Tarçın (Cinnamomum Zeylanicum) WHO Monograph - EN

Definition

Cortex Cinnamomi consists of the dried inner bark of the shoots grown on cut stock of Cinnamomum verum J.S. Presl. (1–5) or of the trunk bark, freed of cork, of Cinnamomum cassia Blume (6–8) (Lauraceae).

Synonyms

Cinnamomum verum J.S. Presl.

Cinnamomum zeylanicum Nees (9–11), Laurus cinnamomum L. (4).

Cinnamomum verum J.S. Presl. is the correct botanical name according to the International Rules of Botanical Nomenclature (11).

Cinnamomum cassia Blume

Cinnamomum aromaticum Nees (7, 12, 13).

Selected vernacular names

Cinnamomum verum J.S. Presl.

Abdalasini, blood-giving drops, canela, canela en raja, cannalavanga pattai, cannelle de ceylan, cannelle dite de Ceylan, cannelier, Ceylon celonzimi cinnamon, Ceylon cinnamon, cinnamon, cinnamon bark, cinnamon tree, cortex cinnamomi ceylanici, dalchini, dalochini, dar sini quirfa, darchini, daruchini, darusila, ecorce de cannelier de Ceylan, echter Kanel, gujerati-dalchini, kannel, kuei-pi, kurundu, kurundu-potu, kulit kayumanis, ob choei, tamalpatra, wild cinnamon, Zimtrinde (2–4, 10, 14, 15).

Cinnamomum cassia Blume

Annan cinnamon, cassia, cassia bark, cassia bark tree, cassia lignea, chinazimt, Chinese cassia, Chinese cinnamon, ching hua yu-kuei, cinnamomi cassiae cortex, cinnamon, cinnamon bark, dalchini, guipi, guizhi, kannan keihi, keihi, keishi, kuei-chíi, lavanga-pattai, lavanga-patti, lurundu, macrophyllos cassia bark tree, rou gui, róugì, Saigon cinnamon, saleekha, taj, toko keihi, Viet Nam cinnamon (6, 7, 12–17).

Description

Cinnamomum verum J.S. Presl.

A moderate-sized evergreen tree; bark rather thick, smooth, pale; twigs often compressed; young parts glabrous except the buds which are finely silky. Leaves opposite or subopposite (rarely alternate), hard and coriaceous, 7.5–20 by 3.8–7.5 cm, ovate or ovate-lanceolate, subacute or shortly acuminate, glabrous and shining above, slightly paler beneath, base acute or rounded; main nerves 3–5 from the base or nearly so, strong, with fine reticulate venation between; petioles 1.3–2.5 cm long, flattened above. Flowers numerous, in silky pubescent, lax panicles usually longer than the leaves; peduncles long, often clustered, glabrous or pubescent; pedicels long. Perianth 5–6mm long; tube 2.5 mm long; segments pubescent on both sides, oblong or somewhat obovate, usually obtuse. Fruit 1.3–1.7 cm long, oblong or ovoid-oblong, minutely apiculate, dry or slightly fleshy, dark purple, surrounded by the enlarged campanulate perianth that is 8 mm in diameter (14).

Cinnamomum cassia Blume

An evergreen tree, up to 10 m high. Leaves alternate, coriaceous, petiolate, oblong, elliptical-oval or oblong-lanceolate, 8–15cm long by 3–4cm wide, tip acuminate, base rounded, entire, 3-nerved; glabrous or underside lightly pubescent; petiole 10 mm long, lightly pubescent. Inflorescence a densely hairy panicle as long as the leaves; panicles cymose, terminal and axillary. Flowers yellowish white, small, in cymes of 2–5. Perianth 6-lobed. No petals. Stamens 6, pubescent. Ovary free, 1-celled. Fruit a globular drupe, 8mm long, red. The bark is used in either channelled pieces or simple quills, 30–40cm long by 3– 10cm wide and 0.2–0.8 cm in thickness. The surface is greyish brown, slightly coarse, with irregularly fine wrinkles and transverse lenticels. Here and there are found scars of holes, indicating the insertion of leaves or lateral shoots; the inner surface is rather darker than the outer, with fine longitudinal striae. The fracture is short, the section of the thicker pieces showing a faint white line (pericyclic sclerenchyma) sometimes near the centre, sometimes near and parallel to the outer margin (14).

Plant material of interest: dried bark, free from the outer cork

General appearance

Cinnamomum verum J.S. Presl.

The bark is about 0.2–0.8 mm thick and occurs in closely packed compound quills made up of single or double quills. The outer surface is smooth, yellowish brown with faint scars marking the positions of leaves and axillary buds and has fine, whitish and wavy longitudinal striations. The inner surface is slightly darker and longitudinally striated. The fracture is short and fibrous (1).

Cinnamomum cassia Blume

The drug is channelled or quilted, 30–40cm long, 3–10cm in diameter, 2–8mm thick. Outer surface greyish brown, slightly rough, with irregular fine wrinkles and transverse raised lenticels, some showing greyish white streaks; inner surface reddish brown, with fine longitudinal striations and exhibiting oily trace on scratching. Texture hard and fragile, easily broken, fracture uneven, outer layer brown and relatively rough, inner layer reddish brown and oily and showing a yellowish brown line between two layers (6).

Organoleptic properties

Odour, characteristic and aromatic (2, 3, 4, 6); taste, characteristic, slightly sweet and fragrant (3,4, 6).

Microscopic characteristics

Cinnamomum verum J.S. Presl.

The outside shows a few discontinuous layers of cortical parenchyma within which is a wide, continuous layer of pericyclic sclerenchyma composed of groups of isodiametric or tangentially elongated sclereids with thickened and pitted walls, and occasional groups of fibres. The phloem is composed of sieve tissue and parenchyma with large secretion cells containing essential oil or mucilage and phloem fibres occurring singly or in small groups, individual fibres 15–25µm in diameter with thickened walls; medullary rays uniseriate or biseriate. Some of the cells contain small acicular crystals of calcium oxalate; the remainder, together with the phloem parenchyma, contain starch granules, simple or 2–4 compound, rarely more than 10µm in diameter (1, 3).

Cinnamomum cassia Blume

The transverse section shows the cork being composed of several layers of cells, the innermost layer with thickened and lignified outer walls. Cortex scattered with stone cells and secretory cells. Pericycle stone cells in groups arranged in an interrupted ring, accompanied by fibre bundles at outer side, the outer walls of stone cells usually thinner. Phloem rays 1 or 2 rows of cells wide, containing minute needle crystals of calcium oxalate; usually 2 or 3 fibres in bundles; oil cells scattered throughout. Parenchymatous cells contain starch granules (6).

Powdered plant material

Cinnamomum verum J.S. Presl.

The powdered drug is yellowish to reddish brown and consists of groups of rounded sclereids with pitted, channelled and moderately thickened walls; numerous colourless fibres, often whole with narrow lumen and thickened, lignified walls and few pits; rarely small acicular crystals of calcium oxalate; abundant starch granules. Cork fragments are absent or very rare (1, 3).

Cinnamomum cassia Blume

Reddish brown. Most fibres singly scattered, long fusiform, 195–920µm long, up to 50µm in diameter, with thickened and lignified wall, pits indistinct. Stone cells subsquare or sub-rounded, 32–88µm in diameter, the walls thickened, some thin at one side. Oil cells sub-rounded or oblong, 45–108µm in diameter. Needle crystals minute, scattered in ray cells. Cork cells polygonal, containing reddish brown contents (1).

Geographical distribution

Cinnamomum verum J.S. Presl.

Native to India and Sri Lanka (4, 11, 14); cultivated in parts of Africa, southeastern India, Indonesia, the Seychelles, South America, Sri Lanka, and the West Indies (4, 10, 11).

Cinnamomum cassia Blume

Found in China, Indonesia, the Lao People’s Democratic Republic, and Viet Nam, (12, 13, 16); mostly cultivated (12).

General identity tests

Macroscopic and microscopic examinations (1–6); and thin-layer chromatographic analysis for the presence of cinnamaldehyde (1–6, 8).

Purity tests

Microbiology

The test for Salmonella spp. in Cortex Cinnamomi products should be negative.The maximum acceptable limits of other microorganisms are as follows (18–20). For preparation of decoction: aerobic bacteria-not more than 10⁷/g; fungi-not more than 10⁵/g; Escherichia coli-not more than 10²/g. Preparations for internal use: aerobic bacteria-not more than 10⁵/g or ml; fungi-not more than 10⁴/g or ml; enterobacteria and certain Gram-negative bacteria-not more than 10³/g or ml;Escherichia coli-0/g or ml.

Foreign organic matter

C. verum: not more than 2% (4, 14). C. cassia: not more than 1% (16).

Total ash

C. verum: not more than 6% (2). C. cassia: not more than 5% (6, 8, 14, 16).

Acid-insoluble ash

C. verum: not more than 4% (4). C. cassia: not more than 2% (14, 16).

Sulfated ash

C. verum: not more than 6% (1, 3). C. cassia: to be established in accordance with national requirements.

Alcohol (90%)-soluble extractive

C. verum: 14–16% (4). C. cassia: to be established in accordance with national requirements.

Pesticide residues

To be established in accordance with national requirements. Normally, the maximum residue limit of aldrin and dieldrin for Cortex Cinnamomi is not more than 0.05 mg/kg (21). For other pesticides, see WHO guidelines on quality control methods for medicinal plants (18) and guidelines for predicting dietary intake of pesticide residues (20).

