolide) have anti-inflammatory properties and inhibit bee

venom PLA2 [68]. Mast cell degranulation can be inhibited with

lavender oil, both in vivo and in vitro [69].

† These oils can help to protect the host from the damaging effects of

the inflammatory components of the immune response as they

control the parasitic infections.

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Antiparasitic effects of plant essential oils

Garlic oil is the only plant essential oil that possesses abroad antimicrobial spectrum, being antibacterial, anti-fungal, antiviral and antiparasitic (for review, see Ref. [19]).It influences the growth of at least 12 different humanand nonhuman parasites. Its allicin component inhibitsEntamoeba histolytica trophozoite growth in vitro(30 mg/ml [19]), whereas lower concentrations inhibit tro-phozoite cysteine proteinase activity in vitro by 90% [20].Allicin, its chemically stable transformation productdiallyl trisulphide (DAT) and ajoene inhibit the growthof various protozoan parasites, including Giardia lamblia(also called Giardia duodenalis), Leishmania major,Leptomonas colosoma, Crithidia fasciculata [19,21],Cryptosporidium baileyi [22], Tetratrichomonas galli-narum, Histomonas meleagridis [23], G. duodenalis [24],Plasmodium berghei [25], Trypanosoma brucei brucei,Trypanosoma brucei rhodesiense, Trypanosoma bruceigambiense, Trypanosoma brucei congolense, Trypanosomaevansi, Trypanosoma equiperdum [21] and Trypanosomacruzi [26]. The modes of action of garlic oil are presented inBox 2.

Of the oils identified in Table 1, apart from garlic, onlyoregano oil is effective against more than two parasites. Inadult human trials, emulsified oil, given orally tovolunteers for six weeks, reduced Blastocystis hominis,Entamoeba hartmanni and Endolimax nana excretion instools to below the limit of detection [27]. When given inthe feed of Eimeria tenella-infected broiler chickens,oregano oil was antiparasitic, as determined by reducedbloody diarrhoea, lesion score and oocyst numbers,

The specific enzymes vary in different genera but for E. histolytica,

allicin inhibits cysteine proteinases, alcohol dehydrogenases [20]

and thioredoxin reductases [19]. Ajoene inhibits T. cruzi prolifer-

ation, possibly by inhibiting phosphatidylcholine biosynthesis [26].

Allicin is toxic to mammalian cells at concentrations O100 mg/ml

(c.f. 5 mg/ml for E. histolytica) [20] because mammalian cells have

much higher levels of glutathione, which enables them to reactivate

enzymes inhibited by allicin [70]. The mode(s) of action of the

components of garlic oil have been investigated only in E. histolytica

and T. cruzi. Ajoene might interfere with protein and lipid trafficking

in the parasite and host cell membranes, irreversibly damaging the

parasite [71]. Inhibition of T. cruzi epimastigote growth by ajoene is

accompanied by changes in the phospholipid composition of the cell

membrane, leading to the previously most abundant phospholipid

(phosphatidylcholine) becoming the least abundant, and its immedi-

ate precursor (phosphatidylethanolamine) becoming the most

abundant. This suggests that ajoene inhibits the final stage of

phosphatidylcholine biosynthesis, altering the phospholipid com-

position of the cell membrane. This can be observed ultrastructur-

ally, with a concentration-dependent alteration in intracellular

membranous structures: 60 mM ajoene causes gross alterations to

the mitochondria and endoplasmic reticulum, and 100 mM ajoene

leads to a general breakdown in the intracellular membrane system

and cell lysis [26].

Nerolidol, the acyclic oxygenated sesquiterpene found in Virola

surinamensis and H. crispiflorus, inhibits protein glucosylation in

P. falciparum in vitro by competing with the biosynthesis of

isoprenoid derivatives, in addition to decreasing the ability of the

intraerythrocytic parasite to synthesize coenzyme Q [5].

