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

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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 P´erez Guti´errez a,∗ , Sylvia Mitchell b , Rosario Vargas Solis c a

Laboratorio de Investigaci´on de Productos Naturales, Escuela Superior de Ingenier´ıa Qu´ımica e Industrias extractivas IPN, Punto Fijo 16, Col. Torres Lindavista C.P. 07708 M´exico, D.F., Mexico b Medicinal Plant Research Group, Biotechnology Centre, 2 St. John’s Close, University of the West Indies, Kingston 7, Jamaica c Laboratorio de Investigaci´ on de Fitofarmacolog´ıa, Universidad Aut´onoma Metropolitana-Xochimilco A.P. 23-181 M´exico, D.F., Mexico Received 18 August 2007; received in revised form 26 January 2008; accepted 29 January 2008 Available online 3 February 2008

Abstract Psidium guajava, is an important food crop and medicinal plant in tropical and subtropical countries is widely used like food and in folk medicine around of the world. This aims a comprehensive of the chemical constituents, pharmacological, and clinical uses. Different pharmacological experiments in a number of in vitro and in vivo models have been carried out. Also have been identified the medicinally important phyto-constituents. A number of metabolites in good yield and some have been shown to possess useful biological activities belonging mainly to phenolic, flavonoid, carotenoid, terpenoid and triterpene. Extracts and metabolites of this plant, particularly those from leaves and fruits possess useful pharmacological activities. A survey of the literature shows P. guajava is mainly known for its antispasmodic and antimicrobial properties in the treatment of diarrhoea and dysentery. Has also been used extensively as a hypoglycaemic agent. Many pharmacological studies have demonstrated the ability of this plant to exhibit antioxidant, hepatoprotection, anti-allergy, antimicrobial, antigenotoxic, antiplasmodial, cytotoxic, antispasmodic, cardioactive, anticough, antidiabetic, antiinflamatory and antinociceptive activities, supporting its traditional uses. Suggest a wide range of clinical applications for the treatment of infantile rotaviral enteritis, diarrhoea and diabetes. © 2008 Published by Elsevier Ireland Ltd. Keywords: Psidium guajava; Myrtaceae; Clinical; Complementary medicine; Phytochemical constituents; Pharmacological actions

Contents 1. 2.

3.

∗

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Use in traditional medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Fruits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Fruit skins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Leaves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Anti-diarrhoeal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Antimicrobial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Acne lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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. 07708 Mexico, D.F., Mexico. E-mail address: [email protected] (R.M.P. Guti´errez).

0378-8741/$ – see front matter © 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.jep.2008.01.025

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4. 5.

6. 7.

3.8. Antioxidant, free radical scavenger and radioprotective activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9. Antigenotoxic and antimutagenic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.10. Anti-allergic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.11. Anticancer/antitumour effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.12. Cardiovascular, hypotensive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.13. Anti-hyperglycemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.14. Effect on muscular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.15. Anti-inflammatory/analgesic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.16. Antinociceptive effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.17. Wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Infantile rotaviral enteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Infectious gastroenteritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Cardiovascular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Dysmenorrhea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Hypoglycaemic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix A. Constituents of Psidium guayava . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Psidium guajava, which is considered a native to Mexico (Rios et al., 1977) extends throughout the South America, European, Africa and Asia. Based on archaeological evidence. It has been used widely and known in Peru since pre-Columbian times. It grows in all the tropical and subtropical areas of the world, adapts to different climatic conditions but prefers dry climates (Stone, 1970). The main traditional use known is as an anti-diarrhoeal. Other reported uses include gastroenteritis, dysentery, stomach, antibacterial colic pathogenic germs of the intestine. Its medicinal usage has been reported in indigenous system of medicines in America more than elsewhere. Psidium guajava Linn. (family Myrtaceae), is commonly called guave, goyave or goyavier in French; guave, Guavenbaum, Guayave in German; banjiro in Japanese; goiaba, goiabeiro in Portugal; arac¸a´ -goiaba, arac¸a´ -guac¸u´ , guaiaba in Brazil; guayaba, guayabo in Espa˜nol and guava in English (Killion, 2000). Psidium guajava is a small tree which is 10 m high with thin, smooth, patchy, peeling bark. Leaves are opposite, short-petiolate, the blade oval with prominent pinnate veins, 5–15 cm long. Flowers are somewhat showy, petals whitish up to 2 cm long, stamens numerous (Stone, 1970). Fruit are fleshy yellow globose to ovoid berry about 5 cm in diameter with an edible pink mesocarp containing numerous small hard white seeds. There has been a tremendous interest in this plant as evidenced by the voluminous work. Therefore, we aimed to compile an up to date and comprehensive review of Psidium guajava that covers its traditional and folk medicine uses, phytochemistry and pharmacology. 1.1. Use in traditional medicine More recent ethnopharmacological studies show that Psidium guajava is used in many parts of the world for the treatment

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of a number of diseases, e.g. as an anti-inflammatory, for diabetes, hypertension, caries, wounds, pain relief and reducing fever (Table 1). Some of the countries with a long history of traditional medicinal use of guava include Mexico and other Central American countries including the Caribbean, Africa and Asia. Some of these uses will be outlined here. Medicinal plants are an important element of the indigenous medical systems in Mexico (Lara and Marquez, 1996). These resources are part of their traditional knowledge. The Popoluca Indians of Veracruz rely on medicinal plants for their health care. They appear to have developed a system whereby they select and continue to use plants that they find the most effective for health care purposes. The folk use of guava has been documented in the indigenous groups of Mexican Indians, Maya, Nahuatl, Zapotec and Popoluca. A decoction of the leaves is used to cure cough. According to communities of Nahuatl and Maya origin and Popoluca of the region of the Tuxtlas, Veracruz, they use a guava leaf decoction to treat digestive suffering associated with severe diarrhoea. This is a frequent disease in rainy weather (Heinrich et al., 1998). P guajava (Myrtaceae) is widely used in Mexico to treat gastrointestinal and respiratory disturbances and is used as an anti-inflammatory medicine (Aguilar et al., 1994). Commonly roots, bark, leaves and immature fruits, are used in the treatment of gastroenteritis, diarrhoea and dysentery. Leaves are applied on wounds, ulcers and for rheumatic pain, while they are chewed to relieve toothache (Heinrich et al., 1998). A decoction of the new shoots is taken as a febrifuge. A combined decoction of leaves and bark is given to expel the placenta after childbirth (Mart´ınez and Barajas, 1991). A water leaf extract is used to reduce blood glucose level in diabetics. This hot tea was very common among the local people of Veracruz (Aguilar et al., 1994). The leaf of Psidium guajava is used traditionally in South African folk medicine to manage, control, and/or treat a plethora

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Table 1 Ethnomedical uses of Psidium guajava Place, country

Part(s) used

Ethno medical uses

Preparation(s)

Reference(s)

Colombia, Mexico

Leaves

Decoction and poultice

Indigenous Maya, Nahuatl, Zapotec and Popoluca of the region Tuxtlas, Veracruz, Mexico Latin America, Mozambique Mexico

Leaves

Gastroenteritis, diarrhoea, dysentery, rheumatic pain, wounds, ulcers, and toothache Cough, diarrhoea

Heinrich et al. (1998), Aguilar et al. (1994) Heinrich et al. (1998), Leonti et al. (2001)

Leaves

Diarrhoea, stomach ache

Infusion or decoction

Pontikis (1996)

Shoots, leaves, bark and leaves mixed, rip fruits

Decoction, poultice

Panama, Cuba, Costa Rica, M´exico, Nicaragua, Panam´a, Per´u, Venezuela, Mozambique, Guatemala, Argentina South Africa

Leaves

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

Mart´ınez and Barajas (1991), Argueta et al. (1994), Linares and Bye (1990), Leonti et al. (2001), Heinrich et al. (1998) Pardo (1999), Jansen and M´endez (1990), Valdiz´an and Maldonado (1972)

