Aetheroleum Anisi, Herbal Medicine

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Defi nition

Aetheroleum Anisi consists of the essential oil obtained by steam distillation

from the dry ripe fruits of Pimpinella anisum L. (Apiaceae) (1–5).1

Synonyms

Anisum offi cinarum Moench, A. vulgare Gaertn., Apium anisum (L.)

Crantz, Carum anisum (L.) Baill., Pimpinella anisum cultum Alef., P. aromatica

Bieb., Selinum anisum (L.) E.H.L. Krause, Sison anisum Spreng.,

Tragium anisum Link (1, 6–8). Apiaceae are also known as Umbelliferae.

Selected vernacular names

Anacio, Anes, Aneis, anice, anice verde, Anis, anisbibernelle, anis verde,

anis vert, anise, anisoon, anisum, anizs, anizsolaj, annsella, badian, badian

rumi, boucage, boucage anis, Gruner Anis, habbat hlawa, jintan manis,

jinten manis, petit anis, pimpinelle, razianag, razianaj, roomy, saunf, sweet

cumin, yansoon (1, 6–10).

Geographical distribution

Indigenous to the eastern Mediterranean region, western Asia and Europe.

Cultivated in southern Europe and northern Africa, and in Argentina,

Bulgaria, Chile, China, India, Islamic Republic of Iran, Japan, Mexico,

Romania, Russian Federation and Turkey (8).

Description

An aromatic annual herb, up to 60 cm high with an erect, cylindrical,

striated, smooth stem. Leaves alternate below, opposite above, the lower

being long-petioled, ovate–orbicular, dentate, the upper with short dilated

petioles, pinnatifi d or ternately pinnate with long, entire or cut cuneate

segments. Infl orescence long-stalked, compound umbel with 8–14 rays;

fl owers small, white, each on a long hairy pedicel. Fruit comprises a

1 The European pharmacopoeia (5) permits the inclusion of the essential oil of Illicium verum Hook.

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mouse-shaped cremocarp with a small stylopod and two minutely pubescent

mericarps that do not readily separate from the carpophore (6, 11).

Plant material of interest: essential oil

General appearance

A clear, colourless or pale yellow liquid, solidifying on cooling, practically

insoluble in water, miscible with alcohol, ether, light petroleum or

methylene chloride (1, 5).

Organoleptic properties

Odour: characteristic, aromatic; taste: sweet, strongly aromatic (1).

Microscopic characteristics

Not applicable.

Powdered plant material

Not applicable.

General identity tests

Thin-layer chromatography for the presence of anethole, anisaldehyde

and linalool. A gas chromatography method is also available (5).

Purity tests

Microbiological

Tests for specifi c microorganisms and microbial contamination limits are

as described in the WHO guidelines on quality control methods for medicinal

plants (12).

Chemical

Soluble in three parts ethanol (90%) at 20 oC (4). Relative density 0.978–

0.994 (5). Refractive index 1.552–1.561 (5). Freezing-point 15–19 oC (5).

Acid value not more than 1.0 (5).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than

0.05 mg/kg (5). For other pesticides, see the European pharmacopoeia (5),

and the WHO guidelines on quality control methods for medicinal plants

(12) and pesticide residues (13).

Heavy metals

For maximum limits and analysis of heavy metals, consult the WHO

guidelines on quality control methods for medicinal plants (12).

Aetheroleum Anisi

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Other purity tests

Tests for foreign organic matter, total ash, acid-insoluble ash, water-soluble

extractive, alcohol-soluble extractive and loss on drying not applicable.

Chemical assays

Contains 0.1–1.5% linalool, 0.5–6.0% methylchavicol, 0.1–1.5% α-terpineol,

< 0.5% cis-anethole, 84–93% trans-anethole, 0.1–3.5% p-anisaldehyde

(5).

Major chemical constituents

The major constituents are trans-anethole (84–93%), cis-anethole (< 0.5%),

methylchavicol (estragole, isoanethole; 0.5–6.0%), linalool (0.1–1.5%) and

p-anisaldehyde (0.1–3.5%) (5). The structures of trans-anethole, methylchavicol,

β-linalool and p-anisaldehyde are presented below.

Medicinal uses

Uses supported by clinical data

None.

Uses described in pharmacopoeias and well established documents

Treatment of dyspepsia and mild infl ammation of the respiratory tract

(14, 15).

Uses described in traditional medicine

As an aphrodisiac, carminative, emmenagogue, galactagogue and insecticide.

Treatment of chronic bronchitis (8, 10).