Arsenic and heavy metals

Recommended lead and cadmium levels are not more than 10mg/kg and 0.3 mg/kg, respectively, in the final dosage form of the plant material (18).

Radioactive residues

For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and plutonium-239, see WHO guidelines on quality control methods for medicinal plants (18).

Other tests

Chemical tests to be established in accordance with national requirements.

Chemical assays

Not less than 1.2% v/w of volatile oil derived from C. verum (1–3) and 1–2% v/w of volatile oil derived from C. cassia (16), containing 60–80% w/w aldehydes calculated as cinnamaldehyde (3,16).

Assay for cinnamaldehyde content by means of thin-layer (1–4, 6) or highperformance liquid chromatographic (21, 22) methods.

Major chemical constituents

The major constituent in both C. verum and C. cassia is cinnamaldehyde, at concentrations of 65–80% (9, 10) and 90% (9) of the volatile oil, respectively.

Cinnamomum verum also contains o-methoxycinnamaldehyde (10). Cinnamomum verum differs from C. cassia in its eugenol and coumarin content. Cinnamomum verum volatile oil contains 10% eugenol, whereas in C. cassia, only a trace quantity of this compound is found (9). Coumarin is present in C. cassia (0.45%), but not in C. verum (21).

Dosage forms

Crude plant material, powder, volatile oil, other galenic preparations. Store in a well-closed glass or metal container (do not use plastic), protected from light and moisture (1–6, 10).

Medicinal uses

Uses supported by clinical data

None.

Uses described in pharmacopoeias and in traditional systems of medicine

The treatment of dyspeptic conditions such as mild spastic conditions of the gastrointestinal tract, fullness and flatulence, and loss of appetite (4, 6, 7, 12). Also used to treat abdominal pain with diarrhoea, and pain associated with amenorrhoea and dysmenorrhoea (6, 12).

Uses described in folk medicine, not supported by experimental or clinical data

The treatment of impotence, frigidity, dyspnoea, inflammation of the eye, leukorrhoea, vaginitis, rheumatism, neuralgia, wounds, and toothache (15).

Pharmacology

Experimental pharmacology

Antibacterial and antifungal activities of the essential oil have been demonstrated in vitro (10). The essential oil of C. verum is active in vitro against the following bacteria: Bacillus subtilis (23, 24),Escherichia coli, Staphylococcus aureus (24, 25), Salmonella typhimurium (26), and Pseudomonas aeruginosa (24). It was also active in vitro against the following fungi: Aspergillus spp.,Cladosporium werneckii (27), Geotrichum candidum, Kloeckera apivulata, Candida lipolytica and C. albicans (23, 28). The antibacterial and fungicidal effects have been attributed toomethoxycinnamaldehyde (9).

The essential oil of C. verum has carminative activity (29) and decreases smooth muscle contractions in guinea-pig trachea and ileum (30), and in dog ileum, colon and stomach (31). The active antispasmodic constituent of the drug is cinnamaldehyde. A reduction of stomach motility in rats and dogs and intestinal motility in mice and a decrease in the number of stress- and serotonininduced ulcers in mice have been described (32–36). An ethanol extract of the drug inhibits histamine- and barium-induced contractions in guinea-pig ileum; the hot-water extract was not active (36).

Contraindications

The drug is contraindicated in cases of fever of unknown origin, pregnancy, stomach or duodenal ulcers (7, 9, 12), and in patients with an allergy to cinnamon or Peru balsam (9).

Warnings

No information available.

Precautions

Drug interactions

Cinnamomum cassia bark extract (2 g in 100 ml) markedly decreased the in vitro dissolution of tetracycline hydrochloride (37). In the presence of C. cassia bark, only 20% of tetracycline was in solution after 30 minutes, in contrast to 97% when only water was used (37). However, the clinical significance of this interaction has not been established. The drug is reported to be incompatible withHalloysitum rubrum (6).

Carcinogenesis, mutagenesis, impairment of fertility

There are insufficient data to evaluate the carcinogenic potential of Cortex Cinnamomi (35). Reports concerning the mutagenicity of the drug are contradictory. Extracts of the plant and cinnamaldehyde have been reported to be both mutagenic and non-mutagenic in Salmonella typhimurium (Ames assay) and in assays using Bacillus subtilis (38, 39). However, the results of these in vitromutagenicity studies are difficult to assess because, at the doses given, the effects may have been due to the antimicrobial effects of the drug (35). Cortex Cinnamomi and cinnamaldehyde gave positive results in chromosomal aberration tests using Chinese hamster cell cultures (35), and inDrosophila test systems (40–43). An aqueous extract of the drug was also negative in the Drosophilatest system (35).

Pregnancy: teratogenic effects

Available data are not sufficient for an adequate benefit/risk assessment. Therefore, Cortex Cinnamomi should not be used during pregnancy. There is one report of teratogenicity of cinnamaldehyde in chick embryos (35), but studies of teratogenicity in chick embryos are of limited usefulness when evaluating the teratogenic potential for humans (35). A methanol extract of the drug given by gastric intubation was not teratogenic in rats (44, 45).

Pregnancy: non-teratogenic effects

Cortex Cinnamomi should not be used during pregnancy. See Contraindications.

Nursing mothers

Available data are not sufficient for an adequate benefit/risk assessment. Therefore, Cortex Cinnamomi should not be used during lactation.

Paediatric use

The safety and efficacy of the drug in children have not been established.

Other precautions

No information available concerning general precautions, or drug and laboratory test interactions.

Adverse reactions

Allergic reactions of the skin and mucosa have been reported (7, 46–49).

Posology

Crude drug-average daily dose, 2–4g (7); volatile oil-average daily dose, 0.05–0.2 g (7); other preparations-average daily dose as above (7).

References

1. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1997.

2. Pharmacopée française. Paris, Adrapharm, 1996.

3. British pharmacopoeia. London, Her Majesty’s Stationery Office, 1988.

4. African pharmacopoeia, 1st ed. Lagos, Organization of African Unity, Scientific, Technical & Research Commission, 1985.

5. Deutsches Arzneibuch 1996. Stuttgart, Deutscher Apotheker Verlag, 1996.

6. Pharmacopoeia of the People’s Republic of China (English ed.). Guangzhou, Guangdong Science and Technology Press, 1992.

7. German Commission E Monograph, Cinnamomi cassiae cortex. Bundesanzeiger, 1990, 22: 1 February.

8. The pharmacopoeia of Japan XIII. Tokyo, The Society of Japanese Pharmacopoeia, 1996.

9. Bisset NG. Max Wichtl’s herbal drugs & phytopharmaceuticals. Boca Raton, FL, CRC Press, 1994:148–150.

10. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier, 1995:451– 453.

11. Klostermans AJGH. Miscellaneous botanical notes. Herbarium Bogoriense, 1965:141– 146.

12. Medicinal plants in China. Manila, World Health Organization, 1989:78–79 (WHO Regional Publications, Western Pacific Series, No. 2).

13. Keys JD. Chinese herbs, their botany, chemistry and pharmacodynamics. Rutland, VT, CE Tuttle, 1976:111.

14. Mukerji B. In: The Indian Pharmaceutical Codex, Vol. I. Indigenous drugs. New Delhi, Council of Scientific & Industrial Research, 1953:70–72.

15. Farnsworth NR, ed. NAPRALERT database. Chicago, University of Illinois at Chicago, IL, August 8, 1995 production (an on-line database available directly through the University of Illinois at Chicago or through the Scientific and Technical Network (STN) of Chemical Abstracts Services).

16. British herbal pharmacopoeia, Part 2. London, British Herbal Medicine Association, 1979:55–57.

17. Chang HM, But PPH, eds. Pharmacology and applications of Chinese materia medica, Vol. 2. Singapore, World Scientific Publishing, 1987:949–951.

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

19. Deutsches Arzneibuch 1996. Vol. 2. Methoden der Biologie. Stuttgart, Deutscher Apotheker Verlag, 1996.

20. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. Geneva, World Health Organization, 1997 (unpublished document WHO/FSF/FOS/97.7; available from Food Safety, WHO, 1211 Geneva 27, Switzerland).

21. Archer AW. Determination of cinnamaldehyde, coumarin and cinnamyl alcohol in cinnamon andCassia by high-performance liquid chromatography. Journal of chromatography, 1988, 447:272–276.

22. Sagara K et al. Determination of Cinnamomi Cortex by high-performance liquid chromatography. Journal of chromatography, 1987, 409:365–370.

23. Raharivelomanana PJ et al. Study of the antimicrobial action of various essential oil extracts from Madagascan plants. II. The Lauraceae. Archives of the Institute of Pasteur Madagascar, 1989, 56:261–271.