Table 1. Plant oils with activity against parasites

Family Botanical name Vulgar name Refs

Activity against more than one parasite

Alliaceae Allium sativum Garlic [19–26]

Lamiaceae Melissa officinalis Lemon balm [34]

Origanum vulgare Oregano [27–29]

Thymus vulgaris Thyme [29,34]

Lauraceae Cinnamomum zeylanicum Cinnamon [23,29,35]

Myrtaceae Melaleuca alternifolia Tea tree [29,34]

Rutaceae Citrus limon Lemon [23]

Activity against Plasmodium species

Alliaceae Allium sativum Garlic [25]

Annonaceae Hexalobus crispiflorus Unknown [5]

Pachypodanthium confine Bohingo

Xylopia aethiopica African guinea pepper

Xylopia phloidora Unknown

Cochlospermaceae Cochlospermum planchonii False cotton or N’Dribala [32,33]

Euphorbiaceae Antidesma laciniatum Unknown [5]

Lamiaceae Tetradenia riparia Nutmeg bush [40]

Myristicaceae Virola surinamensis Light virola [41]

Activity against coccidia and flagellates

Alliaceae Allium sativum Garlic [21–24]

Lamiaceae Origanum vulgare Oregano [28]

Lauraceae Cinnamomum zeylanicum Cinnamon [23]

Rutaceae Citrus limon Lemon [23]

Activity against helminths

Lamiaceae Ocimum gratissimum Basil [38]

Ocimum sanctum Sacred balm or sacred basil [39]

Myrtaceae Melaleuca cajuputi Cajuput [42,43]

Ranunculaceae Nigella sativa Black seed or cumin [37]

Review TRENDS in Parasitology Vol.21 No.10 October 2005464

increased body weight gain and feed conversion ratios, butwas less effective than the favoured drug, lasalocid [28].

Treatment of head lice (Pediculus humanus capitis)with oregano oil (1% aqueous solution) killed 100% ofadult lice and, when followed by a rinse mixture of oil(0.1%), malt vinegar (49.5%) and water (49.5%) 17 hourslater, resulted in a 99.3% mortality rate for the eggs [29].Thyme oil produced a similar adult mortality rate but hadreduced activity (50.8% mortality) against eggs. Treat-ment with the same regimen of cinnamon oil killed 86% ofadult lice and 25.7% of eggs but was less effective thanoregano or thyme oil, although 100% mortality rates wereachieved when ethanol was used as the solvent in theprerinse mixture. Ethanol did not contribute to the lethaleffects of cinnamon oil, and its phenolic compounds weredeemed responsible for its lousicidal activity, possiblythrough louse neurotoxicity or skin irritancy [29].

Plasmodium species

A pharmaceutical product developed from artemisinin,when used in combination with modern synthetic chloro-quine-derived compounds, is effective in the treatment offalciparum malaria [30]. Artemisinin, obtained fromArtemisia annua, has been used since 341 BC as aChinese herbal remedy for malaria [31]. Since the iso-lation of the antimalarial principle in the 1970s [31], it hastaken almost 30 years for artemisinin to become part ofthe Essential Medicines list of the World Health Organ-ization (http://www.who.int/en/), especially when theparasite is resistant to both chloroquine and sulfadoxinepyrimethamine [30].

The increasing multidrug resistance of P. falciparumhas broadened the search for natural plant products assources of novel drugs. A single dose of ajoene (50 mg/kg),

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the condensation product of allicin, given on the day ofinfection, inhibited parasitaemia in murine (P. berghei)malaria, with no observable toxic side effects. When givenin conjunction with 4.5 mg/kg chloroquine, completesuppression of parasitaemia occurred, and further inves-tigations indicated that ajoene potentiated the effect ofchloroquine [25].

In the past 20 years, plants from areas endemic formalaria have been assessed extensively, with the greatestresearch focus being on aqueous and alcoholic extractions.However, little work has been carried out using purifiedessential oils (Table 1). In one study of Cameroonian plantoils, Hexalobus crispiflorus (a rainforest tree found acrosstropical Africa; a decoction of bark is used commonly as apurgative and emetic) was found to have antiplasmodialactivity against the W2 strain of P. falciparum in vitrowith a concentration required to kill 50% of parasitescompared with the control (IC50) of 2 mg/ml [c.f. chloro-quine 30.4 nM (9.7 ng/ml)] [5]. The action of H. crispiflorusoil is thought to be a result of its high sesquiterpenecontent, the active component being nerolidol, whosemode of action is outlined in Box 2. Four other plant oilstested against this strain had lesser antiplasmodialactivity. Pachypodanthium confine (a decoction of thebark is used to treat body lice) had an IC50 of 16.6 mg/ml,Xylopia aethiopica (fruit used as a spice in foods, a coughremedy, for flatulence relief, postpartum tonic, forstomach ache, bronchitis, biliousness and dysentery) anIC50 of 17.8 mg/ml, Xylopia phloidora an IC50 of 17.9 mg/mland Antidesma laciniatum (powdered bark used as anaphrodisiac) an IC50 of 29.4 mg/ml [5].