Leaves

Diabetes mellitus, hypertension

Infusion or decoction

Diabetes mellitus Diarrhoea, antiseptic, Diabetes mellitus Astringent, ulcers, wounds, diarrhoea

Infusion or decoction Infusion or decoction Decoction and poultice

India Ghana Peru

Leaves Leaves Leaf, bark, unripe fruit, roots Leaves, shoots Flower buds, leaves

Decoction or infusion

Kinshasa, Congo

Leaves, bark

Febrifuge, antispasmodic, rheumatism, convulsions, astringent Heart and constipation, conjunctivitis, cough, diarrhoea, digestive problems, dysentery, oedema, gout, haemorrhages, gastroenteritis, gastritis, lung problems, shock, vaginal discharge, vertigo, vomiting, worms Diarrhoea, antiamoebic

Senegal Uruguay

Shoots, roots Leaves

Fiji

Leaves, roots, ripe fruit

Tahiti, Samoa

Whole plant, shoots

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

Leaves

Skin tonic, painful menstruation, miscarriages, uterine bleeding, premature labour in women, wounds Itchy rashes caused by scabies

Leaves

Trinidad

Leaves

Latin America, Central and West Africa, and Southeast Asia Panama, Bolivia and Venezuela Brazil

Leaves

USA

Leaf

Caribbean China Philippines

Bark and leaves Ripe fruit, flowers, and leaves

Decoction or infusion

Externally applied hot on inflammations

Infusion or decoction

Oh et al. (2005), Ojewole (2005) Mej´ıa and Rengifo (2000) Teixeira et al. (2003) Smith and Nigel (1992) Hernandez (1971) Cabieses (1993)

Infusion or decoction, tisane Infusion or decoction Infusion or decoction

Tona et al. (1999)

Juice, the leaves are pounded, squeezed in salt water Infusion or decoction, paste

Word Health Organization (1998)

Boiled preparation

Word Health Organization (1998)

Sores, boils, cuts, sprains

Infusion or decoction

Bacterial infections, blood cleansing, diarrhoea, dysentery Gargle for sore throats, laryngitis and swelling of the mouth, and it is used externally for skin ulcers, vaginal irritation and discharge Dysentery, astringent, used as a bath to treat skin ailments Anorexia, cholera, diarrhoea, digestive problems, dysentery, gastric insufficiency, inflamed mucous membranes, laryngitis, mouth (swelling), skin problems, sore throat, ulcers, vaginal discharge Antibiotic and diarrhoea

Infusion or decoction Decoction

Word Health Organization (1998) Word Health Organization (1998) Mej´ıa and Rengifo (2000)

Decoction

Conway (2002)

Mashed, Decoction

Holetz et al. (2002), Cybele et al. (1995)

Decoction

Smith and Nigel (1992)

Diarrhoea, dysentery Vaginal and uterine wash, especially in leucorrhoea Diarrhoea, coughs, stomach-ache, dysentery, toothaches, indigestion, constipation

Tona et al. (1999) Conway (2002)

Word Health Organization (1998)

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of human ailments, including diabetes mellitus and hypertension (Ojewole, 2005; Oh et al., 2005). Guava has been used widely in the traditional medicine of Latin America and the Caribbean in the treatment of diarrhoea and stomach-aches due to indigestion (Mej´ıa and Rengifo, 2000; Mitchell and Ahmad, 2006a,b). Treatment usually involves a decoction of the leaves, roots, and bark of the plant. It also has been used for dysentery in Panama and as an astringent in Venezuela. A decoction of the bark and leaves is also reported to be used as a bath to treat skin ailments. In Uruguay, a decoction of the leaves is used as a vaginal and uterine wash, especially in leucorrhoea (Conway, 2002). In Costa Rica, a decoction of the flower buds is considered an effective anti-inflammatory remedy (Pardo, 1999). In Peru, it is used for gastroenteritis, dysentery, stomach pain (by acting on the pathogenic microorganisms of the intestine), indigestion, inflammations of the mouth and throat in the form of gargles (Cabieses, 1993). In some tribes of the forest (Tipis), the tender leaves are chewed to control toothaches by their weak sedative effect. Tikuna Indians use the decocted leaves or bark of guava for diseases of the gastrointestinal tract. It is also employed by the Indians of the Amazons for dysentery, sore throats, vomiting, stomach upsets, vertigo, and to regulate menstrual periods, mouth sores, bleeding gums, or used as a douche for vaginal discharge and to tighten and tone vaginal walls after childbirth. Flowers are also mashed and applied to painful eye conditions such as sun strain, conjunctivitis or eye injuries (Smith and Nigel, 1992). Guava jelly is tonic to the heart and constipation (Conway, 2002). In the Philippines the astringent unripe fruit, the leaves, the cortex of the bark and the roots are used for washing ulcers and wounds, as an astringent, vulnerary, and for diarrhoea. Leaves and shoots are used by West Indians in febrifuge and antispasmodic baths; the dust of the leaves is used in the treatment of rheumatism, epilepsy and cholera; and guava leaves tincture is given to children suffering from convulsions (Morton, 1987). In Latin America, Central and West Africa, and Southeast Asia, guava is considered an astringent, drying agent and a diuretic. A decoction is also recommended as a gargle for sore throats, laryngitis and swelling of the mouth, and it is used externally for skin ulcers, vaginal irritation and discharge (Mej´ıa

and Rengifo, 2000). In Mozambique, the decoction of leaves is mixed with the leaves of Abacateira cajueiro, to alleviate the flu, cough and pressed chest. In Mozambique, Argentina, Mexico and Nicaragua, guava leaves are applied externally for inflammatory diseases (Jansen and M´endez, 1990). The use of medicinal plants by the general Chinese population is an old and still widespread practice. Psidium guajava leaves are example of the plant commonly used as popular medicine for diarrhoea which is also used as an antiseptic (Teixeira et al., 2003). In Brazil the fruit and leaves are considered for anorexia, cholera, diarrhoea, digestive problems, dysentery, gastric insufficiency, inflamed mucous membranes, laryngitis, mouth (swelling), skin problems, sore throat, ulcers, vaginal discharge (Holetz et al., 2002). In USA guava leaf extracts that are used in various herbal formulas for a myriad of purposes; from herbal antibiotic and diarrhoea formulas to bowel health and weight loss formulas (Smith and Nigel, 1992). Besides the medicinal uses Psidium guayava is employed as food, in carpentry, in construction of houses and in the manufacture of toys (Table 2). 2. Phytochemistry 2.1. Fruits These are characterized by a low content of carbohydrates (13.2%), fats (0.53%), and proteins (0.88%) and by a highwater content (84.9%), (Medina and Pagano, 2003). Food value per 100 g is: Calories 36–50 kcal, moisture 77–86 g, crude fibre 2.8–5.5 g, ash 0.43–0.7 g, calcium 9.1–17 mg, phosphorus (Conway, 2002), 17.8–30 mg, iron 0.30–0.70 mg (Iwu, 1993), vitamin A 200–400 I.U., thiamine 0.046 mg, riboflavin 0.03–0.04 mg, niacin 0.6–1.068 mg, ascorbic acid 100 mg, vitamin B3 40 I.U. (Fujita et al., 1985; Hernandez, 1971; Conway, 2002). Manganese is also present in the plant in combination with phosphoric, oxalic and malic acids (Nadkarni and Nadkarni, 1999). Hexanal (65.9%), ␥-butyrolactone (7.6%), (E)-2-hexenal (7.4%), (E,E)-2,4-hexadienal (2.2%), (Z)-3-hexenal (2%), (Z)2-hexenal (1%), (Z)-3-hexenyl acetate (1.3%) and phenol

Table 2 Commercial applications of Psidium guajava Fruit Wood and leaves Wood Wood Wood Wood Leaves Leaves Bark Wood flowers

