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Journal of Ethnopharmacology 117 (2008) 1–27

Review

Psidium guajava: A review of its traditional uses,phytochemistry and pharmacology

Rosa Martha Perez Gutierrez a,∗, Sylvia Mitchell b, Rosario Vargas Solis c

a Laboratorio de Investigacion de Productos Naturales, Escuela Superior de Ingenierıa Quımica e Industrias extractivas IPN,Punto Fijo 16, Col. Torres Lindavista C.P. 07708 Mexico, D.F., Mexico

b Medicinal Plant Research Group, Biotechnology Centre, 2 St. John’s Close, University of the West Indies, Kingston 7, Jamaicac Laboratorio de Investigacion de Fitofarmacologıa, Universidad Autonoma Metropolitana-Xochimilco A.P. 23-181 Mexico, D.F., Mexico

Received 18 August 2007; received in revised form 26 January 2008; accepted 29 January 2008Available online 3 February 2008

bstract

Psidium guajava, is an important food crop and medicinal plant in tropical and subtropical countries is widely used like food and in folk medicineround of the world. This aims a comprehensive of the chemical constituents, pharmacological, and clinical uses. Different pharmacologicalxperiments in a number of in vitro and in vivo models have been carried out. Also have been identified the medicinally important phyto-constituents.

number of metabolites in good yield and some have been shown to possess useful biological activities belonging mainly to phenolic, flavonoid,arotenoid, terpenoid and triterpene. Extracts and metabolites of this plant, particularly those from leaves and fruits possess useful pharmacologicalctivities. A survey of the literature shows P. guajava is mainly known for its antispasmodic and antimicrobial properties in the treatment ofiarrhoea and dysentery. Has also been used extensively as a hypoglycaemic agent. Many pharmacological studies have demonstrated the ability of
his plant to exhibit antioxidant, hepatoprotection, anti-allergy, antimicrobial, antigenotoxic, antiplasmodial, cytotoxic, antispasmodic, cardioactive,nticough, antidiabetic, antiinflamatory and antinociceptive activities, supporting its traditional uses. Suggest a wide range of clinical applicationsor the treatment of infantile rotaviral enteritis, diarrhoea and diabetes.
2008 Published by Elsevier Ireland Ltd.

eywords: Psidium guajava; Myrtaceae; Clinical; Complementary medicine; Phytochemical constituents; Pharmacological actions

ontents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.1. Use in traditional medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2. Phytochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.1. Fruits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.2. Fruit skins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.3. Leaves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3. Biological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.1. Anti-diarrhoeal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.2. Antimicrobial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.3. Acne lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.4. Effect on dental plaque . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.5. Antimalarial effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.6. Antitussive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.7. Hepatoprotective effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author at: Punto Fijo No. 16, Col. Torres de Lindavista, C.P. 0770E-mail address: [email protected] (R.M.P. Gutierrez).

378-8741/$ – see front matter © 2008 Published by Elsevier Ireland Ltd.oi:10.1016/j.jep.2008.01.025

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8 Mexico, D.F., Mexico.

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2 R.M.P. Gutierrez et al. / Journal of Ethnopharmacology 117 (2008) 1–27

3.8. Antioxidant, free radical scavenger and radioprotective activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.9. Antigenotoxic and antimutagenic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.10. Anti-allergic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.11. Anticancer/antitumour effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.12. Cardiovascular, hypotensive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83.13. Anti-hyperglycemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83.14. Effect on muscular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.15. Anti-inflammatory/analgesic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.16. Antinociceptive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.17. Wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

4. Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105. Clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

5.1. Infantile rotaviral enteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105.2. Infectious gastroenteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105.3. Cardiovascular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105.4. Dysmenorrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115.5. Hypoglycaemic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Appendix A. Constituents of Psidium guayava . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

Psidium guajava, which is considered a native to MexicoRios et al., 1977) extends throughout the South America,uropean, Africa and Asia. Based on archaeological evidence.

t has been used widely and known in Peru since pre-Columbianimes. It grows in all the tropical and subtropical areas of theorld, adapts to different climatic conditions but prefers dry

limates (Stone, 1970). The main traditional use known is asn anti-diarrhoeal. Other reported uses include gastroenteritis,ysentery, stomach, antibacterial colic pathogenic germs of thentestine.

Its medicinal usage has been reported in indigenous systemf medicines in America more than elsewhere. Psidium guajavainn. (family Myrtaceae), is commonly called guave, goyave oroyavier in French; guave, Guavenbaum, Guayave in German;anjiro in Japanese; goiaba, goiabeiro in Portugal; araca-goiaba,raca-guacu, guaiaba in Brazil; guayaba, guayabo in Espanolnd guava in English (Killion, 2000). Psidium guajava is a smallree which is 10 m high with thin, smooth, patchy, peeling bark.eaves are opposite, short-petiolate, the blade oval with promi-ent pinnate veins, 5–15 cm long. Flowers are somewhat showy,etals whitish up to 2 cm long, stamens numerous (Stone, 1970).ruit are fleshy yellow globose to ovoid berry about 5 cm iniameter with an edible pink mesocarp containing numerousmall hard white seeds. There has been a tremendous interestn this plant as evidenced by the voluminous work. Therefore,e aimed to compile an up to date and comprehensive reviewf Psidium guajava that covers its traditional and folk medicineses, phytochemistry and pharmacology.

.1. Use in traditional medicine

More recent ethnopharmacological studies show that Psid-um guajava is used in many parts of the world for the treatment

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f a number of diseases, e.g. as an anti-inflammatory, for dia-etes, hypertension, caries, wounds, pain relief and reducingever (Table 1). Some of the countries with a long history of tra-itional medicinal use of guava include Mexico and other Centralmerican countries including the Caribbean, Africa and Asia.ome of these uses will be outlined here.

Medicinal plants are an important element of the indigenousedical systems in Mexico (Lara and Marquez, 1996). These

esources are part of their traditional knowledge. The Popolucandians of Veracruz rely on medicinal plants for their health care.hey appear to have developed a system whereby they selectnd continue to use plants that they find the most effective forealth care purposes. The folk use of guava has been documentedn the indigenous groups of Mexican Indians, Maya, Nahuatl,apotec and Popoluca. A decoction of the leaves is used to cureough. According to communities of Nahuatl and Maya originnd Popoluca of the region of the Tuxtlas, Veracruz, they use auava leaf decoction to treat digestive suffering associated withevere diarrhoea. This is a frequent disease in rainy weatherHeinrich et al., 1998).

P guajava (Myrtaceae) is widely used in Mexico to treatastrointestinal and respiratory disturbances and is used as annti-inflammatory medicine (Aguilar et al., 1994). Commonlyoots, bark, leaves and immature fruits, are used in the treatmentf gastroenteritis, diarrhoea and dysentery. Leaves are appliedn wounds, ulcers and for rheumatic pain, while they are chewedo relieve toothache (Heinrich et al., 1998). A decoction of theew shoots is taken as a febrifuge. A combined decoction ofeaves and bark is given to expel the placenta after childbirthMartınez and Barajas, 1991). A water leaf extract is used toeduce blood glucose level in diabetics. This hot tea was very
ommon among the local people of Veracruz (Aguilar et al.,994).
The leaf of Psidium guajava is used traditionally in Southfrican folk medicine to manage, control, and/or treat a plethora

R.M.P. Gutierrez et al. / Journal of Ethnopharmacology 117 (2008) 1–27 3

Table 1Ethnomedical uses of Psidium guajava

Place, country Part(s) used Ethno medical uses Preparation(s) Reference(s)

Colombia, Mexico Leaves Gastroenteritis, diarrhoea, dysentery, rheumaticpain, wounds, ulcers, and toothache

Decoction and poultice Heinrich et al. (1998),Aguilar et al. (1994)

Indigenous Maya,Nahuatl, Zapotec andPopoluca of the regionTuxtlas, Veracruz,Mexico

Leaves Cough, diarrhoea Decoction or infusion Heinrich et al. (1998), Leontiet al. (2001)

Latin America,Mozambique

Leaves Diarrhoea, stomach ache Infusion or decoction Pontikis (1996)

Mexico Shoots, leaves, barkand leaves mixed, ripfruits

Febrifuge, expel the placenta after childbirth,cold, cough hypoglycaemic, affections of theskin, caries, vaginal haemorrhage, wounds,fever, dehydration, respiratory disturbances

