Piper cubeba L. f

Synonyms

Cubeba officinalis Miquel, Piper caudatum Houtt.

Vernacular Names:

Malaysia:

Kemukus, cabai berekur, lada berekur [2]

English:

Java pepper, cubebs, tailed pepper [1]

Indonesia:

Kemukus, cabai Jawa [3]

French:

Poivre de Java [4]

Tamil:

Thippli [4]

Hindi:

Kabab-chini [3]

Vietnamese: Tieu that [4]
Arabic:

Kababah [1]

Chinese: Bi ji, Bi cheng qie [3]

General Information

Description

Piper cubeba is a climbing shrub belonging to the family Piperaceae and grows to a height of 1 m in tropical Asia. The herb is indigenous to Indonesia and Malaysia. It is mostly cultivated in Java and other Indonesian islands for its fruits and essential oil. [1],[4]

This plant came into trade from Malay Archipelago in about the seventh century, and was used then in Europe as a spice. The supplies then came from wild plants but it has been cultivated from time to time in Peninsular Malaysia though not in a persistent way. [5]

Plant Part Used

Dried unripe fruits or berries, entire plant. [5]

Chemical Constituents

The dried P. cubeba fruits contain essential oil consisting of monoterpenes: sabinene, β-elemene, α-thujene, carene, 1,4-cineol and 1,8-cineol; sesquiterpenes: b-caryophyllene, copaene, α- and β-cubebene, d-cadinene, cubebol and germacene; and some lignans including the dibenzylbutyrolactone lignan i.e. (-) cubebin. [1],[4]

Other chemical constituents include allo-aromadendrene, α-muurolene, α-phellandrene, α-pinene, α-terpinene, α-terpineol, asarone, β-bisabolene, β-pinene, bicyclosesquiphellandrene, calamene, cesarone, cubebic acid, cubebinolide, cubenol, epicubenol, g-humulene, g-terpinene, gum, ledol, limonene, linalol, myrcene, nerolidol, ocimene, resinoids, sabinol, and safrole. [6]

A lignan profile of P. cubeba from Indonesia has revealed 13 lignans found in the fruits, 15 in the leaves and only five lignans in the stalk. The structures of the lignans are very biodiversed comprising of furanofuran lignans commonly found in the genus Piper such as cubebin, hinokinin, yatein, isoyatein, and neolignans with an unusual structure such as kadsurin A and piperenone. Other lignans reported elsewhere are: cubebininolide, cubebinone, thujaplicatin trimethylether, cubebinin, clusin, 5-methoxyclusin, 5’-methoxyhinokinin, 2-(3’’,4’’-methylenedioxybenzyl)-3(3’,4’-dimethoxybenzyl) butyrolactone, ascantin, sesamin, dihydrocubebin, hemiarensin, dihydroclusin, β-O-ethylcubebin, α-O-ethylcubebin, heterotropan, magnosalin and 4-hy droxycubebinone. [7]

In the search for new potential trypanocidal drugs, partial synthesis from (-)-cubebin yielded (-)-O-Acetyl cubebin, (-)-O-benzyl cubebin, (-)-O-(N,N-dimethylaminoethyl)-cubebin, (-)-hinokinin,(-)-6,6’-dinitrohinokinin, and (-)-6,6’-diaminohinokinin. [8],[9]

Derivatives of cubebin: (-)-O-acetyl-, (-)-O-methyl-, (-)-O-dimethylethylamine cubebin were synthesized, in an attempt to improve the analgesic and anti-inflammatory activities of cubebin. [10]

Five methylenedioxyphenyl lignans, (-)-clusin, (-)-dihydroclusin, (-)-yatein, (-)-hinokinin, and (-)-dihydrocubebin, were isolated from dried fruits of P. cubeba as potent and selective inhibitors against cytochrome CYP3A4. [11]

Traditional Use:

P. cubebais used in mixtures given as a tonic during confinement. Other, P. cubeba is used as an aphrodisiac. Due to its stimulant, antiseptic and diuretic actions on the mucous membrane of the genitourinary organs, it has been used for a long time to treat gonorrhoea. It is also prescribed to relieve fever, asthma, sunstroke, vomiting, rheumatism, malaria, leucorrhoea and peripheral neuritis. This plant is used in Taiwan to treat gonorrhoea and diabetes. This plant is used to stimulate the appetite and to aid digestion. However, prolonged use may cause diarrhoea. In Indonesia, P. Cubeba is present in native medicines to treat venereal disease, dysentery and other intestinal disorders. [5]

In China, the fruits are known to be a stomachic and a carminative. They are used as a remedy for vomiting, abdominal disorders, indigestion and amoebic dysentery. The fruit is also ingested to treat coughs, bronchitis, sinusitis, sore throats and genitourinary infections. [5]

