Clerodendrum serratum (L.) Moon. - a review on traditional uses, phytochemistry and pharmacological activities.

Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Review

Clerodendrum serratum (L.) Moon. – A review on traditional uses, phytochemistry and pharmacological activities Jagruti J. Patel a, Sanjeev R. Acharya b, Niyati S. Acharya b,n a b

Department of Pharmacognosy, Kalol Institute of Pharmacy, B/h Old Janpath Hotel, National Highway, Kalol, Gujarat, India Department of Pharmacognosy, Institute of Pharmacy, Nirma University, Sarkhej Ahmedabad Highway, Ahmedabad 382481, Gujarat, India

art ic l e i nf o

a b s t r a c t

Article history: Received 18 November 2013 Received in revised form 28 March 2014 Accepted 28 March 2014

Ethnopharmacological relevance: Clerodendrum serratum (L.) Moon. (Verbenaceae) is an important medicinal plant growing in the tropical and warm temperate regions like Africa, Southern Asia; Malaysia and distributed throughout in forests of India and Sri Lanka. It is traditionally valued and reported for treating pain, inflammation, rheumatism, respiratory disorders, fever and malarial fever in India with a long history. To provide a comprehensive overview of the traditional and ethno medicinal uses, phytochemistry and biological activities of C. serratum with clinical and toxicity data and possibly make recommendations for further research. Materials and methods: All relevant worldwide accepted databases were searched for the terms “Clerodendrum”, “Clerodendrum serratum”, “Bharangi” and “Cheruthekku” along with the other literature from Indian classical texts and pharmacopoeias. There was no specific timeline set for the search. The accessible literatures available on C. serratum were collected via electronic search using Pubmed, Scopus, Science Direct and traditional books reports on ethnopharmacology and traditional medicines. Results: C. serratum has played an important role in Indian system of medicine. In addition to the common local use in respiratory diseases, other ethnomedicinal uses include treatment of pain, inflammation, rheumatism and fever especially malarial fever. Scientific studies on extracts and formulations revealed anti-asthmatic, mast cell stabilization and anti-allergic effects of roots of C. serratum. Reported data on pharmacological activities also includes hepatoprotective, anti-oxidant, anti-inflammatory and anticancer potential of the drug. Saponins (terpenoids and steroids), flavonoids and phenolics isolated from roots have been the focus of phytochemical investigations as the biological activity has been ascribed to the saponins, which are known to possess anti-inflammatory and anticancer activity. Isolated bioactives from roots like icosahydropicenic acid and ursolic acid have been claimed to offer anti-allergic and hepatoprotective activity. Conclusions: Therapeutic potential of roots and leaves of C. serratum has been demonstrated in the conditions like asthma, allergy, fever, inflammation and liver disorders attributed to the presence of various flavonoids, phenolics and saponins present in the drug. Many ethnobotanical claims have been confirmed through modern in-vitro and in-vivo pharmacological studies of different extracts and isolates from plant; however, additional studies on the biomarkers are needed to establish mechanism of action and to validate the traditional use of this drug in clinical practices after proper safety assessment. & 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Clerodendrum serratum Bharangi Saponins Antiasthmatic agent Pharmacological activities Chemical compounds studied in this article: Oleanolic acid (PubChem CID: 10494) Queretaroic acid (PubChem CID: 23641088) Serratagenic acid (PubChem CID: 165502) Ursolic acid (PubChem CID: 64945) β-sitosterol (PubChem CID: 222284) Spinasterol (PubChem CID: 5283663) Stigmasterol (PubChem CID: 122544) Caffeic acid (PubChem CID: 689043) Catechin (PubChem CID: 9064) Ferulic acid (PubChem CID: 445858)

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Botanical description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Geographical distribution and habitat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: þ 91 9824513258; fax: þ 91 02717 241916. E-mail addresses: [email protected], [email protected] (N.S. Acharya).

http://dx.doi.org/10.1016/j.jep.2014.03.071 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Patel, J.J., et al., Clerodendrum serratum (L.) Moon. – A review on traditional uses, phytochemistry and pharmacological activities. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.03.071i