Decoction, poultice Martınez and Barajas (1991),Argueta et al. (1994), Linaresand Bye (1990), Leonti et al.(2001), Heinrich et al. (1998)

Panama, Cuba, CostaRica, Mexico,Nicaragua, Panama,Peru, Venezuela,Mozambique,Guatemala, Argentina

Leaves Antiinflamatory Externally applied hot oninflammations

Pardo (1999), Jansen andMendez (1990), Valdizan andMaldonado (1972)

South Africa Leaves Diabetes mellitus, hypertension Infusion or decoction Oh et al. (2005), Ojewole(2005)

Caribbean Leaves Diabetes mellitus Infusion or decoction Mejıa and Rengifo (2000)China Leaves Diarrhoea, antiseptic, Diabetes mellitus Infusion or decoction Teixeira et al. (2003)Philippines Leaf, bark, unripe

fruit, rootsAstringent, ulcers, wounds, diarrhoea Decoction and poultice Smith and Nigel (1992)

India Leaves,shoots

Febrifuge, antispasmodic, rheumatism,convulsions, astringent

Decoction or infusion Hernandez(1971)Ghana

Peru Flower buds, leaves Heart and constipation, conjunctivitis, cough,diarrhoea, digestive problems, dysentery,oedema, gout, haemorrhages, gastroenteritis,gastritis, lung problems, shock, vaginaldischarge, vertigo, vomiting, worms

Infusion or decoction Cabieses (1993)

Kinshasa, Congo Leaves, bark Diarrhoea, antiamoebic Infusion or decoction,tisane

Tona et al. (1999)

Senegal Shoots, roots Diarrhoea, dysentery Infusion or decoction Tona et al. (1999)Uruguay Leaves Vaginal and uterine wash, especially in

leucorrhoeaInfusion or decoction Conway (2002)

Fiji Leaves, roots, ripefruit

Diarrhoea, coughs, stomach-ache, dysentery,toothaches, indigestion, constipation

Juice, the leaves arepounded, squeezed in saltwater

Word Health Organization(1998)

Tahiti, Samoa Whole plant, shoots Skin tonic, painful menstruation, miscarriages,uterine bleeding, premature labour in women,wounds

Infusion or decoction,paste

Word Health Organization(1998)

New Guinea, Samoa,Tonga, Niue, Futuna,Tahiti

Leaves Itchy rashes caused by scabies Boiled preparation Word Health Organization(1998)

Cook Islands Leaves Sores, boils, cuts, sprains Infusion or decoction Word Health Organization(1998)

Trinidad Leaves Bacterial infections, blood cleansing, diarrhoea,dysentery

Infusion or decoction Word Health Organization(1998)

Latin America, Centraland West Africa, andSoutheast Asia

Leaves Gargle for sore throats, laryngitis and swellingof the mouth, and it is used externally for skinulcers, vaginal irritation and discharge

Decoction Mejıa and Rengifo (2000)

Panama, Bolivia andVenezuela

Bark and leaves Dysentery, astringent, used as a bath to treat skinailments

Decoction Conway (2002)

Brazil Ripe fruit, flowers,and leaves

Anorexia, cholera, diarrhoea, digestiveproblems, dysentery, gastric insufficiency,inflamed mucous membranes, laryngitis, mouth(swelling), skin problems, sore throat, ulcers,vaginal discharge

Mashed, Decoction Holetz et al. (2002), Cybele etal. (1995)

USA Leaf Antibiotic and diarrhoea Decoction Smith and Nigel (1992)

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f human ailments, including diabetes mellitus and hypertensionOjewole, 2005; Oh et al., 2005).

Guava has been used widely in the traditional medicine ofatin America and the Caribbean in the treatment of diarrhoeand stomach-aches due to indigestion (Mejıa and Rengifo, 2000;itchell and Ahmad, 2006a,b). Treatment usually involves a

ecoction of the leaves, roots, and bark of the plant. It alsoas been used for dysentery in Panama and as an astringent inenezuela. A decoction of the bark and leaves is also reported toe used as a bath to treat skin ailments. In Uruguay, a decoctionf the leaves is used as a vaginal and uterine wash, especially ineucorrhoea (Conway, 2002). In Costa Rica, a decoction of theower buds is considered an effective anti-inflammatory remedyPardo, 1999).

In Peru, it is used for gastroenteritis, dysentery, stomach painby acting on the pathogenic microorganisms of the intestine),ndigestion, inflammations of the mouth and throat in the formf gargles (Cabieses, 1993). In some tribes of the forest (Tipis),he tender leaves are chewed to control toothaches by theireak sedative effect. Tikuna Indians use the decocted leavesr bark of guava for diseases of the gastrointestinal tract. It islso employed by the Indians of the Amazons for dysentery,ore throats, vomiting, stomach upsets, vertigo, and to regulateenstrual periods, mouth sores, bleeding gums, or used as a

ouche for vaginal discharge and to tighten and tone vaginalalls after childbirth. Flowers are also mashed and applied toainful eye conditions such as sun strain, conjunctivitis or eyenjuries (Smith and Nigel, 1992). Guava jelly is tonic to theeart and constipation (Conway, 2002).

In the Philippines the astringent unripe fruit, the leaves, theortex of the bark and the roots are used for washing ulcers andounds, as an astringent, vulnerary, and for diarrhoea. Leaves

nd shoots are used by West Indians in febrifuge and antispas-odic baths; the dust of the leaves is used in the treatment of

heumatism, epilepsy and cholera; and guava leaves tincture isiven to children suffering from convulsions (Morton, 1987).

In Latin America, Central and West Africa, and Southeast
sia, guava is considered an astringent, drying agent and aiuretic. A decoction is also recommended as a gargle for sorehroats, laryngitis and swelling of the mouth, and it is used exter-ally for skin ulcers, vaginal irritation and discharge (Mejıa
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able 2ommercial applications of Psidium guajava

ruit Food: juice, jelly nectar, concentrated, stuffed of candies,pastes, tinned products, confectionery, etc.

ood and leaves Carpentry and turnery use the leaves to make a black dyeood Engravingsood Spinning topsood Hair combsood Construction of houses

eaves Employed to give a black colour to cottoneaves Serve to dye mattingark Dyes, stains, inks, tattoos and mordantsood flowers The tree may be parasitized by the mistletoe, Psittacanthu

Don, producing the rosette-like malformations called “wowhich are sold as ornamental curiosities. Also the tree is sshade to the coffee and its wood is used in the constructio

opharmacology 117 (2008) 1–27

nd Rengifo, 2000). In Mozambique, the decoction of leavess mixed with the leaves of Abacateira cajueiro, to alleviatehe flu, cough and pressed chest. In Mozambique, Argentina,

exico and Nicaragua, guava leaves are applied externally fornflammatory diseases (Jansen and Mendez, 1990).

The use of medicinal plants by the general Chinese populations an old and still widespread practice. Psidium guajava leavesre example of the plant commonly used as popular medicineor diarrhoea which is also used as an antiseptic (Teixeira et al.,003).

In Brazil the fruit and leaves are considered for anorexia,holera, diarrhoea, digestive problems, dysentery, gastricnsufficiency, inflamed mucous membranes, laryngitis, mouthswelling), skin problems, sore throat, ulcers, vaginal dischargeHoletz et al., 2002). In USA guava leaf extracts that are used inarious herbal formulas for a myriad of purposes; from herbalntibiotic and diarrhoea formulas to bowel health and weightoss formulas (Smith and Nigel, 1992).

Besides the medicinal uses Psidium guayava is employed asood, in carpentry, in construction of houses and in the manu-acture of toys (Table 2).