Another African plant used as a traditional remedy formalaria is Cochlospermum planchonii (N’Dribala or falsecotton), and both the traditional method of usage and the

Review TRENDS in Parasitology Vol.21 No.10 October 2005 465

essential oil have been tested on P. falciparum in vivo andin vitro. In vitro, the oil, whose major constituents areb-caryophyllene, (E,E)–a–farnesene and tetradecan-3-one, inhibited parasite proliferation, as assessed by[3H]-hypoxanthine incorporation (IC50Z22–35 mg/ml for24–72-hour exposure; c.f. chloroquine IC50Z150 mg/ml foreach time exposure) [32]. In vivo, a decoction of plant rootsgiven to adult human volunteers with uncomplicatedfalciparum malaria was as effective as chloroquine treat-ment, albeit with a slightly slower activity [33]. Thus,ethnic medicines can be as effective as pharmaceuticalformulations and should be tested as sources in the searchfor novel drugs.

Leishmania species

Only C. cajucara oil has been used successfully againstLeishmania. Its effect on Leishmania amazonensis hasbeen investigated extensively. In vitro, morphologicalchanges in L. amazonensis promastigotes were observedwithin one hour following the application of 15 ng/ml of oil,leading to nuclear and kinetoplast chromatin destructionfollowed by cell lysis. Treatment of preinfected murinemacrophages with 15 ng/ml of oil caused a 50% reductionin L. amazonensis promastigotes infecting macrophagesand a 60% increase in macrophage NO production inpreinfected macrophages [15]. Linalool, a terpenic alcohol,is the main constituent of the oil, which is moreleishmanicidal than the essential oil [50% lethal doses(LD50) for promastigotes and amastigotes, 8.3 ng/ml and22 ng/ml for the essential oil and 4.3 ng/ml and 15.5 ng/mlfor linalool, respectively]. With little or no observedtoxicity in uninfected and infected murine macrophagesand a potent leishmanicidal action, oil from C. cajucaracould be a useful source of novel drugs.

Trypanosoma species

Garlic oil is the most active plant oil compound, allicinbeing of particular importance. DAT inhibits parasitaemiain many Trypanosoma species, particularly those respon-sible for African trypanosomiasis of humans and livestock[21]. These include T. b. brucei, T. b. rhodesiense, T. b.gambiense, T. b. congolense, T. evansi and T. equiperdum,with DAT inhibiting growth at concentrations comparableto the commercial drug, suramin [DAT IC50Z0.8–5.5 mg/ml(4.5–31 mM); suramin IC50Z10 mM] [21]. In China, DAT isused for treating bacterial and fungal infections, with onlymild side effects [21]. Ajoene is effective against T. cruziepimastigotes and amastigotes, its effect on amastigotesbeing greater than on epimastigotes. Ajoene inhibits pro-liferation of epimastigotes, on contact, at a concentrationof 80 mM, reducing their proliferation by 50% at 40 mM andcausing epimastigote lysis within 24 hours at 100 mM [26].Concentrations as low as 40 mM were sufficient to eradi-cate T. cruzi amastigote infection of Vero cells, within96 hours. With such trypanocidal activity, garlic could beused as an alternative treatment for African trypano-somiasis, considering that current drugs for cerebralinfections (sleeping sickness) are extremely toxic [3]. Themode(s) of action of ajoene are presented in Box 2.

