Flos Caryophylli consists of the dried flower buds of Syzygium aromaticum (L.) Merrill et L.M. Perry (Myrtaceae) (1-5).
Caryophyllus aromaticus L., Eugenia aromatica (L.) Baill., E. caryophylla Thunb., E. caryophyllus (C. Spreng.) Bull. et Harr., Jambosa caryophyllus (Spreng.) Nied., Myrtus caryophyllus Spreng. (1, 5-8).
Selected vernacular names
Benefundi, choji, choko, chouji, choukou, clavero, clavo de olor, clous de girofle, clove, cloves, colve, ding huong, dingxiang, flores caryophylli, Gewürznelken, girofle, giroflier, glove, gurunful, harilik negipuu, kaan phluu, kaan pluu, kade, kanumfari, karafwu, karanho, kau-phlu, konofuru, koronfol, lauang, laung, lawang, Nägelein, osaragbogo-eze, qaranfal, qoranful, qronfel, szegfüszeg, ud-nuwwar (1, 6-9).
Indigenous to the Moluccas and southern Philippines, but currently cultivated in many tropical areas including Africa (e.g. Madagascar and United Republic of Tanzania), South America, Indonesia, Malaysia and Sri Lanka (7,8).
Small evergreen trees, 10-20m high. Leaves opposite, petiolate, lanceolate, pinkish to dark green, with translucent, aromatic glands, have a pungent odour when young. Inflorescence occurs as racemose panicles and bears buds that take on the form of nails before blossoming. Flowers red with 4 concave, overlapping petals that drop off as soon as the flower opens; stamens numerous; 4 calyx lobes. Fruit dark red, fleshy drupe. Buds readily exude oil when pressed or scratched with a fingernail (7).
Plant material of interest: dried flower buds
Flower bud 10-20 mm long, bright reddish-brown to dark brown; lower part (the hypanthium) solid, cylindrical, somewhat flattened, 4-sided, tapering towards the base and bearing at the apex 4 thick, triangular, divergent sepals, alternating with 4 rounded, fragile, unexpanded, membranous, imbricated petals forming a pale, nearly spherical head that encloses numerous stamens, curved inward and inserted on a small disc, and a stiff, slender, erect, single style arising from a depression in the centre. Externally wrinkled; internally, hypanthium contains in its upper portion a 2-celled inferior ovary with numerous ovules attached to the axile placenta; has very large outer zone with numerous shining, oval oil glands near the periphery, numerous vascular bundles in the centre and a dark, lacunose layer abutting on the central zone and columella (1).
Odour: characteristic, strongly aromatic; taste: pungent, spicy, followed by slight numbness (1, 3, 5).
Hypanthium epidermis of small, thick-walled isodiametric cells with very thick cuticle, with stomata with no special subsidiary cells. Parenchymatous layer containing numerous large (up to about 200µm long), oval, radially elongated, schizo-lysigenous oil glands, arranged in 2 or 3 more or less intermixed layers. Layer of parenchyma and collenchyma containing clusters of calcium oxalate crystals, and traversed by small, irregularly arranged vascular bundles consisting of delicate, spiral vessels (up to 20µm in diameter), usually accompanied by isolated fusiform, pericyclic fibres (200-650µm long and up to 40µm in diameter), having strongly thickened lignified walls. Lacunous layer formed of thin-walled parenchyma. The columella consists of a parenchymatous strand with numerous closely arranged, small vascular bundles. Sepals, with epidermis resembling that of hypanthium and having numerous stomata on outer surface; mesophyll with rounded or stellate cells, numerous ovoid oil glands and clusters of calcium oxalate crystals, and traversed by a few slender vascular bundles. Petals, with epidermis formed of cells with straight, thin walls; stomata, absent; mesophyll, undifferentiated, containing oil glands and cells with clusters of calcium oxalate crystals, and traversed by small vascular bundles. Stamens, with filaments having a central vascular strand and oil glands beneath the epidermis; connective tissue, with a large oil gland in the apex of anther walls, with fibrous layer and minute clusters of calcium oxalate crystals along the line of dehiscence. Pollen grains, triangular, tricolpate, 10-20µ in diameter. Style, with epidermis similar to that of hypanthium, and consisting of small collenchyma cells, with clusters of calcium oxalate crystals, radially elongated oil glands, and traversed by 2 narrow vascular strands (1).