. Phytochemistry

.1. Fruits

These are characterized by a low content of carbohydrates13.2%), fats (0.53%), and proteins (0.88%) and by a high-ater content (84.9%), (Medina and Pagano, 2003). Foodalue per 100 g is: Calories 36–50 kcal, moisture 77–86 g,rude fibre 2.8–5.5 g, ash 0.43–0.7 g, calcium 9.1–17 mg, phos-horus (Conway, 2002), 17.8–30 mg, iron 0.30–0.70 mg (Iwu,993), vitamin A 200–400 I.U., thiamine 0.046 mg, riboflavin.03–0.04 mg, niacin 0.6–1.068 mg, ascorbic acid 100 mg, vita-in B3 40 I.U. (Fujita et al., 1985; Hernandez, 1971; Conway,

002). Manganese is also present in the plant in combina-ion with phosphoric, oxalic and malic acids (Nadkarni and
adkarni, 1999).Hexanal (65.9%), �-butyrolactone (7.6%), (E)-2-hexenal
7.4%), (E,E)-2,4-hexadienal (2.2%), (Z)-3-hexenal (2%), (Z)--hexenal (1%), (Z)-3-hexenyl acetate (1.3%) and phenol

gelatines, All the countries Jimenez-Escrig et al. (2001)

for silk Malaya Rodarte (1994)India Rodarte (1994)Guatemala Morton (1987)El Salvador Morton (1987)Nigeria Lucas et al. (2006)Southeast Asia Rodarte (1994)Indonesia Rodarte (1994)Africa Burkill (1985)

s calyculatusod flowers”eeded to given

Mexico Argueta et al. (1994)

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1.6%) were reported from fresh white-flesh guayaba fruit oil.-caryophyllene (24.1%), nerolidol (17.3%), 3-phenylpropylcetate (5.3%) and caryophyllene oxide (5.1%) were isolatedrom essential oil extracted from the fruits (Paniandy et al.,000). Subsequently, the active aromatic constituents in pinkuava fruit the 3-penten-2-ol and 2-butenyl acetate were isolatedJordan et al., 2003). The fruit also contains glykosen 4.14%,accharose 1.62%, and protein 0.3% (Dweck, 2001; Hwang etl., 2002).

The unripe fruit is indigestible, causes vomiting and fever-shness. It changes in chemical composition and the activities ofydrolytic enzymes (the activities of �-amylase and �-amylaseecreased significantly with ripening), chlorophyll, cellulose,emicellulose, and lignin content increased while carotenoidontent decreased. The unripe fruit is high in tannins, is astrin-ent and has a tendency to cause constipation, but it is sometimesmployed in diarrhoea (Jain et al., 2003).

.2. Fruit skins

Ascorbic acid is the main constituent of the skin, secondly inhe firm flesh, and a little content in the central pulp varies from6 mg to 600 mg and may range between 350 mg and 450 mgn nearly ripe fruit (Charles et al., 2006). Canning or othereat processing destroys about 50% of the ascorbic acid. Thetrong odour of the fruit is attributed to its carbonyl compoundsDweck, 2001).

.3. Leaves

Leaves contain essential oil with the main componentseing �-pinene, �-pinene, limonene, menthol, terpenyl acetate,sopropyl alcohol, longicyclene, caryophyllene, �-bisabolene,ineol, caryophyllene oxide, �-copanene, farnesene, humu-ene, selinene, cardinene and curcumene (Zakaria and Mohd,994; Li et al., 1999). Flavonoids, and saponins combined withleanolic acid have been isolated from the leaves (Arima andanno, 2002). Nerolidiol, �-sitosterol, ursolic, crategolic, anduayavolic acids have also been identified (Iwu, 1993). In addi-ion, the leaves contain triterpenic acids as well as flavonoids;vicularin and its 3-l-4-pyranoside with strong antibacterialction (Oliver-Bever, 1986), fixed oil 6%, 3.15% resin, and.5% tannin, and a number of other fixed substances, fat, cel-ulose, tannin, chlorophyll and mineral salts (Nadkarni andadkarni, 1999). Also have been isolated from the leavesf Psidium guajava guavanoic acid, guavacoumaric acid,�-hydroxyursolic acid, jacoumaric acid, isoneriucoumariccid, asiatic acid, ilelatifol d and �-sitosterol-3-O-�-d-lucopyranoside (Begum et al., 2002a,b). In mature leaves,he greatest concentrations of flavonoids were found in July:

yricetin (208.44 mg kg−1), quercetin (2883.08 mg kg−1),uteolin (51.22 mg kg−1) and kaempferol (97.25 mg kg−1)Vargas et al., 2006). Two triterpenoids, 20�-acetoxy-
�,3�-dihydroxyurs-12-en-28-oic acid (guavanoic acid), and�,3�-dihydroxy-24-p-z-coumaroyloxyurs-12-en-28-oic acidguavacoumaric acid), along with six known compounds�-hydroxyursolic acid, jacoumaric acid, isoneriucoumaric
taid

opharmacology 117 (2008) 1–27 5

cid, asiatic acid, ilelatifol d and �-sitosterol-3-O-�-d-lucopyranoside, have been isolated from the leaves ofsidium guajava. guajavolide (2a-,3�-6�-,23-tetrahydroxyurs-2-en-28,20�-olide, and guavenoic acid, were isolated fromresh leaves of Psidium guajava.

Bark: It contains 12–30% of tannin (Burkill, 1997), resin andcrystals of calcium oxalate (Nadkarni and Nadkarni, 1999).Roots: They contain tannins, leukocyanidins, sterols, gallicacid, carbohydrates and salts. Root, stem-bark and all leavescontain a large percentage of tannic acid (Quisumbing, 1978).Seeds: They contain 14% oil, dry weight, with 15% proteins and13% starch (Burkill, 1997), phenolic and flavonoid compoundsincluding quercetin-3-O-�-d-(2′′-O-galloyl-glucoside)-4′-O-vinylpropionate (Michael et al., 2002). Some isolatedcompounds are cytotoxic (Salib and Michael, 2004).Floral bud: Buds have the highest concentrations ofmyricetin (256 mg kg−1), quercetin (3605 mg kg−1), lute-olin (229 mg kg−1), kaempferol (229 mg kg−1) and apigenin(252 mg kg−1) (Vargas et al., 2006).Twigs: Contain calcium (0.30–1.00%), magnesium(0.06–0.30%), phosphorous (0.10–0.38%), potassium(0.21–0.39%), and sodium (0.03–0.20%). The concentra-tion of fluoride ranged from 0.02 ppm to 0.11 ppm, copper(0.02–0.14 ppm), iron (2.86–5.14 ppm), zinc (0.31–0.57 ppm),manganese (0.00–0.26 ppm), and lead (0.00–0.11 ppm)(Okwu and Ekeke, 2003). Contains Flavonoid, sesqui-terpenesalcohols and acids triterpenoids (Hegnauer, 1969).

. Biological activity

Scientific investigations on the medicinal properties of guavaates back to the 1940s. A summary of the findings of thesetudies performed is presented below.

.1. Anti-diarrhoeal

Diarrhoea has long been recognized as one of the mostmportant health problems faced globally particularly by theopulation of developing countries. Each year diarrhoea is esti-ated to kill about 2.2 million people globally, the majority

f whom are infants and children below the age of 5 yearsVenkatesan et al., 2005). Ethanol and aqueous extracts ofsidium guajava at a concentration of 80 �g/ml in an organath, exhibited more than 70% inhibition of acetylcholinend/or KCl solution-induced contractions of isolated guinea-ig ileum. The rates of propulsion in the small intestine in maleprague–Dawley rats as a means of assessing antidiarrhoealctivity of aqueous extracts of the leaf of Psidium guajava usingorphine as the standard drug of reference measured (Tona

t al., 1999; Lutterodt, 1992). A dose of 0.2 ml/kg fresh leafxtract produced 65% inhibition of propulsion. This dose is equi-
able with 0.2 mg/kg of morphine sulphate. The antidiarrhoealction of the extract may be due, in part, to the inhibition of thencreased watery secretions that occur commonly in all acuteiarrhoeal diseases and cholera.

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Quercetin showed significant anti-diarrhoeal activity on theontraction of guinea pig ileum in vitro and the peristalticotion of mouse small intestine, and reduced the permeability

f abdominal capillaries (Heinrich, 1998; Zhang et al., 2003).uercetin and quercetin-3-arabinoside, extracted from the buds

nd leaves of Psidium guajava at concentrations of 1.6 �g/mlhowed a morphine-like inhibition of acetylcholine release inhe coaxially stimulated ileum, together with an initial increasen muscular tone, followed by a gradual decrease (Lutterodt,989). It is also reported that the asiatic acid, also extractedrom the leaves, showed dose-dependent (10–500 �g/ml) spas-olytic activity in spontaneously contracting isolated rabbit

ejunum preparations (Conde et al., 2003). Methanol extractrom leaves (8 �g/ml) of Psidium guajava showed activitygainst simian (SA-11) rotavirus (93.8% inhibition) (Goncalvest al., 2005). In addition, galactose-specific lectin in guayabaas shown to bind to Escherichia coli (a common diarrhoea-

ausing organism), preventing its adhesion to the intestinal wallnd thus preventing infection resulting diarrhoea (Coutino et al.,001).

