DIRECTOR TFG:

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 gastro- intestinal 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 symp- toms of hypertonia, continued crying, atypical ocular movements, twitch- ing, 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 ef- fects, and reports of anethole toxicity in infants (7, 49), use of the oil in preg- nancy and nursing, and in children under the age of 12 years is contraindi- cated.

Warnings

Applications of Aetheroleum Anisi should be limited to inhalation thera- py (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 muta- genic in S. typhimurium strains TA1535, TA100 and TA98 (53). In a fur- ther 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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49 however, this effect is not mediated by a genotoxic event (54). Trans-an- ethole 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 con- cerning drug interactions; drug and laboratory test interactions; and tera- togenic 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 (15).

References

1. Egyptian pharmacopoeia, 3rd ed. Cairo, General Organization for Govern-

ment Printing, 1972.

2. Hungarian pharmacopoeia, 7th ed. Budapest, Medicina Könyvhiadó, 1986. 3. Thai pharmacopoeia. Vol. 1. Bangkok, Department of Medical Sciences,

Ministry of Public Health, 1987.

4. Farmakope Indonesia, 4th ed. Jakarta, Departmen Kesehatan, 1995. 5. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996. 6. African pharmacopoeia. Vol. 1. Lagos, Organization of African Unity, Scien-

tifi c, Technical and Research Commission, 1985.

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WHO monographs on selected medicinal plants

7. Hänsel R et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Bd 6,

Drogen P–Z, 5th ed. [Hager’s handbook of pharmaceutical practice. Vol. 6,

Drugs P–Z, 5th ed.] Berlin, Springer, 1994.

8. de Guzman CC, Siemonsma JS, eds. Plant resources of South-East Asia,

No. 13. Spices. Bogor, PROSEA, 1999.

9. Halmai J, Novak I. Farmakognózia. [Pharmacognosy] Budapest, Medicina Könyvhiadó, 1963.

10. Farnsworth NR, ed. NAPRALERT database. Chicago, IL, University of Illinois at Chicago, 10 January 2001 production (an online database available directly through the University of Illinois at Chicago or through the Scien- tifi c and Technical Network (STN) of Chemical Abstracts Services).

11. Youngken HW. Textbook of pharmacognosy, 6th ed. Philadelphia, PA, Blakiston, 1950.

12. Quality control methods for medicinal plant materials. Geneva, World Health Organization, 1998.

13. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. Geneva, World Health Organization, 1997 (WHO/FSF/FOS/97.7; available from Food Safety, World Health Organization, 1211 Geneva 27, Switzerland). 14. British herbal pharmacopoeia. Exeter, British Herbal Medicine Association,

1996.

15. Blumenthal M et al., eds. The complete German Commission E monographs. Austin, TX, American Botanical Council, 1998.

16. Shukla HS, Tripathi SC. Antifungal substance in the essential oil of anise (Pimpinella anisum L.). Agricultural and Biological Chemistry, 1987, 51:1991–1993.

17. Gangrade SK et al. In vitro antifungal effect of the essential oils. Indian

Perfumer, 1991, 35:46–48.

18. Müller-Riebau F, Berger B, Yegen O. Chemical composition and fungitoxic properties to phytopathogenic fungi of essential oils of selected aromatic plants growing wild in Turkey. Journal of Agricultural and Food Chemistry, 1995, 43:2262–2266.

19. El-Keltawi NEM, Megalla SE, Ross SA. Antimicrobial activity of some Egyptian aromatic plants. Herba polonica, 1980, 26:245–250.

20. Janssen AM et al. Screening for antimicrobial activity of some essential oils by the agar overlay technique. Pharmazeutisch Weekblad (Scientifi c Edition), 1986, 8:289–292.

21. Pepeljnjak S et al. Antimycotic activities of Pimpinella anisum L. fruit and essential oil. In: Ethnopharmacology 2000: challenges for the new millenni-

um, Zurich, Switzerland, 4–7 September, 2000. Zurich, 2000:75 (P2A).

22. Pourgholami MH et al. The fruit essential oil of Pimpinella anisum exerts anticonvulsant effects in mice. Journal of Ethnopharmacology, 1999, 66:211– 215.