Powdered plant material
Dark brown; abundant fragments of collenchyma and parenchyma with clusters of calcium oxalate crystals, fragments of epidermis with thick-walled cells and few stomata; fragments of vascular or parenchyma tissue showing broken or entire oil glands; numerous fragments of vascular bundles with delicate spiral vessels, ranging from 6 to 45µm in diameter, mostly 6-10µm; occasional fusiform, rather thick-walled fibres, 4-20µm wide; numerous pollen grains, appearing either as equilateral triangular, with truncated, emarginate apices, or oval in outline, 10-20µm in diameter; fragments of the fibrous layer of anther wall; clusters of calcium oxalate crystals, 10-15µm in diameter (1, 5).
General identity tests
Macroscopic and microscopic examinations, and thin-layer chromatography for the presence of eugenol and β-caryophyllene (1, 3-5, 10).
Tests for specific microorganisms and microbial contamination limits are as described in the WHO guidelines on quality control methods for medicinal plants (11).
Foreign organic matter
Not more than 4% open buds, peduncles and fruits; not more than 2% deteriorated buds; not more than 0.5% other foreign matter (5).
Not more than 7% (4, 5).
Not more than 0.5% (4).
Not more than 8% (12).
Loss on drying
Not more than 12% (3).
The recommended maximum limit of aldrin and dieldrin is not more than 0.05mg/kg (5). For other pesticides, see the European pharmacopoeia (5), and the WHO guidelines on quality control methods for medicinal plants (11) and pesticide residues (13).
For maximum limits and analysis of heavy metals, consult the WHO guidelines on quality control methods for medicinal plants (11).
Where applicable, consult the WHO guidelines on quality control methods for medicinal plants (11) for the analysis of radioactive isotopes.
Other purity tests
Chemical, water-soluble extractive and alcohol extractive tests to be established in accordance with national requirements.
Contains not less than 15% (v/w) essential oil (1, 12), determined by distillation (5).
Major chemical constituents
The major constituent (up to 20%) is an essential oil, which is characterized by the presence of eugenol (60-95%), eugenol acetate (2-27%), and α- and β-caryophyllene (5-10%) (6, 8, 9, 14, 15). The structures of the major constituents are presented below.
eugenol R = H
eugenol acetate R = CO-CH3
Uses supported by clinical data
Uses described in pharmacopoeias and in traditional systems of medicine
External or local applications for the treatment of toothache, and minor infections of the mouth and skin (7, 14, 16). Also used as an antiseptic for dressing of minor wounds, and, in the form of lozenges, for sore throats and coughs associated with the common cold (7). The essential oil (1-5%) is used in mouthwashes (16).
Uses described in folk medicine, not supported by experimental or clinical data
Treatment of asthma, bleeding gums, dyspepsia, fevers and morning sickness (9).
Ethanol (95%) or aqueous extracts of Flos Caryophylli inhibited the growth in vitro of Staphylococcus aureus (17). The juice of the flower bud inhibited the growth in vitro of Mycobacterium tuberculosis (minimal inhibitory concentration [MIC] 1:160) (18). The powdered crude drug inhibited the growth in vitro of Yersinia enterolitica when added to the medium at a concentration of 1-3% (w/w) (19, 20). An aqueous extract of the flower buds inhibited the growth in vitro of Bacillus subtilis (21). A chloroform extract of the flower buds inhibited the growth in vitro of Cladosporium werneckii (22). A 50% ethanol extract of the flower buds inhibited the growth of Aspergillus fumigatus, Aspergillus niger, Botrytis cinerea, Fusarium oxysporum, Penicillium digitatum, Rhizopus nigricans, Trichophyton mentagrophytes, Candida albicans and Saccharomyces pastorianus at a concentration of 500mg/ml (23).
Eugenol, one of the active constituents of the flower buds, inhibited the growth in vitro of Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa, with an MIC of 0.05, 0.05 and 0.80mg/ml, respectively (24, 25). In other studies, eugenol had a broad spectrum of antibacterial activity in vitro, inhibiting the growth of Clostridium sporogenes, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella pullorum, Staphylococcus aureus, Streptococcus faecalis and Comamonas terrigena at various concentrations (26, 27). Eugenol also had a broad spectrum of antifungal activity in vitro, inhibiting the growth of Alternaria alternata, Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, Cladosporium werneckii, Cladosporium cucumerinum, Colletotrichum capsici, Helminthosporium oryzae, Microsporum canis, Penicillium expansum, Phytophthora parasitica, Rhizopus nodosus, Trichophyton mentagrophytes and T. rubum at various concentrations (27-30).