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J.J. Patel et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Traditional and ethno medicinal uses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.1. Terpenoids, sterols and iridoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4.2. Phenyl propanoids and flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5. Pharmacological investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.1. Mast cell stabilization, anti histaminic, anti allergic and anti-asthmatic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.2. Wound healing activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.3. Effects on immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.4. Hepatoprotective activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 5.5. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 5.6. Antiinfective activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 5.7. Antiinflammatory, antinociceptive, antipyretic and analgesic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 5.8. Vascular activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 5.9. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 5.10. Alpha glucosidase inhibitory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 5.11. Clinical studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 6. Toxicological information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 7. Quality control aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1. Introduction The genus Clerodendrum (Verbenaceae, more recently placed in the Lamiaceae) is a diverse genus with about 560 (Moldenke, 1971) to 580 (Munir, 1989) species of small trees, shrubs or occasionally perennial herbs, mostly in the tropics and subtropics of the old world (Verdcourt, 1992). This genus was first described by Linnacus in 1753 based on the species Clerodendrum infortunatum from India and later Adanson changed the Latinized form “Clerodendrum” to its Greek form “Clerodendron” in 1763. After almost two centuries, Moldenke readopted the Latinized word “Clerodendrum” in 1942 which is now commonly used by taxonomists for classification and description of the genus (Hsiao and Lin, 1995). However, recent phylogenetic studies have reported that genus Clerodendrum traditionally classified in Verbenaceae has now been included in the Lamiaceae and Rotheca serrata (L.) Steane & Mabb. is widely accepted scientific synonym for the species (Harley et al., 2004; Yuan et al., 2010; Stevens, 2012). Clerodendrum species display a high degree of morphological, cytological (Steane et al., 1997) and chemical variations. The genus has been found to contain terpenoids as the major secondary metabolites (Subramanian et al., 1973; Akihisa et al., 1989; Yang et al., 2000d), neo-clerodane diterpenes (Kumari et al., 2003; Pandey et al., 2005), triterpenes (Rangaswami and Sarangan, 1969; Ganapaty and Rao, 1985) and iridoids (Jacke and Rimpler, 1983; Wei et al., 2000b). Phenolic compounds have been frequently reported with phenyl propanoids (Mei et al., 2000; Kim et al., 2001) and flavonoids as a predominant class (Vendantham et al., 1977; Sinha et al., 1981) and few of species have been reported to contain macrocyclic alkaloids (Bashwira and Hootele, 1988; Lumbu and Hootele, 1993) and cyanogenic glycosides (Adsersen et al., 1988; Miller et al., 2006). Some of these compounds have been evaluated for a number of biological activities mainly antiinflammatory (Panthong et al., 2003; Park and Kim, 2007), antiasthmatic (Gupta et al., 1967; Vincent et al., 2012), hepatoprotective (Vidya et al., 2007; Gopal and Sengottuvelu, 2008), antioxidant (Rajlakshmi et al., 2003; Chae et al., 2006), cytotoxicity (Cheng et al., 2001), antitumor (Shi et al., 1993) and for the effects on central nervous system (Zhu et al., 1996). Therapeutic utilities of roots of C. serratum have been indicated in traditional systems of medicine like Ayurveda and Unani. It is commonly known as Blue glory or Beetle killer in English;