23. Elisabetsky E et al. Sedative properties of linalool. Fitoterapia, 1995, 66:407– 414.

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24. Elisabetsky E, Silva Brum LF, Souza DO. Anticonvulsant properties of linalool in glutamate-related seizure models. Phytomedicine, 1999, 6:107–113. 25. Silva Brum LF, Elisabetsky E, Souza DO. Effects of linalool on [3_{H] MK801}

and [3_{H] muscimol binding in mouse cortical membranes. Phytotherapy}

Research, 2001, 15:422–425.

26. Silva Brum LF et al. Effects of linalool on glutamate release and uptake in mouse cortical synaptosomes. Neurochemical Research, 2001, 26:191–194. 27. Chainy GBN et al. Anethole blocks both early and late cellular responses

transduced by tumor necrosis factor: effect on NF-κB, AP-1, JNK, MAPKK and apoptosis. Oncogene, 2000, 19:2943–2950.

28. Reiter M, Brandt W. Relaxant effects on tracheal and ileal smooth muscles of the guinea pig. Arzneimittelforschung, 1985, 35:408–414.

29. Gunn JWC. The carminative action of volatile oils. Journal of Pharmacology

and Experimental Therapeutics, 1920, 16:39–47.

30. Albuquerque AA, Sorenson AL, Leal-Cardoso JH. Effects of essential oil of

Croton zehntneri, and of anethole and estragole on skeletal muscles. Journal of Ethnopharmacology, 1995, 49:41–49.

31. Boskabady MH, Ramazani-Assari M. Relaxant effect of Pimpinella anisum on isolated guinea pig tracheal chains and its possible mechanism(s). Journal

of Ethnopharmacology, 2001, 74:83–88.

32. Sharaf G, Goma N. Phytoestrogens and their antagonism to progesterone and testosterone. Journal of Endocrinology, 1965, 31:289–290.

33. Albert-Puleo M. Fennel and anise as estrogenic agents. Journal of Ethno-

pharmacology, 1980, 2:337–344.

34. Boyd EM, Pearson GL. On the expectorant action of volatile oils. American

Journal of the Medical Sciences, 1946, 211:602–610.

35. Van Dongen K, Leusink H. The action of opium-alkaloids and expectorants on the ciliary movements in the air passages. Archives of International

Pharmacodynamics, 1953, 93:261–276.

36. Boyd EM, Sheppard EP. Effect of steam inhalation of volatile oils on the output and composition of respiratory tract fl uid. Journal of Pharmacology

and Experimental Therapeutics, 1968, 163:250–256.

37. Boyd EM. A review of studies on the pharmacology of the expectorants and inhalants. International Journal of Clinical Pharmacology, 1970, 3:55–60. 38. Boyd EM, Sheppard EP. Inhaled anisaldehyde and respiratory tract fl uid.

Pharmacology, 1970, 3:345–352.

39. Gershbein LL. Regeneration of rat liver in the presence of essential oils and their components. Food and Cosmetics Toxicology, 1977, 15:173–181.

40. Jenner P et al. Food fl avourings and compounds of related structure. I. Acute oral toxicity. Food and Cosmetics Toxicology, 1964, 2:327–343.

41. Newberne P et al. The FEMA GRAS assessment of trans-anethole used as a fl avouring substance. Food and Chemical Toxicology, 1999, 37:789–811. 42. Rompelberg CJ, Verhagen H, Van Bladeren PJ. Effects of the naturally oc-

curring alkenylbenzenes eugenol and trans-anethole on drug-metabolizing enzymes in the rat liver. Food and Chemical Toxicology, 1993, 31:637–645.

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43. Truhaut R et al. Chronic toxicity/carcinogenicity study of trans-anethole in rats. Food and Chemical Toxicology, 1989, 27:11–20.

44. Sangster SA, Caldwell J, Hutt AJ et al. The metabolic dispostion of [methoxy14_{C]-labelled trans-anethole, estragole, and p-propylanisole in hu-} man volunteers. Xenobiotica, 1987, 17:1223–1232.

45. Caldwell J, Sutton JD. Infl uence of dose size on the disposition of trans-[me- thoxy-14C] anethole in human volunteers. Food and Chemical Toxicology, 1988, 26:87–91.