An aqueous extract of the flower buds suppressed the replication of herpes simplex virus (HSV) in vitro at a concentration of 50µg/ml (31). An aqueous extract of the flower buds had antiviral activity against HSV-1 in vitro (IC50 60µg/ml), and in mice (250mg/kg body weight by gastric lavage) (32). A hot aqueous extract of the flower buds suppressed the replication of HSV-1, measles virus and poliovirus-1 in Vero cells in vitro at a concentration of 0.5mg/ml (33). Intragastric administration of a decoction of the flower buds (750mg/kg body weight) decreased HSV-1 genome titres and the severity of HSV infection in mice with recurring herpetic lesions induced by ultraviolet light (34). Eugenol at a concentration of 0.1-10µg/ml demonstrated antiviral activity against HSV and adenovirus-6 in vitro (35). Eugeniin isolated from the flower buds exhibited anti-HSV-1 activity in mice (36).
Topical application of a methanol extract of the flower buds (2mg/ear) suppressed ear oedema in mice induced by 12-O-tetradecanoylphorbol-13-acetate (37). A methanol extract of the flower buds inhibited interleukin-8 production induced by lipopolysaccharide in rat macrophages in vitro at a concentration of 0.1mg/ml (38). Administration of eugenol (100mg/kg body weight by gastric lavage or 50mg/kg body weight intraperitoneally) inhibited carageenan-induced footpad oedema in rats (39-41). Intragastric administration of eugenol to rats (33mg/kg body weight) suppressed footpad and knee oedema induced by Mycobacterium tuberculosis (42). Administration of eugenol to rats (50mg/kg body weight intraperitoneally or 100mg/kg body weight by gastric lavage) inhibited carrageenan-induced footpad oedema (39, 41). Topical application of eugenol to mice and rats at a dose of 0.2-2.0mg/ear suppressed ear oedema induced by 12-O-tetradecanoylphorbol-13-acetate and ethyl phenylpropiolate (43-45). Topical application of eugenol inhibited carrageenaninduced footpad oedema in rats and reversed passive Arthus reaction in rabbits (46). Eugenol inhibited the activities of cyclooxygenase (IC50 12-82µmol/l) and lipoxygenase (IC50 20-100µmol/l) in vitro (41, 46-48). Eugenol also inhibited the biosynthesis of prostaglandin and thromboxane in various biological systems (27, 44, 49-51) and both eugenol and isoeugenol inhibited platelet aggregation (IC50 1.8µmol/l) (46).
A petroleum ether or ethylene chloride extract of the flower buds exhibited strong antioxidant activity in vitro at a concentration of 0.1% (52, 53). A methanol extract of the flower buds inhibited lipid peroxidation induced by carbon tetrachloride, ADP plus arachidonic acid, and ADP plus NADPH (IC50 1.7, 2.6 and 6.4µg/ml, respectively) (54). The antioxidant activity of eugenol has been demonstrated in a wide range of in vitro systems (55-59).
The essential oil had spasmolytic activity in vitro on isolated guinea-pig trachea and intestine (60, 61). Eugenol and caryophyllene had a narcotic effect after intravenous administration of high doses (200-400mg/kg body weight) (27, 62), and a sedative effect after intragastric administration of low doses (1-100mg/kg body weight) to mice (60).
Flos Caryophylli is contraindicated in cases of known allergy to plants of the
No information available.
Carcinogenesis, mutagenesis, impairment of fertility
An aqueous or chloroform-methanol extract of the crude drug was not mutagenic in the Salmonella/microsome assay at concentrations up to 100mg/ml (63, 64). A hot aqueous extract was not mutagenic in the Salmonella/microsome assay using S. typhimurium strains TA98 or TA100 at a concentration of 50mg/disk (63, 65). However, a 95% ethanol extract was mutagenic in the Salmonella/microsome assay using S. typhimurium strain TA102 at a concentration of 10mg/plate (66). Eugenol was not mutagenic in vitro (Salmonella/ microsome assay; up to 600µg/plate) or in vivo (in mice; 200mg/kg body weight, by intramuscular injection) (67-69). Local application of eugenol reduced the carcinogenic activity of benzopyrene (70).