Pharmacology

Experimental pharmacology

Anticonvulsant activity

Intraperitoneal administration of 1.0 ml/kg body weight (bw) of the oil to

mice suppressed tonic convulsions induced by pentylenetetrazole or

maximal electroshock (22). Intraperitoneal administration of 2.5 g/kg bw

of linalool to rodents provided protection against convulsions induced by

pentylene tetrazole, picrotoxin and electroshock (23, 24). Intraperitoneal

administration of 2.5 g/kg bw of linalool to mice interfered with glutamate

function and delayed convulsions induced by N-methyl-d-aspartate

(25). Linalool acts as a competitive antagonist of [3H]-glutamate

binding and as a non-competitive antagonist of [3H]-dizocilpine binding

in mouse cortical membranes. The effects of linalool were investigated on

[3H]-glutamate uptake and release in mouse cortical synaptosomes. Linalool,

1.0 mmol/l, reduced potassium-stimulated glutamate release (26).

These data suggest that linalool interferes with elements of the excitatory

glutamatergic transmission system.

Anti-infl ammatory activity

Anethole is a potent inhibitor of tumour necrosis factor (TNF)-induced

nuclear factor (NF)-κβ activation, inhibitor-κβα phosphorylation and

degradation, and NF-κβ reporter gene expression in vitro, demonstrating

that anethole suppresses infl ammation by inhibiting TNF-induced cellular

responses (27).

Aetheroleum Anisi

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Antispasmodic activity

The oil inhibited the phasic contractions of ileal myenteric plexus-longitudinal

muscle preparations isolated from guinea-pigs in vitro, median effective

dose 60 mg/l (28). The oil, 1:20 000, decreased the rate and extent

of contractions in intestinal smooth muscle isolated from rats, cats or rabbits

in vitro, and antagonized the stimulant activity of acetylcholine, barium

chloride, pilocarpine and physostigmine (29). Anethole, 0.05–1.00 mg/

ml, blocked twitching induced by acetylcholine and caffeine in toad rectus

abdominis and sartorius muscles, but had no effect on skeletal muscle

twitching induced by nerve stimulation in isolated rat diaphragm (30).

Bronchodilatory activity

The oil, 1.0 mmol/l, had relaxant effects in precontracted, isolated guineapig

tracheal chains indicating a bronchodilatory effect. It also induced a

parallel rightwards shift in the methacholine-response curve (methacholine

is a muscarinic receptor antagonist), indicating that the bronchodilatory

activity may be due to an inhibitory effect of the oil on the

muscarinic receptors (31).

Estrogenic activity

Subcutaneous administration of 0.1 ml of the oil to ovariectomized rats

had an estrogenic effect equivalent to that of 0.1 μg of estradiol (32). Intraperitoneal

administration of 0.1 ml of the oil had a uterine relaxation effect

in female rats (32). Anethole is thought to be the estrogenic component

of the oil; polymers of this compound, such as dianethole and

photoanethole, have also been suggested (33).

Expectorant activity

Intragastric administration of 10.0–50.0 mg/kg bw of the oil to guineapigs

increased bronchial secretions, demonstrating an expectorant effect

(34). Intragastric administration of two drops of the oil as an emulsion

with gummi arabicum to cats induced hypersecretion of the respiratory

tract (35). However, other researchers have demonstrated that administration

of the oil to cats by steam inhalation had no effect on respiratory

tract fl uid except when given in toxic doses, which increased the output

(36). Administration of the oil by inhalation to anaesthetized rabbits did

not appreciably affect respiratory tract fl uids until doses of 720.0 mg/kg

bw and over were used in a vaporizer (36, 37). At this dose, 20% of the

animals died and there was local irritation of the lining of the respiratory

tract, which appeared as congestion at 6 hours and progressed to leukocytic

infi ltration and destruction of the ciliated mucosa at 24 hours (36).

Inhalation of 1 ml/kg bw of anisaldehyde in anaesthetized rabbits signifi -

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cantly increased (P < 0.05) the volume of respiratory fl uid collected for

4–6 hours after treatment and decreased the specifi c gravity of the fl uid in

treated animals compared with untreated controls (38).

Liver effects

Subcutaneous administration of 100.0 mg/kg bw of the oil per day for

7 days stimulated liver regeneration in partially hepatectomized rats (39).

Toxicology

The oral median lethal dose (LD50) of anisaldehyde in rats was 1.51 g/kg

bw, with death occurring within 4–18 hours following depression of the

central nervous system (40). The oral LD50 in guinea-pigs was 1.26 g/kg

bw, death occurring after 1–3 days (40).