46. Sangster SA, Caldwell J, Smith RL. Metabolism of anethole. II. Infl uence of dose size on the route of metabolism of trans-anethole in the rat and mouse.

Food and Chemical Toxicology, 1984, 22:707–713.

47. Garcia-Bravo B et al. Occupational contact dermatitis from anethole in food handlers. Contact Dermatitis, 1997, 37:38–39.

48. Fraj J et al. Occupational asthma induced by aniseed. Allergy, 1996, 51:337– 339.

49. Gorelick NJ. Genotoxicity of trans-anethole in vitro. Mutation Research, 1995, 326:199–209.

50. Chandler RF, Hawkes D. Aniseed – a spice, a fl avor, a drug. Canadian Phar-

maceutical Journal, 1984, 117:28–29.

51. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC Press, 1994.

52. Sekizawa J, Shibamoto T. Genotoxicity of safrole-related chemicals in micro- bial test systems. Mutation Research, 1982, 101:127–140.

53. Swanson AB et al. The mutagenicities of safrole, estragole, eugenol, trans- anethole, and some of their known or possible metabolites for Salmonella

typhimurium mutants. Mutation Research, 1979, 60:143–153.

54. Marshall AD, Caldwell J. Lack of infl uence of modulators of epoxide me- tabolism on the genotoxicity of trans-anethole in freshly isolated rat hepato- cytes assessed with the unscheduled DNA synthesis assay. Food and Chemi-

cal Toxicology, 1996, 34:337–345.

55. Dhar SK. Anti-fertility activity and hormonal profi le of trans-anethole in rats. Indian Journal of Physiology and Pharmacology, 1995, 39:63–67.

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Defi nition

Fructus Anisi consists of the dried fruits of Pimpinella anisum L. (Apiaceae) (1–3).

Synonyms

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

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

matica Bieb., Selinum anisum (L.) E.H.L. Krause, Sison anisum Spreng., Tragium anisum Link (1, 2, 4, 5). Apiaceae are also known as Umbelliferae.

Selected vernacular names

Anacio, Änes, Aneis, anice, anice verde, Anis, anisbibernelle, anis verde, anis vert, anise, anisoon, anisum, ánizs, anizsolaj, annsella, badian, badian rumi, boucage, boucage anis, Grüner Anis, habbat hlawa, jintan manis, jinten manis, petit anis, pimpinelle, razianag, razianaj, roomy saunf, sweet cumin, yansoon (1, 2, 4–7).

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 (5, 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, di- lated petioles, pinnatifi d or ternately pinnate with long, entire or cut cu- neate segments. Infl orescence long-stalked, compound umbel with 8–14 rays; fl owers small, white, each on a long hairy pedicel. Fruit comprises a mouse-shaped cremocarp with a small stylopod and two minutely pubes- cent mericarps that do not readily separate from the carpophore (2, 9).

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Plant material of interest: dried ripe fruits

General appearance

Cremocarp, partly separated into its mericarps, often entire, remaining attached to a slender pedicel 2–12 mm long; pear-shaped, 3–6 mm long and 2–3 mm wide, enlarged at the base and tapering at the apex, some- what laterally compressed, crowned with a disc-like nectary; stylopod ends with the remains of two diverging styles; greyish or greenish-grey, seldom greyish-brown. Mericarp externally rough to the touch owing to the presence of numerous very short, stiff hairs; marked with fi ve very slightly raised, fi liform, pale-brown primary ridges; commissural sur- face, nearly fl at, with two dark brownish, longitudinal areas, containing vittae, separated by a middle paler area; internally comprises a pericarp with numerous branched vittae in the dorsal side and usually only two large ones in the commissural side, a large white oily endosperm, not deeply grooved on the commissural side, and a small apical embryo. Carpophore forked, passing at the apex into the raphe of each pericarp (1, 2).

Organoleptic properties

Odour: characteristic, aromatic; taste: sweet, strongly aromatic (1, 2).