No information available on general precautions or precautions concerning drug interactions; drug and laboratory test interactions; teratogenic and nonteratogenic effects in pregnancy; nursing mothers; or paediatric use. Therefore,
Flos Caryophylli should not be administered during pregnancy or lactation or to children without medical supervision.
Allergic contact dermatitis has been reported in patients who were regularly exposed to Flos Caryophylli or who already had dermatitis of the fingertips (71).
Crude drug, extracts, tincture (1:5, 25% ethanol), lozenges and mouthwash. Store in a well-closed container, protected from light (1, 5).
(Unless otherwise indicated)
Daily dosage: crude drug 3-5g as an infusion (preferably taken hot), three times daily; 25% ethanol extract (1:1) 3-5ml; tincture (1:5, 25% ethanol) 10-25ml (2).
1. African pharmacopoeia. Vol. 1, 1st ed. Lagos, Organization of African Unity, Scientific Technical & Research Commission, 1985.
2. British herbal pharmacopoeia. London, British Herbal Medicine Association, 1996.
3. Pharmacopoeia of the People’s Republic of China. Vol. I (English ed.). Beijing, Chemical Industry Press, 1997.
4. The Japanese pharmacopoeia, 13th ed. (English ed.). Tokyo, Ministry of Health and Welfare, 1996.
5. European pharmacopoeia, 3rd ed. Strasbourg, Council of Europe, 1996.
6. Blaschek W et al., eds. Hagers Handbuch der pharmazeutischen Praxis. Folgeband 2: Drogen A-K, 5th ed. Berlin, Springer-Verlag, 1998.
7. Iwu MM. Handbook of African medicinal plants. Boca Raton, FL, CRC Press, 1993.
8. Bisset NG. Herbal drugs and phytopharmaceuticals. Boca Raton, FL, CRC Press, 1994.
9. Farnsworth NR, ed. NAPRALERT database. Chicago, University of Illinois at Chicago, IL, February 9, 1998 production (an online database available directly through the University of Illinois at Chicago or through the Scientific and Technical Network [STN] of Chemical Abstracts Services).
10. Wagner H, Bladt S. Plant drug analysis. Berlin, Springer-Verlag, 1996.
11. Quality control methods for medicinal plant materials. Geneva, World Health Organization, 1998.
12. Pharmacopée française. Paris, Adrapharm, 1996.
13. Guidelines for predicting dietary intake of pesticide residues, 2nd rev. ed. Geneva, World Health Organization, 1997 (document WHO/FSF/FOS/97.7).
14. Bruneton J. Pharmacognosy, phytochemistry, medicinal plants. Paris, Lavoisier, 1995.
15. Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics, 2nd ed. New York, NY, John Wiley & Sons, 1996:174-177.
16. Blumenthal M et al., eds. The complete German Commission E monographs. Austin, TX, American Botanical Council, 1998.
17. Perez C, Anesini C. Antibacterial activity of alimentary plants against Staphylococcus aureus growth. American Journal of Chinese Medicine, 1994, 22:169-174.
18. Fitzpatrick FK. Plant substances active against Mycobacterium tuberculosis. Antibiotics and Chemotherapy, 1954, 4:528.
19. Al-Khayat MA, Blank G. Phenolic spice constituents sporostatic to Bacillus subtilis. Journal of Food Science, 1985, 50:971-980.
20. Bara MTF, Vanetti MCD. Antimicrobial effect of spices on the growth of Yersinia enterocolitica. Journal of Herbs, Spices and Medicinal Plants, 1995, 3:51-58.
21. Ungsurungsie M et al. Mutagenicity screening of popular Thai spices. Food and Chemical Toxicology, 1982, 20:527-530.
22. Sharma A et al. Microbiological status and antifungal properties of irradiated spices. Journal of Agricultural Food and Chemistry, 1984, 32:1061-1063.
23. Guerin JC, Reveillere HP. Antifungal activity of plant extracts used in therapy. II. Study of 40 plant extracts against 9 fungi species. Annales de Pharmacie française, 1985, 43:77-81.
24. Himejima A, Kubo I. Antimicrobial agents from Licaria puchuri-major and their synergistic effects with polygodial. Journal of Natural Products, 1992, 55:620-625.
