Passiflora Revisao

Journal of Ethnopharmacology 94 (2004) 123
Review
Passiora: a review update

Kamaldeep Dhawan a, , Sanju Dhawan b , Anupam Sharma b
b
Department of Drugs Control Administration, Government of Haryana State, Sector-6, Panchkula 134109, India University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
Received 26 April 2002; received in revised form 12 February 2004; accepted 23 February 2004 Available online 19 June 2004
Abstract This review describes the morphology, microscopy, traditional and folklore uses, phyto-constituents, pharmacological reports, clinical applications and toxicological reports of the prominent species of the genus Passiora. Flavonoids, glycosides, alkaloids, phenolic compounds and volatile constituents have been reported as the major phyto-constituents of the Passiora species. A few species of Passiora have been used for curing various ailments, the most important being Passiora incarnata Linneaus which possesses signicant CNS depressant properties. The studies performed by the authors with the newly isolated benzoavone (BZF) moiety from P. incarnata have been discussed. In the concluding part, various virgin areas of research on the species of this genus have been highlighted with a view to explore, isolate and identify the medicinally important phyto-constituents which could be utilized to alleviate various diseases affecting the mankind. 2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Passiora; P. incarnata; Passiora edulis; Morphology; Flavonoids; Anxiolytics
1. Introduction The genus Passiora, comprising about 500 species, is the largest in family Passioraceae (the Passion ower family) (Hickey and King, 1988; Maout and Decaisne, 1876; Rendle, 1959). The species of this genus are distributed in the warm temperate and tropical regions of the New World; they are much rarer in Asia, Australia, and tropical Africa. Several species are grown in the tropics for their edible fruits, the most widely grown being Passiora edulis Sims (Passion fruit or purple granadilla) (McGuire, 1999). Many other are grown outdoors in the warmer parts of the world or in the glasshouses for their exotic owers.
2. Botany (morphology and microscopy) The plants of genus Passiora are shrubs and herbs, mostly climbers with auxillary tendrils. Stem herbaceous or
author. 1068 Sector-38-B, Chandigarh 160038, India. Tel.: +91-172-2691069; fax: +91-172-2582884. E-mail address: kdd@glide.net.in (K. Dhawan).
Corresponding
woody, generally climbing, very rarely arborescent. Leaves alternate, sometimes simple, entire, lobed or palmate, sometimes compound, imparipinnate; stipules germinate at the base of petioles, rarely absent; tendril axillary, arising from sterile pedicels. Flowers bisexual or unisexual, regular. The large receptacle is often hollowed out like a cup or basin, and bears numerous lamentous or annular appendages between the corolla and stamens, which may be brightly colored and form a conspicuous corona of great diversity. Calyx of 35 free or basely connate, imbricate sepals. Corolla of 35 free or basely connate petals, rarely absent. Stamens 35 (10) inserted either at the bottom of the perianth, or at the base or top of gynophore; laments subulate or liform, free or monoadelphous and sheathing the gynophore; anthers versatile, introrse, two-celled, dehiscence longitudinal. Ovary superior, more or less stipitate, very rarely sessile, unilocular, of 35 united carpels containing several or many anatropous ovules on parietal placentas. Styles equal in number to the placentas, cohering at the base, distinct at the top, spreading, simple or branched, or 35 separate styles; stigmas clavate or peltate, sometimes sub-two-lobed; ovules numerous, anatropous, 12 seriate, attached to 35 parietal linear placentas by
0378-8741/$ see front matter 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jep.2004.02.023
K. Dhawan et al. / Journal of Ethnopharmacology 94 (2004) 123
longer or shorter funicles, enlarged into a cupule at the umbilicus. Fruit 1-celled, an indehiscent berry or a capsule with 35 semi-placentiferous valves. Seeds numerous; funicle dilated into a pulpy cupuliform or saccate aril; testa crustaceous, foveolate, easily separable from the membranous endopleura, which bears a longitudinal raphe. Embryo straight, occupying the axis of a eshy dotted albumen; cotyledons foliaceous, at; radicle cylindric, near the hilum, centrifugal. Pollination is effected by insects, in the attraction of which the remarkable corona developments play an important part; the owers are often strongly scented and nectar is secreted on the receptacle. Extraoral nectories occur on the leaf stalks. The taxonomy, morphology, growth form, site requirements and the related horticulture aspects of P. incarnata have been extensively reviewed (McGuire, 1999). Since Passiora is an exotic genus and many of the species are cultivated for their beautiful ornamental owers, the information pertaining to the cultivation and gardening aspects of the Passion owers can be gathered from the Passiora Society International (Schappert, 1999). The microscopic aspects of Passiora were described rst by Solereder in 1908 (Solereder, 1908). In his work, it has been observed that there is an absence of anatomical characters distinctive of the genus and common to all its members. It is characteristic of the mature leaves that no special type of the arrangement of the neighbouring cells around the guard-cells can be detected, i.e., stomata are anomocytic in nature. The leaves of most of the members of the genus Passiora are dorsiventral in structure. However, Passiora mooreana Hook. and Passiora reticulata Engl. have centric or almost centric structure. The mesophyll shows only a few special features. The middle layers of spongy tissues contain thickened and pitted cells; in Passiora arborea Spreng. and Passiora citrifolia Mast., numerous spicular cells, with an irregular course occur in the mesophyll. The epidermal cells have straight or undulated lateral walls. In many species of Passiora, the epidermis of leaf and stem is characterized by cuticular protuberances, whilst in other sections these structures are only of isolated occurrence, e.g., in Passiora spinosa Mast. The stomata usually occur on the lower side of the leaf. The vascular bundles in the smaller veins are usually embedded. They may or may not be accompanied by sclerenchyma. Clusters of calcium oxalate are present in the tissue of the leaf and axis in the form of prisms and cluster crystals. In Passiora caerulea Linn. spindle shaped bodies occur in the mesophyll-cells; these bodies are situated in the cell-sap, and are probably of the nature of crystalloids. In the epidermis of the leaf of Passiora rotundifolia Linn. and Passiora ichthyura Mast., sphaero-crystalline masses of unknown nature occur. Among internal secretory organs the most noteworthy are the intercellular, spherical and apparently schizogenous secretory receptacles in the interior of the leaf. The leaf has tanniniferous cells, which in certain species of Passiora are developed as tannin-sacs;
these mostly have wide lumina, often have thick walls and are frequently considerably elongated in vertical direction. In the species of Passiora both forms of trichomes occur, with walls of varying thickness. In species, viz., Passiora clathrata Mast., Passiora foetida Linn., Passiora lepidota Mast. and Passiora villosa Vell., the glandular trichomes have a multi-seriate stalk, which is of variable length and, when long, sometimes contains a vascular bundle. The glandular head consists of multi-seriate core of elongated cells, which, as it were, forms the continuation of the stalk, and of a secretory palisade-like epidermis. In addition to the glandular trichomes, glandular spots are also seen on the lower side of the leaf in some species of Passiora. In a supercial section radially elongated epidermal cells are observed at the periphery of the glandular spots; nearer the center these are adjoined by cells, the walls of which become more and more thickened and their luminae narrower, so that the actual glandular spot is enclosed by a rampart of thick-walled cells. These cells then pass over into the secretory tissue, the cells of which have a polygonal outline in the surface-view, but are seen to be moderately elongated in a transverse section of the leaf. Several layers of these prismatic cells lie one above another; nally, towards the interior of the leaf, they merge into a small-celled tissue lled with cluster crystals. The large sessile or shortly stalked glands, which occur so frequently on the petioles, are merely a modication of these glandular spots. The axis, even in the climbing forms, has a normal structure. The formation of cork usually takes place supercially, in the epidermis or in the subepidermal layer of cells. Transformation of the outermost layer of cortical cells into the cork-cambium occurs in most species of Passiora. The cork cells have thin walls. The spongy cork of Passiora suberosa Linn. consists of cells, which are strongly elongated radially and are not suberized. The primary cortex frequently contains collenchymatous tissue. The pericycle includes isolated groups of bast-bres or a sclerenchymatous ring. Isolated groups of bast-bres occur in species of Passiora. The strongly thickened walls of bast-bres in Passiora acerifolia Cham. et Schlecht. and Passiora pulchella H.B.K. become violet on treating a transverse section with chlorzinciodine solution, while the network of middle-lamellae is stained yellowish. The wood of Passiora species is characterized by variable breadth of medullary rays. Broad medullary rays occur both in climbing species and in those which do not climb (Passiora arborea Spruce). In the genus Passiora, which climbs by means of tendrils, especially in Passiora spicata Mart., the diameter of vessels attains 0.22 mm. The structure of the wall of the vessel, where it is in contact with the parenchyma of the medullary rays, varies. Wood parenchyma is scantily developed; the wood-prosenchyma may have either distinctly bordered or simple pits. The wood-prosenchyma with simple pits is occasionally septate by means of delicate divisionwalls.
The British Herbal Pharmacopoeia (1983), United States Homoeopathic Pharmacopoeia 1981, Homoeopathic Pharmacopoeia of India 1974, Pharmacopoeia Helvetica 1987, Deutsches Arzneibuch 1997 Homeopathie 1981, Pharmacopee Francaise (1965) and many of the herbal compendiums and Materia Medica contain monographs of only one species, i.e., P. incarnata Linn. This species is also known by various other common names, viz., Maypop, Maracuja, Passion Vine, Carkifelek, Zahril Aalaam and Prempushpi. However, in the Pharmacopoeia of Brazil, Passiora alata Dryand. is reported as the Passion ower instead of P. incarnata (Farmacopeia Brasileira, 1959). The microscopic characteristics of leaf of P. incarnata are also described in the British Herbal Pharmacopoeia, 1983 (British Herbal Pharmacopoeia, 1983) and the Deutsches Arzneibuch 1997 (DAB, 1997).