24. Janssen AM et al. Screening for antimicrobial activity of some essential oils by the agar overlay technique. Pharmaceutisch Weekblad (Sci. ed.), 1986, 8:289–292.

25. George M, Pandalai KM. Investigations on plant antibiotics. Part IV. Further search for antibiotic substances in Indian medicinal plants. Indian journal of medical research, 1949, 37:169–181.

26. Sivaswamy SN et al. Mutagenic activity of south Indian food items. Indian journal of experimental biology, 1991, 29:730–737.

27. Morozumi S. A new antifungal agent in cinnamon. Shinkin to shinkinsho, 1978, 19:172–180.

28. Conner DE, Beuchat LR. Effects of essential oils from plants on growth of food spoilage yeasts.Journal of food science, 1984, 49:429–434.

29. Harries N, James KC, Pugh WK. Antifoaming and carminative actions of volatile oils. Journal of clinical pharmacology, 1978, 2:171–177.

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

31. Plant OH, Miller GH. Effects of carminative volatile oils on the muscular activity of the stomach and colon. Journal of pharmacology and experimental therapeutics, 1926, 27:149.

32. Harada M, Yano S. Pharmacological studies on Chinese cinnamon. II. Effects of cinnamaldehyde on the cardiovascular and digestive systems. Chemical and pharmaceutical bulletin, 1975, 23:941–947.

33. Plant OH. Effects of carminative volatile oils on the muscular movements of the intestine. Journal of pharmacology and experimental therapeutics, 1921, 22:311– 324.

34. Akira T, Tanaka S, Tabata M. Pharmacological studies on the antiulcerogenic activity of Chinese cinnamon. Planta medica, 1986, 52:440–443.

35. Keller K. Cinnamomum Species. In: DeSmet PAGM, Keller K, Hänsel R, Chandler RF, eds.,Adverse reactions of herbal drugs. Berlin, Springer-Verlag, 1992:105–114.

36. Itokawa H et al. Studies on the constituents of crude drugs having inhibitory activity against contraction of the ileum caused by histamine or barium chloride. Screening test for the activity of commercially available crude drugs and the related plant materials. Shoyakugaku zasshi, 1983, 37:223–228.

37. Miyazaki S, Inoue H, Nadai T. Effect of antacids on the dissolution behavior of tetracycline and methacycline. Chemical and pharmaceutical bulletin, 1977, 27:2523– 2527.

38. Mahmoud I, Alkofahi A, Abdelaziz A. Mutagenic and toxic activities of several spices and some Jourdanian medicinal plants. International journal of pharmacognosy, 1992, 30:81–85.

39. Kasamaki A et al. Genotoxicity of flavouring agents. Mutation research, 1982, 105:387–392.

40. Ishidate M. Primary mutagenicity screening of food additives currently used in Japan. Food chemistry and toxicology, 1984, 22:623–636.

41. Venkatasetty R. Genetic variation induced by radiation and chemical agents in Drosophila melanogaster. Dissertation abstracts international B, 1972, 32:5047–5048.

42. Woodruff RC, Manson JM, Valencia R, Zimmering S. Chemical mutagenesis testing in Drosophila. Results of 53 coded compounds tested for the National Toxicology Program. Environmental mutagenesis, 1985, 7:677–702.

43. Abraham SK, Kesavan PC. A preliminary analysis of the genotoxicity of a few species inDrosophila. Mutation research, 1985, 143:219–224.

44. Abramovici A, Rachmuth-Roizman P. Molecular structure–teratogenicity relationships of some fragrance additives. Toxicology, 1983, 29:143–156.

45. Lee EB. Teratogenicity of the extracts of crude drugs. Korean journal of pharmacognosy, 1982, 13:116–121.

46. Nixon R. Vignette in contact dermatology. Cinnamon allergy in bakers. Australian journal of dermatology, 1995, 36:41.

47. Hausen BJM. Allergiepflanzen-Pflanzenallergene. Landsberg, Ecomed, 1988:95–96.

48. Calnan CD. Cinnamon dermatitis from an ointment. Contact dermatitis, 1976, 2:167– 170.

49. Drake TE, Maibach HI. Allergic contact dermatitis and stomatitis caused by cinnamic aldehyde-flavored toothpaste. Archives of dermatology, 1976, 112:202–203.

 

Papatya (Chamomilla Recutita) WHO Monograph – EN

Definition

Flos Chamomillae consists of the dried flowering heads of Chamomilla recutita (L.) Rauschert (Asteraceae) (1–4).

Synonyms

Matricaria chamomilla L., M. recutita L., M. suaveolens L. (3).

In most formularies and reference books, Matricaria chamomilla L. is regarded as the correct species name. However, according to the International Rules of Botanical Nomenclature, Chamomilla recutita (L.) Rauschert is the legitimate name for this species (5). Asteraceae are also known as Compositae.

Selected vernacular names

Baboonig, babuna, babunah camomile, babunj, bunga kamil, camamilla, camomile, chamomile, camomilla, chamomille allemande, campomilla, chamomille commune, camomille sauvage, fleurs de petite camomille, flos chamomillae, german chamomile, hungarian chamomile, Kamille, Kamillen, kamitsure, kamiture, manzanilla, manzanilla chiquita, manzanilla comun, manzanilla dulce, matricaire, matricaria flowers, pin heads, sweet false chamomille, sweet feverfew, wild chamomile (3, 6–9).

Description

Herbaceous annual; 10–30 cm in height, with erect, branching stems and alternate, tripinnately divided leaves below and bipinnately divided leaves above, both types having almost filiform lobes; the capitulum (to 1.5 cm in diameter) comprises 12–20 white ligulate florets surrounding a conical hollow receptacle on which numerous yellow tubular (disk) florets are inserted; the inflorescence is surrounded by a flattened imbricated involucre; fruit small, smooth, yellowish (3, 7, 10).

Plant material of interest: flower heads

General appearance

Flos Chamomillae consists of conical flower heads, each bearing a few white ligulate florets and numerous yellowish orange to pale yellow tubular or disk florets on conical, narrow hollow receptacles with a short peduncle; disk florets perfect and without a pappus; ray florets pistillate, white, 3-toothed and 4- veined; involucre hemispherical, composed of 20–30 imbricate, oblanceolate and pubescent scales; peduncles weak brown to dusky greenish yellow, longitudinally furrowed, more or less twisted and up to 2.5 cm long; achenes more or less obovoid and faintly 3- to 5-ribbed; pappus none, or slightly membranous crown (7, 11).

Organoleptic properties

Odour, pleasant, aromatic; taste, aromatic and slightly bitter (1–3).

Microscopic characteristics

Receptacle and bracteoles with schizogenous secretory ducts; vascular bundles with phloem fibres; spiral, annular and reticulate but pitted vessels; lignified cells at the bases of the ovaries absent; nearly all parts of florets bear compositetype glandular hairs with short, biseriate stalk and enlarged head, formed of several tiers, each of two cells; ovary with longitudinal bands of small mucilage cells; stigma with elongated papillae at the apex; pollen grains, spherical or triangular, with numerous short spines (3).

Powdered plant material

Powdered Flos Chamomillae is greenish yellow to yellowish brown; spiny pollen grains numerous, 18–25µm in diameter; fragments of yellow or white corolla, with polygonal, small epidermal cells having straight or slightly wavy walls, sometimes papillosed, and sometimes bearing glandular hairs of composite type; fragments of the fibrous layer of anther; fragments from ovary, with glandular hairs and rows of small mucilage cells; green fragments of parenchyma of involucre; stigma with papillae; cells of the achenes with sclariform perforations in walls; fragments of fibrovascular bundles with spiral, annular and reticulate vessels and sclerenchyma fibres; fragments of involucral bracts with epidermis having elliptical stomata up to 30µm in length, also vessels and fibres; occasional fibre from the stems; minute cluster crystals of calcium oxalate, up to 10µm in diameter; fragments of lignified parenchyma of the filaments and occasional fragments of vessels (3, 7, 10).

Geographical distribution

The plant is indigenous to northern Europe and grows wild in central European countries; it is especially abundant in eastern Europe. Also found in western Asia, the Mediterranean region of northern Africa, and the United States of America. It is cultivated in many countries (3, 7–13).

General identity tests

The drug is identified by its macroscopic and microscopic characteristics, and by thin-layer chromatography (1–3).

Purity tests

Microbiology

The test for Salmonella spp. in Flos Chamomillae products should be negative. The maximum acceptable limits of other microorganisms are as follows (1, 14, 15). For preparation of decoction: aerobic bacteria-not more than 10⁷/g; fungi-not more than 10⁵/g; Escherichia coli-not more than 10²/g. Preparations for internal use: aerobic bacteria-not more than 10⁵/g or ml; fungi-not more than 10⁴/g or ml; enterobacteria and certain Gram-negative bacteria-not more than 10³/g or ml;Escherichia coli-0/g or ml. Preparations for external use: aerobic bacteria-not more than 10²/g or ml; fungi-not more than 10²/g or ml; enterobacteria and certain Gram-negative bacteria-not more than 10¹/g or ml.