The essential oils of lemon balm (balmint), peppermint,thyme and tea tree have been tested in vitro for activity

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against T. brucei, with varying degrees of success. Tea treeoil (TTO) is most trypanocidal, followed by thyme,peppermint and lemon balm [34]. Thyme oil inhibitsT. b. brucei growth, in vitro, at a level comparable tosuramin [the effective dose for killing 50% of parasites(ED50) for thyme oilZ0.4 mg/ml; the ED50 for suraminZ0.5 mg/ml] [34]. Balmint oil has activity in vitro againstT. brucei and L. major. Although treatment is available forboth, they are either expensive or have severe side effects.Balmint oil inhibits T. brucei growth (ED50Z3.9 mg/ml;suramin ED50Z0.5 mg/ml) and L. major growth (ED50Z7 mg/ml; amphotericin B ED50Z0.3 mg/ml) [34]. TTO mightprovide the alternative to suramin for treating trypano-somiasis (ED50Z0.5 mg/ml for both compounds). A majorconstituent of TTO is terpinen-4-ol, which has a greaterinhibitory action on T. brucei bloodstream forms (ED50Z0.02 mg/ml) and was O1000 fold more toxic to the parasitethan to the human lymphocytic cell line HL-60 (similar tosuramin) [34]. Further investigation into the trypanocidalactivity of terpinen-4-ol should be undertaken to deter-mine its effectiveness as a novel drug. Because all of theoils tested exhibited greater parasite toxicity thanmammalian (HL-60 cell line) toxicity, they could also besources of novel drugs.

Coccidia and flagellates

Garlic has parasiticidal activity against Cryptosporidiumspp. [22], and the flagellates T. gallinarum, H.meleagridis[23] and G. duodenalis [21,24] (Table 1). In chicken, agarlic extract was only partially effective, causing a 24.4%reduction in C. baileyi oocyst output. The two commer-cially available derivatives of the anticoccidial drugtriazinone were no more effective, and none of the drugscould be recommended for chemoprophylaxis or therapy ofcryptosporidiosis in chicken [22].

The antiflagellate activity of garlic is more encourag-ing. Whole-garlic extract and allicin, ajoene and DATexhibit antigiardial activity, including a loss of flagellarmovement and motility, loss of osmoregulation, discfragmentation, internalization of flagella [24] and growthinhibition [21]. Both T. gallinarum and H. meleagridisare killed by garlic extract but its mode of action is notknown [23].

Similarly, the oils of cinnamon and lemon have activityagainst T. gallinarum and H. meleagridis, in vivo inchicken [23] (Table 1). The effective minimal lethalconcentration of cinnamon oil for T. gallinarum andH. meleagridis was 0.25 ml/ml and 0.5 ml/ml, respectively,and that of lemon oil was 0.125 ml/ml and 1 ml/ml,respectively [23]. In addition to its antiflagellate activity,cinnamon oil possesses insecticidal properties. Filterpaper impregnated with 10 mg/g of cinnamon oil, whenfed to termites (Coptotermes formosanus), killed themwithin seven days [35]. The active component is cinna-maldehyde, which was more effective at lower concen-trations (1 mg/g) than the oil [35]. Oregano oil, given in thefeed of chicken experimentally infected with the coccidianE. tenella, reduced oocyst excretion and increased hostsurvival [28]. Although oregano oil was less efficaciousthan lasalocid, it could be a source of novel anticoccidialdrugs but its pharmacoactive components have yet to be

Review TRENDS in Parasitology Vol.21 No.10 October 2005466

identified. When undiluted thyme oil was tested onin vitro-derived G. lamblia cysts, a 60 minute exposuretime was as effective as metronidazole in killing cysts(thyme oil 91.1% death; metronidazole 89.4% death) [36].

Helminths

Few oils have been tested against helminths (Table 1),particularly those pathogenic to humans, primarilybecause of the difficulty in maintaining their life cyclesin vitro. However, in vivo work has been extensivelycarried out with Nigella sativa (black seed or blackcumin). The oil from black cumin seeds, when given toSchistosoma mansoni-infected mice, reduced parasite eggburden by augmenting the host protective immuneresponse and reduced S.mansoni-induced hepatic damage[37]. This is explained in Box 1.