3. Ethno-pharmacology The discovery of several thousands years old seeds of Passiora from the archaeological sites at Virginia and North America provides strong evidences of the pre-historic use of the fruits by the ancient Red Indian people (Gremillion, 1989). The early European travelers in North America noted that Algonkian Indians in Virginia and Creek people in Florida ate fruits of Passiora from cultivated as well as wild sources (Beverley, 1947). The then European settlers also consumed the fruit and praised its avor, thereby, suggesting the pre-historic consumption of Passiora as a fruit crop (Brickell, 1968). The use of Passiora as a medicine was lauded for the rst time by a Spanish researcher Monardus in Peru in 1569 as the beautiful owers of Passiora appeared to him to be symbolic of the passion of Christ (Taylor, 1996). Various species of Passiora have been used extensively in the traditional system of therapeutics in many countries. The extract of Passiora alata (fragrant granadilla) with aloes was reputed benecial in atrophy of various parts (Felter and Lloyd, 1983). In Brazil, the said species, known as Maracuja has been put to use as an anxiolytic, sedative, diuretic and an analgesic (Oga et al., 1984). Passiora caerulea (blue Passion ower), native of Brazil and introduced into Britain in 17th century, is the most vigorous and tender species having traditional use of its fruit as a sedative and anxiolytic (Hickey and King, 1988; Kirtikar and Basu, 1975; Rendle, 1959). Passiora caerulea was used medicinally in Uruguay but no details are available (Watt and Breyer-Brandwijk, 1962). In West Indies, Mexico, the Netherlands and South America, the root has been used as a sedative and vermifuge. In Italy, the plant has been used as an anti-spasmodic and sedative. In Mauritius, a tincture and an extract of the plant had been used as a remedy for insomnia due to various nervous conditions but not due to
pain. The root has been used as a diuretic and a decoction of leaf as an emetic. In Argentine folk medicine, the aerial parts of Passiora caerulea are used as mild anti-microbial agents in diseases like catarrh and pneumonia (Anesini and Perez, 1993). Passiora capsularis is a reputed emmenagogue (Felter and Lloyd, 1983). Passiora contrayerva is a reputed counter-poison, deobstruent and cordial (Felter and Lloyd, 1983). Passiora edulis has been used as a sedative, diuretic, anthelmintic, anti-diarrheal, stimulant, tonic and also in the treatment of hypertension, menopausal symptoms, colic of infants in South America (Chopra et al., 1956; Kirtikar and Basu, 1975; Mowrey, 1993). In Madeire, the fruit of Passiora edulis is regarded as a digestive stimulant and is used as a remedy for gastric carcinoma (Watt and Breyer-Brandwijk, 1962). In Nagaland (India), fresh leaves of Passiora edulis are boiled in little amount of water and the extract is drunk for the treatment of dysentery and hypertension (Jamir et al., 1999). Fruits are eaten to get relief from constipation. Passiora foetida leaf infusion has been used to treat hysteria and insomnia in Nigeria (Nwosu, 1999). The plant is widely cultivated in India (Kirtikar and Basu, 1975). The leaves are applied on the head for giddiness and headache; a decoction is given in bilious-ness and asthma. The fruit is used as an emetic. In La Reunion, the leaves are considered emmenagogue and are also prescribed in hysteria. In Brazil, the herb is used in the form of lotions or poultices for erysipelas, and skin diseases with inammation (Chopra et al., 1944). The Materia Medica Americana, a Latin work, published in Germany in 1787, mentions the use of P. incarnata to treat epilepsy of the aged. An ancient report describes the use of this plant in spasmodic disorders and insomnia of infants and the old (Bartram, 1995; CSIR, 1966a,b). Passiora incarnata is a popular traditional European remedy (Handler, 1962) as well as a homoeopathic medicine (Rawat, 1987) for insomnia, anxiety, and has been used as a sedative tea in North America (Bergner, 1995). The plant has been used as analgesic, anti-spasmodic, anti-asthmatic, wormicidal and sedative in Brazil; as sedative and narcotic in Iraq; in diseased conditions like dysmenorrhea, epilepsy, insomnia, neurosis and neuralgia in Turkey; to cure hysteria and neurasthenia in Poland; in diarrhea, dysmenorrhea, neuralgia, burns, hemorrhoids and insomnia in America (Taylor, 1996). P. incarnata has been used for morphine deaddiction in the traditional system of medicine in India (Lad, 2000; Vasudev, 1955). Passiora laurifolia Linn. (yellow granadilla, Jamaica honeysuckle) is used to treat nervous heart palpitations in Trinidad (Raintree Nutrition, 1999). The juice of Passiora maliformis Linn. is used for intermittent fevers in Brazil. Passiora quadrangularis Linn. (giant granadilla) is used throughout the Caribbean as a sedative and for headaches. Leaf tea is taken for high blood pressure and diabetes (Seaforth et al., 1983). In Mauritius and Rodrigues, bath
of leaf-docoction of Passiora suberosa is used to treat skin diseases. Root decoction is used as an emmenagogne and is useful in hysteria (Fakim et al., 1993). In Central America, stems of Passiora pedunculata Mast., the aerial parts of Passiora sexora Juss. and Passiora vitifolia HBK have been used against snakebites (Morton, 1981). In view of the wide-spread traditional and ethno-pharmacological reports on the members of genus Passiora, a review of literature on the specic species of Passiora can be a sterling stuff which could glorify the magical healing potentials of the phyto-constituents reported from this genus; perhaps one of the oldest being put to use by the mankind during the processes of scientic advancements towards the re-exploration of our traditional heritages.
4. Phyto-constituents Alkaloids, phenols, glycosyl avonoids and cyanogenic compounds are known in the genus. Literature survey has revealed that a number of reports are available on Passiora incarnata and Passiora edulis, while only sporadic reports are there on other species of Passiora. Thus, Passiora incarnata and Passiora edulis have been dealt with as separate heads in the following passages, and the remaining species of Passiora have been presented in a tabular form. 4.1. Phyto-constituents of P. incarnata 4.1.1. Flavonoids Flavonoids are reported to be the major phyto-constituents of P. incarnata. These include apigenin (1), luteolin (2), quercetin (3), kaempferol (4) (Gavasheli et al., 1974), 6- -d-allopyranosyl-8- -xylopyranosyl-apigenin (Grandolini et al., 1997); C-glycosyl avonoids vitexin (5), isovitexin (6) (Lutomski et al., 1981), orientin (7), isoorientin (8), schaftoside (9), isoschaftoside, isovitexin2 -O-glucopyranoside, isoorientin-2 -O-gluco-pyranoside, 2-glucosylapigenin, isoscoparin-2 -O-glucoside, 2 -Oglucosyl-6-C-glucosylapigenin, 6- -d-glucopyranosyl-8- d-ribopyranosyl apigenin and swertisin (Chimichi et al., 1998; Congora et al., 1986; Geiger and Markham, 1986; Li et al., 1991; Proliac and Raynaud, 1988; Rahman et al., 1997). The greatest accumulation of avonoids has been reported to be in leaves and the highest concentration of isovitexin was found to be between the pre-owering and owering stages (Menghini et al., 1993). During various quantitative studies, it was observed that the ethanol free liquid extract of P. incarnata contains higher contents of avonoids as compared to the commercial preparations. Amongst various other species of the genus, Passiora incarnata contains highest content of isovitexin (Menghini et al., 1993). 4.1.2. Alkaloids P. incarnata contains simple indole alkaloids based on -carboline ring system namely harman (10), harmol (11), harmine (12), harmalol (13) and harmaline (14) (Poethke et al., 1970). Content of harman (10) and harmine (12), determined by direct spectrouorimetric methods on TLC plates, has been reported to be 1020 g/100 ml in the medicinal uid extract of P. incarnata (Bennati, 1971). Recently, all types of -carboline alkaloids have been analyzed quantitatively by HPLC with selective uorometric detection (Tsuchiya et al., 1999). The vegetative parts of green house grown P. incarnata contain 0.012 and 0.007% of harman (10) and harmine (12), respectively, while the content of these alkaloids in the plant grown in elds has been reported as 0.005% and nil, respectively (Lohdenk and Kating, 1974; Lutomski and Nourcka, 1968; Rehwald et al., 1995).
4.1.3. Miscellaneous phyto-constituents Various other constituents which have been reported from P. incarnata include -benzo-pyrone derivative maltol (15) (Aoyagi et al., 1974), carbohydrates such as rafnose, sucrose, d-glucose and d-fructose (Gavasheli et al., 1975); essential oil containing hexanol (1.4%), benzyl alcohol (4.1%), linalool (3.2%), 2-phenylethyl alcohol (1.2%), 2-hydroxy benzoic acid methyl ester (1.3%), carvone (8.1%), trans-anethol (2.6%), eugenol (1.8%), isoeugenol (1.6%), -ionone (2.6%), -bergamotol (1.7%) and phytol (1.9%) (Buchbauer and Jirovetz, 1992); various constituents responsible for typical odor of Passiora incarnata such as limonene, cumene, -pinene, prezizaene, zizaene, and zizanene (Buchbauer et al., 1992); twenty one amino acids (Gavasheli et al., 1974), and a cyanogenic glycoside gynocardin (16) (Spencer and Seigler, 1984).
4.2. Phyto-constituents of Passiora edulis 4.2.1. Glycosides From the methanol extract of air dried leaves, a cyclopropane triterpine glycoside, named Passiorine (17) was isolated, chemically which was reported to be (22R),(24S)-22,28-epoxy-24-methyl-1 ,3 ,24,28-tetrahydroxy-9,19-cyclo-9 -lanostan-4-oic acid -d-glucosyl ester (Bombardelli et al., 1975). Passiora edulis has been reported to be rich in glycosides which include avonoid glycosides, viz., luteolin-6-C-chinovoside, luteolin-6-C-fucoside (Mareck et al., 1991); cyclopentenoid cyanohydrin glycosides passicapsin (18) and passibiorin (19) (Olafsdottir et al., 1989); cyanogenic glycosides passicoriacin (20), epipassicoriacin and epitetraphyllin B (Seigler and Spencer, 1989) cyanogenic- rutinoside {(R)mandelonitrile- -l-rhamnopyranosyl- d-glucopyranoside} (21) (Chassagne and Crouzet, 1998) amygdalin (22), prunasin, mandelonitrile rhamnopyranosyld-glucopyranoside, sambunigrin (Chassagne et al., 1996); 6-O- -l-arabinopyranosyl- -d-glucopyranosides of linalool, benzyl alcohol and 3 methyl-but-2en-1-ol (Chassagne et al., 1996); -d-glucopyranoside and 6-O- l-rhamnopyranosyl- -d-glucopyranoside of methyl salicylate and -d-glucopyranoside of eugenol (Chassagne et al., 1997).