Microscopic characteristics

Pericarp epidermis consists of cells with striated cuticle, many of which project into short, conical, curved, thick-walled, unicellular, sometimes bicellular, non-glandular hairs, with bluntly pointed apex and fi nely warty cuticles. Mesocarp formed of thin-walled parenchyma, traversed longitudinally by numerous schizogenous vittae, with brown epithelial cells and, in each primary ridge, by a small vascular bundle, accompanied by a few fi bres; also a patch of porous or reticulate lignifi ed cells in the middle of the commissural side, but not in the ridges. Endocarp com- posed of narrow, tangentially elongated, thin-walled cells, except when adjacent to the reticulate cells in the mesocarp, where it is formed of po- rous, lignifi ed and reticulately thickened cells. Testa consists of one layer of tangentially elongated cells with yellowish-brown walls, closely ad- hering to the endocarp except along the commissural surface, where separated by a large cavity. Endosperm formed of polygonal thick-walled cellulosic cells containing fi xed oil and many aleurone grains, each en- closing one globoid and one or two microrosette crystals of calcium oxalate with dark centres. Carpophore traversed by a vascular bundle of fi bres and spiral vessels (1, 2).

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Powdered plant material

Grey, greenish-brown or yellowish-brown, characterized by numerous, almost colourless fragments of endosperm; abundant minute oil globules; numerous warty simple hairs 25–100 μm long and 10–15 μm wide. Frag- ments of pericarp with yellowish-brown, comparatively narrow, branch- ing vittae, usually crossed by the cells of the endocarp, the ratio of the width of these cells to that of the vittae varying from 1:7 to 1:5. Few fi bres and very scanty pitted lignifi ed parenchyma; aleurone grains 2–15 μm in diameter. Microrosette crystals of calcium oxalate 2–10 μm in diameter, each containing a minute air bubble (1, 2).

General identity tests

Macroscopic and microscopic examinations (2, 3), and thin-layer chro- matography for the presence of anethole (3).

Purity tests

Microbiological

Tests for specifi c microorganisms and microbial contamination limits are as described in the WHO guidelines on quality control methods for me- dicinal plants (10).

Foreign organic matter

Not more than 2.0% (3).

Total ash

Not more than 12.0% (3).

Acid-insoluble ash

Not more than 2.5% (1, 3).

Loss on drying

Not more than 7.0% (3).

Pesticide residues

The recommended maximum limit of aldrin and dieldrin is not more than 0.05 mg/kg (3). For other pesticides, see the European pharmacopoeia (3), and the WHO guidelines on quality control methods for medicinal plants (10) and pesticide residues (11).

Heavy metals

For maximum limits and analysis of heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (10).

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Radioactive residues

Where applicable, consult the WHO guidelines on quality control meth- ods for medicinal plants (10) for the analysis of radioactive isotopes.

Other purity tests

Chemical, water-soluble extractive and alcohol-soluble extractive tests to be established in accordance with national requirements.

Chemical assays

Contains not less than 2% (v/w) essential oil (3). A high-performance liquid chromatography method for the analysis of phenylpropanoid con- stituents is available (12).

Major chemical constituents

Contains 1.5–5.0% essential oil, the major constituents of which are linalool (0.1–1.5%), methylchavicol (estragole, isoanethole; 0.5–6.0%), α- terpineol (0.1–1.5%), cis-anethole (< 0.5%), trans-anethole (84–93%), p- anisaldehyde (0.1–3.5%) (3). The structures of trans-anethole, methyl- chavicol, β-linalool and p-anisaldehyde are presented below.

Medicinal uses

Uses supported by clinical data

No information available.

Uses described in pharmacopoeias and well established documents

Treatment of dyspepsia and mild infl ammation of the respiratory tract (13, 14).

Uses described in traditional medicine

As an aphrodisiac, carminative, emmenagogue, galactagogue and tonic, and for treatment of asthma, bronchitis, diarrhoea, fever, spasmodic cough, fl atulent colic and urinary tract infections (5, 7, 15).

Pharmacology

Experimental pharmacology

Analgesic and central nervous system activity

Intraperitoneal or intragastric administration of a dried ether extract of the fruits dissolved in normal saline did not potentiate barbiturate-

trans-anethole H3CO CH3 H3CO CH2 methylchavicol H3C CH2 CH3 H OH and enantiomer β-linalool p-anisaldehyde CHO H3CO SMPvol3 layout.indd 56 SMPvol3 layout.indd 56 10.8.2007 12:10:0010.8.2007 12:10:00

57 induced sleeping time when administered to mice in doses of up to 200.0 mg/kg body weight (bw) (16).