Foreign organic matter

Not more than 10% stems and not more than 2% foreign organic matter (3). No flowering heads ofAnthemis cotula L. or A. nobilis L. (7).

Total ash

Not more than 13% (2).

Acid-insoluble ash

Not more than 4% (11).

Moisture

Not more than 12% (12).

Pesticide residues

To be established in accordance with national requirements. Normally, the maximum residue limit of aldrin and dieldrin for Flos Chamomillae is not more than 0.05 mg/kg (1). For other pesticides, see WHO guidelines on quality control methods for medicinal plants (14) and guidelines for predicting dietary intake of pesticide residues (16).

Heavy metals

Recommended lead and cadmium levels are no more than 10 and 0.3mg/kg, respectively, in the final dosage form of the plant material (14).

Radioactive residues

For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and plutonium-239, see WHO guidelines on quality control methods for medicinal plants (14).

Other tests

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

Chemical assays

Contains not less than 0.4% v/w of essential oil (1–3). Total volatile oil content is determined by pharmacopoeial methods (1–3).

Thin-layer (1, 2) and gas–liquid (17) chromatography for volatile oil constituents, and high-performance liquid chromatography for flavonoids (18, 19).

Major chemical constituents

Flos Chamomillae contains an essential oil (0.4–1.5%), which has an intense blue colour owing to its chamazulene content (1–15%). Other major constituents include α-bisabolol and related sesquiterpenes (up to 50% of the oil). Apigenin and related flavonoid glycosides constitute up to 8% (dry weight) of the drug (10, 18).

Dosage forms

Dried flower-heads, liquid extract (1:1 in 45% alcohol), tinctures and other galenicals (11). Store in well-closed containers, protected from light (1–3).

Medicinal uses

Uses supported by clinical data

Internal use

Symptomatic treatment of digestive ailments such as dyspepsia, epigastric bloating, impaired digestion, and flatulence (3, 7, 8, 10, 11, 20, 21). Infusions of camomile flowers have been used in the treatment of restlessness and in mild cases of insomnia due to nervous disorders (21, 22).

External use

Inflammation and irritations of the skin and mucosa (skin cracks, bruises, frostbite, and insect bites) (10, 23), including irritations and infections of the mouth and gums, and haemorrhoids (10, 11, 20,21, 23).

Inhalation

Symptomatic relief of irritations of the respiratory tract due to the common cold (24).

Uses described in pharmacopoeias and in traditional systems of medicine

Adjuvant in the treatment of minor inflammatory conditions of the gastrointestinal tract (24).

Uses described in folk medicine, not supported by experimental or clinical data

As an antibacterial and antiviral agent, an emetic, and an emmenagogue. It is also used to relieve eye strain, and to treat urinary infections and diarrhoea (13).

Pharmacology

Experimental pharmacology

Both camomile extract and (-)-α-bisabolol demonstrated antipeptic activity in vitro (25, 26). A hydroalcoholic extract of camomile inhibited the growth of Staphylococcus aureus, Streptococcus mutans, group B Streptococcus, and Streptococcus salivarius, and it had a bactericidal effect in vitroon Bacillus megatherium and Leptospira icterohaemorrhagiae (27). In vitro, the volatile oil of camomile also inhibited Staphylococcus aureus and Bacillus subtilis (28). In vitro, camomile extracts inhibited both cyclooxygenase and lipoxygenase (29), and thus the production of prostaglandins and leukotrienes, known inducers of inflammation. Both bisabolol and bisabolol oxide have been shown to inhibit 5-lipoxygenase, but bisabolol was the more active of the two compounds (30). Numerous in vivo studies have demonstrated the anti-inflammatory effects of the drug. The antiinflammatory effects of camomile extract, the essential oil, and the isolated constituents have been evaluated in yeast-induced fever in rats and against ultraviolet radiation-induced erythema in guinea-pig models (31). The principal anti-inflammatory and antispasmodic constituents of camomile appear to be the terpene compounds matricin, chamazulene, (-)-α-bisabololoxides A and B, and (-)-α-bisabolol (32–39). While matricin and (-)-α-bisabolol have been isolated from the plant, chamazulene is actually an artefact formed during the heating of the flowers when an infusion or the essential oil is prepared (10). The anti-inflammatory effects of these compounds in various animal models, such as inhibition of carrageenin-induced rat paw oedema, have been demonstrated (30), although their activity was somewhat less than that of salicylamide (39). In the mouse model for croton oil-induced dermatitis, topical application of either the total camomile extract, or the flavonoid fraction only, was very effective in reducing inflammation (34). Apigenin and luteolin were more active than indometacin and phenylbutazone (34). Activity decreased in the following order: apigenin > luteolin > quercetin > myricetin > apigenin-7-glucoside > rutin (34). The spasmolytic activity of camomile has been attributed to apigenin, apigenin-7-O-glucoside (10, 36) and (-)-α-bisabolol, which have activity similar to papaverine (10, 35).

Intradermal application of liposomal apigenin-7-glucoside inhibited, in a dose-dependent manner, skin inflammations induced in rats by xanthine oxidase and cumene hydroperoxide (38).

Intraperitoneal administration to mice of a lyophilized infusion of camomile decreased basal motility, exploratory and motor activities, and potentiated hexobarbital-induced sleep (40). These results demonstrated that in mice camomile depresses the central nervous system (40).

Clinical pharmacology

A double-blind study of the therapeutic effects of a camomile extract on reepithelialization and drying of wound weeping after dermabrasion demonstrated a statistically significant decrease in the wound size and drying tendency (41).

In clinical trials, topical application of a camomile extract in a cream base was found to be superior to hydrocortisone 0.25% for reducing skin inflammation (42). In an international multicentre trial camomile cream was compared with hydrocortisone 0.25%, fluocortin butyl ester 0.75% and bufexamac 5% in the treatment of eczema of the extremities (42). The camomile cream was shown to be as effective as hydrocortisone and superior to the other two treatments, but no statistical analysis was performed. Camomile preparations have also been found to be beneficial in the treatment of radiation mucositis owing to head and neck radiation and systemic chemotherapy (43).

Contraindications

Camomile is contraindicated in patients with a known sensitivity or allergy to plants of the Asteraceae (Compositae) such as ragweed, asters, and chrysanthemums (21).

Warnings

No information available.

Precautions

Carcinogenesis, mutagenesis, impairment of fertility

No mutagenic effects were found in Salmonella typhimurium strains TA 97a, TA 98, TA 100 and TA 104, with or without metabolic activation (44).

Pregnancy: teratogenic effects

No adverse effects reported in vivo (45).

Other precautions

No information available concerning general precautions, drug interactions, drug and laboratory test interactions, non-teratogenic effects on pregnancy, nursing mothers, or paediatric use.

Adverse reactions

The presence of lactones in Flos Chamomillae-based preparations may cause allergic reactions in sensitive individuals and there have been reports of contact dermatitis due to camomile preparations (46–48). It should be noted that very few cases of allergy were specifically attributed to German camomile (49). A few cases of anaphylactic reactions to the ingestion of Flos Chamomillae have also been reported (50–52).

Posology

Internal use

Adult dose of flower head: average daily dose 2–8g, 3 times a day (7, 8, 11); of fluid extract 1: 1 in 45% ethanol: dose 1–4ml, 3 times a day (6, 11). Child dose of flower head: 2 g, 3 times daily; of fluid extract (ethanol 45–60%): single dose 0.6–2ml (11). Should not be used by children under 3 years old.

External use

For compresses, rinses or gargles: 3–10% (30–100g/l) infusion or 1% fluid extract or 5% tincture (11). For baths: 5 g/l of water or 0.8 g/l of alcoholic extract. For semisolid preparations: hydroalcoholic extracts corresponding to 3– 10% (30–100g/kg) of the drug. For vapour inhalation: 6g of the drug or 0.8 g of alcoholic extract per litre of hot water (11).

References

1. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1997.

2. Pharmacopée française. Paris, Adrapharm, 1996.

3. African pharmacopoeia, 1st ed. Lagos, Organization of African Unity, Scientific, Technical & Research Commission, 1985.

4. Estra farmakope Indonesia. Jakarta, Cetakan Kedua, Hal 152, Departemen Kesehatan, Republik Indonesia, 1974.

5. Rauschert S. Nomenklatorische Probleme in der Gattung Matricaria L. Folia geobotanica phytotaxonomica, 1990, 9:249–260.

6. Farnsworth NR, ed. NAPRALERT database. Chicago, University of Illinois at Chicago, IL, August 8, 1995 production (an on-line database available directly through the University of Illinois at Chicago or through the Scientific and Technical Network (STN) of Chemical Abstracts Services).

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

8. The Indian Pharmaceutical Codex. Vol. I. Indigenous drugs. New Delhi, Council of Scientific & Industrial Research, 1953.

9. Leung A, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics, 2nd ed. New York, John Wiley, 1996.

10. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier, 1995.