4.2.2. Phenols 4-Hydroxy- -ionol, 4-oxo- -ionol, 4-hydroxy-7,8dihydro- -ionol, 4-oxo-7,8-dihydro- -ionol, 3-oxo- -ionol, isomeric 3-oxo retro- -ionols, 3-oxo-7,8-dihydro- -ionol, 3-hydroxy-1,1,6 - trimethyl - 1,2,3,4- tetrahydronaphthalene vomifoliol and dehydrovomifoliol (Winterhalter, 1990), terpene alcohols linalool and -terpeneol (Challier et al., 1990), terpene diols (E) and (Z)-2,6-dimethyl-octa-2,7diene-1,6-diol, 2,6-dimethyl-octa-3,7-dien-2,6-diol, 2,6dimethyl-1,8-octanediol, 2,6-dimethyl-octa-1,7-diene-3,6diol, ionol derivatives oxygenated in position 3, and 2,5dimethyl-4-hydroxy-3-(2H)-furanone (furaneol) have been identied (Chassagne et al., 1999). Two new ionones I and II were isolated (23, 24) (Naf et al., 1977) for the rst time from Passiora edulis.
Paul, 1961), limonene (Kuhlmann, 1984), 2-tridecanone (62.9%), (9Z)-octadecenoic acid (16.6%), 2-pentadecanone (6.2%), hexadecanoic acid (3.2%), 2-tridecanol (2.1%), octadecanoic acid (2%) and caryophyllene oxide (2%) (Arriaza et al., 1997). Amino acids: proline, aspartic acid, glutamic acid, serine, alanine (Fang and Ling, 1984).
4.2.3. Alkaloids The alkaloids reported to be present are harman (10), harmine (12), harmaline (13) and harmalol (14) and the highest concentration (0.12 mg%) of harman alkaloids is present in the leaves (Lutomski and Malek, 1975; Lutomski et al., 1975). 4.2.4. Miscellaneous phyto-constituents Apart from glycosides, phenols and alkaloids, various miscellaneous phyto-constituents reported from Passiora edulis include: Carotenoids: phytoene, phytouene, -carotene, neurosporene, -carotene, lycopene, prolycopene, monoepoxy- -carotene, -cryptoxanthin, -citraurin, antheraxanthin, violaxanthin, neoxanthin (Mercadente et al., 1998), -carotene, -carotene, -cryptoxanthin, -apocarotenol (Goday and Rodriguez, 1994). l-ascorbic acid (Wekesa et al., 1996). Anthocyanins: cyanidin-3-O- -glucopyranoside and cyanidin-3-O- -galactopyranoside (Chang and Su, 1998), cyanidin-3-glucoside, cyanidin-3-6 -malonyl glucoside, pelargonidine-3-glucoside (Kidoey et al., 1997). -Lactones: -hexa, -deca and -docecalacetone; hepta, -octa and -nona lactone (Nitz et al., 1990), four alkylated -lactones (Bernreuther et al., 1989). Flavor components: esters (Yamaguchi et al., 1983), 3methyl-thiohexan-1-ol, 2-methyl-4-propyl-1, 3-oxathione enantiomers (Mosandl and Heusinger, 1983), edulans I and II (25, 26) (Whiteld et al., 1974). Volatile oil constituents: hexyl caproate and butyrate, and ethyl caproate and butyrate (95%) (Dawes and
Carbohydrates: fructose, glucose, sucrose, maltose, lactose (Fang and Chang, 1981) and pectin (Simpson et al., 1984). Minerals: Na, K, Mg, Ca, Zn, Al, Mn, Fe (Nogueira et al., 1998). Enzyme cytoplasmic pyruvate kinase (Guo and Li, 1993). Cycloartane triterpenes, cyclopassioic acids AD, and their saponins, cyclopassiosides IVI (Yoshikawa et al., 2000), from the leaves and stems of Passiora edulis, which on further purication by silica-gel chromatography gave cyclopassioic acids EG and their saponins, cyclopassiosides VIIXI (27), respectively (Yoshikawa et al., 2000).
5. Other Passiflora species and their phyto-constituents Table 1 summarizes the phyto-constituents of various other species of Passiora. The species have been arranged in alphabetical order.
6. Pharmacological reports Irrespective of the presence of a large variety of phytoconstituents in the genus Passiora, only a few reports regarding the pharmacological investigations on the plants of this genus are available. Most of the pharmacological work has been carried out on the CNS depressant effects of various species. A group of Brazilian researchers have performed thorough pharmacological studies on Passiora alata leaves using mice as the experimental animals (Oga et al., 1984). The uid extract from leaves of Passiora alata prepared according to the procedures described in the French Pharmacopoeia, VIII edition (Pharmacopee
Francaise, 1965) was evaporated under reduced pressure at 50 C to yield a dry extract, which was further dissolved in water for pharmacological studies. On intraperitoneal administration to mice at a dose of 150 mg/kg, the Passiora alata extract reduced amphetamine-induced spontaneous motor activity, prolonged pentobarbital induced sleep time at 150 mg/kg i.p., increased the onset time and survival period on pentylenetetrazole-induced-seizures in the animals at 75 and 150 mg/kg and also potentiated the analgesic effect at 75 and 150 mg/kg of the extract relative to indoprofen as a reference standard analgesic; all the pharmacological effects being observed in dose-dependent manner. The LD50 value of this extract was 456 mg/kg. Recently, the hydro-
K. Dhawan et al. / Journal of Ethnopharmacology 94 (2004) 123 Table 1 Phyto-constituents of various Passiora species Species Passiora adenopoda Moc. & Sesse Passiora alata Dryand. Passiora ambigua Linn. Passiora apetala Linn. Passiora biora Domb. Phyto-constituents
Passiora bryonioides H.B.K.
Passiora caerulea Linn. Passiora calcarata Mast. Passiora capsularis Lam. Passiora coactilis Linn.
Passiora Passiora Passiora Passiora Passiora
coccinea Aubl. cochinchinensis Spreng. colinvauxii Linn. coriacea Fuss. cyanea Mast.
Cyanogenic glycosides linamarin (28), lotaustralian (29) (Spencer et al., 1986) C-glycosyl avonoids 2 -xylosylvitexin and small amount of vitexin (5), isovitexin (6) and orientin (7) (Ulubelen et al., 1982) Flavonoid saponarin (Ulubelen et al., 1982) Cyanogenic glycoside Passibiorin (19) (Olafsdottir et al., 1997) O- and C-glycosylavones; 4 -O-rhamnosylswertisin, luteolin-7-O-neohesperidoside together with swertisin, swertiajaponin, 4 -O-rhamnosyl-swertiajaponin, 2 -O-rhamnosylisoorientin and 2 -O-rhamnosylisovitexin (McCormick and Mabry, 1983); cyanogenic glycosides passibiorin (19) and epipassibiorin (Spencer and Seigler, 1985) Flavone derivatives saponaretin, vitexin, apigenin-7-monoglucoside and two kaempferol-3-biosides (Poethke et al., 1970) Alkaloid harman (10) (Poethke et al., 1970) A avone chrysin (Speroni et al., 1996), cyanogenic glycoside sulphate tetraphyllin B-4-sulphate and epitetraphyllin B-4-sulphate (Seigler et al., 1982) Passiorine (17) (Bombardelli et al., 1975) Passicapsin (18); Cyanogenic bisglycoside 4-bi-vinosyltetraphyllin B (Fischer et al., 1982) C-glycosyl avones 4 -O-glucosyl-2 -O-rhamnosyl orientin, 4 -O-glucosyl-2 -O-rhamnosyl-vitexin, vitexin, 4 -O-glucosylvitexin, isovitexin (6), isoorientin (8), 4 -O-glucosyl orientin, 2 -O-rhamnosyl orientin, scoparin, 2 -O-rhamnosyl scoparin and 8-C-glucosyl-diosmetin (Escobar et al., 1983) Cyanogenic glycoside passicoccin (30) (Spencer and Seigler, 1985) Flavonoids naringin and apigenin-7-O-glucoside; Amino acids; Carbohydrates (Ma et al., 1982) Cyanogenic glycoside passibiorin (19) (Adsersen et al., 1993) Cyanogenic glycoside barterin (31) (Olafsdottir et al., 1989) C-glycosyl avonoid 2 -xylosylvitexin and coumarin esculetin (Ulubelen et al., 1981) Flavonoids pachypodol, 7,4 -dimethoxyapigenin, ermanin (32), 4 ,7-O-dimethyl-naringenin, 3,5-dihydroxy-4,7-dimethoxy avanone (Echeverri and Suarez, 1985; Echeverri and Suarez, 1989) C-glycosyl avonoids chrysoeriol, apigenin (1), isovitexin (6), vitexin (5), 2 -xylosylvitexin, luteolin-7- -dglucoside, kaempferol (4) (Ulubelen et al., 1982); Cyanohydrin glycosides tetraphyllin A (33), tetraphyllin B (34), tetraphyllin B sulphate, deidaclin (35), volkenin (36) (Andersen et al., 1998); Fatty acids linoleic acid and linolenic acid (Hasan et al., 1980); alpha-pyrones named passioricins (Echeverri et al., 2001) A sulphate ester of tetraphyllin B (Jaroszewski and Fog, 1989) Cyanogenic glycoside passibiorin (19) (Olafsdottir et al., 1997) Pantothenic acid, ascorbic acid (CSIR, 1966b) Passiorine (17) (Bombardelli et al., 1975) Cyanogenic glycosides linamarin (28), lotaustralin (29) and passibiorin (19) (Spencer and Seigler, 1985) Flavonoids vitexin (5), orientin (7), 6-hydroxy luteolin 6,7-dimethyl ether and luteolin-7- -d-glycoside; Coumarin esculetin (Ulubelen et al., 1981) Ascorbic acid (Uzcategui, 1985) Passiorine (17); Volatile constituents: 30 alkane, alkene, aromatic and terpene hydrocarbons; 4 aldehydes; 11 ketones; 36 alcohols; 4 lactones, 5 fatty acids; 47 esters (Froehlich et al., 1989) Cyanohydrin glucoside linamarin (28) (Olafsdottir et al., 1992) C-glycosyl avonoid 2 -xylosylvitexin; Sterols -sitosterol and its 3 -d-glucoside; Sugarsglucose, fructose, galactose (Ulubelen et al., 1981) Flavonoids quercetin-7, 3 -dimethyl ether, isoscoparin, isovitexin, apigenin-7-glucoside, vitexin (5), chrysoeriol, isoscutellarein-8-methyl ether, quercetin (3), isorhamnetin, luteolin (2), isoorientin (8), luteolin-7-glucoside, selagin, 6-methoxy kaempferol, vicenin-2, 2 -O-glucosyl vitexin, 2 -O-rhamnosyl vitexin and a avone tricetin 4-methyl ether (Ulubelen et al., 1984) C-glycosyl avones isovitexin (6), isoorientin (8), isoorientin-4 - -d-glucoside, luteolin-7- -d-glucoside (McCormick and Mabry, 1981) Linamarin (28), lotaustralian (29), linustatin (37) and neolinustatin (38) (Spencer et al., 1986) C-glycosyl avonoids isovitexin, 2-xylosyl vitexin, a mixture of vicenin-2, schaftoside (9) and isoschaftoside, luteolin-7-O-glucoside and chlorgenic acid (Ulubelen et al., 1982) C-glycosides vitexin (5), isovitexin (6), isomollupentin (6-C-arabinosyl-apigenin), isovitexin-7-rhamnosylglucoside and isomollupentin-7-rhamnosylglucoside (Ayanoglu et al., 1982) Passiorine (17) (Bombardelli et al., 1975); Triterpene glycoside quadranguloside (39) (Orsini et al., 1986), oleanolic acid-3-sophoroside (Orsini et al., 1987) Monoterpenoids: (2E)-2,6-dimethyl-2,5 heptadienoic acid, (2E)-2,6 dimethyl-2,5 hepta dienoic acid- -d-glucopyranosyl ester, (5E)-2,6-dimethyl-5,7-octadiene-2,3-diol and (3E)-3,7 dimethyl-3-octene-1,2,6,7-tetrol (Osorio et al., 2000) Sulphate ester of tetraphyllin B (Jaroszewski and Fog, 1989) Flavonoids isovitexin, luteolin-7-O-glucoside and 7-O-galactoside, xylosyl vitexin, apigenin (1), apigenin-7-O-glucoside and luteolin (2) (Ulubelen and Mabry, 1983)
Passiora foetida Linn.