Pre-Clinical Data

Pharmacology

Trypanocidal activity

Chagas’ disease caused by Trypanosoma cruzi infection has been a difficult disease to control. The clinical treatment of infected patients with benznidazole causes serious side effects and is not effective for the treatment of the chronic phase of the disease. In the search for new therapeutic compounds, researchers have paid special attention to natural products and among them the biological active compounds of P. cubeba. Recently, the studies was evaluated previously synthesized five (-)-cubebin derivative compounds, (-)-O-acetyl cubebin, (-)-O-benzyl cubebin and (-)-O-(N,N-dimethylaminoethyl)-cubebin, (-)-hinokinin, and (-)-6,6’-dinitrohinokinin in an in vitro assay against T.cruzi.  The results showed that (-)-hinokinin is the most active compound with an IC50 value of 0.7 mM, similar to that displayed by benznidazole (0.8 mM). The data obtained showed P. cubeba as a very important potential source for obtaining new lead compounds for the treatment of Chagas’ disease. [8]

Analgesic and anti-inflammatory activity

In an attempt to further improve the analgesic and anti-inflammatory activity of cubebin, the derivatives of cubebin were partially synthesized and their possible activities evaluated. The three derivatives; (-)-O-acetyl cubebin, (-)-O-methyl cubebin and (-)-O-dimethylethylamine cubebin (30 mg/kg), administered orally 30 minutes before the injection of carrageenin, inhibited the formation of oedema by 68%, 65% and 70%, respectively, 3 hours after the injection of the inflammatory stimulus. In conclusion, these compounds showed anti-inflammatory and analgesic activities similar to that observed for the NSAIDs. [10]

Anti-inflammatory and antinociceptive activity:

In a search for more effective medicinal plants having anti-inflammatory, anti-allergic and analgesic effects, one of the three plants selected was P. cubeba. The selection was based on their inhibitory action on nitrite production of microphages and antioxidant actions in vitro. In this study, anti-inflammatory activities were determined by carrageenan-induced paw oedema, arachidonic acid-induced ear oedema and formaldehyde-induced arthritis in mice. The result showed that methanolic extract of this herb caused 45% inhibition of oedema as compared to the control group. In the case of the effect of the plant extract on DNFB-induced delayed-type hypersensitivity, P. cubeba showed significant inhibitory effect after oral administration daily for seven days at a dose of 200 mg/kg. [12]

Toxicities

No documentation

Clinical Data

Clinical Trials

No documentation

Adverse Effects in Human:

No documentation

Use in Certain Conditions

Pregnancy / Breastfeeding

No documentation

Age Limitations

Neonates / Adolescents

No documentation

Geriatrics

No documentation

Chronic Disease Conditions

No documentation

Interactions

Interactions with drugs

P. cuceba interacts with antacids, H2 blockers and proton pump inhibitor. [13]

Interactions with Other Herbs / Herbal Constituents

No documentation

Contraindications

Contraindications

P. cubeba may irritate the gastrointestinal (GI) tract, contraindicated in individuals with infectious or inflammatory GI conditions. [13]

P. cubeba is contraindicated in individuals with nephritis. [13]

Case Reports

No documentation

References

    1. Cubeb-Wikipedia, the free encyclopedia, http:// en.wikipedia.org/wiki/Cubeba [accessed on 22 Oct 2007]
    2. Mohan, J.F. Major Medicinal Plants: Botany, Culture and Uses. Charles C. Thomas Publisher: Springfield. 1977; pp 360.
    3. Cubeb Pepper http://www.uni-graz.at/~karzer/eng/Pipe_cub.html [accessed on 2nd July 2007]
    4. Wiart, C. Medicinal Plants of the Asia-Pacific: Drugs for the Fure?World Scientific Publishing Co. Pte. Ltd., Singapore. 2006; pp 41-2.
    5. Herbal Medicine Research Centre, Institute for Medical Research, Kuala Lumpur.   Compendium of Medicinal Plants Used in Malaysia. 2002; 2:226-227.
    6. Dr. Duke’s Phytochemical and Ethnobotanical Databases.
    7. Elfahmi et al. Lignan profile of Piper cubeba, an Indonesian medicinal plant. Biochemical Systematics and Ecology. 2007; 35:397-402.
    8. De Souza, V.A. et al. Trypanocidal activity of (-)-cubebin derivatives against free amastigote forms of Trypanocidal cruzi. Bioorganic & Medicinal Chemistry Letters. 2005; 15: 303-7.
    9. Da Silva, R.,et al. Synthesis and biological activity evaluation of lignan lactones derived from (-)-cubebin. Bioorganic & Medicinal Chemistry Letters. 2005; 15: 1033-7.
    10. Souza, G.H.B. et al. Analgesic and anti-inflammatory activities evaluation of (-)-O-acetyl, (-)-O-methyl, (-)-O-dimethylethylamine cubebin and their preparation from (-)-cubebin. Il Farmaco. 2004;  59:55-61.
    11. Usia, T. et al. Metabolite-cytochrome P450 complex formation by methylenedioxyphenyl lignans of Piper cubeba: Mechanism-based inhibition. Life Sciences. 2005; 76: 2381-91.
    12. Choi, E-M. & Hwang, J-K. Investigation of anti-inflammatory and antinociceptive activities of Piper cubeba, Physalis angulata and Rosa hybrida. J. Ethnopharmacol. 2003 ;89:171-5.
    13. Natural Medicines Comprehensive Database: Monograph, http://www.naturaldatabase.com/ [accessed on 22 Oct 2007]