Food: juice, jelly nectar, concentrated, stuffed of candies, gelatines, pastes, tinned products, confectionery, etc. Carpentry and turnery use the leaves to make a black dye for silk Engravings Spinning tops Hair combs Construction of houses Employed to give a black colour to cotton Serve to dye matting Dyes, stains, inks, tattoos and mordants The tree may be parasitized by the mistletoe, Psittacanthus calyculatus Don, producing the rosette-like malformations called “wood flowers” which are sold as ornamental curiosities. Also the tree is seeded to give shade to the coffee and its wood is used in the construction

All the countries

Jimenez-Escrig et al. (2001)

Malaya India Guatemala El Salvador Nigeria Southeast Asia Indonesia Africa Mexico

Rodarte (1994) Rodarte (1994) Morton (1987) Morton (1987) Lucas et al. (2006) Rodarte (1994) Rodarte (1994) Burkill (1985) Argueta et al. (1994)

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(1.6%) were reported from fresh white-flesh guayaba fruit oil. 3-caryophyllene (24.1%), nerolidol (17.3%), 3-phenylpropyl acetate (5.3%) and caryophyllene oxide (5.1%) were isolated from essential oil extracted from the fruits (Paniandy et al., 2000). Subsequently, the active aromatic constituents in pink guava fruit the 3-penten-2-ol and 2-butenyl acetate were isolated (Jordan et al., 2003). The fruit also contains glykosen 4.14%, saccharose 1.62%, and protein 0.3% (Dweck, 2001; Hwang et al., 2002). The unripe fruit is indigestible, causes vomiting and feverishness. It changes in chemical composition and the activities of hydrolytic enzymes (the activities of ␣-amylase and ␤-amylase decreased significantly with ripening), chlorophyll, cellulose, hemicellulose, and lignin content increased while carotenoid content decreased. The unripe fruit is high in tannins, is astringent and has a tendency to cause constipation, but it is sometimes employed in diarrhoea (Jain et al., 2003). 2.2. Fruit skins Ascorbic acid is the main constituent of the skin, secondly in the firm flesh, and a little content in the central pulp varies from 56 mg to 600 mg and may range between 350 mg and 450 mg in nearly ripe fruit (Charles et al., 2006). Canning or other heat processing destroys about 50% of the ascorbic acid. The strong odour of the fruit is attributed to its carbonyl compounds (Dweck, 2001). 2.3. Leaves Leaves contain essential oil with the main components being ␣-pinene, ␤-pinene, limonene, menthol, terpenyl acetate, isopropyl alcohol, longicyclene, caryophyllene, ␤-bisabolene, cineol, caryophyllene oxide, ␤-copanene, farnesene, humulene, selinene, cardinene and curcumene (Zakaria and Mohd, 1994; Li et al., 1999). Flavonoids, and saponins combined with oleanolic acid have been isolated from the leaves (Arima and Danno, 2002). Nerolidiol, ␤-sitosterol, ursolic, crategolic, and guayavolic acids have also been identified (Iwu, 1993). In addition, the leaves contain triterpenic acids as well as flavonoids; avicularin and its 3-l-4-pyranoside with strong antibacterial action (Oliver-Bever, 1986), fixed oil 6%, 3.15% resin, and 8.5% tannin, and a number of other fixed substances, fat, cellulose, tannin, chlorophyll and mineral salts (Nadkarni and Nadkarni, 1999). Also have been isolated from the leaves of Psidium guajava guavanoic acid, guavacoumaric acid, 2␣-hydroxyursolic acid, jacoumaric acid, isoneriucoumaric acid, asiatic acid, ilelatifol d and ␤-sitosterol-3-O-␤-dglucopyranoside (Begum et al., 2002a,b). In mature leaves, the greatest concentrations of flavonoids were found in July: Myricetin (208.44 mg kg−1 ), quercetin (2883.08 mg kg−1 ), luteolin (51.22 mg kg−1 ) and kaempferol (97.25 mg kg−1 ) (Vargas et al., 2006). Two triterpenoids, 20␤-acetoxy2␣,3␤-dihydroxyurs-12-en-28-oic acid (guavanoic acid), and 2␣,3␤-dihydroxy-24-p-z-coumaroyloxyurs-12-en-28-oic acid (guavacoumaric acid), along with six known compounds 2␣-hydroxyursolic acid, jacoumaric acid, isoneriucoumaric

5

acid, asiatic acid, ilelatifol d and ␤-sitosterol-3-O-␤-dglucopyranoside, have been isolated from the leaves of Psidium guajava. guajavolide (2a-,3␤-6␤-,23-tetrahydroxyurs12-en-28,20␤-olide, and guavenoic acid, were isolated from fresh leaves of Psidium guajava. Bark: It contains 12–30% of tannin (Burkill, 1997), resin and crystals of calcium oxalate (Nadkarni and Nadkarni, 1999). Roots: They contain tannins, leukocyanidins, sterols, gallic acid, carbohydrates and salts. Root, stem-bark and all leaves contain a large percentage of tannic acid (Quisumbing, 1978). Seeds: They contain 14% oil, dry weight, with 15% proteins and 13% starch (Burkill, 1997), phenolic and flavonoid compounds including quercetin-3-O-␤-d-(2 -O-galloyl-glucoside)-4 -Ovinylpropionate (Michael et al., 2002). Some isolated compounds are cytotoxic (Salib and Michael, 2004). Floral bud: Buds have the highest concentrations of myricetin (256 mg kg−1 ), quercetin (3605 mg kg−1 ), luteolin (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 concentration 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-terpenes alcohols and acids triterpenoids (Hegnauer, 1969). 3. Biological activity Scientific investigations on the medicinal properties of guava dates back to the 1940s. A summary of the findings of these studies performed is presented below. 3.1. Anti-diarrhoeal Diarrhoea has long been recognized as one of the most important health problems faced globally particularly by the population of developing countries. Each year diarrhoea is estimated to kill about 2.2 million people globally, the majority of whom are infants and children below the age of 5 years (Venkatesan et al., 2005). Ethanol and aqueous extracts of Psidium guajava at a concentration of 80 ␮g/ml in an organ bath, exhibited more than 70% inhibition of acetylcholine and/or KCl solution-induced contractions of isolated guineapig ileum. The rates of propulsion in the small intestine in male Sprague–Dawley rats as a means of assessing antidiarrhoeal activity of aqueous extracts of the leaf of Psidium guajava using morphine as the standard drug of reference measured (Tona et al., 1999; Lutterodt, 1992). A dose of 0.2 ml/kg fresh leaf extract produced 65% inhibition of propulsion. This dose is equitable with 0.2 mg/kg of morphine sulphate. The antidiarrhoeal action of the extract may be due, in part, to the inhibition of the increased watery secretions that occur commonly in all acute diarrhoeal diseases and cholera.