Passiora Passiora Passiora Passiora Passiora Passiora
hybrida Nees indecora H.B.K. laurifolia Linn. lechenaultii DC lutea Linn. menispermifolia H.B.K.
Passiora molliseria DC Passiora mollissima Bayley Passiora morifolia Mast. Passiora oerstedii Mast. Passiora palmeri Linn.
Passiora pavonis Mast. Passiora pendens Linn. Passiora pittieri Passiora platyloba Fuss. Passiora quadrangularis Linn.
Passiora racemosa Brot. Passiora sanguinolenta Mast& Linden
10 Table 1 (Continued ) Species Passiora serratifolia Linn. Passiora serratodigitata Linn. Passiora sexora Fuss. Passiora suberosa Linn.
Phyto-constituents C-glycosyl avonoids vitexin (5), isovitexin (6), orientin (7), 2 -xylosyl vitexin and 2 -xylosyl isovitexin (Ulubelen and Mabry, 1980) Serratin I (40) and its 7- -glucoside; C-glycosylavone 2 -xylosylvitexin, 2 -xylosylisovitexin, vitexin (5), isoorientin (8), vicenin and orientin (7) (Ulubelen et al., 1982) Flavonoids 6-di-C-glycosylavones, 6-mono-C-glycosylavones, luteolin-7-O-glucoside, luteolin (2) (McCormick and Mabry, 1982) Cyanogenic glycosides passisuberosin (41), epipassisuberosin (Spencer and Seigler, 1987); Anthocyanins cyanidin-3-(6 -malonylglucoside), 3-glucoside of cyanidin, delphinidin, petunidin, pelargonidin and anthocyanin acetylated with malonic acid (Kidoey et al., 1997) Cyanogenic glycoside barterin (31) (Olafsdottir et al., 1989) Cyanogenic glycosides passibiorin (19) and epipassibiorin (Spencer and Seigler, 1985) 4-Hydroxy-2-cyclopentenone (Perry et al., 1991) Cyanogenic glycoside Passitrifasciatin (42) (Olafsdottir et al., 1991; Spencer and Seigler, 1985) Flavonoids vitexin (5), isovitexin (6), luteolin-7-O-galactoside, esculetin, isoorientin (8) (Ulubelen and Mabry, 1983) Cyanohydrin glycosides passibiorin (19) (Olafsdottir et al., 1997) Cyanohydrin glycoside linamarin (28) (Olafsdottir et al., 1988) Cyanogenic glycosides linamarin (28), linustatin (21) (Fischer et al., 1982; Spencer et al., 1986); Cyanohydrin glycoside barterin (31) (Olafsdottir et al., 1989)
Passiora Passiora Passiora Passiora Passiora
subpeltata Orteg. talamansis tetrandra Banks & Soland. trifasciata Lem. trinervia Poir.
Passiora vespertilio Ker-Gawl. Passiora violacea Vell. Passiora warmingii Mast.
ethanol extract of leaves of Passiora alata and Passiora edulis have been evaluated at three dose levels (50, 100 and 150 mg/kg) to conrm the anxiolytic effects in accordance with the traditional reports of these two species, known as maracuja in Brazil (Petry et al., 2001). The pharmacological effects of chrysin, a monoavonoid, occurring in Passiora caerulea were examined in mice (Wolfman et al., 1994). Chrysin, at a dose of 1 mg/kg induced signicant anxiolytic behavior in mice by increasing the number of entries as well as the time spent by mice in open arms of the elevated plus maze apparatus. During a comparison between diazepam (6 mg/kg) and chrysin for their myorelaxant effects, chrysin did not exhibit myorelaxant effect in the horizontal wire test even at the dose range of 0.630 mg/kg, suggesting that chrysin was an anxiolytic devoid of sedative or muscle relaxant counter effects, unlike that of diazepam which exhibited a myorelaxant effect. Chrysin, a naturally occuring monoavonoid in Passiora caerulea was found to be a ligand for central as well as peripheral benzodiazepine receptors (Medina et al., 1990). When administered to mice by intracerebroventricular route, chrysin prevented the expression of tonicclonic seizers induced by pentylenetetrazole, also conrming thereby the presence of benzodiazepine-like compounds in Passiora caerulea. Aqueous extract of Passiora edulis has been reported to exhibit non specic CNS depressant effects in mice, rats and healthy human volunteers, whereas, it was also noted that some samples of Passiora edulis had a non-specic CNS-depressant effect (Maluf et al., 1991). In another report on CNS depressant effects of Passiora edulis, it was noted that the aqueous extract of the plant prolonged barbiturate-induced as well as morphineinduced sleep time in mice and also partially blocked the amphetamine-induced stimulant effects (Do et al., 1983).