11. British herbal pharmacopoeia. London, British Herbal Medicine Association, 1990.

12. Polish pharmacopoeia. Warsaw, 1965.

13. Tyler VE, Brady LR, Robbers JE, eds. Pharmacognosy, 9th ed. Philadelphia, Lea & Febiger, 1988.

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

15. Deutsches Arzneibuch 1996. Vol. 2. Methoden der Biologie. Stuttgart, Deutscher Apotheker Verlag, 1996.

16. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. Geneva, World Health Organization, 1997 (unpublished document WHO/FSF/FOS/97.7; available from Food Safety, WHO, 1211 Geneva 27, Switzerland).

17. Carle R, Fleischhauer I, Fehr D. Qualitätsbeurteilung von Kamillenölen. Deutsche Apotheker Zeitung, 1987, 127:2451–2457.

18. Dölle B, Carle R, Müller W. Flavonoidbestimmung in Kamillenextraktpräparaten. Deutsche Apotheker Zeitung, 1985, 125(Suppl. I):14–19.

19. Redaelli C, Formentini L, Santaniello E. Reversed-phase high-performance liquid chromatography analysis of apigenin and its glucosides in flowers of Matricaria chamomilla and chamomille extracts. Planta medica, 1981, 42:288–292.

20. Carle R, Isaac O. Die Kamille-Wirkung and Wirksamkeit. Zeitschrift für Phytotherapie, 1987, 8:67–77.

21. Carle R, Gomaa K. Chamomile: a pharmacological and clinical profile. Drugs of today, 1992, 28:559–565.

22. Gould L, Reddy CVR, Gomprecht RF. Cardiac effect of chamomile tea. Journal of clinical pharmacology, 1973, 13:475–479.

23. Hormann HP, Korting HC. Evidence for the efficacy and safety of topical herbal drugs in dermatology. Part 1. Anti-inflammatory agents. Phytomedicine, 1994, 1:161– 171.

24. Weiß RF. Kamille-"Heilpflanze 1987″. Kneipp-Blätter, 1987, 1:4–8.

25. Thiemer VK, Stadler R, Isaac O. Biochemische Untersuchungen von Kamilleninhaltsstoffen.Arzneimittel-Forschung, 1972, 22:1086–1087.

26. Isaac O, Thiemer K. Biochemische Untersuchungen von Kamilleninhaltsstoffen. Arzneimittel-Forschung, 1975, 25:1086–1087.

27. Cinco M et al. A microbiological survey on the activity of a hydroalcoholic extract of chamomile.International journal of crude drug research, 1983, 21:145–151.

28. Aggag ME, Yousef RT. Study of antimicrobial activity of chamomile oil. Planta medica, 1972, 22:140–144.

29. Wagner H, Wierer M, Bauer R. In vitro inhibition of prostaglandin biosynthesis by essential oils and phenolic compounds. Planta medica, 1986:184–187.

30. Ammon HPT, Kaul R. Pharmakologie der Kamille und ihrer Inhaltsstoffe. Deutsche Apotheker Zeitung, 1992, 132(Suppl. 27):3–26.

31. Jakovlev V et al. Pharmacological investigations with compounds of chamomile. II. New investigations on the antiphlogistic effects of (-)-α-bisabolol and bisabolol oxides. Planta medica, 1979, 35:125–240.

32. Jakovlev V, Isaac O, Flaskamp E. Pharmakologische Untersuchungen von Kamilleninhaltsstoffen. VI. Untersuchungen zur antiphlogistischen Wirkung von Chamazulen und Matricin. Planta medica, 1983, 49:67–73.

33. Tubaro A et al. Evaluation of anti-inflammatory activity of chamomile extract after topical application. Planta medica, 1984, 51:359.

34. Della Loggia R. Lokale antiphlogistische Wirkung der Kamillen-Flavone. Deutsche Apotheker Zeitung, 1985, 125(Suppl. 1):9–11.

35. Della Loggia R et al. Evaluation of the anti-inflammatory activity of chamomile preparations.Planta medica, 1990, 56:657–658.

36. Lang W, Schwandt K. Untersuchung über die glykosidischen Bestandteile der Kamille. Deutsche Apotheker Zeitung, 1957, 97:149–151.

37. Mann C, Staba J. The chemistry, pharmacology, and commercial formulations of chamomile. In: Craker LE, Simon JE, eds., Herbs, spices, and medicinal plants: recent advances in botany, horticulture and pharmacology, Vol. I. Phoenix, AZ, Oryx Press, 1986:233–280.

38. Fuchs J, Milbradt R. Skin anti-inflammatory activity of apigenin-7-glucoside in rats. Arzneimittel-Forschung, 1993, 43:370–372.

39. Albring M et al. The measuring of the anti-inflammatory effect of a compound on the skin of volunteers. Methods and findings in experimental and clinical pharmacology, 1983, 5:75–77.

40. Della Loggia R et al. Depressive effects of Chamomilla recutita (L.) Rausch. tubular flowers, on central nervous system in mice. Pharmacological research communications, 1982, 14:153–162.

41. Glowania HJ, Raulin C, Svoboda M. The effect of chamomile on wound healing- a controlled clinical-experimental double-blind study. Zeitschrift für Hautkrankheiten, 1986, 62:1262–1271.

42. Aertgeerts P et al. Vergleichende Prüfung von Kamillosan® Creme gegenüber steroidalen (0.25% Hydrocortison, 0.75% Fluocortinbutylester) und nichtsteroidalen (5% Bufexamac) Externa in der Erhaltungstherapie von Ekzemerkrankungen. Zeitschrift für Hautkrankheiten, 1985, 60:270–277.

43. Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: a study of 98 patients. Journal of prosthetic dentistry, 1991, 66:361–369.

44. Rivera IG et al. Genotoxicity assessment through the Ames test of medicinal plants commonly used in Brazil. Environmental toxicology and water quality, 1994, 9:87–93.

45. Leslie GB, Salmon G. Repeated dose toxicity studies and reproductive studies on nine Bio-Strath herbal remedies. Swiss medicine, 1979, 1:1–3.

46. Dstychova E, Zahejsky J. Contact hypersensitivity to camomile. Ceskoslovenska dermatologie, 1992, 67:14–18.

47. Subiza J et al. Allergic conjunctivitis to chamomile tea. Annals of allergy, 1990, 65:127–132.

48. Paulsen E, Andersen KE, Hausen BM. Compositae dermatitis in a Danish dermatology department in one year. Contact dermatitis, 1993, 29:6–10.

49. Hausen BM, Busker E, Carle R. Über das Sensibilisierungsvermögen von Compositenarten. VII. Experimentelle Untersuchungen mit Auszügen und Inhaltsstoffen von Chamomilla recutita (L.) Rauschert und Anthemis cotula L. Planta medica, 1984:229–234.

50. Benner MH, Lee HJ. Anaphylactic reaction to chamomile tea. Journal of allergy and clinical immunology, 1973, 52:307–308.

51. Casterline CL. Allergy to chamomile tea. Journal of the American Medical Association, 1980, 244:330–331.

52. Subiza J et al. Anaphylactic reaction after the ingestion of chamomile tea: a study of cross-reactivity with other composite pollens. Journal of allergy and clinical immunology, 1989, 84:353–358.

 