25. Kubo I et al. Naturally occurring anti-acne agents. Journal of Natural Products, 1994, 57:9-17.
26. Deans SG, Svoboda KP. Antibacterial activity of French tarragon (Artemisia dracunculus L.) essential oil and its constituents during ontogeny. Journal of Horticultural Science, 1988, 63:503-508.
27. Laekeman GM et al. Eugenol, a valuable compound for in vitro experimental research and worthwhile for further in vivo investigation. Phytotherapy Research, 1990, 4:90-96.
28. Garg SC, Siddiqui N. Antifungal activity of some essential oil isolates. Pharmazie, 1992, 47:467-468.
29. Rahalison L et al. Antifungal tests in phytochemical investigations: comparison of bioautographic methods using phytopathogenic and human pathogenic fungi. Planta Medica, 1994, 60:41-44.
30. Thompson DP. Fungitoxic activity of essential oil components on food storage fungi. Mycologia, 1989, 81:151-153.
31. Takechi M, Tanaka Y. Purification and characterization of antiviral substance from the bud Syzygium aromatica. Planta Medica, 1981, 42:69-74.
32. Kurokawa M et al. Efficacy of traditional herbal medicines in combination with acyclovir against herpes simplex 1 infection in vitro and in vivo. Antiviral Research, 1995, 27:19-37.
33. Kurokawa M et al. Antiviral traditional medicines against herpes simplex virus (HSV-1), poliovirus, and measles virus in vitro and their therapeutic efficacy for HSV-1 infection in mice. Antiviral Research, 1993, 22:175-188.
34. Kurokawa M et al. Prophylactic efficacy of traditional herbal medicines against recurrent herpes simplex virus type 1 infection from latently infected ganglia in mice. Journal of Dermatological Sciences, 1997, 14:76-84.
35. Lembke A, Deininger R. Wirkung von Bestandteilen ätherischer Öle auf Bakterien, Pilze und Viren. In: Reuter HD, Deininger R, Schulz V, eds. Phytotherapie, Grundlagen-Klinik-Praxis. Stuttgart, Hippokrates Verlag, 1988.
36. Kurokawa M et al. Purification and characterization of eugenin as an anti-herpes virus compound from Geum japonicum and Syzygium aromaticum. Journal of Pharmacology and Experimental Therapeutics, 1998, 284:728-735.
37. Yasukawa K et al. Inhibitory effect of edible plant extracts on 12-Otetradecanoylphorbol-13-acetate-induced ear oedema in mice. Phytotherapy Research, 1993, 7:185-187.
38. Lee GI et al. Inhibitory effects of oriental herbal medicines on IL-8 induction in lipopolysaccharide-activated rat macrophages. Planta Medica, 1995, 61:425-428.
39. Bennett A et al. The biological activity of eugenol, a major constituent of nutmeg (Myristica fragrans): studies on prostaglandins, the intestine and other tissues. Phytotherapy Research, 1988, 2:124-130.
40. Reddy ACP, Lokesh BR. Studies on anti-inflammatory activity of spice principles and dietary N-2 polyunsaturated acids on carrageenan-induced inflammation in rats. Annals of Nutrition and Metabolism, 1994, 38:349-358.
41. Saeed SA et al. Eugenol: a dual inhibitor of platelet-activating factor and arachidonic acid metabolism. Phytomedicine, 1995, 2:23-28.
42. Sharma JN et al. Suppressive effects of eugenol and ginger oil on arthritic rats. Pharmacology, 1994, 49:314-318.
43. Pongprayoon U. Pharmacognostic studies on the Thai medicinal plant Ipomoea pes-caprae (L.) R.Br. (Pak bung ta lae). Acta Pharmaceutica Nordica, 1991, 3:184-186.
44. Pongprayoon U et al. Compounds inhibiting prostaglandin synthesis isolated from Ipomoea pes-caprae. Planta Medica, 1991, 57:515-518.
45. Pongprayoon U. Inhibition of ethyl phenylpropiolate-induced rat-ear oedema by compounds isolated from Ipomoea pes-caprae (L.) R.Br. Phytotherapy Research, 1992, 6:104-107.
46. Dewhirst FE. Structure/activity relationship for inhibition of prostaglandin cyclooxygenase by phenolic compounds. Prostaglandins, 1980, 20:209-222.