Essential oils from two basil species have potentanthelmintic properties. A 0.5% concentration of Ocimumgratissimum (wild basil or tree basil) oil completelyinhibits the hatching of Haemonchus contortus eggsisolated from experimentally infected sheep and goats.The same concentration was equally effective for eugenol,the main constituent of the oil, and was comparable tothe same concentration of thiabendazole [38]. In the

Table 2. Known toxicity of plant oils

Botanical name (family) Vulgar name Toxicity

Allium sativum (Alliaceae) Garlic Cytotox

nontoxi

Hexalobus crispiflorus

(Annonaceae)

Unknown Cytotox

Pachypodanthium confine

(Annonaceae)

Bohingo Cytotox

Xylopia aethiopica

(Annonaceae)

African guinea pepper Cytotox

Cochlospermum planchonii

(Cochlospermaceae)

False cotton or N’Dribala Ranges

to cytoto

Cochlospermum regium

(Cochlospermaceae)

Unknown Ranges

modera

Antidesma laciniatum

(Euphorbiaceae)

Unknown Cytotox

Croton cajucara

(Euphorbiaceae)

Sacaca Ranges

cytotoxi

Melissa officinalis

(Lamiaceae)

Lemon balm Nontoxi

Ocimum gratissimum

(Lamiaceae)

Basil Macrop

totoxic,

Origanum vulgare

(Lamiaceae)

Oregano European Nontoxi

Thymus vulgaris

(Lamiaceae)

Thyme Ranges

weak cy

Cinnamomum zeylanicum

(Lauraceae)

Cinnamon Ranges

modera

Virola surinamensis

(Myristicaceae)

Light virola None

Melaleuca alternifolia

(Myrtaceae)

Tea tree Ranges

cytotoxi

Nigella sativa

(Ranunculaceae)

Black seed or cumin Ranges

chronic

Citrus limon (Rutaceae) Lemon PhototoaAbbreviations: CA, chromosomal aberrations; MTT, methylthiazole tetrazolium; NRU, n

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free-living Caenorhabditis elegans nematode model,Ocimum sanctum (holy basil or sacred basil) oil andeugenol were both effective in inhibiting nematode growthat levels comparable to that of recognized drugs (levami-sole, p-anisaldehyde) [39].

Future perspectives

In the absence of vaccines, the most cost-effectivetreatment intervention for parasitic diseases is chemo-therapy. However, single-drug approaches, the emergenceand re-emergence of parasitic diseases, and the appear-ance of drug- and multidrug-resistant organisms(P. falciparum and helminths), together with the severityof toxic side effects, compliance, availability and cost(particularly in endemic foci), and the ineffectiveness ofcurrent drug therapy for cryptosporidiosis necessitatefurther efforts into the discovery of novel drugs fromeither natural or synthetic sources. In some endemic fociof parasitism, plants and their extracts are the onlyreadily available forms of treatment, and this knowledgemust be preserved and scientifically examined forpotentially novel drugs.

As with drugs, plant oils can also have adverse or toxicside effects. Oils that interfere with parasite development,

type Mode of actiona Refs

ic, genotoxic, lethal,

c

Induces CA and SCEs,

pulmonary oedema

[44,45]

ic Unknown [5]

ic Unknown [5]

ic Topoisomerase-mediated

DNA damage, cell replication

inhibition

[46,47]

from no major effects

xic

Unknown [32,33,48]

from nontoxic to

te acute

Unknown [49]

ic Unknown [5]

from nontoxic to

c

Protein inhibition,

mitochondrial inhibition,

antimutagenic, apoptosis,

NRU and MTT assay

[50,51]

c Unknown [34,52]

hage function, hepa-

hepatocarcinogenic

Antiphagocytic, enzyme

alterations, formation of DNA

adducts

[14,53,54]

c Unknown [27]

from nontoxic to

totoxicity

Inhibits DNA synthesis [55,56]

from nontoxic to

te allergic reactions

Nausea, abdominal pain, oral

burning, ‘rush’

[5,57,58]

Unknown [41]

from slight to severe

city

Interaction with cell mem-

brane, reduced histamine-

induced inflammation,

ataxia, drowsiness, con-

fusion, motor function loss

[59–61]

from nontoxic to

toxicity

Hepatoprotective? [62,63]

xic Unknown [6]

eutral red uptake; SCEs, sister chromatid exchanges.