A methanolic leaf extract (8 �g/ml) of Psidium guajava alsohowed activity against simian (SA-11) rotavirus (93.8% inhi-ition) (Goncalves et al., 2005). In addition, galactose-specificectin isolated from guava fruit ripe were shown to bind toscherichia coli (a common diarrhoea-causing organism), pre-enting its adhesion to the intestinal wall and thus preventingnfection resulting diarrhoea (Coutino et al., 2001).

.2. Antimicrobial

The inhibitory effects of aqueous and alcoholic extracts ofhe Psidium guajava (root as well as leaves) on the growthf Staphylococcus aureus, Streptococcus mutans, Pseudomonaseruginosa, Salmonella enteritidis, Bacillus cereus, Proteuspp., Shigella spp. and Escherichia coli, causal agent of intesti-al infections in humans were examined using the in vitro agarell diffusion method (Chah et al., 2006).Methanolic root extract was further separated by column

hromatograph, yielding four antibacterial compounds. Threentibacterial substances have been detected in the leaves whichre derivatives of quercetin (Prabu et al., 2006; Arima andanno, 2002).In another study, it was observed that methanolic extract from

ruit ripe have fungicidal action against Arthrinium sacchari001 and Chaetomium funicola M002 strains (Sato et al., 2000).Aqueous and methanolic extracts of the leaves are effective

nhibitors of growth spore formation, and enterotoxin produc-ion of Clostridium perfringens type A. No enterotoxins wereetected when extracts were added to the media at less than theIC for growth (Garcia et al., 2002).Psidium guajava leaf and bark tinctures were subjected to in

itro sensitivity tests by serial dilution at concentrations rangingrom 5% to 15% against six test dermatophytes, viz., Trichophy-
on tonsurans, Trichophyton rubrum, Trichosporon beigelii,
icrosporum fulvum, Microsporum gypseum and Candida albi-ans. Bark tincture exhibited higher efficacy in controlling theycelial growth of dermatophytes than the leaf tincture.

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The bark tincture showed fungicidal activity at different con-entrations but exhibited only fungistatic property in case ofandida albicans (Dutta and Das, 2000).

Ethanolic extract from the shell of ripe fruit presenting activ-ty on Streptococcus mutans and Escherichia coli (Neira andamirez, 2005). Results supported the utilization of Psidiumuajava in traditional medicine for intestinal diseases producedy microorganisms.

.3. Acne lesions

Acne vulgaris is a chronic inflammatory disease involvingolonization of Propionibacterium acnes, plus activation of neu-rophils and lymphocytes. Circumstantial evidence suggests thatntigen-independent and -dependent immune responses againstropionibacterium acnes are involved in the pathogenesis of

nflammatory acne. Epidermal keratinocytes are also suggestedo be involved in initiation and progression of cutaneous inflam-

ation. Psidium guajava leaf extracts have potent antimicrobialctivities against Propionibacterium acnes and may be benefi-ial in treating acne especially when they are known to haventi-inflammatory activities (Qadan et al., 2005).

.4. Effect on dental plaque

The adhesion of early settlers of dental plaque to the toothurface has a role in the initiation of the development of den-al plaque. The hydrophobic surface properties of the bacteriaell wall are indirectly responsible for the adhesion of the bac-eria cell to the acquired pellicle on the tooth surfaces. Toothrushing is considered a superior technique for reducing plaqueccumulation. Chemical agents may be used to reduce plaqueccumulation on tooth surfaces. The treatment of the earlylaque settlers with 1 mg/ml aqueous extract leaf of Psidiumuajava reduced the cell-surface hydrophobicity of Staphylo-occus sanguinis, Staphylococcus mitis and Actinomyces sp. by4.1%, 49.9% and 40.6%, respectively (Razak et al., 2006).hese results provide some scientific rationale for its use in

he treatment of dental diseases and suggested that guava leafxtracts may inhibit the caries-inducing properties of Strepto-occus and thus may be beneficial for the dental care.

.5. Antimalarial effects

The parasite lactate dehydrogenase (pLDH) assay method,recently developed in vitro enzymatic method for evaluating

ntimalarial compounds, was used to examine the antiplas-odial activities of the aqueous leaf, stem-bark and fruit

xtracts of Psidium guajava. An in vitro antiplasmodial assayarried out using a chloroquine-sensitive strain of malarialarasite, Plasmodium falciparum D10 showed antigiardiasicctivity with trophozoite mortality (87% ± 1.0); guava stem-
ark extract showed IC50 values of 10–20 �g/ml (Ponce et al.,994; Nundkumar and Ojewole, 2002). In another study, leavesnd stem bark of Psidium guajava inhibited Entamoeba histolyt-ca growth with MAC < 10 �g/ml (Tona et al., 1998).

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.6. Antitussive effects

In another report, the water infusion from Psidium guajavaeaves decreased the frequency of coughing induced by capsaicinerosol as compared to the control, within 10 min after injectionf the extract (Jaiarj et al., 1999). Infusion on isolated rat trachealuscle showed one directly stimulated muscle contraction and

lso synergized with the stimulatory effect of pilocarpine. Thisffect was antagonized by atropine (Pranee et al., 1999). Theseesults suggest that guava leaf extract could be recommended ascough remedy.

.7. Hepatoprotective effects

The hepatoprotective effect of an aqueous leaf extract ofsidium guajava was studied on rat liver damage induced by car-on tetrachloride by monitoring serum transaminase (aspartatemino transferase and serum alanine amino transferase), alkalineosphatase, serum cholesterol, serum total lipids and histopatho-ogical alterations. The leaf extract at doses of 500 mg/kgroduced significant hepatoprotection (Roy et al., 2006).

Pretreatment with asiatic acid (a triterpenoid extracted fromsidium guajava leaves and fruit) at doses of 25 mg/kg, 50 mg/kgr 100 mg/kg significantly blocked the LPS (lipopolysaccharide)nd (d-galactosamine) d-GalN-induced increases in both serumspartate aminotransferase and serum alanine aminotransferaseevels, showing improved nuclear condensation, amelioratedroliferation and less lipid deposition (Gao et al., 2006). Sev-ral studies have indicated the ability of guava to reduce severalarameters associated with liver injury.

.8. Antioxidant, free radical scavenger andadioprotective activities

Cellular damage or oxidative injury arising from freeadicals or reactive oxygen species (ROS) now appears toe the fundamental mechanism underlying a number ofuman neurodegenerative disorders, diabetes, inflammation,iral infections, autoimmune pathologies and digestive sys-em disorders. Free radicals are generated through normal

etabolism of drugs, environmental chemicals and other xeno-iotics as well as endogenous chemicals, especially stressormones (adrenalin and noradrenalin) (Masuda et al., 2003).ried leaves of Psidium guajava were extracted with hotater. The total phenolic content in the extract was deter-ined spectrophotometrically according to Folin–Ciocalteu’s

henol method and calculated as gallic acid equivalent (GAE).remarkably high total phenolic content 575.3 ± 15.5 were

btained (Qian and Nihorimbere, 2004). The antioxidant activ-ty of lyophilized leaf extracts was determined using free radicalPPH (2,2-diphenyl-1-picrylhydryzyl) scavenging. The resultsbtained showed that ascorbic acid was a substantially moreowerful antioxidant than the extracts from guava leaf (Qian
nd Nihorimbere, 2004; Thaipong et al., 2005). These antiox-dant properties are associated with its phenolic compoundsuch as protocatechuic acid, ferulic acid, quercetin and guavin
(Thaipong et al., 2005), quercetin, ascorbic acid, gallic acid

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nd caffeic acid (Jimenez et al., 2001). Guava leaf extracts are aotential source of natural antioxidants (Ojan and Nihorimbere,004).

Other studies show that guava fruits also exert antioxidantnd radioprotective activity in the assay with technetium-99m(99m)Tc] (Abreu et al., 2006).

.9. Antigenotoxic and antimutagenic effects

Generation of DNA damage is considered to be an impor-ant initial event in carcinogenesis. A considerable battery ofssays exists for the detection of different genotoxic effectsf compounds in experimental systems, or for investigationsf exposure to genotoxic agents in environmental or occupa-ional settings. Treatment with the aqueous whole plant extractsf Psidium guajava afforded protection (anti-genotoxic activ-ty) against mitomycin C, nalidixic acid and hydrogen peroxidethree genotoxins) (Bartolome et al., 2006). In another study,pre-treatment with an aqueous guava leaf extract was found

o be effective in inactivating the mutagenicity of direct-actingutagens 4-nitro-o-phenylenediamine and 2-aminofluorene in

he tester strains of Salmonella typhimurium. Therefore aqueouseaf extracts of Psidium guajava show promising antigeno-oxic/antimutagenic activity (Grover and Bala, 1993).