Extract of Passiora edulis has exhibited mild anti-fungal activity against Microsporum gypseum, Chrysosporium tropicum and Trichophyton terrestre (Qureshi et al., 1997). Authors opine that the only one species, i.e., Passiora incarnata also known as Passion ower, maypops, maracuja or prem-pushpi is perhaps, the one in the entire genus which has been used extensively as an anxiolytic and sedative throughout the world since time immemorial. That is why, P. incarnata deserves to be described, identied and explored properly. In this part of the review, the maximum possible pharmacological informations on this particular species has been compiled. Maltol (15), a -benzopyrone derivative, and ethyl maltol were evaluated for their CNS-depressant effects (Aoyagi et al., 1974). Maltol and ethyl maltol, obtained by sublimation of 2N hydrochloric acid fraction of P. incarnata were reported to potentiate hexobarbital-induced sleep, inhibit pentylenetetrazole-induced convulsions and also decreased amphetamine-induced hyperactivity in mice. Ethyl maltol was reported to be more potent as an anti-convulsant than maltol, but comparatively less potent in decreasing the spontaneous motor-activity. The uid extract of Passiora incarnata was studied for its neuropharmacolo-gical effects on rats (Speroni and Minghetti, 1988). The ethanolic extract from leaves and stems of P. incarnata having a water content of about 50%, was evaporated under reduced pressure at 45 C to remove ethanol. Then water was added to reach half the volume of uid extract at the start and the pH of this aqueous solution was adjusted to 5.6. This solution was then freeze-dried and suspended in saline for pharmacological evaluations. On intraperitoneal injection, the extract signicantly prolonged sleeping time at 80 and 160 mg/kg in mice, protected animals from convulsive effects of pentylenetetrazole by causing an increase in the onset time and survival time in the PTZ-treated mice, decreased the amphetamine-
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induced locomotor activity in a dose-dependent manner and also increased the tail-ick latency in rats at 160 mg/kg doses. However, the CNS depressant effect could not be ascribed either to alkaloids or avonoids present in the extract. Lyophilized hydroalcoholic and aqueous extracts of P. incarnata as well as the individual phyto-constituents viz., maltol (15), avonoids and harman (1014) alkaloids were assessed for their effects in mice (Soulimani et al., 1997). Fresh aerial parts of P. incarnata were preserved in liquid nitrogen and ground at a low temperature (60 C) to obtain a cryo-grinding. Thirty grams of the cryo-ground powder were added to 300 ml of (30%) ethanol and were left to macerate for 12 h; a second maceration was performed at 35 C for 12 h. After lteration, ethanol was evaporated at low pressure at 35 C and the extract was freeze-dried. An aqueous extract (10%, w/w) was prepared according to the protocols described above, but ethanol was replaced by distilled water. The aqueous extract showed sedative effects at doses of 400 and 800 mg/kg, by decreasing the locomotor activity and also potentiated the induction of sleeping by pentobarbital in mice. The hydro-alcoholic extract did not show such sedative effect. Instead, it enhanced locomotor activity, suggestive of an anxiolytic effect at 400 mg/kg in mice. Though, these investigations conrmed the CNS depressant properties of P. incarnata, yet, the exact mode of action of the extracts and the individual phyto-constituents could not be understood in this extensive pharmacological experimental study conducted by Soulimani et al. The recent pharmacological studies conducted by Zanoli et al. (Zanoli et al., 2000) have attributed the biological effects of P. incarnata to a avonoid chrysin. Though, in these studies, the said authors have evaluated the avonoid chrysin for its anxiolytic and sedative properties, it was not made clear whether chrysin was isolated from the plant prior to attributing the biological effects of Passiora incarnata to chrysin only. In these studies, chrysin, when administered at a dose of 50 mg/kg in rats intra-peritonially, did not inuence the pentobarbital-induced sleeping time in rats, decreased the locomotor activity at 25 mg/kg and also exhibited anxiolytic activity at a dose of 1 mg/kg which was manifested by the increased latent-time spent in the light-dark compartment model of anxiety. During the exhaustive pharmacognostic and biological studies on a few important plants of the genus Passiora, authors have reported novel ndings on P. incarnata which may throw some light over the earlier inconclusive and slightly contradictory reports on P. incarnata and Passiora edulis. Aerial parts of P. incarnata were procured from a cultivated source Rati Ram Nursery, village Khurrampur, district Saharanpur, Uttar Pradesh, India and its authenticity was conrmed from the reference specic available at the Forest Research Institute, Dehradun, Uttar Pradesh, India, where a voucher specimen sample was also deposited (Number 1325/2000). Authentic specimen sample of Passiora edulis was procured from the Medicinal Plants Garden of the University Institute of Pharmaceutical Sciences, Pan-
jab University, Chandigarh, India. All the biological activity studies were carried out at the Pharmacognosy Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. The studies were performed using mice (Swiss albino, both sexes), rats (Wistar rats, both sexes) and guinea pigs procured from the Disease Free Small Animal House of the Haryana Agriculture University, Hissar, India and were housed at the standard laboratory conditions at the Central Animal House, Panjab University, Chandigarh, India. All the experimental protocols involving use of animals were approved by the Institutional Ethical Committee of Panjab University, Chandigarh. During a comparative study, only P. incarnata methanol extract exhibited signicant anxiolytic activity at a dose of 125 mg/kg in mice, whereas, Passiora edulis did not show any signicant anxiolytic activity in any of the extracts/doses evaluated (i.e., petroleum ether, chloroform and water) using the modied elevated plus-maze model of anxiety, 2 mg/kg p.o. diazepam as a standard anxiolytic, and the vehicle (comprising 66.6%, w/w, sucrose in water) as a control (Dhawan et al., 2001b). The petroleum ether, chloroform, methanol and water extracts of the segregated leaves, stems, owers, roots and the entire plant of Passiora incarnata were evaluated for determining the relative anxiolytic proles of the segregated plant parts and the whole plant respectively after making their suspension in the vehicle (simple syrup) using experimental animals mice and the elevated plus-maze model as the laboratory model for evaluating anxiety. Only the methanol extract of leaves of P. incarnata exhibited signicant anxiolytic activity (100 mg/kg p.o.) in mice, whereas, the petroleum ether, chloroform and water extracts were found to be devoid of activity. Using elevated plus-maze model of anxiety in mice, it was observed and reported that none of the extracts of roots of P. incarnata exhibited signicant anxiolytic activity comparable to that of the control (simple syrup) and the standard anxiolytic dose of diazepam (2 mg/kg) (Dhawan et al., 2001c). The methanol extracts of leaves, stems, owers, and whole plant exhibited anxiolytic effects at 100, 125, 200, and 300 mg/kg, respectively. These results show that roots and owers of P. incarnata act as natural adulterants by causing a signicant increase in the anxiolytic dose. Therefore, separation of these parts is recommended prior to any pharmacological, phytochemical and standardization studies on P. incarnata. (Kumar, 2001). Subsequently, it has been reported that only the leaves of P. incarnata should be used for performing biological studies as the leaves contain the maximum concentration of the bioactive constitutents. The methanol extract of leaves were useful in suppressing SO2 -induced cough in mice at 100 mg/kg p.o. dose, using suspension of codeine phosphate (10 and 20 mg/kg) in simple syrup (simple syrup being used as a control, as well as the vehicle) as a standard anti-tussive (Dhawan and Sharma, 2002a). Using a 7-days treatment regimen, the same methanol extract of leaves at a dose of 100 mg/kg p.o. was found to possess signicant spasmolytic properties as it prevented 10% acetylcholine
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chloride-induced dyspnoea in guine pigs which was evaluated using an aerosol chamber with 1 kg/cm2 as the constant pressure. The anti-asthmatic properties of the methanol extract of leaves of P. incarnata have been postulated due to its inuence over the -adreno-receptors (Dhawan et al., 2003b). The methanol extract of leaves of P. incarnata possessed signicant aphrodisiac properties in male mice as the extract treated male animals exhibited increased mounting behavior in presence of non-estrous female mice, relative to the control, i.e., simple syrup (Dhawan et al., 2002a). All these biological activites reported by the authors are in accordance with the ethno-pharmacological reports regarding the use of P. incarnata in the traditional system of therapeutics. A comparative study was performed taking the bioactive methanol extract of aerial parts of P. incarnata and the mother tincture preparations of P. incarnata (30 ml) of various reputed homoeopathic medicines, available in the local market, e.g., SBL Private Limited, Ghaziabad, India (SBL), Dr. Reckeweg & Co., Gmbh D-64625, Bensheim, Germany (DRCG), Dr. Willmar Schwabe India Pvt. Ltd., NOIDA (DWSI), Dr. Willmar Schwabe, DHU-Arzneimittel, Germany (DWSG) and Bhandari Homoeopathic Laboratories, Ghaziabad (BHL) were procured from the local market (Dhawan et al., 2002c). Thirty ml quantity of these ve tinctures were dried under vacuum using Buchi 461 Rotavapor and the solvent-free extracts of P. incarnata were preserved in a vacuum desicator. The market extracts were further subdivided into four doses, viz., 100, 200, 300 and 400 mg/kg by suspending the dried extract in the vehicle comprising simple syrup and 1% w/w of carboxymethylcellulose (CMC). The biological (anxiolytic) effects exhibited by the marketed preparations were found to be different from that of the methanol extract of P. incarnata being used by the authors in the laboratory studies. All these preparations exhibited the maximum anxiolytic activity in mice (on elevated plus-maze apparatus) at different doses. It could be opined through this exercise that the inconsistancy in biological activity of plant preparations could be dealt with, only if the available pharmacopoeial monographs of a particular plant-derived medicine could be substantiated with the denate informations on certain vital nger-print parameters, i.e., leaf-constants, physico-chemical parameters, TLC proles, and reporting of a specic bioactive marker compound (Dhawan et al., 2001a). The same extract, i.e., the bioactive methanol extract of P. incarnata was further subjected to bioactivity-directed fractionation, chromatographic and partitioning methods to reach at an almost pure fraction, which further exhibited signicant anxiolytic activity at 10 mg/kg in mice using diazepam as a standard anxiolytic on the elevated plus-maze model of anxiety (Dhawan et al., 2001d). The UV, LCMS, GCMS, IR, 1 H, 13 C NMR characterization studies have conrmed the presence of a benzoavone (BZF) moiety, never reported from P. incarnata earlier, that has been accounted for the CNS properties of this poten-
tial plant (Dhawan et al., 2001d,e,f; Dhawan, 2002). This phyto-moiety has basic structure comprising a benzene ring fused at 6, 7 position of a avone compound. The complete chemical structure of BZF phyto-moiety isolated from the methanol extract of aerial parts of P. incarnata cannot be published due to patent considerations. The isolation of a tri-substituted benzoavone moiety as the main bioactive phyto-constituent of P. incarnata is a signicant breakthrough, which gives the authors a major leap forward not only in understanding the mode of action of P. incarnata but also in exploring the unexplored virtues of the plant in countering the menace of substance/drug addiction.