Antimicrobial activity

A 95% ethanol extract of the fruits, 50 μl/plate, inhibited the growth of

Staphylococcus aureus in vitro (17). A dried methanol extract of the fruits

inhibited the growth of Helicobacter pylori in vitro, minimum inhibitory concentration (MIC) 100.0 μg/ml (18). A decoction of the fruits did not inhibit the growth of Aspergillus niger, Escherichia coli, Pseudomonas ae-

ruginosa, Salmonella typhi or Staphylococcus aureus in vitro at concentra-

tions of up to 62.5 mg/ml (19). An ethanol extract of the fruits inhibited the growth of Candida albicans, C. krusei, C. parapsilosis, C. tropicalis,

Microsporum gypseum, Rhodotorula rubra and Saccharomyces cerevisiae,

MIC 0.097%, and Geotrichum spp., MIC 1.562% (20).

Anticonvulsant activity

Intraperitoneal administration of 4.0 mg/kg bw of a dried 95% ethanol extract of the fruits dissolved in normal saline to mice inhibited convul- sions induced by supramaximal electroshock. At the same dose, the ex- tract was ineffective against convulsions induced by pentylenetetrazole and strychnine (21).

Intraperitoneal administration of 2.5 g/kg bw of linalool to rodents pro- vided protection against convulsions induced by pentylenetetrazole, picro- toxin, and electroshock (22, 23). Intraperitoneal administration of 2.5 g/kg bw of linalool to mice interfered with glutamate function and delayed N- methyl-d-aspartate-induced convulsions (24). Linalool acts as a competi- tive antagonist of [3_{H]-glutamate binding and as a non-competitive antago-}

nist of [3_{H]-dizocilpine binding in mouse cortical membranes. The effects}

of linalool on [3_{H]-glutamate uptake and release in mouse cortical synapto-}

somes were investigated. Linalool, 1.0 mmol/l, reduced potassium-stimu- lated glutamate release (25). These data suggest that linalool interferes with elements of the excitatory glutamatergic transmission system.

Anti-infl ammatory activity

External application of 2.0 mg of a methanol extract of the fruits inhibited ear infl ammation induced by 12-O-tetradecanoyl phorbol-13-acetate in mice (26). External application of 20.0 μl of an ethyl acetate or hexane extract of the fruits did not inhibit ear infl ammation induced by

O-tetradecanoyl phorbol-13-acetate in mice; application of 20.0 μl of a

methanol extract was weakly active in the same assay (27). Anethole is a potent inhibitor of tumour necrosis factor (TNF)-induced nuclear factor (NF)-κβ activation, inhibitor-κβα phosphorylation and degradation, and

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WHO monographs on selected medicinal plants

NF-κβ reporter gene expression in vitro, demonstrating that anethole sup- presses infl ammation by inhibiting TNF-induced cellular responses (28).

Bronchodilatory activity

The fruits, 1.0 mmol/l, had signifi cant (P < 0.05) relaxant effects in pre- contracted, isolated guinea-pig tracheal chains in vitro, indicating a bron- chodilatory effect. At the same dose, the fruits induced a parallel right- wards shift in the methacholine-response curve, indicating that the bronchodilatory activity may be due to an inhibitory effect on the musca- rinic receptors (29).

Hypotensive activity

Intravenous administration of 50.0 mg/kg bw of a dried 50% ethanol ex- tract of the fruits dissolved in normal saline to dogs decreased blood pres- sure (30). Intragastric administration of an aqueous extract of the fruits reduced atropine-induced hypertension at a dose of 10.0% (no further information available) (31). Administration of an unspecifi ed extract of the fruits had a diuretic effect in rabbits, which was blocked by pre- treatment with morphine (32).

Platelet aggregation inhibition

A methanol extract of the fruits, 500.0 μg/ml, inhibited collagen-induced platelet aggregation in human platelets (33).

Smooth muscle stimulant activity

An aqueous extract of the fruits, 10.0% in the bath medium, stimulated contractions of isolated frog rectus abdominis muscle and rat jejunum strips (31). Anethole, 0.05–1.00 mg/ml, blocked twitching induced by acetylcholine and caffeine in toad rectus abdominis and sartorius muscles,

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