.10. Anti-allergic effects

Th1 polarization is one of the mechanisms underlying theherapeutic effects of herbal medicine. The action of anti-allergicgents from Psidium guajava on T cell immunity in mice wasnvestigated. Studies were carried out on methanol and aqueousxtracts of Psidium guajava leaves. These extracts cause potentnhibition of histamine release from mast cells, and blocked IL-0-mediated, in vitro induction of T regulatory (Tr) cells fromD4+ splenocytes of C57BL/6 mice. The extracts also shifted

he Th1/Th2 balance to a Th1 dominant status by directly atten-ating Tr cell activity. Psidum guajava leaf extracts showednti-allergic activity on T cell immunity in mice (Seo et al.,005).

.11. Anticancer/antitumour effects

An aqueous extract of Psidium guajava leaves inhibited (theiability) of the cancer cell line DU-145 in a dose-dependentanner. At 1.0 mg/ml, the extract reduced the viability of PCaU-145 (the androgen independent PCa cells) to 36.1% and.6%, respectively after 48 h and 72 h of incubations (Chen et al.,007). Essential oil extracted from leaves of Psidium guajavaas highly effective in reducing the growth of human mouth

pidermal carcinoma (KB) and murine leukemia (P388) cellines when they were treated with different concentrations ofhe oil ranging from 0.019 mg/ml to 4.962 mg/ml. Guava leafil showed the highest anti-proliferative activity with an IC50
alue of 0.0379 mg/ml (four times more potent than vincristine)n P388 cell lines (Manosroi et al., 2006); an effect mostlyttributed to the monoterpenes present in the essential oil (Citot al., 2003). A chemopreventive effect was also demonstrated

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n another study of a methanol leaf extract on mice-induced can-er inoculated with B16 melanoma cells. A significant decreasen the incidence and average number of animals with canceras found compared to the control group (Fernandes et al.,995). These findings suggest that Psidium guajava aqueouseaf extracts are efficacious for the prevention of tumour devel-pment by depressing Tr cells and subsequently shifting to Th1ells (Seo et al., 2005).

Furthermore, jacoumaric acid (isolated from guava seeds)as evaluated for its antitumour effect; it was found to signifi-

antly reduce the incidence of tumours (Numata et al., 1989).hytochemical investigations of the acetone extract of Psidiumuajava seeds has led to the isolation of phenyl-ethanoidlycosides (1-O-3,4-dimethoxy-phenylethyl-4-O-3,4-imethoxy cinnamoyl-6-O-cinnamoyl-beta-d-glucopyranosend 1-O-3,4-dimethoxyphenylethyl-4-O-3,4-dimethoxyinnamoyl-beta-d-glucopyranose) which showed cytotoxicctivities in vitro against Ehrlich ascites cells (EAC) andeukaemia P3888 cells (Salib and Michael, 2004). Thesending suggested that Psidium guaijava extracts have theotential to be developed as new chemotherapeutic agents torevent or to inhibit the growth of tumours and cancers.

.12. Cardiovascular, hypotensive effects

The effect of an aqueous leaf extract of Psidium guajava onyocardial injury was studied in the model of global ischemia

ollowed by reperfusion. High-energy phosphates and malon-ialdehyde in the reperfused hearts were significantly reducedith the plant extract (Conde et al., 2003). In another study,

queous leaf extract of Psidium guajava exhibited cardiopro-ective effects against myocardial ischemia-reperfusion injury insolated rat hearts. Augmentation of endogenous antioxidants,

aintenance of the myocardial antioxidant status and significantestoration of most of the altered hemodynamic parameters mayave contributed to its cardioprotective effect (Yamashiro et al.,003). The cardio-inhibitory actions in rats and guinea pigs ofhe aqueous leaf extract of Psidium guajava also appeared toe due to cholinergic involvement in the mechanism of action.jewole (2005) showed that the aqueous leaf extract causedypotension in the experimental animal model used via cholin-rgic mechanisms. Moreover, acute intravenous administrationsf the leaf extract (50–800 mg/kg i.v.) produced dose-dependent,ignificant reductions in systemic arterial blood pressures andeart rates of hypertensive, Dahl salt-sensitive rats. Althoughhe exact mechanisms of action of the extract remain specula-ive at present, it is unlikely that the extract causes hypotensionn the mammalian experimental animal model used via cholin-rgic mechanisms since its cardiodepressant effects are resistanto atropine pre-treatment (Ojewole, 2005).

Belemtougri et al. (2006) found that aqueous and ethanoliceaf extracts of Psidium guajava inhibits intracellular calciumelease (Chiesi and Schwaller, 1994; Apisariyakul et al., 1999).
queous leaf extract of Psidium guajava significantly and dose-ependently (0.25–2 mg/ml) contracted the aorta rings. Theffect was evaluated also in the presence of nifedipine and phen-olamine. The sensitivity of the aortic rings to cumulative doses
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f Psidium guajava was significantly enhanced in the presence ofhentolamine suggesting that the effect of Psidium guajava waso a large extent mediated by activation of an alpha-adrenoceptornd to a lesser extent by acting via calcium ion channel (Olatunjit al., 2007). A guava leaf extract may therefore be benefi-ial for the prevention of cardiovascular diseases, also since itsraditional use in hypertension is well established.

.13. Anti-hyperglycemic

The rapidly increasing diabetes mellitus is becoming a seri-us threat to human health in all parts of the world. The controlnd treatment of diabetes and its complications mainly dependn the chemical or biochemical agents, but the fact is that itas never been reported that someone had recovered totallyrom diabetes. With the distinctive traditional medical opinionsnd natural medicines mainly originated in herbs, traditionaledicine offers good clinical opportunities and shows a bright

uture in the therapy of diabetes mellitus and its complications.he effect of Psidium guajava bark, leaves and fruit as anti-iabetic agents has been studied by several authors. Mukhtar etl. (2006) evaluated anti-hyperglycaemic activity of the ethanolxtract obtained from the stem bark of Psidium guajava onlood glucose levels of normal, alloxan-induced hyperglycaemicats and normal glucose loaded rats. The results showed thatthanol stem bark extract exhibited statistically significant hypo-lycaemic activity in alloxan-induced, hyperglycaemic rats butas devoid of significant hypoglycaemic effect in normal andormal glucose loaded rats.

In another study, a decoction of Psidium guajava leavesas screened for hypoglycaemic activity on alloxan-inducediabetic rats. In both acute and sub-acute tests, the waterxtract, at an oral dose of 250 mg/kg, showed statisticallyignificant hypoglycaemic activity (Mukhtar et al., 2004).he treatment with Psidium guajava aqueous leaf extract

0.01–0.625 mg/ml) showed significant inhibition on LDLlycation in a dose-dependent manner. Tannins, flavonoids, pen-acyclic triterpenoids, guiajaverin, quercetin, and other chemicalompounds present in the plant are speculated to account forhe observed hypoglycaemic and hypotensive effects of the leafxtract (Ojewole, 2005; Wang et al., 2005).

Psidium guajava is an excellent anti-LDL glycative agenthose potential therapeutic uses can be extended to the pre-ention of a variety of cardiovascular and neurodegenerativeiseases associated with glycations (Hsieh et al., 2007). Oh etl. (2005) demonstrated that the methanol extract from Psidiumuajava leaves exhibited significant inhibitory effect on PTP1Bprotein tyrosine phosphatase 1B) in Lepr[db/Lepr[db] miceomozygous for the diabetes spontaneous mutation (Leprdb)ecome identifiably obese around 3–4 weeks of age. Theseomozygous mutant mice are polyphagic, polydipsic, andolyuric. Blood glucose lowering effect of the methanol extractas observed after i.p. dose of 10 mg/kg, with an antidiabetic

ffect via the inhibition of PTP1B.In one study, oral administrations of 100 mg/kg, 150 mg/kg

nd 250 mg/kg of juice from ripe guava fruit caused significantypoglycemia in normoglycemic and STZ-treated, diabetic rats

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Cheng and Yang, 1983). Although effective duration of guava isess potent than chlorpropamide and metformin. Moreover, acutentravenous administrations of the fruit’s juice produced signif-cant reductions in systemic arterial blood pressures and heartates of hypertensive patients. Some investigators suggested thathe hypoglycaemic components in guava fruits might involversolic acid, oleanolic acid, arjunolic acid and glucuronic acidChang, 1982).