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Quercetin showed significant anti-diarrhoeal activity on the contraction of guinea pig ileum in vitro and the peristaltic motion of mouse small intestine, and reduced the permeability of abdominal capillaries (Heinrich, 1998; Zhang et al., 2003). Quercetin and quercetin-3-arabinoside, extracted from the buds and leaves of Psidium guajava at concentrations of 1.6 ␮g/ml showed a morphine-like inhibition of acetylcholine release in the coaxially stimulated ileum, together with an initial increase in muscular tone, followed by a gradual decrease (Lutterodt, 1989). It is also reported that the asiatic acid, also extracted from the leaves, showed dose-dependent (10–500 ␮g/ml) spasmolytic activity in spontaneously contracting isolated rabbit jejunum preparations (Conde et al., 2003). Methanol extract from leaves (8 ␮g/ml) of Psidium guajava showed activity against simian (SA-11) rotavirus (93.8% inhibition) (Goncalves et al., 2005). In addition, galactose-specific lectin in guayaba was shown to bind to Escherichia coli (a common diarrhoeacausing organism), preventing its adhesion to the intestinal wall and thus preventing infection resulting diarrhoea (Couti˜no et al., 2001). A methanolic leaf extract (8 ␮g/ml) of Psidium guajava also showed activity against simian (SA-11) rotavirus (93.8% inhibition) (Goncalves et al., 2005). In addition, galactose-specific lectin isolated from guava fruit ripe were shown to bind to Escherichia coli (a common diarrhoea-causing organism), preventing its adhesion to the intestinal wall and thus preventing infection resulting diarrhoea (Couti˜no et al., 2001). 3.2. Antimicrobial The inhibitory effects of aqueous and alcoholic extracts of the Psidium guajava (root as well as leaves) on the growth of Staphylococcus aureus, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella enteritidis, Bacillus cereus, Proteus spp., Shigella spp. and Escherichia coli, causal agent of intestinal infections in humans were examined using the in vitro agar well diffusion method (Chah et al., 2006). Methanolic root extract was further separated by column chromatograph, yielding four antibacterial compounds. Three antibacterial substances have been detected in the leaves which are derivatives of quercetin (Prabu et al., 2006; Arima and Danno, 2002). In another study, it was observed that methanolic extract from fruit ripe have fungicidal action against Arthrinium sacchari M001 and Chaetomium funicola M002 strains (Sato et al., 2000). Aqueous and methanolic extracts of the leaves are effective inhibitors of growth spore formation, and enterotoxin production of Clostridium perfringens type A. No enterotoxins were detected when extracts were added to the media at less than the MIC for growth (Garcia et al., 2002). Psidium guajava leaf and bark tinctures were subjected to in vitro sensitivity tests by serial dilution at concentrations ranging from 5% to 15% against six test dermatophytes, viz., Trichophyton tonsurans, Trichophyton rubrum, Trichosporon beigelii, Microsporum fulvum, Microsporum gypseum and Candida albicans. Bark tincture exhibited higher efficacy in controlling the mycelial growth of dermatophytes than the leaf tincture.

The bark tincture showed fungicidal activity at different concentrations but exhibited only fungistatic property in case of Candida albicans (Dutta and Das, 2000). Ethanolic extract from the shell of ripe fruit presenting activity on Streptococcus mutans and Escherichia coli (Neira and Ramirez, 2005). Results supported the utilization of Psidium guajava in traditional medicine for intestinal diseases produced by microorganisms. 3.3. Acne lesions Acne vulgaris is a chronic inflammatory disease involving colonization of Propionibacterium acnes, plus activation of neutrophils and lymphocytes. Circumstantial evidence suggests that antigen-independent and -dependent immune responses against Propionibacterium acnes are involved in the pathogenesis of inflammatory acne. Epidermal keratinocytes are also suggested to be involved in initiation and progression of cutaneous inflammation. Psidium guajava leaf extracts have potent antimicrobial activities against Propionibacterium acnes and may be beneficial in treating acne especially when they are known to have anti-inflammatory activities (Qadan et al., 2005). 3.4. Effect on dental plaque The adhesion of early settlers of dental plaque to the tooth surface has a role in the initiation of the development of dental plaque. The hydrophobic surface properties of the bacteria cell wall are indirectly responsible for the adhesion of the bacteria cell to the acquired pellicle on the tooth surfaces. Tooth brushing is considered a superior technique for reducing plaque accumulation. Chemical agents may be used to reduce plaque accumulation on tooth surfaces. The treatment of the early plaque settlers with 1 mg/ml aqueous extract leaf of Psidium guajava reduced the cell-surface hydrophobicity of Staphylococcus sanguinis, Staphylococcus mitis and Actinomyces sp. by 54.1%, 49.9% and 40.6%, respectively (Razak et al., 2006). These results provide some scientific rationale for its use in the treatment of dental diseases and suggested that guava leaf extracts may inhibit the caries-inducing properties of Streptococcus and thus may be beneficial for the dental care. 3.5. Antimalarial effects The parasite lactate dehydrogenase (pLDH) assay method, a recently developed in vitro enzymatic method for evaluating antimalarial compounds, was used to examine the antiplasmodial activities of the aqueous leaf, stem-bark and fruit extracts of Psidium guajava. An in vitro antiplasmodial assay carried out using a chloroquine-sensitive strain of malarial parasite, Plasmodium falciparum D10 showed antigiardiasic activity with trophozoite mortality (87% ± 1.0); guava stembark extract showed IC50 values of 10–20 ␮g/ml (Ponce et al., 1994; Nundkumar and Ojewole, 2002). In another study, leaves and stem bark of Psidium guajava inhibited Entamoeba histolytica growth with MAC < 10 ␮g/ml (Tona et al., 1998).

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3.6. Antitussive effects In another report, the water infusion from Psidium guajava leaves decreased the frequency of coughing induced by capsaicin aerosol as compared to the control, within 10 min after injection of the extract (Jaiarj et al., 1999). Infusion on isolated rat tracheal muscle showed one directly stimulated muscle contraction and also synergized with the stimulatory effect of pilocarpine. This effect was antagonized by atropine (Pranee et al., 1999). These results suggest that guava leaf extract could be recommended as a cough remedy. 3.7. Hepatoprotective effects The hepatoprotective effect of an aqueous leaf extract of Psidium guajava was studied on rat liver damage induced by carbon tetrachloride by monitoring serum transaminase (aspartate amino transferase and serum alanine amino transferase), alkaline posphatase, serum cholesterol, serum total lipids and histopathological alterations. The leaf extract at doses of 500 mg/kg produced significant hepatoprotection (Roy et al., 2006). Pretreatment with asiatic acid (a triterpenoid extracted from Psidium guajava leaves and fruit) at doses of 25 mg/kg, 50 mg/kg or 100 mg/kg significantly blocked the LPS (lipopolysaccharide) and (d-galactosamine) d-GalN-induced increases in both serum aspartate aminotransferase and serum alanine aminotransferase levels, showing improved nuclear condensation, ameliorated proliferation and less lipid deposition (Gao et al., 2006). Several studies have indicated the ability of guava to reduce several parameters associated with liver injury. 3.8. Antioxidant, free radical scavenger and radioprotective activities Cellular damage or oxidative injury arising from free radicals or reactive oxygen species (ROS) now appears to be the fundamental mechanism underlying a number of human neurodegenerative disorders, diabetes, inflammation, viral infections, autoimmune pathologies and digestive system disorders. Free radicals are generated through normal metabolism of drugs, environmental chemicals and other xenobiotics as well as endogenous chemicals, especially stress hormones (adrenalin and noradrenalin) (Masuda et al., 2003). Dried leaves of Psidium guajava were extracted with hot water. The total phenolic content in the extract was determined spectrophotometrically according to Folin–Ciocalteu’s phenol method and calculated as gallic acid equivalent (GAE). A remarkably high total phenolic content 575.3 ± 15.5 were obtained (Qian and Nihorimbere, 2004). The antioxidant activity of lyophilized leaf extracts was determined using free radical DPPH (2,2-diphenyl-1-picrylhydryzyl) scavenging. The results obtained showed that ascorbic acid was a substantially more powerful antioxidant than the extracts from guava leaf (Qian and Nihorimbere, 2004; Thaipong et al., 2005). These antioxidant properties are associated with its phenolic compounds such as protocatechuic acid, ferulic acid, quercetin and guavin B (Thaipong et al., 2005), quercetin, ascorbic acid, gallic acid