Gotu Cola (Centella asiatica) WHO Monograph – EN

Definition
Herba Centellae consists of the dried aerial parts or the entire plant of Centella asiatica (L.) Urban. (Apiaceae) (1–5).
Synonyms
Centella coriacea Nannfd., Hydrocotyle asiatica L., Hydrocotyle lunata Lam. and Trisanthus cochinchinensis Lour. (1, 3, 6). Apiaceae are also known as Umbelliferae.
Selected vernacular names
Artaniyae-hindi, Asiatic pennywort, barmanimuni, barmi, bhram buti, boabok, bodila-ba-dinku, bokkudu, brahma manduki, brahmi ghi, brahmi-buti, brahmi, bua bok, bua-bok, centella, chhota mani-muni, chi-hsueh-ts’ao, ghi brahmi, ghod tapre, ghodtapre, ghortapre, gotu kola, gotukola, herba pegagan, herba kakikuda, hydrocotyle, hydrocotyle asiatique, idrocotile, imsen korokla, Indian pennywort, Indian water navelwort, Indischer Wassernabel, karinga, karivana, kudangal, luei gong gen, lièn tièn tháo, mandooka parni, mandukaparni, mandukparni, manimuni, marsh pepperwort, matoyahuho, matoyahuhu, mrang-khua, mtwigahuwu, pa-na-e-khaa-doh, phác chèn, phaknok, phalwaen, rau má, saraswathiaaku, takip-kohol, thalkuri, thankuni, thol-kuri, tilkushi, titjari, tono’itahi, tsubo-kusa, tungchian, vallari, vallarei, vitovitolenge, water pennywort, waternavel, yahon-yahon, yerba de chavos (3–11).
Description
A slender trailing herb, rooting at the nodes. Leaves 1.3–6.3 cm diameter, orbicular reniform, more or less cupped, entire, crenate or lobulate, glabrous; leaf stalks 2–5 cm long; peduncle about 6 mm, often 2–3 nates; pedicels nil; bracts small, embracing the flowers; inflorescence in single umbel, bearing 1–5 flowers, sessile, white or reddish; fruit small, compressed, 8mm long, mericarps longer than broad, curved, rounded at top, 7–9-ridged, secondary ridges as prominent as the primary, reticulate between them; pericarp much thickened; seed compressed laterally (1, 4, 7).
Plant material of interest: aerial part or entire plant
General appearance
A slender herb. Stems long, prostrate, emerging from the leaf-axils of a vertical rootstock, filiform, often reddish, with long internodes and rooting at the nodes; leaves thin, long-petioled, several from the rootstock and 1–3 from each node of the stems, 1.3–6.3 cm diameter, orbicular reniform, more or less cupped, entire, crenate or lobulate, glabrous; petioles very variable in length, 7.5–15cm long or more, channelled; stipules short, adnate to the petioles forming a sheathing base (4, 5).
Organoleptic properties
Colour, greyish green; odour, characteristic; taste, slightly bittersweet (4, 5).
Microscopic characteristics
Greyish green with stomata on both surfaces of the leaf, 30 by 28µm, mostly rubiaceous type. Palisade cells differentiated into 2 layers of cells, 45 by 25µm; spongy parenchyma of about 3 layers of cells with many intercellular spaces, some with crystals of calcium oxalate; midrib region shows 2 or 3 layers of parenchymatous cells without chloroplastids; petiole shows epidermis with thickened inner walls; collenchyma of 2 or 3 layers of cells; a broad zone of parenchyma; 7 vascular bundles within parenchymatous zone, 2 in projecting arms and 5 forming the central strand; vessels 15–23µm in diameter. Some parenchymatous cells contain crystals of calcium oxalate. Fruits, epidermis of polygonal cells, trichomes similar to the leaves, sheets of elongated parquetry layer cells, bundles of narrow annular vessels, and parenchymatous cells contain single large prisms of calcium oxalate (4).
Geographical distribution
The plant is indigenous to the warmer regions of both hemispheres, including Africa, Australia, Cambodia, Central America, China, Indonesia, the Lao People’s Democratic Republic, Madagascar, the Pacific Islands, South America, Thailand, southern United States of America, and Viet Nam. It is especially abundant in the swampy areas of India, the Islamic Republic of Iran, Pakistan, and Sri Lanka up to an altitude of approximately 700m (1, 4, 6, 8, 10, 11).
General identity tests
Macroscopic and microscopic examinations; and microchemical tests for the presence of triterpenes and reducing sugars (1, 4).
Purity tests
Microbiology
The test for Salmonella spp. in Herba Centellae products should be negative. The maximum acceptable limits of other microorganisms are as follows (12–14). For preparation of decoction: aerobic bacteria-not more than 10⁷/g; fungi-not more than 10⁵/g; Escherichia coli-not more than 10²/g. Preparations for internal use: aerobic bacteria-not more than 10⁵/g or ml; fungi-not more than 10⁴/g or ml; enterobacteria and certain Gram-negative bacteria-not more than 10³/g or ml; Escherichia coli-0/g or ml.
Foreign organic matter
Not more than 2% (4).
Total ash
Not more than 19% (2, 3).
Acid-insoluble ash
Not less than 6% (2).
Water-soluble extractive
Not less than 6% (2, 3).
Alcohol-soluble extractive
Not less than 9.5% (2, 3).
Pesticide residues
To be established in accordance with national requirements. Normally, the maximum residue limit of aldrin and dieldrin in Herba Centellae is not more than 0.05 mg/kg (14). For other pesticides, see WHO guidelines on quality control methods for medicinal plants (12) and guidelines for predicting dietary intake of pesticide residues (15).
Heavy metals
Recommended lead and cadmium levels are not more than 10 and 0.3mg/kg, respectively, in the final dosage form of the plant material (12).
Radioactive residues
For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and plutonium-239, see WHO guidelines on quality control methods for medicinal plants (12).
Other purity tests
Chemical tests, and tests for drug interactions and moisture to be established by national authorities.
Chemical assays
Contains not less than 2% triterpene ester glycosides (asiaticoside and madecassoside) (10). Determination of asiaticoside and related triterpene ester glycosides by thin-layer chromatography (16) and spectroscopic analysis (17).
Major chemical constituents
The major principles in Herba Centellae are the triterpenes asiatic acid and madecassic acid, and their derived triterpene ester glycosides, asiaticoside and madecassoside (8, 10, 11).

Dosage forms
Dried drug for infusion (18); galenic preparations for oral administration (10). Powder or extract (liquid or ointment) for topical application (1, 4). Package in well-closed, light-resistant containers.
Medicinal uses
Uses supported by clinical data
Treatment of wounds, burns, and ulcerous skin ailments, and prevention of keloid and hypertrophic scars (10, 18–21). Extracts of the plant have been employed to treat second- and third-degree burns (19). Extracts have been used topically to accelerate healing, particularly in cases of chronic postsurgical and post-trauma wounds (19). Extracts have been administered orally to treat stressinduced stomach and duodenal ulcers (10).
Uses described in pharmacopoeias and in traditional systems of medicine
Herba Centellae is reported to be used in the treatment of leprous ulcers and venous disorders (5, 6, 8,10, 22).
Studies suggest that extracts of Centella asiatica cause regression of inflammatory infiltration of the liver in cirrhosis patients (10, 23). Further experimentation is needed to confirm these findings.
Uses described in folk medicine, not supported by experimental or clinical data
Therapy of albinism, anaemia, asthma, bronchitis, cellulite, cholera, measles, constipation, dermatitis, diarrhoea, dizziness, dysentery, dysmenorrhoea, dysuria, epistaxis, epilepsy, haematemesis, haemorrhoids, hepatitis, hypertension, jaundice, leukorrhoea, nephritis, nervous disorders, neuralgia, rheumatism, smallpox, syphilis, toothache, urethritis, and varices; and as an antipyretic, analgesic, anti-inflammatory, and “brain tonic” agent (4, 5, 7). Poultices have been used to treat contusions, closed fractures, sprains, and furunculosis (7).
Pharmacology
Experimental pharmacology
The pharmacological activity of Centella asiatica is thought to be due to several saponin constituents, including asiaticoside, asiatic acid, and madecassic acid (10). In vitro, each of these compounds stimulated the production of human collagen I, a protein involved in wound healing (24). Stimulation of collagen synthesis in foreskin fibroblast monolayer cultures by an extract from Herba Centellae has also been reported (25). Asiaticoside accelerated the healing of superficial postsurgical wounds and ulcers by accelerating cicatricial action (21). Asiaticoside stimulates the epidermis by activating the cells of the malpighian layer in porcine skin, and by keratinization in vitro (26). Topical application of asiaticoside promoted wound healing in rats and significantly increased the tensile strength of newly formed skin (21, 27).
Extracts of C. asiatica, and in particular its major triterpene ester glycoside, asiaticoside, are valuable in the treatment of hypertrophic scars and keloids (21). Asiaticoside has been reported to decrease fibrosis in wounds, thus preventing new scar formation (21). The mechanism of action appears to be twofold: by increasing the synthesis of collagen and acidic mucopolysaccharides, and by inhibiting the inflammatory phase of hypertrophic scars and keloids. It has further been proposed that asiaticoside interferes with scar formation by increasing the activity of myofibroblasts and immature collagen (21).
Extract of Herba Centellae effectively treated stress-induced stomach and duodenal ulcers in humans (10, 28). Oral administration of C. asiatica extract to rats produced a dose-dependent reduction in stress-induced gastric ulceration, and the antiulcer activity was similar to that of famotidine (29). The mechanism of action appears to be associated with a central nervous system-depressant activity of C. asiatica, owing to an increase in the concentration of GABA (γ-aminobutyric acid) in the brain (29).
A 70% ethanol extract of the drug administered intraperitoneally to mice produced anticonvulsant activity (30).
Clinical pharmacology
In clinical trials, an extract of C. asiatica in a 1% salve or 2% powder accelerated healing of wounds (31). A formulation containing asiaticoside as the main ingredient healed 64% of soiled wounds and chronic or recurrent atony that was resistant to usual treatment (21). In an open clinical study, treatment of 20 patients with soiled wounds and chronic or recurrent atony with a galenical formulation containing 89.5% C. asiatica healed 64% and produced improvement in another 16% of the lesions studied (20). Local application of an extract of the drug to second- and third-degree burns expedited healing, prevented the shrinking and swelling caused by infection, and further inhibited hypertrophic scar formation (11).
Twenty-two patients with chronic infected skin ulcers were treated with a cream containing a 1% extract of C. asiatica (32). After 3 weeks of treatment, 17 of the patients were completely healed and the ulcer size in the remaining 5 patients was decreased (32). Another trial using the same cream preparation demonstrated similar results (33). A standardized extract of Herba Centellae was reported to treat ulcus cruris (indolent leg ulcers) effectively in clinical trials (34, 35). In a double-blind study, no significant effect on healing was observed in patients with ulcus cruris after oral treatment with asiaticoside (36).
Oral administration of C. asiatica or asiaticoside and potassium chloride capsules was reported to be as effective as dapsone therapy in patients with leprosy (37). In a controlled study of 90 patients with perforated leg lesions owing to leprosy, application of a salve of the plant produced significantly better results than a placebo (11, 22, 38).
Clinical trials of the drug have demonstrated its antiulcer activity after oral administration (28, 39, 40). Fifteen patients with peptic or duodenal ulcer were treated with a titrated extract of Herba Centellae (60.0 mg/person). Approximately 93% of the patients exhibited a definite improvement in subjective symptoms and 73% of the ulcers were healed as measured by endoscopic and radiological observations (28).
Clinical studies of Herba Centellae in the treatment of various venous disorders has demonstrated a positive therapeutic effect (11). In patients suffering from venous insufficiency who were treated with a titrated extract of the drug, venous distension and oedema improved significantly, as compared with controls (41).
Contraindications
Allergy to plants of the Apiaceae family.
Warnings
No information available.
Precautions
Carcinogenesis, mutagenesis, impairment of fertility
Asiaticoside has been implicated as a possible skin carcinogen in rodents after repeated topical application (42). Further experimentation is needed to substantiate this claim.
Other precautions
No information was available concerning drug interactions, drug and laboratory test interactions, teratogenic or non-teratogenic effects on pregnancy, nursing mothers, or paediatric use.
Adverse reactions
Allergic contact dermatitis has been associated with topical application of C. asiatica (21, 43, 44). However, further testing revealed that these reactions may be due to other ingredients in the preparations (45).
Posology
Oral dose: 0.33–0.68 g or by oral infusion of a similar amount three times daily (4–6).
References
1. African pharmacopoeia, 1st ed. Lagos, Organization of African Unity, Scientific, Technical & Research Commission, 1985.
2. Materia medika Indonesia, Jilid I. Jakarta, Departemen Kesehatan, Republik Indonesia, 1977.
3. Vietnam materia medica. Hanoi, Ministry of Health, 1972.
4. The Indian pharmaceutical codex. Vol. I. Indigenous drugs. New Delhi, Council of Scientific & Industrial Research, 1953.
5. British herbal pharmacopoeia, Part 2. London, British Herbal Medicine Association, 1979.
6. Iwu MM. Handbook of African medicinal plants. Boca Raton, FL, CRC Press, 1993.
7. Medicinal plants in Viet Nam. Manila, World Health Organization, 1990 (WHO Regional Publications, Western Pacific Series, No. 3).
8. Tyler VE, Brady LR, Robbers JE, eds. Pharmacognosy, 9th ed. Philadelphia, Lea & Febiger, 1988.
9. Medicinal plants of India, Vol. 1. New Delhi, Indian Council of Medical Research, 1976.
10. Kartnig T. Clinical applications of Centella asiatica (L.) Urb. In: Craker LE, Simon JE, eds., Herbs, spices, and medicinal plants: recent advances in botany, horticulture, and pharmacology, Vol. 3. Phoenix, AZ, Oryx Press, 1988:145–173.
11. Farnsworth NR, Bunyapraphatsara N, eds. Thai medicinal plants. Bangkok, Prachachon, 1992.
12. Quality control methods for medicinal plant materials. Geneva, World Health Organization, 1998.
13. Deutsches Arzneibuch 1996. Vol. 2. Methoden der Biologie. Stuttgart, Deutscher Apotheker Verlag, 1996.
14. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1997.
15. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. Geneva, World Health Organization, 1997 (unpublished document WHO/FSF/FOS/97.7; available from Food Safety, WHO, 1211 Geneva 27, Switzerland).
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Bupleurum (Bupleurum falcatum) WHO Monograph – EN