Anti-LDL (low density lipoprotein) glycative agents werenvestigated using aqueous decoctions of Psidium guajavaruit ripe at concentrations of 0.01–0.625 mg/ml (Hsieh etl., 2005). The results have revealed that guava fruits exhibitxcellent antiglycation effect, being a rather powerful and effec-ive inhibitor of LDL glycation in both glucose and glyoxalnduced models. The antiglycation activities of guava fruitere relevantly and directly related to its polyphenolic con-

ent (extractable polyphenols 2.62–7.79%), yet it seemed to ushat Psidium guajava fruit also possesses a rather specific andomewhat different degree of free-radical scavenging ability,hus it was speculated that the reaction mechanism of guavaight have occurred in the initiation rather than the propagation

hase, a mechanism being quite different from the conventionalree-radical scavenging by the polyphenolics. This problem isndeed worth exploring in further studies.

.14. Effect on muscular system

Degenerative muscular diseases, such as muscular dystrophy,ave been the target of regenerative cell therapy. Although satel-ite cells play central roles in skeletal muscle regeneration thatntrinsically occurs after muscle injury, their application to cellherapy is confronted with difficulties (Endo, 2007). Water and

ethanolic leaf extracts from Psidium guajava showed antag-nistic effects on caffeine induced calcium release from thearcoplasmic reticulum of rat skeletal muscle cells in a dose-ependent-manner showing a clear calcium-antagonistic effectBelemtougri et al., 2006). Aqueous leaf infusions of Psidiumuajava could block the L-type calcium membrane channelsConde et al., 2003). Guava may therefore be beneficial foratients with muscular dystrophy (Lamb, 2000).

.15. Anti-inflammatory/analgesic

A decoction of Psidium guajava leaves is used worldwideor the treatment of various inflammatory ailments includingheumatism. The numerous polyphenolic compounds, triter-enoids and other chemical compounds present in the plantay account for the observed anti-inflammatory and analgesic

ffects of the leaf extracts. The anti-inflammatory property ofhe aqueous leaf extract was investigated in rats, using freshgg albumin induced pedal (paw) oedema, while the analgesicffect of the plant extract was evaluated by the hot-plate andcetic acid test models of pain in mice. Psidium guajava aque-
us extract (50–800 mg/kg, i.p.) produced dose-dependent andignificant inhibition of fresh egg albumin-induced acute inflam-ation (oedema) in rats. The leaf extract (50–800 mg/kg, i.p.)
lso produced dose-dependent and significant analgesic effects

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gainst thermally and chemically induced nociceptive pain inice (Ojewole, 2006).The anti-inflammatory and analgesic activities of 70%

thanolic extract of leaves of Psidium guajava were also inves-igated in rats using the carrageenan induced hind paw oedema

odel. Extracts which exhibited anti-inflammatory activityere screened for analgesic activity using the Randall–Selittoethod in rats. The extracts were administered at a dose of

00 mg/kg, p.o. Aspirin (300 mg/kg, p.o.) was employed as theeference drug. Psidium guajava leaves showed significant anti-nflammatory activity with an inhibition of 58% (Muruganandant al., 2001).

The essential oil, steam-distilled from leaves of Psidiumuajava, was given orally to rats to study its effects on thexudative and proliferative phases of the inflammatory reactioncarrageenan induced paw oedema and cotton pellet inducedranuloma models). The essential oil (0.8 mg/kg) significantlyeduced oedema formation induced by carrageenan while at.4 mg/kg and 0.8 mg/kg the oil also significantly reduced gran-loma formation induced by cotton pellets (Kavimani et al.,997).

.16. Antinociceptive effects

The hexane, ethyl acetate and methanol extracts of Psidiumuajava leaves showed activity on the central nervous system inice. The three extracts exhibited mostly antinociceptive effects

n chemical and thermal tests of analgesia. The extracts also pro-uced dose-dependent prolongation of pentobarbitone-inducedleeping time (Shaheen et al., 2000). Shortly after intraperitonealdministration of this methanol extract, typical narcotic-likeffects were observed including catalepsy, analgesia, straub tail,hallow respiratory movements and exophthalmos. Doses of.3–6.6 mg/kg i.p. depressed spontaneous locomotor activitynd tunnel running was curtailed. Higher doses abolished thepontaneous locomotor reflex action (Lutterodt and Maleque,988).

These results lend pharmacological credence to the uses ofhe plant in the management and/or control of painful, arthriticnd other inflammatory conditions.

It was also reported in another study that the antinocicep-ive effect of leaf essential oil from Psidium guajava and itsonstituent, �-pinene produced a significant antinociceptiveffect in the formalin test probably mediated by endoge-ously released adenosine (Santos et al., 1998). Hexane, ethylcetate and methanol extracts of Psidium guajava leaves onhe central nervous system in mice exhibited mostly dose-ependent antinociceptive effects in chemical and thermal testsf analgesia. The extracts also produced dose-dependent pro-ongation of pentobarbitone-induced sleeping time. However,hey had variable and mostly non-significant effects on loco-

otor coordination, locomotor activity or exploration (Shaheent al., 2000). A bio-guided fractionation of the hexane extract
btained from Psidium guajava leaves led to the isolation ofesquiterpenes with depressant activities on the central ner-ous system. The relaxant properties of the Psidium guajavaexane extract are largely due to the presence of terpenes,

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specially caryophyllene-oxide and �-selinene, which potenti-ted pentobarbital sleeping time and the latency of convulsionsnduced by leptazol in mice. Calcium concentration–responseurves showed a rightward displacement when hexane extractas added to isolated guinea-pig ileum depolarized with K+

60 mm) and cumulative concentrations of CaCl2, suggestinghat caryophyllene-oxide, a known Ca2+ antagonist agent coulde responsible for the blockade of extracellular Ca2+ (Meckest al., 1996).

.17. Wound healing

The wound healing properties of a methanolic leaf extractf Psidium guajava were determined using the excision woundodel. More than 90% wound healing was observed after 14

ays post-surgery, whereas 72% healing was observed in theistilled water treated group (Chah et al., 2006).

. Toxicology

This toxicologic study was conducted using dry leaves ofsidium guajava L. In this plant material, acute toxicologictudy by the following methods: mean lethal dose LD50 testn Swiss mice and alternative toxicology (acute toxic classes)n Wistar rats. We also made the genotoxic of 2 extracts, onef aqueous type, and the other of henaxic type in an in vitroystem of short-term somatic segregation induction assay in thespergillus nidulans fungus and an in vivo assay of the dry drug

n mouse bone marrow micronuclei induction test. No deathsere observed in the toxicological results of the two experi-ental models in the dose range using up to 2 g/kg/b.w. Acute

oxicity tests in rats and mice have proven the LD50 of guava leafxtracts to be more than 5 g/kg. In vitro genotoxicity and muta-enicity tests on Psidium guajava in human peripheral bloodymphocytes found no disturbances in cell division (Jaiarj et al.,999; Manosroi et al., 2006). The histological results did notuggest any damage attributable to toxicity of the studied plantaterial. In the in vitro study with Aspergillus nidulans D-30,

esults indicated a lack of genotoxic effect of these extracts,s well as in the mouse bone marrow micronucelus inductionystem (Martinez et al., 2001).

. Clinical trials

.1. Infantile rotaviral enteritis

A pilot study was carried out at the Nanfang Hospital, Firstilitary Medical University, and Guangzhou on Psidium gua-

ava (PG) leaf decoction for treating infantile rotaviral enteritis.ixty-two patients of rotaviral enteritis were randomly divided

nto the verum group treated with PG and the control groupreated with Gegen Qinlian decoction. The time for ceasing diar-hoeal, the content of Na+ in blood, the content of Na+ and
lucose in stool, and the rate of negative conversion of humanotavirus (HRV) antigen were observed. The rate of recoveryn 3 days for the treated group was 87.1%, significantly higherhan that of the control group (58.1%). The time of ceasing
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iarrhoeal of the treated group (25.1 ± 9.5 h) was significantlyhorter than that of the control group (38.7 ± 15.2 h, P < 0.01).he content of Na+ and glucose in stool was reduced obviously

n the treated group, while the reduction in the control group wasnsignificant; the treated group was significantly superior to theontrol group. The rate of negative conversion of HRV in faecesf the treated group was 87.1%, significantly better than that ofhe control (58.1%). The treatment with PG has good curativeffect on infantile rotaviral enteritis (Wei et al., 2000).