In another study, the authors evaluated the effect of the bioactive fraction of P. incarnata on the reversal of morphine tolerance and dependence in mice (Dhawan et al., 2001g,f). Mice were rendered tolerant and dependent on morphine by administration of morphine sulfate (10 mg/kg p.o.) twice daily for 9 days. Concurrent co-administration of BZF of P. incarnata (10100 mg/kg) with morphine for 9 days attenuated naloxone-precipitated withdrawal jumps on the 10th day. Co-administration of BZF during induction phase (days 19) delayed the development of tolerance to the analgesic effect of morphine, which was measured using tail-ick analgesiometer. This particular study on morphine reversal effects of P. incarnata is in accordance with the ethno-pharmacological reports about the use of the plant extract in morphine-deaddiction which mention the traditional use of P. incarnata in morphine deaddiction in the traditional system of medicine in India (Lad, 2000; Vasudev, 1955). In the light of various reports (NicoNo, 2001), mentioning the usefulness of P. incarnata in tobacco addiction, studies have been performed by using four doses (1, 5, 10 and 20 mg/kg) of the bioactive BZF moiety isolated from aerial parts of P. incarnata. In a 7-days experimental regimen, mice (n = 5) were given nicotine hydrogen tartrate (2 mg/kg), and combinations of nicotine with four doses of BZF (NnP-1, NnP-5, NnP-10 and NnP-20) q.i.d., by s.c. route. At the end of the 7-days treatments, naloxone was given to all the mice groups to induce abrupt cessation of nicotine. Mice treated with 10 and 20 mg/kg dose of BZF concurrently with nicotine, did not exhibit signicant number of withdrawal jumps relative to the addict group (Nn group). It was evident that mice receiving these two doses of the nicotinePassiora combination treatments (NnP-10 and NnP-20 groups) had no craving, as the animals did not become dependent on nicotine. Even an acute single administration of BZF moiety of P. incarnata to the nicotine addict mice (N group) could afford prevention of nicotine-dependence-oriented withdrawal
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effects at the highest dose of BZF (20 mg/kg) only, and the lower doses were almost inert (Dhawan et al., 2002d). Mice were administered 10 mg/kg b.i.d. (twice a day) dose of 9 -tetrahydrocannabinol ( 9 -THC), p.o. (per oral), for 6 days to make them dependent upon cannabinoids. Concurrently, the other groups of mice were administered 9 -THC along with 10 and 20 mg/kg b.i.d. doses of BZF orally for 6 days. Upon measuring the locomotor activity during the treatment regimen, it was reported that the mice receiving BZF and 9 -THC together, developed signicantly less tolerance and dependence, relative to the mice receiving 9 -THC alone. Upon administration of SR-141716A, a selective cannabinoid-receptor antagonist (10 mg/kg p.o.) to all the groups of mice on the 7th day, an articial withdrawal was produced due to an abrupt decline of 9 -THC levels in mouse brain. However, the typical withdrawal effects like paw tremors and head shakes, were signicantly less in the mice administered with 9 -THC + BZF for 6 days. Upon administration of 20 mg/kg dose of BZF to mice showing severe symptoms of withdrawal due to administration of SR141716A, there was a marked attenuation of the withdrawal effects, thereby, suggesting the usefulness of BZF in the expression of withdrawal effects of 9 -THC. Thus, BZF when administered concurrently with 9 -THC prevented the development of tolerance and dependence of cannabinoids in mice. Even an acute administration of BZF (20 mg/kg p.o.) signicantly blocked the expression of withdrawal effects in 9 -THC-dependent mice (Dhawan et al., 2002e). In the light of the established usefulness of the benzoavone moiety in counteracting the withdrawal effects of substances like morphine, cannabinoids and nicotine by the authors, the bioactive benzoavone moiety was given in mice treated with addictive dose (2 g/kg, bid for 6 days) of ethyl alcohol, in order to evaluate its effectiveness in countering alcohol dependence and expression of the ethanolwithdrawal-induced hyper-anxiety (manifested in the form of increased locomotor activity) (Dhawan et al., 2002h). In a 7 days regimen, different groups of mice were administered vehicle, alcohol, and alcohol + four doses (10, 20 and 50 mg/kg of the benzoavone moiety) of Passiora incarnata; all treatments (chronic) being administered orally, twice daily for 6 days. Similarly, three other groups of mice were rendered addict upon alcohol by administration of the addictive dose (2 g/kg, bid for 6 days) of ethyl alcohol, and a single acute administration of 10, 20 and 50 mg/kg dose of benzoavone moiety was given on the 7th day. In both, chronic and acute administrations, the benzoavone moiety signicantly prevented the expression of withdrawal effects of alcohol as there was a signicant decrease in anxietyoriented behavior in mice that received benzoavone moiety of P. incarnata. The chronic administration of P. incarnata with alcohol had better preventive effects than the single acute treatment with P. incarnata in alcohol-dependent mice. In light of the dependence and addiction-liabilities of benzodiazepines, a non-habit forming anxiolytic drug is the dire need of the hour. The BZF moiety which was earlier re-
ported to exhibit anxiolytic properties at 10 mg/kg p.o. dose in mice, was evaluated for its dependence-liabilities at three doses (10, 50 and 100 mg/kg) upon a chronic 21-days treatment in mice. The three doses of BZF exhibited a normal ambulatory behavior on 25th day after the treatment for 21 days, conrming thereby, that BZF moiety had no addiction or dependence even upon a long-term use in mice. Even in the case of diazepam, the BZF moiety prevented the development of diazepam-dependence and expression of withdrawal effects when administered concurrently with 20 mg/kg p.o. dose of diazepam, for a period of 21 days. The ambulatory activity was used as the measure of physiological and physical manifestation of chronic diazepam withdrawal-oriented relapse of anxiety in the animals. The ambulatory activity of different co-treatments of 20 mg/kg diazepam and BZF (10, 50 and 100 mg/kg) revealed a dose-dependent preventive effect, as the 100 mg/kg dose of BZF afforded almost full prevention of diazepam dependence in mice receiving the combination treatments in the 21-days treatment regimen (Dhawan et al., 2002f; Dhawan et al., 2003a). To evaluate the androgenic and testosterogenic effects of BZF and the avonoid chrysin, authors performed studies to describes the potential usefulness of bio-avonoids for countering the deleterious effects of aging upon the male sexuality in 2 years old rats. A avone chrysin from Passiora caerulea and the benzoavone moiety (BZF) were administered to 2 years old male rats for a period of 30 days. After cessation of these treatments, there was a signicant improvement in the over-all sexual functions in male rats which were given the bio-avonoids, relative to the control. The rats receiving chrysin (1 mg/kg) and BZF (10 mg/kg) exhibited increased libido, when they were allowed to interact with non-estrous female rats. Additionally, the rats upon 30-days treatment with bio-avonoids had increased sperm count, greater fertilization potential as well as litter size, when they were allowed to interact with proven proestrous female rats of the similar strain. Between the two, BZF was more potent than chrysin, as an anti-aromatase agent and exhibited better effects upon sexual system of the 2 years old rats. Plant avonoids, thus, act as potent phytoestrogens, and have tremendous clinical and therapeutic utilizations against physiological and biochemical effects of aging (Dhawan et al., 2002b). The BZF moiety was also found to be very useful in preventing the chronic-drug-induced decline in libido, fertility and virility in male rats, in studies performed by the authors. Separate groups of healthy male rats were given 9 -THC (10 mg/kg p.o.), nicotine hydrogen tartrate (2 mg/kg, sub-cutaneously) or ethanol (3 g/kg p.o.), alone as well as in combination with BZF (10 or 20 mg/kg p.o.) over a period of 30 days at a stretch. After 30-days treatment regimen, the THC-, ethanol- or nicotine-treated mice had a signicant loss of libido (recorded by observing the mounting behavior with non-estrous female rats), decrease in the sperm count, and also decrease in the number of impregnated pro-estrous female rats, relative to the rat-groups
14
which were given co-treatments of THCBZF (Dhawan and Sharma, 2003), nicotineBZF (Dhawan and Sharma, 2002b) and ethanolBZF. The results of these exhaustive studies make the authors opine that BZF also prevents the drug/substance induced decline in fertility, libido, etc. Encouraged by the interesting results with the BZF moiety in counteracting the withdrawal-oriented dependence of various substances of abuse, it was desirable to study the mode of action. Since, benzoavone moieties are the strongest inhibitors (Aldrich Catalog, 1996) of the enzyme aromatase (a member of cytochrome P-450 family), they are very signicant in the metabolism of sex-steroids (Kao et al., 1998; Kellis and Vickery, 1984). It is postulated that BZF inhibit the metabolic conversion of androgens (testosterone) to estrogens, thereby increaseing free teststerone and decreasing free estrogen (Chen et al., 1997). The free teststerone accounts for the non-appearence of withdrawal effects of substances like morphine, nicotine, cannabinoids, ethanol and even benzodiazepines. This hypothesis holds good in light of the well-established fact that the sex-steroids (or neuro-steroids) are the pivotal body chemicals which are responsible for symptoms like anxiety, depression, insomnia, epilepsy, nervous fatigue and stress. Neuro-steroids are also instrumental in our sexual behavior and performance (Crmoux, 2000; Leonard, 1985). Since, there are incontrovertible evidences that chronic consumers of morphine, tobacco, cannabinoids and ethanol suffer from decline in libido, sexual fertility and virility due to severe fall in the plasma-testosterone levels, administration of BZF restores the normal testosterone levels by stopping the aromatization of testosterone to estrogen (INFOFAX, 2001; INFOFAX, 2001; Kane, 2001). Secondly, BZF also facilitates the body to produce more testosterone by eliminating the so called negative feedback loop, that otherwise reduces natural testosterone production due to chronic treatment with drugs and substances like morphine, nicotine, cannabinoids and alcohol (Lee et al., 1994; Schwontkowski, 1994). The mechanism that BZF might act by inhibiting the enzyme aromatase, thus, preventing the metabolic degradation of testosterone to estrogen, postulated by the author has been duly acknowledged as well as lauded recently (Dhawan, 2003). A multi-component herbal preparation Euphytose that has been used in France since 1927 for curing anxiety states comprises powder extracts of the following herbs: 50 mg valerian (Valeriana ofcinalis), 40 mg Passion ower (P. incarnata), 15 mg kola nut (Cola nitida), 15 mg guarana (Paullinia cupana), 10 mg hawthorn (Crataegus oxycantha), and 10 mg black horehound (Ballota foetida). The dosage of placebo or the formula was two tablets three times daily for 28 days (Bourin et al., 1997). The multi-center, doubleblind, placebo-controlled general practice study of 182 outpatients randomized into two parallel groups, who after a 7-days placebo treatment prior to active treatment continued to show a score of over 20 in the 14-item Hamilton anxiety scale (HAM-A). The MontgomeryAsberg depres-
sion rating scale was applied to exclude depressed patients. The results showed a signicant decrease in the HAM-A scale already on day 7, and on day 28 in scores of psychic anxiety (P = 0.025) and somatic anxiety (P = 0.011) compared to baseline, whereas, there were no signicant changes in the placebo group scores. Those scoring less than 10 on the HAM-A scale at the end of the treatment period (cured) numbered 23 (25.3%) in the placebo group versus 39 (42.9%) in the formula group. Eighty-three percent (83%) of the formula group reported an improved social life versus 65% in the placebo group. Mild adverse effects occurred in four patients in the formula group and 8 in the placebo group. The ethanolic extract of P. incarnata exhibited antiinammatory properties at a dose of 125500 mg/kg in rats against inammations induced by cotton pallets, dextran and carrageenin (Borrelli et al., 1996).