47. Dohi T et al. Inhibition of lipoxygenase by phenolic compounds. Japanese Journal of Pharmacology, 1991, 55:547-550.
48. Naidu KA. Eugenol - an inhibitor of lipoxygenase-dependent lipid peroxidation. Prostaglandins, Leukotrienes and Essential Fatty Acids, 1995, 53:381-383.
49. Chen SJ et al. Antiplatelet and calcium inhibitory properties of eugenol and sodium eugenol acetate. General Pharmacology, 1996, 27:629-633.
50. Srivastava KC. Antiplatelet principles from a food spice clove (Syzygium aromaticum L.). Prostaglandins, Leukotrienes and Essential Fatty Acids, 1993, 48:363-372.
51. Wagner H et al. In vitro inhibition of prostaglandin biosynthesis by essential oils and phenolic compounds. Planta Medica, 1986, 3:184-187.
52. Saito Y et al. The antioxidant effects of petroleum ether-soluble and -insoluble fractions from spices. Eiyo To Shokuryo, 1976, 29:505-510.
53. Kramer RE. Antioxidants in clove. Journal of the American Oil and Chemical Society, 1985, 62:111-113.
54. Kumazawa N et al. Protective effects of various methanol extracts of crude drugs on experimental hepatic injury induced by carbon tetrachloride in rats. Yakugaku Zasshi, 1990, 110:950-957.
55. Aruoma OI et al. Commentary reaction of plant-derived and synthetic antioxidants with trichloromethylperoxyl radicals. Free Radical Research, 1995, 22:187-190.
56. Davcheva Y et al. Study of the inhibiting activity of eugenol and isoeugenol by chemiluminescence. Oxidation Communications, 1995, 18:250-255.
57. Kumaravelu P et al. The antioxidant effect of eugenol on CCl4-induced erythrocyte damage in rats. Nutritional Biochemistry, 1996, 7:23-28.
58. Uchida M et al. Antioxidative effect of sesamol and related compounds on lipid peroxidation. Biological and Pharmaceutical Bulletin, 1996, 19:623-626.
59. Wie MB et al. Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures. Neuroscience Letters, 1997, 225:93-96.
60. Wagner H, Sprinkmeyer L. Über die pharmakologische Wirkung von Melissengeist. Deutsche Apotheker Zeitung, 1973, 113:1159-1166.
61. Reiter M, Brandt W. Erschlaffende Wirkung auf die glatte Muskulatur von Trachea und Ileum des Meerschweinchens. Arzneimittel-Forschung, 1985, 35:408-414.
62. Sell AB, Carlini EA. Anesthetic action of methyleugenol and other eugenol derivatives. Pharmacology, 1976, 14:367-377.
63. Morimoto I et al. Mutagenicity screening of crude drugs with Bacillus subtilis recassay and Salmonella/microsome reversion assay. Mutation Research, 1982, 97:81-102.
64. Rockwell P, Raw I. A mutagenic screening of various herbs, spices and food additives. Nutrition and Cancer, 1979, 1:10-15.
65. Yamamoto H et al. Studies on the mutagenicity of crude drug extracts. I. Yakugaku Zasshi, 1982, 102:596-601.
66. Mahmoud I et al. Mutagenic and toxic activities of several spices and some Jordanian medicinal plants. International Journal of Pharmacognosy, 1992, 30:81-85.
67. Green NR, Savage JR. Screening of safrole, eugenol, their ninhydrin-positive metabolites and selected secondary amines for potential mutagenicity. Mutation Research, 1978, 57:115-121.
68. Sekizawa J et al. Genotoxicity of safrole-related chemicals in microbial test systems. Mutation Research, 1982, 101:127-140.
69. Amonkar AJ et al. Hydroxychavicol: a new phenolic antimutagen from betel leaf. Food Chemistry and Toxicology, 1986, 24:1321-1324.
70. Merek K, Junginger H, Thiele B. Einige pflanzliche Substanzen als antikanzerogene Phytotherapie. In: Reuter HD, Deininger R, Schulz V, eds. Phytotherapie, Grundlagen-Klinik-Praxis. Stuttgart, Hippokrates Verlag, 1988.
71. Seetharam KA, Pasricha JS. Condiments and contact dermatitis of the fingertips. Indian Journal of Dermatology, Venereology and Leprology, 1987, 53:325-328.