.2. Infectious gastroenteritis

In the Laboratory of Medicinal Plants Research Unit of Neu-ological Diseases, Mexico, a randomized double-blind trialxamined the efficacy of a standardized aqueous leaf extractsidium guajava ([QG-5] estimated at quercetin-equivalentmg per 500 mg capsule) versus placebo in 100 patientsith infectious gastroenteritis. The experimental group (n = 50)

eceived 1 capsule of QG-5 orally every 8 h for 3 days, while theontrol group (n = 50) received the same regimen with match-ng placebo capsules. Conventional oral rehydration therapyas initiated in both groups. Outcome measures included num-er of daily stools, consistency, presence of mucus, degree ofbdominal pain, number of spasms in 24 h, fever, and number ofomiting episodes. Results indicated a significant difference inutcome measures favouring the experimental group, mostly dueo an antispasmolytic effect, which helped reduce the number ofpisodes of abdominal pain. No adverse effects were reportedor patients treated with QG-5 (Lozoya et al., 2002). Besidesonstipation, no serious adverse reactions have been reported inatients taking QG-5. Guava is commercially available in cap-ules, liquids, powders, and tablets in a standardized form forastroenteritis.

In Cuba, a longitudinal randomized double blind study wasarried out among 100 adult patients with acute diarrhoea. Theffect of an oral treatment with 10 ml tincture from Psidiumuajava dissolved in water, every 8 h, on the treatment of diar-hoea was determined. The results revealed that this 20% leafincture significantly reduced the time to ceasing diarrhoea ando adverse reactions were detected (Echemendia and Moron,004). Guava offers an effective and safe alternative treatmentor patient with diarrhoea disease.

.3. Cardiovascular effects

Evidence from a randomized, single-blind, clinical trial sug-ests that by adding moderate amounts of guava fruit to the diet,hanges in dietary fatty acids and carbohydrates may decreaseipoprotein metabolism and blood pressure. Two groups ofatients (N = 120) were assessed over 12 weeks; each groupeceived ripe guava fruit, preferably before meals. At the end ofhe period, approximately half of the patients had a net decreasen serum total cholesterol (9.9%), triglycerides (7.7%), and
lood pressure (9/8 mm Hg), with a net increase in high-densityipoprotein (HDL) cholesterol (8%) (Singh et al., 1992).
A single-blind, randomized, controlled trial of 145 hyperten-ive patients found similar results. Patients received a fibre and

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otassium enriched diet containing 0.5–1 kg of guava daily orheir usual diet; alcohol, caffeine, cholesterol, fat, and salt intakeere similar in both groups. After 4 weeks, systolic and diastolicressures improved, decreases occurred in serum total choles-erol and triglycerides, and there was a mild increase in the ratiof total cholesterol/HDL-cholesterol in the guava group (Singht al., 1993).

In another trial conducted for a 9-week period in “Institutemahiran Belia Negara”, Hulu Langat, Selangor, Malaysia,randomized double-blind study of 122 people examined the

ffects of consuming 400 g/day of guava fruit on total antiox-dant status and lipid profile (total cholesterol, triglycerides,ow-density lipoprotein [LDL] and HDL cholesterol). Consump-ion of guava fruit reduced oxidative stress and blood cholesterolevels. Thus, it could reduce the risk of disease caused by freeadical activities and high cholesterol in the blood (Rahmat etl., 2004).

.4. Dysmenorrhea

A double-blinded randomized clinical trial was conductedn 197 women with primary dysmenorrhea. Four interven-ion groups were defined: two leaf extract doses (3 mg/daynd 6 mg/day); ibuprofen (1200 mg/day); placebo (3 mg/day).articipants were followed up individually for 4 months. Theain outcome variable was abdominal pain intensity measured

ccording to a visual analogue scale (VAS). The average age ofarticipants was 19 years; menarche occurred around 12 yearsf age. Participants had menstrual cycles of 28 or 29 days, withenstruation lasting 5 days and pain intensity mean of 8.2 on

he VAS. During each successive treatment cycle, participantsxperienced a lower pain intensity score. Multiple regressionnalysis, after adjusting each cycle for baseline pain, treat-ent compliance and other variables, showed that the group

eceiving 6 mg/day leaf extract had significantly reduced painntensity (p < 0.001). This effect was maintained in cycles 2 and, although the reduction in the mean of pain intensity was lower.he group receiving the 3 mg/day extract did not show a con-istent effect throughout the three cycles. The guava leaf extracttandardized to 6 mg flavonol/day, reduced menstrual pain sig-ificantly compared with conventional treatment and placeboVladislavovna et al., 2007; Svetlana et al., 2007).

.5. Hypoglycaemic effect

In China, a multicentric randomized controlled trial was con-ucted to evaluate the efficacy of guava in the management ofiabetes. The mean age of participants was 59.6-year-old andverage duration of diabetes was 5.4 years. Oral administrationapsules containing 500 mg of aqueous leaf extract from Psid-um guajava to 50 diabetic patients showed hypoglycaemic lessotent than chlorpropamide and metformin. Thus, it is suggestedhat guava may be employed to improve and/or prevent diabetes

ellitus (Cheng and Yang, 1983).Guava is a tropical fruit that contains high levels of dietary

bre and could have health potential in the management of bloodlucose level in diabetic subjects. Oral administration of cap-

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ules containing 500 mg of Psidium guajava fruit in 40 patientshowed a reduction in blood glucose level in weeks 3, 4 and 5ith changes in glucose level of −12.3%, −24.79% and −7.9%

espectively as compared with the diabetic control group. Thistudy showed that supplementation of 0.517 g/day could reduceasting blood glucose level but the mean was not significantYusof and Said, 2004).

. Summary

Psidium guajava is a well-known medicinal plant that is fre-uently prescribed in various indigenous systems of medicinespecially those of Central America and Africa. Guava extracts,raditionally prepared (infusions, decoctions, tinctures of thearks and leaves and ripe fruit) by many widely separatedultures for eons of time for various uses (Table 1) have, as sum-arised in this review, been shown by the application of modern

cientific methods to indeed possess multiple disease ameliorat-ng properties. Such properties have been further explained byeveral studies detailing the specific bioactivity of individualhytochemicals extracted from guava and on clinical studies.

Extracts and phytochemicals isolated from Psidium guajavaeaves have been shown to have multiple disease ameliorat-ng effects caused by microbial pathogens (Table 1). Its mostidespread traditional use has been for the treatment of diar-

hoea. Leaf extracts of Psidium guajava, as reviewed here, haveeen found to have antimicrobial activity against several bacte-ia, fungi, viruses and parasites, with proven ability to ameliorateiarrhoeal, and also gastroenteritis, dental plaque, acne, infantileotaviral enteritis and even malaria suggesting wide antimicro-ial activity. The activity guided purification resulted in thesolation of quercetin, quercetin-3-arabinoside, and asiatic acidhich showed significant anti-diarrhoeal activity.Another traditional use of guava has been in the treatment

f coughs; experimental data presented here show that guavaeaf extract do indeed exert an inhibitory effect on frequency ofoughing.

Research summarised here also indicates that guava leavesrovide antioxidant and other effects providing beneficial pro-ective properties to the heart and liver with an improvement in

yocardial and muscular function. In other animal studies guavaeaf extracts showed anti-allergic, anti-inflammatory, analgesic,edative, and central nervous system (CNS) depressant activity.

hile these are not known folk uses per se, they help to explainuch folk recipes as the use of leaf extracts for rheumatic pain,onvulsions, vomiting and menstrual pain. The effect on diar-hoeal, for example seems to be due to its antimicrobial activity,ut also in other ways as discussed in Section 3.1.

Leaves are the part of the plant that is most frequently usedn the forms of decoction. The studies performed by the authorsave been discussed. Most of the pharmacological and chemi-al work has been carried out on the leaf, reveals the connectionetween medicinal herbs and cultural beliefs toward healing.
uava leaves contain tannins as well as �-sitosterol, flavonoids,
riterpenoids, volatile oil. The main traditional use is for the treat-ent of the gastrointestinal disorders (diarrhoea, stomach pain,

astroenteritis, indigestion, and dysentery) and dermatologic

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onditions (boils, skin, infection, and ulcers). The recommendedosage for acute diarrhoea is 0.5–1.0 cup of decoction (take aandful of leaves to make a decoction with 1 l of water) 3–5imes daily.