7. Toxicology Though herbal products are generally regarded as safe, yet, on account of the occurrence of cyanogenic constituents in Passiora species, their toxicity can not be ruled out. Human beings have the physiological ability to detoxify cyanide satisfactorily, given an adequate protein diet (Jones, 1998). The United States FDA has reported 15 cases of toxicity occurring due to the consumption of multi-ingredient patent medicinal products in which Passiora species formed one of the constituent (USFDA, 2000). There have been reports of erratic heart beat and tachycardia, severe headache, pulmonary emboli, hepatitis, diarrhoea, pneumonia, weakness in upper extremities, intracerebral hemorrhage with difculty in speaking, etc., which have been documented by the USFDA. A stray case of death has also been reported due to the consumption of a patent drug Cybergenics HG 6 of L & S Research Corp. However, all these products were multiingredient formulations and the reported toxicities can not be solely ascribed to Passion ower. The unripe fruits of Passiora adenopoda have caused poisoning due to the presence of HCN, which is produced in the pericarp and aril of the unripe fruits as well as in the primary stem, petiole, bracts and stipules (Saenz and Nassar, 1972). However, the ripe fruits were devoid of HCN. Passiora alata is reported to contain etiologic agents of Ig E-mediated occupational asthma and rhinitis (Giavina et al., 1997). The plant is therefore a persistent risk for the personals working with this species. Passiora edulis has shown hepatobiliary and pancreatic toxicity in animals and humans (Maluf et al., 1991). P. incarnata is listed as safe herbal sedative by the FDA of America (HerbClip, 1996) and none of the available monographs of P. incarnata mention the toxicity or any contra-indication of this plant. Since the physiological actions and the mode of CNS depressant activity have not been well documented, it has been advised to take P. incarnata with caution when taken along with other CNS depressants or stimulants (Felter and
15
Lloyd, 1983). A few individuals have experienced emesis with this plant even at medicinal doses. Moderate doses act as anti-spasmodic or somewhat narcotic. Excessive doses have produced spasms and even paralysis in animals. It has been advised not to take P. incarnata with procarbazine anti-neoplastic drugs, possibly to minimize CNS depression (Martin, 1978). The neuromuscular relaxing effects of P. incarnata have been enhanced by the use of the aminoglycoside antibiotic like clindamycin. There has been a report that a 34 years old female patient developed severe nausea, vomiting, drowsiness and ventricular tachycardia following self medication with P. incarnata (Fisher et al., 2000). Five patients have been reported to suffer altered consciousness after taking a herbal preparation Relaxir , which is prepared from P. incarnata (Solbakken et al., 1997). The extract of the plant is being evaluated in Japan for its possible teratogenic effects (Hirakawa et al., 1981). Herbal preparations containing P. incarnata as one of the ingredients have caused vasculitis in patients suffering from insomnia (Smith et al., 1993). Vitexin (5), a phyto-constituent present in various Passiora species has exhibited anti-thyroid activity during in vivo and in vitro studies using rats as experimental animals (Gaitan et al., 1995). The popular American Magazine US Pharmacist has discouraged the use of P. incarnata in lactating mothers (US Pharmacist, 2001). Due to the presence of passiorine (17) and harmin alkaloids (1014), the plant is reported as a general environmental toxic grass by the University of California in their Environmental Toxicological Newsletter (Environmental Toxicology Newsletter, 1983). During the 9th meeting of the Complementary Medicines Evaluation Committee in 1998 at Melbourne, the harmful effects of harmala alkaloids in P. incarnata were accounted for their side-effects and the long-term prescription of harman alkaloids (1014) was strictly prohibited in Australia (CMEC9, 1998). A severe contra-indication of P. incarnata with a synthetic MAO inhibitor drug Phenelzine (NARDIL ) has been highlighted (Miller, 1998).
8. Clinical applications Amongst the 500 species of the genus Passiora, P. incarnata is the one which has extensive clinical applications throughout the world. The worldwide clinical applications are evident from the fact that Passiora incarnata is an ofcial plant drug in British Herbal Pharmacopoeia, 1983, Homoeopathic Pharmacopoeia of India 1974, United States Homoeopathic Pharmacopoeia 1981, Pharmacopoeia Helvetica 1987 and the pharmacopoeias of Egypt, France, Germany and Switzerland. The plant has also been described in the British Herbal Compendium 1992, the European Scientic Cooperative on Phytotherapy (ESCOP) monographs 1997, Deutsches Arzneibuch (DAB) 1997, Deutsches Homopathisches Arzneibuch (DHAB) 1978, Bundesanzeiger (Banz). Monographien der Kommission E 1998 and American Materia Medica 1983. Discovered
in 1569 in Peru, Passiora incarnata was introduced into medicine in 1840 by Dr. L. Phares of Mississippi. The use of this plant recently has been revived by Professor I.J.M. Goss of Georgia, having introduced it into Eclectic practice (Hoch, 1934). In a non-randomized clinical observatory trial, Schellenberg et al. (Schellenberg et al., 1993) pharmacologically evaluated a combination product Biral-neu comprising valerian root and Passion ower (P. incarnata) extracts. For comparative purposes, 20 ambulatory patients diagnosed with affective and psychosomatic disorders received either the extract combination or the neuroleptic drug Propaphenin . Central activity and vigilance were quantitatively controlled using EEG brain mapping. For clinical improvements, CIPS inventory was taken from a selfrating depression and anxiety scale. The combination of the plant extracts reduced occipital region central hyperactivity after 2 weeks, as evidenced by signicant increases (P < 0.01) in selective alpha-power and theta-power. For those treated with the neuroleptic agent, the major power increase was found after 6 weeks. The anxiety and depression index showed a similar decrease in all the patients. The researchers concluded that the combination product containing P. incarnata was more efcient than Propaphenin has a remarkable position as a herbal sedative in the OTC market, yet its effectiveness has only been conrmed to a limited degree by controlled therapeutics and clinical studies (Schulz et al., 1997). The plant extract in combination with the extracts of other herbs has been subjected to double-blind, placebo-controlled studies in patients with anxiety related disorders (Bourin et al., 1997), dementia and behavioral problems in aged patients (OBrien, 1998). Two multiple crossover studies, each involving 12 adult female subjects, were performed to screen the acute sedative effects of extracts of Valeriana ofcinalis, Lavandula angustifolia, P. incarnata, Piper methysticum, Mellisa ofcinalis, Eschscholzia californica, Hypericum perforatum and Ginkgo biloba. Both studies were placebo-controlled, and a single dose of 10 mg diazepam was used as an active reference drug. All drugs were administered as a single dose. Prior to administration, as well as 2 and 3 h after administration, EEG was recorded from two leads (FzCz and OzT6) under vigilance-controlled and resting conditions for 5 min. Tiredness was rated by the subjects on a visual analogue scale. The EEG was digitized and stored for later analysis of the absolute and relative power of seven factorially dened frequency bands. Under diazepam, the power in the theta-frequency band decreased while it increased in the beta-band. Some plant extracts increased power in the theta-frequency band but had no effect on beta frequency range. Self-rated tiredness increased under diazepam and some of the plant extracts but not with the placebo. The sedative effects of plant extracts could be evaluated by quantitative EEG analysis and by self assessment (Schulz et al., 1998). The EEG patterns of rats under a chronic treatment with P. incarnata for 3 weeks supported the sedative
16
and CNS depressant effects of the plant (Sopranzi et al., 1990). The clinical applications of P. incarnata have been forced chiey upon the nervous system (Felter and Lloyd, 1983). It proves specially useful in insomnia of infants and old people. The herb relieves nervous irritability resulting from prolonged illness, menstrual disturbances and mental overwork. It calms the restlessness of typhoid fever. The sleep produced by P. incarnata is rich in REM sleep, resulting into freshness on awakening. One of the earliest clinical applications of the plant was for the relief of tetanus. The drug is highly effective in convulsions when given prior to an approaching attack. Passiora incarnata is praised for its control over spasms of childhood. Spasms due to meningeal inammations have been controlled with it. The plant is useful in spasmodic dysmenorrhea, neuralgic pain, rectal pain or even cardiac pain. An aqueous extract has been lauded as an application over burns, hemorrhoids, painful ulcers and ulcerating carcinomata. The double-blind clinical studies performed recently on 36 out-patients suffering from generalized anxiety disorders (GADs) has afrmed that efcacy of the Passiora incarnata extract (45 drops per day) was comparable to that 30 mg per day dose of oxazepam (Akhondzadeh et al., 2001). A total of 65 opiates addicts were assigned randomly to treatment with Passiora extract plus clonidine tablet or clonidine tablet plus placebo drop during a 14-days doubleblind clinical trial. All patients met the DSM IV criteria for opioid dependence. The xed daily dose was 60 drops of Passiora extract and a maximum daily dose of 0.8 mg of clonidine administered in three divided doses. The severity of the opiate withdrawal syndrome was measured on days 0, 1, 2, 3, 4, 7 and 14 using the Short Opiate Withdrawal Scale (SOWS). Both protocols were equally effective in treating the physical symptoms of withdrawal syndromes. However, the Passiora plus clonidine group showed a signicant superiority over clonidine alone in the management of mental symptoms. These results suggested that Passiora extract may be an effective adjuvant agent in the management of opiate withdrawal (Akhondzadeh et al., 2001). Herpes Tincture containing P. incarnata, Astragalus membranous and Lomatium dissectum has been used in Homoeopathy as a treatment for various sexually transmitted diseases and is also effective against HIV (Pizzorno and Murray, 1999). Dr. J. Lutomski has specically lauded the role of P. incarnata preparations for sexual activity in females, by stating Die Bedeutung der Passionsblume in der Heilkunde {the meaning of passion ower in medical science} (Lutomski et al., 1981). Passionower preparations are particularly useful in nervous manifestations of menstrual problems, menopause, and sexual activity, in females (Chevallier, 1996). That is why, P. incarnata extracts have been used as female-tonics and adaptogens. The plant is particularily useful in nerves that are on edge. An average dose of passionower in a solid natural form is aproximately 500 mg and there are no known or serious contradictions of passionower, according to Dr. Taylor in his book, The Hon-
est Herbal (Tyler, 1993). The role of Passiora incarnata has also been appreciated in cancer patients (Payne, 2001). The phobia, fear and anxiety on acount of cancer cause adrenal hormone release, the physiological effects of which include activation of adipocyte lipase (resulting in mobilization of free fatty acids) and partial inhibition of protein synthesis, i.e., the plasma amino acids which are readily utilized by normal cells for protein synthesis are only partially used, resulting in an increase in the availability of amino acids to meet tumor cell metabolic needs. It is vitally important, therefore, to provide the cancer patient with anxiolytic phytomedicine to minimize fear and anxiety related stress. The extract of P. incarnata alongwith other allied herbs is quite useful in ameliorating stress in cancer patients. This practice is being adopted in Japan. The Dietary Supplement Health & Education Act of 1994 (DSHEA) has exempted herbs like passionower, valerian, ginkgo and ginseng from the purview of the Food & Drug Administration of the USA for their benefecial effects in the estrogen replacement therapy (ERT) in post-menopausal women (Ross et al., 2000). Passiora alata is reported to be ofcial in the Pharmacopoeia of Brazil (Reynolds, 1996). A liquid oral solution of the plant in a dose of 5 ml thrice a day is recommended in the insomnia, anxiety, dry cough, irritation of the respiratory mucosa, nervous disturbances of the menopause and some painful conditions (Monteiro Da Silva Ltda, 2000). Spray-dried powders prepared from the 40% ethanolic extractive solutions of Passiora edulis aerial parts, and Aerosil 200 as an adjuvant, have been used in insomnia in Brazil (DeSouza et al., 2000).