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and caffeic acid (Jimenez et al., 2001). Guava leaf extracts are a potential source of natural antioxidants (Ojan and Nihorimbere, 2004). Other studies show that guava fruits also exert antioxidant and radioprotective activity in the assay with technetium-99m [(99m)Tc] (Abreu et al., 2006). 3.9. Antigenotoxic and antimutagenic effects Generation of DNA damage is considered to be an important initial event in carcinogenesis. A considerable battery of assays exists for the detection of different genotoxic effects of compounds in experimental systems, or for investigations of exposure to genotoxic agents in environmental or occupational settings. Treatment with the aqueous whole plant extracts of Psidium guajava afforded protection (anti-genotoxic activity) against mitomycin C, nalidixic acid and hydrogen peroxide (three genotoxins) (Bartolome et al., 2006). In another study, a pre-treatment with an aqueous guava leaf extract was found to be effective in inactivating the mutagenicity of direct-acting mutagens 4-nitro-o-phenylenediamine and 2-aminofluorene in the tester strains of Salmonella typhimurium. Therefore aqueous leaf extracts of Psidium guajava show promising antigenotoxic/antimutagenic activity (Grover and Bala, 1993). 3.10. Anti-allergic effects Th1 polarization is one of the mechanisms underlying the therapeutic effects of herbal medicine. The action of anti-allergic agents from Psidium guajava on T cell immunity in mice was investigated. Studies were carried out on methanol and aqueous extracts of Psidium guajava leaves. These extracts cause potent inhibition of histamine release from mast cells, and blocked IL10-mediated, in vitro induction of T regulatory (Tr) cells from CD4+ splenocytes of C57BL/6 mice. The extracts also shifted the Th1/Th2 balance to a Th1 dominant status by directly attenuating Tr cell activity. Psidum guajava leaf extracts showed anti-allergic activity on T cell immunity in mice (Seo et al., 2005). 3.11. Anticancer/antitumour effects An aqueous extract of Psidium guajava leaves inhibited (the viability) of the cancer cell line DU-145 in a dose-dependent manner. At 1.0 mg/ml, the extract reduced the viability of PCa DU-145 (the androgen independent PCa cells) to 36.1% and 3.6%, respectively after 48 h and 72 h of incubations (Chen et al., 2007). Essential oil extracted from leaves of Psidium guajava was highly effective in reducing the growth of human mouth epidermal carcinoma (KB) and murine leukemia (P388) cell lines when they were treated with different concentrations of the oil ranging from 0.019 mg/ml to 4.962 mg/ml. Guava leaf oil showed the highest anti-proliferative activity with an IC50 value of 0.0379 mg/ml (four times more potent than vincristine) on P388 cell lines (Manosroi et al., 2006); an effect mostly attributed to the monoterpenes present in the essential oil (Cit´o et al., 2003). A chemopreventive effect was also demonstrated

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in another study of a methanol leaf extract on mice-induced cancer inoculated with B16 melanoma cells. A significant decrease in the incidence and average number of animals with cancer was found compared to the control group (Fernandes et al., 1995). These findings suggest that Psidium guajava aqueous leaf extracts are efficacious for the prevention of tumour development by depressing Tr cells and subsequently shifting to Th1 cells (Seo et al., 2005). Furthermore, jacoumaric acid (isolated from guava seeds) was evaluated for its antitumour effect; it was found to significantly reduce the incidence of tumours (Numata et al., 1989). Phytochemical investigations of the acetone extract of Psidium guajava seeds has led to the isolation of phenyl-ethanoid glycosides (1-O-3,4-dimethoxy-phenylethyl-4-O-3,4dimethoxy cinnamoyl-6-O-cinnamoyl-beta-d-glucopyranose and 1-O-3,4-dimethoxyphenylethyl-4-O-3,4-dimethoxy cinnamoyl-beta-d-glucopyranose) which showed cytotoxic activities in vitro against Ehrlich ascites cells (EAC) and leukaemia P3888 cells (Salib and Michael, 2004). These finding suggested that Psidium guaijava extracts have the potential to be developed as new chemotherapeutic agents to prevent or to inhibit the growth of tumours and cancers. 3.12. Cardiovascular, hypotensive effects The effect of an aqueous leaf extract of Psidium guajava on myocardial injury was studied in the model of global ischemia followed by reperfusion. High-energy phosphates and malondialdehyde in the reperfused hearts were significantly reduced with the plant extract (Conde et al., 2003). In another study, aqueous leaf extract of Psidium guajava exhibited cardioprotective effects against myocardial ischemia-reperfusion injury in isolated rat hearts. Augmentation of endogenous antioxidants, maintenance of the myocardial antioxidant status and significant restoration of most of the altered hemodynamic parameters may have contributed to its cardioprotective effect (Yamashiro et al., 2003). The cardio-inhibitory actions in rats and guinea pigs of the aqueous leaf extract of Psidium guajava also appeared to be due to cholinergic involvement in the mechanism of action. Ojewole (2005) showed that the aqueous leaf extract caused hypotension in the experimental animal model used via cholinergic mechanisms. Moreover, acute intravenous administrations of the leaf extract (50–800 mg/kg i.v.) produced dose-dependent, significant reductions in systemic arterial blood pressures and heart rates of hypertensive, Dahl salt-sensitive rats. Although the exact mechanisms of action of the extract remain speculative at present, it is unlikely that the extract causes hypotension in the mammalian experimental animal model used via cholinergic mechanisms since its cardiodepressant effects are resistant to atropine pre-treatment (Ojewole, 2005). Belemtougri et al. (2006) found that aqueous and ethanolic leaf extracts of Psidium guajava inhibits intracellular calcium release (Chiesi and Schwaller, 1994; Apisariyakul et al., 1999). Aqueous leaf extract of Psidium guajava significantly and dosedependently (0.25–2 mg/ml) contracted the aorta rings. The effect was evaluated also in the presence of nifedipine and phentolamine. The sensitivity of the aortic rings to cumulative doses

of Psidium guajava was significantly enhanced in the presence of phentolamine suggesting that the effect of Psidium guajava was to a large extent mediated by activation of an alpha-adrenoceptor and to a lesser extent by acting via calcium ion channel (Olatunji et al., 2007). A guava leaf extract may therefore be beneficial for the prevention of cardiovascular diseases, also since its traditional use in hypertension is well established. 3.13. Anti-hyperglycemic The rapidly increasing diabetes mellitus is becoming a serious threat to human health in all parts of the world. The control and treatment of diabetes and its complications mainly depend on the chemical or biochemical agents, but the fact is that it has never been reported that someone had recovered totally from diabetes. With the distinctive traditional medical opinions and natural medicines mainly originated in herbs, traditional medicine offers good clinical opportunities and shows a bright future in the therapy of diabetes mellitus and its complications. The effect of Psidium guajava bark, leaves and fruit as antidiabetic agents has been studied by several authors. Mukhtar et al. (2006) evaluated anti-hyperglycaemic activity of the ethanol extract obtained from the stem bark of Psidium guajava on blood glucose levels of normal, alloxan-induced hyperglycaemic rats and normal glucose loaded rats. The results showed that ethanol stem bark extract exhibited statistically significant hypoglycaemic activity in alloxan-induced, hyperglycaemic rats but was devoid of significant hypoglycaemic effect in normal and normal glucose loaded rats. In another study, a decoction of Psidium guajava leaves was screened for hypoglycaemic activity on alloxan-induced diabetic rats. In both acute and sub-acute tests, the water extract, at an oral dose of 250 mg/kg, showed statistically significant hypoglycaemic activity (Mukhtar et al., 2004). The treatment with Psidium guajava aqueous leaf extract (0.01–0.625 mg/ml) showed significant inhibition on LDL glycation in a dose-dependent manner. Tannins, flavonoids, pentacyclic triterpenoids, guiajaverin, quercetin, and other chemical compounds present in the plant are speculated to account for the observed hypoglycaemic and hypotensive effects of the leaf extract (Ojewole, 2005; Wang et al., 2005). Psidium guajava is an excellent anti-LDL glycative agent whose potential therapeutic uses can be extended to the prevention of a variety of cardiovascular and neurodegenerative diseases associated with glycations (Hsieh et al., 2007). Oh et al. (2005) demonstrated that the methanol extract from Psidium guajava leaves exhibited significant inhibitory effect on PTP1B (protein tyrosine phosphatase 1B) in Lepr[db/Lepr[db] mice homozygous for the diabetes spontaneous mutation (Leprdb ) become identifiably obese around 3–4 weeks of age. These homozygous mutant mice are polyphagic, polydipsic, and polyuric. Blood glucose lowering effect of the methanol extract was observed after i.p. dose of 10 mg/kg, with an antidiabetic effect via the inhibition of PTP1B. In one study, oral administrations of 100 mg/kg, 150 mg/kg and 250 mg/kg of juice from ripe guava fruit caused significant hypoglycemia in normoglycemic and STZ-treated, diabetic rats