Bharangi (means glorious) in Hindi; Angaravalli, Kharashaka (with rough leaves), Padma (flowers look like lotus), Vatari (an enemy of vata dosa), Kasaghni (which alleviates cough) in Sanskrit and Cheruthekku in Tamil (Kirtikar and Basu, 1999; Ayurvedic Pharmacopoeia of India, 2001). In ancient and later ayurvedic literature, Bharangi has been widely mentioned in the treatment of Swasa and Kapha (Respiratory ailments) as a constituent of various groups of medicines. C. serratum has a long history to be used as a traditional medicine to treat asthma, inflammatory and infectious disorders. There has been a great interest in C. serratum, as evidenced by many studies carried out in recent years on roots and its formulations for antiasthmatic potential. An increasing number of phytopharmacological studies have been carried out on this plant to validate various traditional uses with scientific support and majority of the reports indicated usefulness of the roots and leaves of the plant for the treatment of respiratory disorders, fever, inflammation and liver disorders. In addition, in-vivo and in-vitro experiments indicated that C. serratum plant extracts contain a wide spectrum of pharmacological properties (Praveenkumar and Nishteswar, 2013) including antiinflammatory (Narayanan et al., 1999), antioxidant (Bhujbal et al., 2009b; Ismail and Leelavathi, 2011; Mohamed et al., 2012), anti-asthmatic (Bhujbal et al., 2009a; Thalla et al., 2012), anticancer (Zalke et al., 2010; Chinchali et al., 2011), hepatoprotective (Vidya et al., 2007) and antibacterial (Narayanan et al., 2004; Vidya et al., 2010). Initial search on this plant from Ayurvedic Pharmacopoeia of India and traditional literature indicated around 18 formulations containing C. serratum roots as one of the ingredients (ranging from 0.14%w/w to 7.69%w/w) for the treatment of various ailments. Ethnomedicinal reports have also advocated C. serratum as one of the potential traditional medicines in India claimed for the treatment of asthma, inflammation, wounds, snake bite, liver diseases, fever and headache. It has been established that triterpenes like oleanolic acid, ursolic acid and phenolics are responsible for most of the biological activities reported for the plant but detail investigation into precise mechanism with biomarker analysis is required for roots of this plant. Systematic search on C. serratum in scientific databases indicated its vast traditional significance with less numbers of comprehensive reviews till date, hence present review has been performed with a view to provide a systematic analysis of reports on chemical constituents, pharmacological effects and safety aspects of C. serratum in order to



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Fig. 1. Clerodendrum serratum (a) C. serratum plant; (b) leaf; (c) flower; (d) root

evaluate local and traditional uses of this species. This review also highlights, analyzes and critically assesses the pharmaceutical potential of roots of this undervalued plant for development as an alternative and effective remedy for the treatment of asthma.

little or no endosperm (Ayurvedic Pharmacopoeia of India, 2001; Bhangri, 2004, 2012a,, 2012b, 2012c; Clerodendrum serratum, 2010) (Fig. 1). 2.2. Geographical distribution and habitat

2. Botany 2.1. Botanical description C. serratum is a perennial woody shrub native to East India and Malaysia, up to 3–8 ft in height with blunt quadrangular stems. Mature roots are hard, woody and cylindrical in shape with 1–1.5 cm in diameter, 2–3 cm in length and are pale brown externally and yellowish brown internally. Young roots are smooth or finely longitudinally striated while the older ones are somewhat rough, longitudinally ridged or furrowed and exfoliated at places exposing the inner wood. It breaks with hard fracture and has acrid taste and characteristic odor. The bark is acrid, thin, breaks with short fracture and easily separated from a broad wood showing marked medullary rays and concentric growth rings. Leaves are compound (usually three at the node), arranged oppositely, narrowly obovate to oblong with serrate margin, glabrous surface, acute apex and stout petioles. Flowers are blue with many long cylindrical thyrsus and flowering occur in the month of August–September. They are bisexual, zygomorphic and rarely sub-actinomorphic and bracteolate. They show corolla with a slender tube, five spreading lobes, epipetalous stamens, 1 or 2-celled longitudinally dehiscing anther and persistent disc with sub-terminal, gynobasic style and superior ovary with 2-cell having 2-ovules in each. Fruits are subglobose and glabrous drupes with 5–14 mm length and 5–8 mm width and usually separating into pyrenes at maturity. The seeds are four lobed and oblong with

C. serratum is a small perennial shrub growing in moist deciduous forests and occasionally in plains of peninsular India and the Western and Eastern Himalayas up to 1400 ft above sea level (Sharma et al., 2009). It is found in lower Himalayas from Kumaun eastwards, west Bengal and Bihar and distributed throughout in forests of Sri Lanka and India. It is documented to be found in South Africa, Madagascar, South Asia and South East Asian countries also. Few genera are also found in the tropical America, Northern Australia and extending north into the temperate zone in Eastern Asia (Moldenke, 1948; Mabberley, 2008). In India, these species have been regionally considered as vulnerable in Northern India (WWF India and ZOO/CBSG India, 1997) and endangered in Chhattisgarh and Madhya Pradesh region (Ved et al., 2003).