9. Conclusions Despite tremendous advancements in the eld of medical therapeutics, the studies conducted at the National Institute of Mental Health, Bethesda, the USA (NIMH), reveal the alarming increase in CNS related disorders, the main two being anxiety and insomnia (Murray and Lopez, 2001; NIMH, 2001). A datum of the NIMH reports that anxiety related disorders will engulf every 7 out of 10 individuals in the USA alone, by 2020. Even in the developing countries, where 4/5th of the planets people live, the next decade will bring a dramatic change in the health-care needs of the people, as the anxiety-oriented disorders will replace their traditional enemies, i.e., the infectious diseases (Cherr, 1999; Zal, 2000). Pharmaceutical options in the treatment of anxiety have included the benzodiazepines, anti-depressants (MAO inhibitors and TCAs), -blockers, azaspirones and some anti-convulsants (OBrien and Woody, 1986). These products, however, can cause serious problems of sedation, cognitive changes and addiction liabilities. The general public, in search of safe, cheap and effective treatment for their anxiety, tension and stress, are starting to turn to nonpharmaceutical herbal products and other alternative medications (Newell et al., 1996). In view of the dire need of a safe,
17
effective and cheaper anxiolytic, various plants especially Passiora incarnata have a great scope of clinical exploitation in the years to come. The plant has a long traditional use as an anxiolytic and sedative. A perusal of literature on bioactivity of Passiora reveals that researchers throughout the world have opined differently and have postulated their own school of thought based on their observations. The harmala alkaloids and avonoids have been reported as the main important constituents of P. incarnata. The harmala alkaloids, due to their MAO enzyme inhibiting properties have been suggested to be the main bioactive phyto-constituents (Bradley, 1992; NF, 1926; Pletscher et al., 1959; Reynolds, 1996). The avonoid chrysin (Zanoli et al., 2000) and a -pyrone derivative maltol (15) have also been accounted for their role in the CNS depressant activity of the plant (Aoyagi et al., 1974). In the latest reports, the sedative and anxiolytic activity of P. incarnata has been attributed to the benzodiazepine and GABA receptors mediated biochemical processes in the body (Simmen et al., 1999; Viola et al., 1998). The plant is reported to be a depressant to the motor side of the spinal cord, reducing arterial pressure and increasing rate of respiration (Pletscher et al., 1959). Contrary to these reports, the exhaustive pharmacological work by Soulimani et al. (Soulimani et al., 1997), has ruled out the role of any of the known phyto-constituents in P. incarnata which could have been responsible for the sedative and anxiolytic activity of this plant. Authors, therefore, conclude that there is no consensus of opinions between the various postulated hypotheses pertaining to the bioactivity of this plant. Authors attribute this lacuna to the confusing identity of P. incarnata which has bafed the researchers and botanists since 1843 (Hooker, 1843). Due to the similar morphologic and microscopic characteristics of Passiora incarnata and Passiora edulis, the two plants have often been reported as synonymous (Chakravarty, 1949; Jackson, 1895). The confounding resemblance of Passiora incarnata with Passiora edulis which was rst reported in 1843 even persists till date as is evident from a survey of the literature (Finzelberg, 1999; Kuntz, 1999; McGuire, 1999; Raintree Nutrition, 1999; Scheper, 1998; Vecchia, 1998). Passiora edulis is mainly grown for its edible fruits (McGuire, 1999) and rarely nds mention in the reports as a potent hypnosedative (Maluf et al., 1991). In fact, the two plants are so much alike as to bafe even a plant taxonomist (Kumar, 1999). Moreover, comparison would be possible only if we have specimens of both the plants. Authors have established the key differential parameters between P. incarnata and Passiora edulis so as to properly identify the accurate plant out of these two identical species (Dhawan et al., 2001a; Dhawan et al., 2000). After establishing the correct identity, it has been possible to perform systematic pharmacological studies on the proper bioactive plant, i.e., P. incarnata and its un-imaginable virtues have been reported on account of the isolation of a tri-substituted benzoavone moiety from the plant. The isolation of a BZF moiety from P. incarnata
has been a signicant breakthrough which makes us understand the inconclusive reports by earlier researchers. This moiety merits human trials and its exact and full chemical identity can not be disclosed here for our right to protect the patent over it, though, the useful structure and the postulated mode of action of this tri-substituted BZF moiety has been presented here for the interests and benets of a reader. By way of several experimental studies, the anxiolytic, antitussive, anti-asthmatic and aphrodisiac effects of P. incarnata have been conrmed in the crude methanol extract of this plant. Further, a novel tri-substituted benzoavone moiety has been isolated and reported which has exhibited its usefulness in the addiction of morphine, ethanol, nicotine, cannabinoids and diazepam. This BZF moiety has also exhibited substance-induced decline in sexual parameters in male animals, besides, exhibiting its own use as a virilityenhancing agent. The plants over other species of Passiora also have promising scope for a future research. Fluorine is a very common industrial pollutant that has severe toxic effects also. Due to its strong electro-negativity, uorine can form complex with biologically active substances. Chrysin, reportedly present in Passiora incarnata can form complexes with metals due to its anti-oxidant activities. Chrysin as well as other avonoids of P. incarnata appear to exert a benecial effect in chronic exposure to industrial toxins including uorine compounds (Liwiec et al., 2000). In an experimental study conducted by Liwiec et al., the effect of avonoid chrysin (20 mg/kg for 3 months) was evaluated in rats intoxicated with NaF for a constant period of 3 months. After 3 months, the various enzymes viz., aspartate aminotransferace (AspAT), alanine aminotranferace (AlAT), cholinesterase (ChE), alkaline-phosphatase (AP) and bilirubin concentrations in serum were measured. Intoxicated animals had higher levels of AspAT, AlAT and ChE. This increase was suppressed by chrysin. AP activity was reduced in intoxicated animals. These ndings suggest the promising role of chrysin-enriched diet as a supportive-cum-preventive measure in exposure to uorine compounds. Passiora tetrandra which has got anti-bacterial activity against Escherihia coli, Bacillus subtilis and Pseudomonas aeruginosa can also have potential to be another plantderived antibiotic (Perry et al., 1991). The plant has also exhibited cytotoxicity to P-388 murine leukemia cells. Passicol consisting of polyacetylenic compounds has also exhibited anti-bacterial and anti-fungal activities (Nicolls et al., 1973). This compound has been detected in Passiora caerulea and Passiora edulis. Thus, the above species of Passiora can offer newer anti-bacterial and anti-fungal agents, if worked upon. Ermanin (32) having deterrent activity against Dione juno larvae has been isolated from Passiora foetida(Echeverri et al., 1991). Ermanin can be a good pesticide against such pests and insects. In Passiora quadrangularis, the presence of angiotensin converting enzyme inhibitor and aldose reductase enzyme inhibitor
18
has been reported (Okamoto and Yoshizawa, 1994). The plant thus, can be a hunting ground for the discovery of a novel anti-hypertensive agent. Recently, it has been observed that chrysin which is present in many species of Passiora has got testosterone boosting properties (Jarrow Formulas Inc., 2000). Interestingly, Passion ower when smoked with Lobelia has shown laudable result in deaddicting the nicotine/cigarette smokers (NicoNo, 2001; Viable Herbal Solutions, 2001). Passion ower is recognized as a dietary supplement and approved avoring agent by the US government and the Council of Europe. Till 1978, this herb enjoyed OTC status in the USA (Horatio et al., 1948). The genus Passiorais a good source of bioavonoids, i.e., chrysin, apigenin, kaempferol, quercetin, apigenin, and genistein, etc., which have tremendous therapeutic potentials as anti-oxidants, immuno-modulators, antianxiety agents and anti-carcinogens (Merken and Beecher, 2001; Murcia et al., 2001). The benzoavone moiety, being the strongest aromatase inhibitor, and various avonoids from other species of Passiora, can also be exploited for its postulted use in various mental disorders, especially arising out of addiction of tobacco, opiates, cannabinoids, alcohol, and synthetic anxiolytics (Brounstein, 1995; Capasso et al., 1998). Species of Passiora have also been put to use as OTC preparations throughout the world in symptoms like andropause, menopause, as calming therapy for hyperactive-children, in case of severe anxiety due to insomnia, restlessness and nervous edgy, and also in various sexual dysfunctions in males as well as females (Aubert and Anthoine, 1985; Blumenthal et al., 1998; Chua, 2002; Cooper and Ritchie, 2000; Environmental Toxicology Newsletter, 1983; Foster and Dube, 1990; Fremerman, 1998; Gagiu et al., 1978; Grandolini et al., 1997; Hoffman, 1984; Holt and Comac, 1998; Incledon, 2001; Jarrow Formulas Inc., 2000; Johnson, 1995; Lam, 2001; Lycos, 2001; Marx, 2001; Melissa, 2000; Pelissero et al., 1996). Our exhaustive pharmacological studies using the BZF moiety of P. incarnata were also based on the various reports mentioning the use of extracts, tea, tincture, and even tablets of P. incarnata against various addiction-prone substances. Thus, the various species of Passiora, besides their ornamental and exotic values, can prove to be useful sources of newer biological molecules which can be potent phytopharmaceuticals in the future. This genus is a boon and blessing and a panacea for the ailing masses. The varied therapeutic uses described in our report prove Passiora true to its platonic name, i.e., passion of Christ.
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