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(Cheng and Yang, 1983). Although effective duration of guava is less potent than chlorpropamide and metformin. Moreover, acute intravenous administrations of the fruit’s juice produced significant reductions in systemic arterial blood pressures and heart rates of hypertensive patients. Some investigators suggested that the hypoglycaemic components in guava fruits might involve ursolic acid, oleanolic acid, arjunolic acid and glucuronic acid (Chang, 1982). Anti-LDL (low density lipoprotein) glycative agents were investigated using aqueous decoctions of Psidium guajava fruit ripe at concentrations of 0.01–0.625 mg/ml (Hsieh et al., 2005). The results have revealed that guava fruits exhibit excellent antiglycation effect, being a rather powerful and effective inhibitor of LDL glycation in both glucose and glyoxal induced models. The antiglycation activities of guava fruit were relevantly and directly related to its polyphenolic content (extractable polyphenols 2.62–7.79%), yet it seemed to us that Psidium guajava fruit also possesses a rather specific and somewhat different degree of free-radical scavenging ability, thus it was speculated that the reaction mechanism of guava might have occurred in the initiation rather than the propagation phase, a mechanism being quite different from the conventional free-radical scavenging by the polyphenolics. This problem is indeed worth exploring in further studies. 3.14. Effect on muscular system Degenerative muscular diseases, such as muscular dystrophy, have been the target of regenerative cell therapy. Although satellite cells play central roles in skeletal muscle regeneration that intrinsically occurs after muscle injury, their application to cell therapy is confronted with difficulties (Endo, 2007). Water and methanolic leaf extracts from Psidium guajava showed antagonistic effects on caffeine induced calcium release from the sarcoplasmic reticulum of rat skeletal muscle cells in a dosedependent-manner showing a clear calcium-antagonistic effect (Belemtougri et al., 2006). Aqueous leaf infusions of Psidium guajava could block the L-type calcium membrane channels (Conde et al., 2003). Guava may therefore be beneficial for patients with muscular dystrophy (Lamb, 2000). 3.15. Anti-inflammatory/analgesic A decoction of Psidium guajava leaves is used worldwide for the treatment of various inflammatory ailments including rheumatism. The numerous polyphenolic compounds, triterpenoids and other chemical compounds present in the plant may account for the observed anti-inflammatory and analgesic effects of the leaf extracts. The anti-inflammatory property of the aqueous leaf extract was investigated in rats, using fresh egg albumin induced pedal (paw) oedema, while the analgesic effect of the plant extract was evaluated by the hot-plate and acetic acid test models of pain in mice. Psidium guajava aqueous extract (50–800 mg/kg, i.p.) produced dose-dependent and significant inhibition of fresh egg albumin-induced acute inflammation (oedema) in rats. The leaf extract (50–800 mg/kg, i.p.) also produced dose-dependent and significant analgesic effects

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against thermally and chemically induced nociceptive pain in mice (Ojewole, 2006). The anti-inflammatory and analgesic activities of 70% ethanolic extract of leaves of Psidium guajava were also investigated in rats using the carrageenan induced hind paw oedema model. Extracts which exhibited anti-inflammatory activity were screened for analgesic activity using the Randall–Selitto method in rats. The extracts were administered at a dose of 300 mg/kg, p.o. Aspirin (300 mg/kg, p.o.) was employed as the reference drug. Psidium guajava leaves showed significant antiinflammatory activity with an inhibition of 58% (Muruganandan et al., 2001). The essential oil, steam-distilled from leaves of Psidium guajava, was given orally to rats to study its effects on the exudative and proliferative phases of the inflammatory reaction (carrageenan induced paw oedema and cotton pellet induced granuloma models). The essential oil (0.8 mg/kg) significantly reduced oedema formation induced by carrageenan while at 0.4 mg/kg and 0.8 mg/kg the oil also significantly reduced granuloma formation induced by cotton pellets (Kavimani et al., 1997). 3.16. Antinociceptive effects The hexane, ethyl acetate and methanol extracts of Psidium guajava leaves showed activity on the central nervous system in mice. The three extracts exhibited mostly antinociceptive effects in chemical and thermal tests of analgesia. The extracts also produced dose-dependent prolongation of pentobarbitone-induced sleeping time (Shaheen et al., 2000). Shortly after intraperitoneal administration of this methanol extract, typical narcotic-like effects were observed including catalepsy, analgesia, straub tail, shallow respiratory movements and exophthalmos. Doses of 3.3–6.6 mg/kg i.p. depressed spontaneous locomotor activity and tunnel running was curtailed. Higher doses abolished the spontaneous locomotor reflex action (Lutterodt and Maleque, 1988). These results lend pharmacological credence to the uses of the plant in the management and/or control of painful, arthritic and other inflammatory conditions. It was also reported in another study that the antinociceptive effect of leaf essential oil from Psidium guajava and its constituent, ␣-pinene produced a significant antinociceptive effect in the formalin test probably mediated by endogenously released adenosine (Santos et al., 1998). Hexane, ethyl acetate and methanol extracts of Psidium guajava leaves on the central nervous system in mice exhibited mostly dosedependent antinociceptive effects in chemical and thermal tests of analgesia. The extracts also produced dose-dependent prolongation of pentobarbitone-induced sleeping time. However, they had variable and mostly non-significant effects on locomotor coordination, locomotor activity or exploration (Shaheen et al., 2000). A bio-guided fractionation of the hexane extract obtained from Psidium guajava leaves led to the isolation of sesquiterpenes with depressant activities on the central nervous system. The relaxant properties of the Psidium guajava hexane extract are largely due to the presence of terpenes,

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especially caryophyllene-oxide and ␤-selinene, which potentiated pentobarbital sleeping time and the latency of convulsions induced by leptazol in mice. Calcium concentration–response curves showed a rightward displacement when hexane extract was added to isolated guinea-pig ileum depolarized with K+ (60 mm) and cumulative concentrations of CaCl2 , suggesting that caryophyllene-oxide, a known Ca2+ antagonist agent could be responsible for the blockade of extracellular Ca2+ (Meckes et al., 1996).

diarrhoeal of the treated group (25.1 ± 9.5 h) was significantly shorter than that of the control group (38.7 ± 15.2 h, P < 0.01). The content of Na+ and glucose in stool was reduced obviously in the treated group, while the reduction in the control group was insignificant; the treated group was significantly superior to the control group. The rate of negative conversion of HRV in faeces of the treated group was 87.1%, significantly better than that of the control (58.1%). The treatment with PG has good curative effect on infantile rotaviral enteritis (Wei et al., 2000).

3.17. Wound healing

5.2. Infectious gastroenteritis

The wound healing properties of a methanolic leaf extract of Psidium guajava were determined using the excision wound model. More than 90% wound healing was observed after 14 days post-surgery, whereas 72% healing was observed in the distilled water treated group (Chah et al., 2006).

In the Laboratory of Medicinal Plants Research Unit of Neurological Diseases, Mexico, a randomized double-blind trial examined the efficacy of a standardized aqueous leaf extract Psidium guajava ([QG-5] estimated at quercetin-equivalent 1 mg per 500 mg capsule) versus placebo in 100 patients with infectious gastroenteritis. The experimental group (n = 50) received 1 capsule of QG-5 orally every 8 h for 3 days, while the control group (n = 50) received the same regimen with matching placebo capsules. Conventional oral rehydration therapy was initiated in both groups. Outcome measures included number of daily stools, consistency, presence of mucus, degree of abdominal pain, number of spasms in 24 h, fever, and number of vomiting episodes. Results indicated a significant difference in outcome measures favouring the experimental group, mostly due to an antispasmolytic effect, which helped reduce the number of episodes of abdominal pain. No adverse effects were reported for patients treated with QG-5 (Lozoya et al., 2002). Besides constipation, no serious adverse reactions have been reported in patients taking QG-5. Guava is commercially available in capsules, liquids, powders, and tablets in a standardized form for gastroenteritis. In Cuba, a longitudinal randomized double blind study was carried out among 100 adult patients with acute diarrhoea. The effect of an oral treatment with 10 ml tincture from Psidium guajava dissolved in water, every 8 h, on the treatment of diarrhoea was determined. The results revealed that this 20% leaf tincture significantly reduced the time to ceasing diarrhoea and no adverse reactions were detected (Echemendia and Moron, 2004). Guava offers an effective and safe alternative treatment for patient with diarrhoea disease.