Definition

Radix Bupleuri consists of the dried root of Bupleurum falcatum L. or B. falcatum L. var.scorzonerifolium (Willd.) Ledeb. (Apiaceae) (1, 2).

Synonyms

Bupleurum chinense D.C. and B. scorzonerifolium Willd. have been treated as different species (1) but are actually synonyms of B. falcatum L. var. scorzonerifolium (3). Apiaceae are also referred to as Umbelliferae.

Selected vernacular names

Beichaihu, bupleurum root, ch'ai hu, chaifu, chaihu, chaiku-saiko, Chinese thorowax root, juk-siho, kara-saiko, mishima-saiko, nanchaihu, northern Chinese thorowax root, radix bupleur, saiko, shi ho, shoku-saiko, wa-saiko, Yamasaiko (1–5).

Description

A perennial herb up to 1m tall; base woody and the rhizome branching. Stem slender, flexuous, branches spreading. Basal leaves lanceolate, upper lamina broad, lower narrowed into a petiole, veins 7, apex acute, mucronate; middle and upper leaves linear to lanceolate, gradually shorter, falcate, veins 7–9, base slightly amplexicaul, apex acuminate. Involucre of 1–3 minute bracts or lacking. Rays 5–8. Involucel of 5 minute, 3-veined bractlets, shorter than the flowering umbellet. Pedicels shorter than the fruits. Fruit oblong, 3–4 mm long; furrows 3- vittate (4, 6).

Plant material of interest: dried roots

General appearance

Single or branched root, of long cone or column shape, 10–20 cm in length, 0.5– 1.5 cm in diameter; occasionally with remains of stem on crown; externally light brown to brown and sometimes with deep wrinkles; easily broken, and fractured surface somewhat fibrous (2).

Organoleptic properties

Odour, characteristic, slightly aromatic to rancid; taste, slightly bitter (1, 2).

Microscopic characteristics

Transverse section reveals often tangentially extended clefts in cortex, the thickness reaching a third to a half of the radius, and cortex scattered with a good many intercellular schizogenous oil canals 1.5–3.5 cm in diameter; vessels lined radially or stepwise in xylem, with scattered fibre groups; in the crown pith also contains oil canals; parenchyma cells filled with starch grains and some oil drops. Starch grains composed of simple grains, 2–10µm in diameter, or compound grains (2).

Powdered plant material

Information not available. Description to be established by appropriate national authorities.

Geographical distribution

Indigenous to northern Asia, northern China, and Europe (4, 6).

General identity tests

Macroscopic and microscopic examinations (1, 2), microchemical detection for saponins (1, 2), and thin-layer chromatographic analysis for triterpene saponins with reference to saikosaponins (2).

Purity tests

Microbiology

The test for Salmonella spp. in Radix Bupleuri should be negative. The maximum acceptable limits of other microorganisms are as follows (7–9). For preparation of decoction: aerobic bacteria-not more than 10⁷/g; fungi-not more than 10⁵/g; Escherichia coli-not more than 10²/g.

Chemical

Contains triterpene saponins (saikosaponins). Quantitative level to be established by appropriate national authorities, but should be not less than 1.5% according to literature data.

Foreign organic matter

Not more than 10% of stems and leaves (2). No roots of B. longiradiantum Turcz., which is toxic (1, 5). Not more than 1% of other foreign matter (2).

Total ash

Not more than 6.5% (2).

Acid-insoluble ash

Not more than 2% (2).

Dilute ethanol-soluble extractive

Not less than 11% (2).

Pesticide residues

To be established in accordance with national requirements. Normally, the maximum residue limit of aldrin and dieldrin for Radix Bupleuri is not more than 0.05 mg/kg (9). For other pesticides, see WHO guidelines on quality control methods for medicinal plants (7) and WHO guidelines for predicting dietary intake of pesticide residues (10).

Heavy metals

Recommended lead and cadmium levels are no more than 10 and 0.3mg/kg, respectively, in the final dosage form of the plant material (7).

Radioactive residues

For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and plutonium-239, see WHO guidelines on quality control methods for medicinal plants (7).

Other tests

Tests for moisture and for water-soluble extractive to be established by national authorities.

Chemical assays

Total saikosaponins determination by colorimetric analysis (11), and highperformance liquid chromatography analysis for saikosaponins A, B1, B2, and D (12, 13).

Major chemical constituents

The major constituents are triterpene saponins, including saikosaponins A, B1–4, D, E, F and H and related compounds including saikogenins A–G (5, 14). Two biologically active polysaccharides, bupleurans 2IIb and 2IIc, have also been isolated from the roots of B. falcatum (15, 16). Representative structures of saikosaponins are presented in the figure.

Dosage forms

Decoction (5). Store crude plant material in a dry environment protected from moths, light, and moisture (1, 2).

Medicinal uses

Uses supported by clinical data

None.

Uses described in pharmacopoeias and in traditional systems of medicine

Treatment of fever, pain, and inflammation associated with influenza, and the common cold (1, 2, 5). The drug is also used as an analgesic for the treatment of distending pain in the chest and hypochondriac regions, and for amenorrhoea (1). Extracts have been used for the treatment of chronic hepatitis, nephrotic syndrome, and autoimmune diseases (1, 5).

Uses described in folk medicine, not supported by experimental or clinical data

Treatment of deafness, dizziness, diabetes, wounds, and vomiting (5).

Pharmacology

Experimental pharmacology

Antipyretic and analgesic activity

A number of in vivo studies have confirmed the antipyretic activity of Radix Bupleuri in the treatment of induced fevers in animals. Oral administration of a Bupleurum decoction (5 g/kg) to rabbits with a heat-induced fever decreased body temperature to normal levels within 1.5 hours (5). Subcutaneous injection of an aqueous ethanol extract of Bupleurum roots (2.2 ml/kg, 1.1 g crude drug/ml) significantly reduced fevers in rabbits injected with Escherichia coli (17).