Review TRENDS in Parasitology Vol.21 No.10 October 2005 467

but also exhibit toxic effects on mammalian cells, arepresented in Table 2. Synthesized oils, of known chemicalcomposition, particularly for expensive or rare naturaloils, are currently manufactured by the essential oilindustry, and this procedure can be applied to thechemical synthesis of antiparasitic drugs, to enable toxiccomponents to be omitted.

The low density of plant oils and their rapid diffusionacross cell membranes can enhance the targeting of activecomponents within oils to endoparasites. It might alsooffer alternative delivery routes, including transcu-taneous delivery following scarification or patch appli-cation. For infections such as uncomplicated falciparummalaria and trypanosomiasis, plant oils can be as effectiveas commercially available synthetic drugs but furthercollaborative research into their usefulness and toxicity isrequired. The potential variability of active ingredient(s)must also be addressed.

Considering the increasing databases available forparasite and plant genomes, database mining will assistthe discovery of new genes and understanding theirfunction(s), which could identify current treatmentinadequacies and discover useful drug targets and drugswith better efficacy, lower toxicity and higher activityagainst resistant organisms. Further research into para-site and plant genomics and proteomics, targetingcompounds unique to parasite biochemical pathways,together with effective multicentre trials in endemicareas, should determine the roles that plants and theiroils have in controlling parasitic infections.

References

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56 Haroun, E.M. et al. (2002) Effect of feeding Cuminum cyminum fruits,Thymus vulgaris leaves or their mixture to rats. Vet. Hum. Toxicol. 44,67–69

57 Perry, P.A. et al. (1990) Cinnamon oil abuse by adolescents. Vet. Hum.Toxicol. 32, 162–164

58 Hoskins, J.A. (1984) The occurrence, metabolism, and toxicity ofcinnamic acid and related compounds. J. Appl. Toxicol. 4, 283–292

59 Soderberg, T.A. et al. (1996) Toxic effects of some conifer resin acidsand tea tree oil on human epithelial and fibroblast cells. Toxicology107, 99–109

60 Del Beccaro, M.A. (1995) Melaleuca oil poisoning in a 17 month-old.Vet. Hum. Toxicol. 37, 557–558

61 Koh, K.J. et al. (2002) Tea tree oil reduces histamine-induced skininflammation. Br. J. Dermatol. 147, 1212–1217

62 Mansour, M.A. et al. (2001) Effects of volatile oil constituents ofNigella sativa on carbon tetrachloride-induced hepatotoxicity in mice:evidence for antioxidant effects of thymoquinone. Res. Commun. Mol.Pathol. Pharmacol. 110, 239–251

63 Ali, B.H. and Blunden, G. (2003) Pharmacological and toxicologicalproperties of Nigella sativa. Phytother. Res. 17, 299–305

64 Brand, C. et al. (2002) Tea tree oil reduces histamine-induced oedemain murine ears. Inflamm. Res. 51, 283–289

65 Singh, S. (1999) Mechanism of action of anti-inflammatory effectof fixed oil of Ocimum basilicum Linn. Indian J. Exp. Biol. 37,248–252

66 Maciel, M.A. et al. (2000) Ethnopharmacology, phytochemistry andpharmacology: a successful combination in the study of Crotoncajucara. J. Ethnopharmacol. 70, 41–55

67 Hiruma-Lima, C.A. et al. (2002) Effect of essential oil obtained fromCroton cajucara Benth. on gastric ulcer healing and protective factorsof the gastric mucosa. Phytomedicine 9, 523–529

68 Ichihara, Y. et al. (1992) Cajucarinolide and isocajucarinolide: anti-inflammatory diterpenes from Croton cajucara. Planta Med. 58,549–551

69 Kim, H.M. and Cho, S.H. (1999) Lavender oil inhibits immediate-type allergic reaction in mice and rats. J. Pharm. Pharmacol. 51,221–226

70 Rabinkov, A. et al. (1998) The mode of action of allicin: trapping ofradicals and interaction with thiol containing proteins. Biochim.Biophys. Acta 1379, 233–244

71 Elmendorf, H.G. and Haldar, K. (1993) Secretory transport inPlasmodium. Parasitol. Today 9, 98–102

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