4. Toxicology This toxicologic study was conducted using dry leaves of Psidium guajava L. In this plant material, acute toxicologic study by the following methods: mean lethal dose LD50 test in Swiss mice and alternative toxicology (acute toxic classes) in Wistar rats. We also made the genotoxic of 2 extracts, one of aqueous type, and the other of henaxic type in an in vitro system of short-term somatic segregation induction assay in the Aspergillus nidulans fungus and an in vivo assay of the dry drug in mouse bone marrow micronuclei induction test. No deaths were observed in the toxicological results of the two experimental models in the dose range using up to 2 g/kg/b.w. Acute toxicity tests in rats and mice have proven the LD50 of guava leaf extracts to be more than 5 g/kg. In vitro genotoxicity and mutagenicity tests on Psidium guajava in human peripheral blood lymphocytes found no disturbances in cell division (Jaiarj et al., 1999; Manosroi et al., 2006). The histological results did not suggest any damage attributable to toxicity of the studied plant material. In the in vitro study with Aspergillus nidulans D-30, results indicated a lack of genotoxic effect of these extracts, as well as in the mouse bone marrow micronucelus induction system (Martinez et al., 2001). 5. Clinical trials

5.3. Cardiovascular effects 5.1. Infantile rotaviral enteritis A pilot study was carried out at the Nanfang Hospital, First Military Medical University, and Guangzhou on Psidium guajava (PG) leaf decoction for treating infantile rotaviral enteritis. Sixty-two patients of rotaviral enteritis were randomly divided into the verum group treated with PG and the control group treated with Gegen Qinlian decoction. The time for ceasing diarrhoeal, the content of Na+ in blood, the content of Na+ and glucose in stool, and the rate of negative conversion of human rotavirus (HRV) antigen were observed. The rate of recovery in 3 days for the treated group was 87.1%, significantly higher than that of the control group (58.1%). The time of ceasing

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

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potassium enriched diet containing 0.5–1 kg of guava daily or their usual diet; alcohol, caffeine, cholesterol, fat, and salt intake were similar in both groups. After 4 weeks, systolic and diastolic pressures improved, decreases occurred in serum total cholesterol and triglycerides, and there was a mild increase in the ratio of total cholesterol/HDL-cholesterol in the guava group (Singh et al., 1993). In another trial conducted for a 9-week period in “Institut Kemahiran Belia Negara”, Hulu Langat, Selangor, Malaysia, a randomized double-blind study of 122 people examined the effects of consuming 400 g/day of guava fruit on total antioxidant status and lipid profile (total cholesterol, triglycerides, low-density lipoprotein [LDL] and HDL cholesterol). Consumption of guava fruit reduced oxidative stress and blood cholesterol levels. Thus, it could reduce the risk of disease caused by free radical activities and high cholesterol in the blood (Rahmat et al., 2004). 5.4. Dysmenorrhea A double-blinded randomized clinical trial was conducted in 197 women with primary dysmenorrhea. Four intervention groups were defined: two leaf extract doses (3 mg/day and 6 mg/day); ibuprofen (1200 mg/day); placebo (3 mg/day). Participants were followed up individually for 4 months. The main outcome variable was abdominal pain intensity measured according to a visual analogue scale (VAS). The average age of participants was 19 years; menarche occurred around 12 years of age. Participants had menstrual cycles of 28 or 29 days, with menstruation lasting 5 days and pain intensity mean of 8.2 on the VAS. During each successive treatment cycle, participants experienced a lower pain intensity score. Multiple regression analysis, after adjusting each cycle for baseline pain, treatment compliance and other variables, showed that the group receiving 6 mg/day leaf extract had significantly reduced pain intensity (p < 0.001). This effect was maintained in cycles 2 and 3, although the reduction in the mean of pain intensity was lower. The group receiving the 3 mg/day extract did not show a consistent effect throughout the three cycles. The guava leaf extract standardized to 6 mg flavonol/day, reduced menstrual pain significantly compared with conventional treatment and placebo (Vladislavovna et al., 2007; Svetlana et al., 2007). 5.5. Hypoglycaemic effect In China, a multicentric randomized controlled trial was conducted to evaluate the efficacy of guava in the management of diabetes. The mean age of participants was 59.6-year-old and average duration of diabetes was 5.4 years. Oral administration capsules containing 500 mg of aqueous leaf extract from Psidium guajava to 50 diabetic patients showed hypoglycaemic less potent than chlorpropamide and metformin. Thus, it is suggested that guava may be employed to improve and/or prevent diabetes mellitus (Cheng and Yang, 1983). Guava is a tropical fruit that contains high levels of dietary fibre and could have health potential in the management of blood glucose level in diabetic subjects. Oral administration of cap-

11

sules containing 500 mg of Psidium guajava fruit in 40 patients showed a reduction in blood glucose level in weeks 3, 4 and 5 with changes in glucose level of −12.3%, −24.79% and −7.9% respectively as compared with the diabetic control group. This study showed that supplementation of 0.517 g/day could reduce fasting blood glucose level but the mean was not significant (Yusof and Said, 2004). 6. Summary Psidium guajava is a well-known medicinal plant that is frequently prescribed in various indigenous systems of medicine especially those of Central America and Africa. Guava extracts, traditionally prepared (infusions, decoctions, tinctures of the barks and leaves and ripe fruit) by many widely separated cultures for eons of time for various uses (Table 1) have, as summarised in this review, been shown by the application of modern scientific methods to indeed possess multiple disease ameliorating properties. Such properties have been further explained by several studies detailing the specific bioactivity of individual phytochemicals extracted from guava and on clinical studies. Extracts and phytochemicals isolated from Psidium guajava leaves have been shown to have multiple disease ameliorating effects caused by microbial pathogens (Table 1). Its most widespread traditional use has been for the treatment of diarrhoea. Leaf extracts of Psidium guajava, as reviewed here, have been found to have antimicrobial activity against several bacteria, fungi, viruses and parasites, with proven ability to ameliorate diarrhoeal, and also gastroenteritis, dental plaque, acne, infantile rotaviral enteritis and even malaria suggesting wide antimicrobial activity. The activity guided purification resulted in the isolation of quercetin, quercetin-3-arabinoside, and asiatic acid which showed significant anti-diarrhoeal activity. Another traditional use of guava has been in the treatment of coughs; experimental data presented here show that guava leaf extract do indeed exert an inhibitory effect on frequency of coughing. Research summarised here also indicates that guava leaves provide antioxidant and other effects providing beneficial protective properties to the heart and liver with an improvement in myocardial and muscular function. In other animal studies guava leaf extracts showed anti-allergic, anti-inflammatory, analgesic, sedative, and central nervous system (CNS) depressant activity. While these are not known folk uses per se, they help to explain such folk recipes as the use of leaf extracts for rheumatic pain, convulsions, vomiting and menstrual pain. The effect on diarrhoeal, for example seems to be due to its antimicrobial activity, but also in other ways as discussed in Section 3.1. Leaves are the part of the plant that is most frequently used in the forms of decoction. The studies performed by the authors have been discussed. Most of the pharmacological and chemical work has been carried out on the leaf, reveals the connection between medicinal herbs and cultural beliefs toward healing. Guava leaves contain tannins as well as ␤-sitosterol, flavonoids, triterpenoids, volatile oil. The main traditional use is for the treatment of the gastrointestinal disorders (diarrhoea, stomach pain, gastroenteritis, indigestion, and dysentery) and dermatologic

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conditions (boils, skin, infection, and ulcers). The recommended dosage for acute diarrhoea is 0.5–1.0 cup of decoction (take a handful of leaves to make a decoction with 1 l of water) 3–5 times daily. The ripe guava fruit, on the other hand, has been shown here and in other reviews (Hwang et al., 2002) to be a very useful nutraceutical with important properties that can affect the maintenance of health and prevention of many diseases. All parts of the fruit can be eaten, with the skin actually possessing the highest vitamin C level. The fruit and its juice have been documented to lower blood sugar levels in normal and diabetic animals and humans, ameliorate rheumatism (analgesic and anti-inflammatory effects), while reducing blood pressure, triglycerides and cholesterol levels. Interestingly, guava bark and leaves have also been shown to have important antioxidant and anti-diabetic properties with the bark being more active. This lends pharmacological credence to the folkloric, ethnomedical uses of the plant in the management or control of adult-onset, type 2 diabetes mellitus and hypertension in some rural communities. As well as the traditional preparations, individual chemicals have been shown to exhibit previously unknown properties. The inherent cytotoxicity of triterpenes in the seeds and leaf is the most promising and should be better explored in the search for new antineoplastic agents because the leaf oil has been shown to be four times more potent than vincristine. Most importantly, Psidium guajava has been used for a long period of time with no serious adverse effects reported or documented.