Oral administration of saikosaponins to rats produced hypothermic and antipyretic effects (5). Furthermore, intraperitoneal injection of the volatile oil (300mg/kg) or saponins (380 and 635 mg/kg) isolated from B. chinense (B. falcatum) roots effectively decreased fever in mice induced by yeast injections (18). Oral administration of 200–800mg/kg of a crude saponin fraction to mice produced sedative, analgesic, and antipyretic effects, but no anticonvulsant effect or reduction in muscle tone was observed (14). Saikosaponins are believed to be the major active antipyretic constituents in Radix Bupleuri extracts.

Analgesic activity of Bupleurum extracts is also supported by in vivo studies. Injections of a crudeBupleurum extract or purified sapogenin A inhibited writhing induced by intraperitoneal injection of acetic acid in mice (5). The saikosaponins appear to be the active analgesic constituents of the drug. Intraperitoneal injection of mice with a total saponin fraction derived from B. chinense (B. falcatum) produced a marked analgesic effect on the pain induced by electroshock (5). Moreover, orally administered saikosaponins were reported to have an analgesic effect in mice (tail pressure test) (5).

Sedative effects

In vivo studies have also confirmed the sedative effects of Radix Bupleuri. Both the crude saikosaponin fraction and saikogenin A are reported to have signifi- cant sedative effects (5). In vivo studies, using the rod climbing test, demonstrated that the sedative effect of the saikosaponins (200–800mg/kg) in mice was similar to that of meprobamate (100mg) (5). Oral administration of saikosides extracted fromB. chinense (B. falcatum) or saikosaponin A has also been reported to prolong cyclobarbital sodium-induced sleep (5). Furthermore, intraperitoneal injection of saikogenin A inhibited rod climbing in mice and antagonized the stimulant effects of metamfetamine and caffeine (5).

Anti-inflammatory activity

Anti-inflammatory activity of Radix Bupleuri has been demonstrated by in vivo studies. Intraperitoneal injection of the saponin fraction, the volatile oil, or a crude extract from B. chinense (B. falcatum) significantly inhibited carrageenin-induced rat paw oedema (5). The saikosaponins are the active antiinflammatory constituents of the drug (19, 20). Oral administration of a crude saikosaponin fraction (2 g/kg) from B. falcatum inhibited dextran-, serotonin-, or croton oil-induced rat paw oedema (5, 21). Structure–activity correlations have revealed that saikosaponins A and D both have anti-inflammatory activity, while saikosaponin C does not (22). The potency of anti-inflammatory activity of the saikosaponins is similar to that of prednisolone (5).

Immune regulation activity

In vitro studies have demonstrated that a hot-water extract from the root of B. falcatum enhanced the antibody response and inhibited mitogen-induced lymphocyte transformation (23). An acidic pectic polysaccharide, bupleuran 2IIb, isolated from the roots of B. falcatum, was found to be a potent enhancer of immune complex binding to macrophages (24). The activity of this polysaccharide appeared to be due to its ability to enhance the Fc receptor function of macrophages. This study has shown that the binding of glucose oxidase– antiglucose oxidase complexes (a model of immune complexes) to murine peritoneal macrophages was stimulated by treatment with the polysaccharide (24). Bupleuran 2IIb appears to up-regulate both FcRI and FcRII receptor expression on the macrophage surface in a dose-dependent manner (25). The upregulation of the Fc receptor by bupleuran 2IIb depends on an increase in intracellular calcium and activation of calmodulin (25). Only saikosaponin D has been shown to enhance Fc receptor expression of thioglycollate-elicited murine peritoneal macrophages in vitro (26). This activity appears to be due to the translocation of FcR from the internal pool to the cell surface. In vitro studies with saikosaponin D have shown that this compound was able to control bidirectionally the growth response of T lymphocytes stimulated by concanavalin A, anti-CD3 monoclonal antibody, and calcium ionophore A23187 plus phorbol 12-myristate 13-acetate (27). Saikosaponin D also promoted interleukin-2 production and receptor expression, as well as c-fos gene transcription (28). The results of this study suggest that saikosaponin D exerts its immunostimulant effects by modification of T lymphocyte function (28).

Antiulcer activity

Antiulcer activity of Radix Bupleuri has been demonstrated both in vivo and in vitro. A polysaccharide fraction of a hot-water extract of the root of B. falcatum was reported to inhibit significantly hydrochloric acid- or ethanol-induced ulcerogenesis in mice (15). The polysaccharide fraction (BR-2, 100mg/kg) had potent antiulcer activity, and its activity was similar to that of sucralfate (100 mg/kg) (29). BR-2 significantly protected against a variety of gastric lesions, water-immersion stress ulcer and pylorus-ligation ulcer in mice and rats (29). By oral, intraperitoneal, or subcutaneous administration, BR-2 was further found to be effective against hydrochloric acid- or ethanol-induced gastric lesions suggesting that BR-2 acted both locally and systemically (29). The mechanism of antiulcer action appears to be due to a reinforcement of the protective mucosal barrier as well as an antisecretory action on acid and pepsin (30). Saponins isolated from B. falcatum root have also been reported to have weak antiulcer activity in the pylorus-ligation ulcer model (30).

Hepatoprotectant activity

Crude saponins of B. falcatum, administered orally to rats at a daily dose of 500mg/kg for 3 days, normalized liver functions as determined by serum alkaline phosphatase levels in rats treated with carbon tetrachloride (31). Treatment of rats with saikosaponins 2 hours before treatment with D-galactosamine inhibited the increase in serum aspartate aminotransferase and alanine aminotransferase levels produced by damage of liver tissues (31). Conversely, saikosaponins did not affect an increase in serum alanine aminotransferase and experimental cirrhosis in rats caused by carbon tetrachloride intoxication (32).

Clinical pharmacology

Antipyretic activity

The antipyretic activity of B. chinense (B. falcatum) has been investigated in patients with fevers caused by the common cold, influenza, malaria, and pneumonia (5). In one clinical study of 143 patients treated with the herb, fevers subsided within 24 hours in 98.1% of all cases of influenza, and in 87.9% of all cases of the common cold (5, 33). In another study, 40 patients with fever of pathological origin had a significant reduction in fever (1–2°C), but the antipyretic effect of Radix Bupleuri in these patients was transient unless combined with antibiotic therapy (5, 34).

Contraindications

No information available.

Warnings

Radix Bupleuri causes sedation when used in large doses (5); therefore, patients should be cautious when operating a motor vehicle or hazardous machinery.

Precautions

Drug interactions

The use of alcohol, sedatives and other central nervous system depressants in conjunction with Radix Bupleuri may cause synergistic sedative effects. No clinical studies have evaluated this possible interaction; however, patients should be cautioned about taking the drug with alcohol, sedatives, or other drugs known to cause depression of the central nervous system.

Carcinogenesis, mutagenesis, impairment of fertility

Methanolic extracts of B. chinense (B. falcatum) were not mutagenic in the modified Ames test usingSalmonella typhimurium TA 98 and TA 100, in the presence or absence of rat liver S-9 mix (35, 36). Furthermore, hot-water extracts of Bupleurum were shown to have antimutagenic activity in AFB1-induced mutagenesis in the mouse Salmonella typhi/mammalian microsomal system (Ames test) (strain TA 98) and in the in vivo mouse bone marrow cell chromosome aberration and mouse bone marrow eosinophil micronucleus test (37). There is one report that a hot-water extract of B. falcatum enhanced the mutagenic activity of Trp-P-1 with S9 mix in Salmonella typhimurium (38).

Pregnancy: teratogenic and non-teratogenic effects

No data available; therefore, B. falcatum should not be administered during pregnancy.

Nursing mothers

Excretion of the drug into breast milk and its effects on the newborn infant have not been established; therefore, Bupleurum should not be administered to nursing women.

Paediatric use

Guidelines for the administration of the drug to children are not available.

Other precautions

No information available concerning general precautions or drug and laboratory test interactions.

Adverse reactions

Mild lassitude, sedation, and drowsiness have been reported as frequent sideeffects (5). Large doses have also been reported to decrease appetite and cause pronounced flatulence and abdominal distension. Three incidents of allergic reactions were reported in patients given intramuscular injections of the drug (5).

Posology

Generally, doses of 3–9g/day (1).

References

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16. Yamada H, Hirano M, Kiyohara H. Partial structure of an anti-ulcer pectic polysaccharide from the roots of Bupleurum falcatum L. Carbohydrate research, 1991, 219:173– 192.

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30. Shibata M et al. Some pharmacological studies on the crude drugs possessing antiinflammatory properties of the Bupleurum and the leaves of fig. Shoyakugaku zasshi, 1976, 30:62–66.

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32. Zhao MQ et al. Preventive and therapeutic effects of glycyrrhizin, glycyrrhetic acid and saikosides on experimental cirrhosis in rats. Yao hsueh hsueh pao, 1983, 18:325– 331.

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