The ripe guava fruit, on the other hand, has been shown herend in other reviews (Hwang et al., 2002) to be a very use-ul nutraceutical with important properties that can affect theaintenance of health and prevention of many diseases. All

arts of the fruit can be eaten, with the skin actually possess-ng the highest vitamin C level. The fruit and its juice haveeen documented to lower blood sugar levels in normal and dia-etic animals and humans, ameliorate rheumatism (analgesicnd anti-inflammatory effects), while reducing blood pressure,riglycerides and cholesterol levels. Interestingly, guava bark andeaves have also been shown to have important antioxidant andnti-diabetic properties with the bark being more active. Thisends pharmacological credence to the folkloric, ethnomedicalses of the plant in the management or control of adult-onset,ype 2 diabetes mellitus and hypertension in some rural commu-ities.

As well as the traditional preparations, individual chemicalsave been shown to exhibit previously unknown properties. Thenherent cytotoxicity of triterpenes in the seeds and leaf is the

ost promising and should be better explored in the search forew antineoplastic agents because the leaf oil has been shown
o be four times more potent than vincristine.
Most importantly, Psidium guajava has been used for a longeriod of time with no serious adverse effects reported or docu-ented.

tjs

A

tructure Source

henolic compounds isolated from Psidium guajava

Leaf and roots, Okuda et al. (1Quisumbing (1978)

Leaf and fruit, Okuda et al. (19

Leaf, Liang et al. (2005)


. Conclusion

The pharmacological studies conducted on Psidium guajavandicate the immense potential of this plant in the treat-ent of conditions such as diarrhoeal, gastroenteritis and

otavirus enteritis, wounds, acne, dental plaque, malaria, aller-ies, coughs, diabetes, cardiovascular disorder, degenerativeuscular diseases, inflammatory ailments including rheumatism

nd menstrual pain, liver diseases, cancer, etc. Not surprisingly,uava also exhibits antioxidant and anti-inflammatory effects asxidative injury underlies many of these diseases. However, theiverse pharmacological activities of guava extracts and isolatedhytochemicals have only been assayed in in vitro tests usingaboratory animals, and the results obtained may not necessarilye portable to the situation in humans. While there are gaps inhe studies conducted so far, which need to be bridged in order toxploit the full medicinal potential of guava, it is still very clearhat this is a plant with tremendous widespread use now and alsoith extraordinary potential for the future. On the basis of the low

oxicity of guava extracts and derived phytochemicals and theirse as nutraceutical (fruit) and medicinal (leaves, bark, seeds,oots) agents, backed by proven activity of both the traditionalormulations (infusions, decoctions, tinctures) and their derivedhytochemicals (phenolics, flavonoids, carotenoids, triterpenes,ssential oil constituents and others), further research, clinicalrials and product development can only cement Psidium gua-ava as a very important part of our biodiversity to respect andustainably use for generations to come.

ppendix A. Constituents of Psidium guayava

Activities

984), Cardioprotective effects againstischemia-reperfusion. Antioxidant, Yamashiro et al.(2003).

84). Antioxidant, Thaipong et al. (2005)

Antibacterial activities. Antioxidant, Zhou et al.(2007)


Appendix A (Continued )

*

Structure Source Activities

Leaf, Zhu et al. (1997) Antioxidant, Misra and Seshadri (1968), Qian andNihorimbere (2004)

Leaf, Liang et al. (2005), Qian andNihorimbere (2004)

Antioxidant, capacity radical scavenging activity,antimutagenic/anticarcinogenic effect, inflammationinhibiting and endothelial protective properties, Liand Chang (2005)

Leaf, stem-bark, and roots, Misra andSeshadri (1968)

Possesses analgesic and antiinflammatoryproperties, Ojewole (2006)

Leaf and fruit, Okuda et al. (1984), Zhuet al. (1997)

Antioxidant, Okuda et al. (1984)

Flavonoids isolated from Psidium guajava

Leaf flowers and fruit, Liang et al. (2005) Antidiarrhoea effect, Zhang et al. (2003). Exhibitedantioxidant and spasmolytic effects, Formica andRegelson (1995), Yamashiro et al. (2003). Alsoshowed inhibition on skeletal muscles contraction,Chaichana and Apisariyakul (1996); Inducedreduction of presynaptic molecular activity,Apisariyakul et al. (1999) Also showed vasodilatoreffects, Duarte et al. (1993)




Leaf, flowers and fruit Nadkarni andNadkarni (1999)

Leaf flowers and fruit Liang et al. (2005)


Acylated flavonol glycoside Seeds, Michael et al. (2002)

Leaf and fruit Liang et al. (2005)

Leaf and fruit Liang et al. (2005)





Leaf and fruit, Prabu et al. (2006) Showed antimicrobial activity against Streptococcusmutans, Prabu et al. (2006)

Leaf and fruit, Arima and Danno (2002) Showed antimicrobial activity against Salmonellaenteritidis and Bacillus cereus, Arima and Danno(2002)

Leaf and fruit, Arima and Danno (2002) Showed antimicrobial activity against Salmonellaenteritidis and Bacillus cereus, Arima and Danno(2002)

Leaf and fruit, Liang et al. (2005)




Leaf and fruit, Liang et al.(2005)

Carotenoids isolated from Psidium guajava

Leaf and fruit,Mercadante et al. (1999)

Acts as a chain-breakingantioxidant and thus protectscell against photo-oxidationPalozza and Krinsky (1992)






Leaf and fruit Mercadanteet al. (1999)




Leaf and fruit, Mercadante et al. (1999)

Cytokinins isolated from Psidium guajava

Leaf and fruit, Nagar and Rao (1981)

Zeatin riboside Leaf and fruit, Nagar and Rao (1981)Zeatin nucleotide Leaf and fruit, Nagar and Rao (1981)

Triterpenes isolated from Psidium guajava

Leaf and fruit, Siddiqui et al. (2002)

Leaf and fruit, Begum et al. (2002a)

Leaf and fruit, Begum et al. (2002a)




Leaf and fruit, Begum et al. (2004)

Leaf and fruit, (Begum et al., 2002a,b)

Leaf and fruit, (Begum et al., 2002a)

Leaf and fruit, (Begum et al., 2004)

Leaf, (Begum et al., 2002a)




Leaf and fruit, Begum et al.(2004)

Leaf and fruit, Begum et al.(2002a)

Leaf and fruit, Begum et al.(2002a,b)

Showed spasmolytic, Conde-Garcia et al. (2003),antioxidative, anti-inflammatory andhepatoprotective activities, Gao et al. (2006)

Leaf and fruit, (Begum et al.,2002a,b)

Leaf and fruit, Begum et al.(2002a,b)




Leaf and fruit, Begum et al. (2004)

Seeds, Salib and Michael (2004)

Seeds, Salib and Michael (2004) Showed cytotoxic activities in vitroagainst Ehrlich ascites Carcinomacells (EAC) and leukaemia P3888cells Salib and Michael (2004)

Constituents from the essential oil of Psidium guajava

Fruit, Li et al. (1999) Content: 18.81%. Cytotoxic to brineshrimp larvae, Cito et al. (2003)

Fruit, Li et al. (1999) Content: 11.80%. Antiinflammatoryand inhibition of nitric oxideproduction; in vitro antitumour, Sianiet al. (1999)

Leaf, Li et al. (1999 Content 10.27%, Li et al. (1999)




Leaf, Oliver-Bever (1986) Content 7.36%, Oliver-Bever (1986)

Leaf, (Li et al., 1999) Antiinflammatory and inhibition ofnitric oxide production; in vitroantitumour (Siani et al., 1999)

Leaf, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)








Leaf, Li et al. (1999)





Fruit, (Jordan et al., 2003)

Fruit, Jordan et al. (2003)

Fruit, Jordan et al. (2003))

Fruit, Jordan et al. (2003)




Micellaneous

Flowers, roots, Jordan et al. (2003)

Leaves, fruit, Fujita et al. (1985)

Leaves, fruit, Fujita et al. (1985)

Leaves, fruit, Radha and Chandrasekaran(1997)





Seeds, Salib and Michael (2004) Showed cytotoxic activities in vitroagainst Ehrlich ascites Carcinomacells (EAC) and leukemia P3888cells Salib and Michael (2004)


Seeds, Salib and Michael (2004)

Seeds, Salib and Michael (2004) Showed cytotoxic activities in vitroagainst Ehrlich ascites Carcinomacells (EAC) and leukemia P3888cells Salib and Michael (2004)

R

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