7. Conclusion The pharmacological studies conducted on Psidium guajava indicate the immense potential of this plant in the treatment of conditions such as diarrhoeal, gastroenteritis and rotavirus enteritis, wounds, acne, dental plaque, malaria, allergies, coughs, diabetes, cardiovascular disorder, degenerative muscular diseases, inflammatory ailments including rheumatism and menstrual pain, liver diseases, cancer, etc. Not surprisingly, guava also exhibits antioxidant and anti-inflammatory effects as oxidative injury underlies many of these diseases. However, the diverse pharmacological activities of guava extracts and isolated phytochemicals have only been assayed in in vitro tests using laboratory animals, and the results obtained may not necessarily be portable to the situation in humans. While there are gaps in the studies conducted so far, which need to be bridged in order to exploit the full medicinal potential of guava, it is still very clear that this is a plant with tremendous widespread use now and also with extraordinary potential for the future. On the basis of the low toxicity of guava extracts and derived phytochemicals and their use as nutraceutical (fruit) and medicinal (leaves, bark, seeds, roots) agents, backed by proven activity of both the traditional formulations (infusions, decoctions, tinctures) and their derived phytochemicals (phenolics, flavonoids, carotenoids, triterpenes, essential oil constituents and others), further research, clinical trials and product development can only cement Psidium guajava as a very important part of our biodiversity to respect and sustainably use for generations to come. Appendix A. Constituents of Psidium guayava

Structure

Source

Activities

Leaf and roots, Okuda et al. (1984), Quisumbing (1978)

Cardioprotective effects against ischemia-reperfusion. Antioxidant, Yamashiro et al. (2003).

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

Antioxidant, Thaipong et al. (2005)

Leaf, Liang et al. (2005)

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

Phenolic compounds isolated from Psidium guajava

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13

Appendix A (Continued ) Structure

Source

Activities

Leaf, Zhu et al. (1997)

Antioxidant, Misra and Seshadri (1968), Qian and Nihorimbere (2004)

Leaf, Liang et al. (2005), Qian and Nihorimbere (2004)

Antioxidant, capacity radical scavenging activity, antimutagenic/anticarcinogenic effect, inflammation inhibiting and endothelial protective properties, Li and Chang (2005)

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

Possesses analgesic and antiinflammatory properties, Ojewole (2006)

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

Antioxidant, Okuda et al. (1984)

Leaf flowers and fruit, Liang et al. (2005)

Antidiarrhoea effect, Zhang et al. (2003). Exhibited antioxidant and spasmolytic effects, Formica and Regelson (1995), Yamashiro et al. (2003). Also showed inhibition on skeletal muscles contraction, Chaichana and Apisariyakul (1996); Induced reduction of presynaptic molecular activity, Apisariyakul et al. (1999) Also showed vasodilator effects, Duarte et al. (1993)

*

Flavonoids isolated from Psidium guajava

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Appendix A (Continued ) Structure

Source

Leaf, flowers and fruit Nadkarni and Nadkarni (1999)

Leaf flowers and fruit Liang et al. (2005)

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)

Activities

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15

Appendix A (Continued ) Structure

Source

Activities

Leaf flowers and fruit Liang et al. (2005)

Leaf and fruit, Prabu et al. (2006)

Showed antimicrobial activity against Streptococcus mutans, Prabu et al. (2006)

Leaf and fruit, Arima and Danno (2002)

Showed antimicrobial activity against Salmonella enteritidis and Bacillus cereus, Arima and Danno (2002)

Leaf and fruit, Arima and Danno (2002)

Showed antimicrobial activity against Salmonella enteritidis and Bacillus cereus, Arima and Danno (2002)

Leaf and fruit, Liang et al. (2005)

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Appendix A (Continued ) Structure

Source

Activities

Leaf and fruit, Liang et al. (2005)

Carotenoids isolated from Psidium guajava

Leaf and fruit, Mercadante et al. (1999)

Leaf and fruit, Mercadante et al. (1999)

Leaf and fruit, Mercadante et al. (1999)

Leaf and fruit, Mercadante et al. (1999)

Leaf and fruit, Mercadante et al. (1999)

Leaf and fruit, Mercadante et al. (1999)

Leaf and fruit Mercadante et al. (1999)

Acts as a chain-breaking antioxidant and thus protects cell against photo-oxidation Palozza and Krinsky (1992)

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17

Appendix A (Continued ) Structure

Source

Leaf and fruit, Mercadante et al. (1999)

Cytokinins isolated from Psidium guajava

Leaf and fruit, Nagar and Rao (1981)

Zeatin riboside Zeatin nucleotide

Leaf and fruit, Nagar and Rao (1981) 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)

Activities

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Appendix A (Continued ) Structure

Source

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)

Activities

R.M.P. Guti´errez et al. / Journal of Ethnopharmacology 117 (2008) 1–27 Appendix A (Continued ) Structure

Source

Activities

Leaf and fruit, Begum et al. (2004)

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

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

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

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

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

19

20

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Appendix A (Continued ) Structure

Source

Activities

Leaf and fruit, Begum et al. (2004)

Seeds, Salib and Michael (2004)

Seeds, Salib and Michael (2004)

Showed cytotoxic activities in vitro against Ehrlich ascites Carcinoma cells (EAC) and leukaemia P3888 cells Salib and Michael (2004)

Fruit, Li et al. (1999)

Content: 18.81%. Cytotoxic to brine shrimp larvae, Cit´o et al. (2003)

Fruit, Li et al. (1999)

Content: 11.80%. Antiinflammatory and inhibition of nitric oxide production; in vitro antitumour, Siani et al. (1999)

Leaf, Li et al. (1999

Content 10.27%, Li et al. (1999)

Constituents from the essential oil of Psidium guajava

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21

Appendix A (Continued ) Structure

Source

Activities

Leaf, Oliver-Bever (1986)

Content 7.36%, Oliver-Bever (1986)

Leaf, (Li et al., 1999)

Antiinflammatory and inhibition of nitric oxide production; in vitro antitumour (Siani et al., 1999)

Leaf, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)

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Appendix A (Continued ) Structure

Source

Leaf, Li et al. (1999)

Fruit, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)

Fruit, Kenneth et al. (1970)

Fruit, (Jordan et al., 2003)

Fruit, Jordan et al. (2003)

Fruit, Jordan et al. (2003))

Fruit, Jordan et al. (2003)

Activities

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23

Appendix A (Continued ) Structure

Source

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)

Leaves, fruit, Radha and Chandrasekaran (1997)

Activities

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Appendix A (Continued ) Structure

Source

Activities

Seeds, Salib and Michael (2004)

Showed cytotoxic activities in vitro against Ehrlich ascites Carcinoma cells (EAC) and leukemia P3888 cells Salib and Michael (2004)

Leaves, fruit, Radha and Chandrasekaran (1997)

Seeds, Salib and Michael (2004)

Seeds, Salib and Michael (2004)

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