The safety and metabolism of trans-anethole were evaluated in rats as

a model for assessing the potential for hepatotoxicity in humans exposed

to the compound as a fl avouring agent. In chronic dietary studies in rats,

hepatotoxicity was observed when the estimated daily hepatic production

of anethole epoxide exceeded 30 mg/kg bw. Chronic hepatotoxicity and a

low incidence of liver tumours were observed at a dietary intake of transanethole

of 550.0 mg/kg bw per day (41). The effects of trans-anethole on

drug metabolizing enzymes were assessed in rats; intragastric administration

of 125.0 mg/kg or 250.0 mg/kg bw per day for 10 days had no effect

on total cyctochrome P450 content in liver microsomes (42). In a chronic

feeding study, trans-anethole was administered to rats in the diet at concentrations

of 0, 0.25%, 0.5% and 1.0% for 117–121 weeks, giving an average

dose of 105–550.0 mg/kg bw per day. No abnormalities related to

treatment were observed with the exception of a very low incidence of

hepatocarcinomas in female animals treated with the 1.0% dose (43).

The acute oral LD50 of anethole in rats was 2090.0 mg/kg bw; repeated

doses of 695.0 mg/kg bw caused mild liver lesions consisting of slight discoloration,

mottling and blunting of the lobe edges (33).

Clinical pharmacology

The absorption of anethole from the gastrointestinal tract was assessed in

healthy volunteers. The drug was rapidly absorbed from the gastrointestinal

tract and rapidly eliminated in the urine (54–69%) and through

the lungs (13–17%). The principal metabolite was 4-methoxyhippuric

acid (approximately 56%); other metabolites were 4-methoxybenzoic

acid and three other unidentifi ed compounds (44, 45). Increases in drug

dose did not alter the pattern of metabolite distribution in humans, contrary

to fi ndings in animal models (46).

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Adverse reactions

Contact dermatitis was reported in a cake factory worker after external

exposure to a 5% concentration of Aetheroleum Anisi (47). Occasional

allergic reactions to the oil affecting the skin, respiratory tract and gastrointestinal

tract are reported (15). Inhalation of powdered Fructus Anisi

induced an allergic effect in one subject with asthma. Skin-prick tests

showed a positive reaction to the fruits and the patient had high specifi c

anti-aniseed immunoglobulin E antibodies in his blood (48). Anethole

toxicity in infants has been reported, and presents clinically with symptoms

of hypertonia, continued crying, atypical ocular movements, twitching,

cyanosis, vomiting and lack of appetite (7, 49). Ingestion of 1.0–5.0 ml

of the oil can result in nausea, vomiting, seizures and pulmonary oedema

(50). In cases of overdose (> 50 mg/kg), the ingestion of milk and alcohol

is contraindicated owing to increased resorption.

Contraindications

Aetheroleum Anisi is contraindicated in cases of known allergy to aniseed

and anethole (48). Owing to the traditional use of the oil as an emmenagogue

and to induce labour, its experimental estrogenic and potential mutagenic effects,

and reports of anethole toxicity in infants (7, 49), use of the oil in pregnancy

and nursing, and in children under the age of 12 years is contraindicated.

Warnings

Applications of Aetheroleum Anisi should be limited to inhalation therapy

(51).

Precautions

Carcinogenesis, mutagenesis, impairment of fertility

Inconsistent results have been reported concerning the mutagenicity of

trans-anethole in the Salmonella/microsome assay. One group showed

that anethole was mutagenic (52), another that it was very weakly mutagenic

in S. typhimurium strains TA1535, TA100 and TA98 (53). In a further

study, trans-anethole (concentrations not specifi ed) did not increase

the mutant frequency in the Salmonella/microsome assay, but did increase

mutant frequency in the L5178Y mouse-lymphoma TK+/- assay in a

dose-dependent manner, with metabolic activation (49). Trans-anethole

did not induce chromosome aberrations in vitro in the Chinese hamster

ovary cell assay (49). Trans-anethole was weakly hepatocarcinogenic in

female rats when administered at a dose of 1% in the diet for 121 weeks;

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however, this effect is not mediated by a genotoxic event (54). Trans-anethole

was investigated for its antifertility activity in rats, after intragastric

administration of doses of 50.0 mg/kg bw, 70.0 mg/kg bw and 80.0 mg/kg

bw (55). Anti-implantation activity of 100% was observed in animals

treated with the highest dose. The compound has been reported to show

estrogenic, antiprogestational, androgenic and antiandrogenic activities

(55).

Pregnancy: non-teratogenic effects

See Contraindications.

Nursing mothers

See Contraindications.

Paediatric use

See Contraindications.

Other precautions

No information available on general precautions or on precautions concerning

drug interactions; drug and laboratory test interactions; and teratogenic

effects in pregnancy.

Dosage forms

Essential oil. Preparations containing 5–10% essential oil for inhalation

are also available. Store in a well-fi lled, tightly sealed container, protected

from light and heat (5).

Posology

(Unless otherwise indicated)

Average daily dose for internal use: essential oil 0.3 g; equivalent for other

preparations