3. Traditional and ethno medicinal uses C. serratum (Bharangi) is popularly used in indigenous systems of medicine for the treatment of respiratory disorders especially asthma in a crude combination with several other drugs like Sati (Hedychium spicatum Sm. Zingiberaceae) and Pushkarmoola (Inula racemosa Hook. f. Asteraceae) and also present in capsule or tablet form of various strengths (Sharma et al., 2002; Vaidya, 2005). This plant is documented for its usefulness in many ailments in various Ayurvedic texts like “Samhitas” and “Nighantu” by different authors.



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Susruta and Bhavamisra had described this plant particularly for respiratory complaints viz. colds, bronchitis, bronchial asthma and tuberculosis as it effectively liquefies the mucous (Nighantu, 2005; Bhavamishra, 2006). Roots and leaves of Bharangi have great medicinal value and claimed to be useful in pain, inflammation, rheumatism, respiratory disorders and fever especially in malarial fever. Ayurvedic properties of C. serratum are: Rasa (taste): Katu (pungent/acrid), Tikta (bitter), Kasaya (astringent); Guna (properties): Laghu (light), Ruksa (non-unctuous); Virya (potency): Usna (heat); Vipaka (transformation with digestion), Katu (pungent) (Ayurvedic Pharmacopoeia of India, 2001). Due to its pungent and bitter nature, Bharangi is considered to normalize the vitiated Kapha (cough) and Vata (air) doshas. Owing to its Snigdha and Madhura nature, it acts as an expectorant and useful in hiccough and hoarseness of voice. The combination of Bharangi and Pippali (2:1) with honey is an effective remedy for hiccough. Susruta had mentioned it as a panacea for epilepsy and also as stanyasodhaka (lactodepurant). Vagbhata had cited its usefulness in cough and Charaka had categorized it as purisa sangrahaniya means giving form to feces. According to Raja Nighantu, it is useful in asthma, cough, fever, worms, burning sensation and in wounds (Pandit, 2006). The plant is used as appetizer, blood purifier, digestive, laxative and also in anorexia (Nadkarni et al., 1954; Pullaiah, 2006;

Bharangi (Clerodendrum sp.) – An Amazing Plant, 2010; Bhangri, 2012a, 2012b, 2012c). Roots of C. serratum are pungent, bitter, acrid and useful as carminative, depurative, expectorant, anti-spasmodic, stimulant, appetizer and anthelmintic (Shah, 2006). Roots are reported to be used clinically for the treatment of bronchitis, asthma, fever, blood diseases, tumors, inflammations, burning sensation, epilepsy, malaria, ulcer and wounds (Vidya et al., 2007). The root juice with ginger is used to relieve bronchospasms in asthma and reduce the attacks of dyspnea while the root powder is given along with sugar or as jam in hiccough. The decoction of root is extremely effective in edema over body, especially due to kapha and used in worm infestations while decoction of sesame seeds (tila) mixed with ghee, jaggery, C. serratum root powder and trikatu powder (Ayurvedic formula with equal proportion of three drugs viz. rhizomes of Zinziber officinale Roscoe., Zingiberaceae and fruits of Piper longum Linn. and Piper nigrum L., Piperaceae) is used as the best remedy for amenorrhea and uterine tumor (Sharma et al., 2002). The root paste has been applied on the forehead to alleviate headache (Table 1). Leaves are used as a vegetable and in fever, malarial fever and hiccough in Konkan region. Externally the leaves are used for cephalgia and ophthalmia while the pulp is used to mitigate the

Table 1 Ayurvedic formulas containing C. serratum. Name of formulaa

Plant part used

Proportion (%w/w)

Indications

Traditional text reference

Agastya haritaki rasayana Amrtaprasa ghrita

Root

0.82

Hiccough, cough, asthma, malaria/intermittent fever and astringent

Root

0.3

Ayaskrti

Root

0.14

Thirst, burning sensation, fever, bleeding disorder, cough, asthma, debility due to chest injury, oligospermia (due chronic illness), weakness, aphasia, discoloration, hiccough, emesis, syncope, heart disease, disease of female genital tract, urinary diseases Anemia, diabetes, urinary tract infections, obesity, skin diseases and vitiligo

Astangahrdaya, Cikitsasthana, Adhyaya 3:125–130 1/2 Astangahrdaya, Cikitsasthana, Adhyaya 3:93–97

Bharangi guda

0.24

Bharngyadi kvatha churna Candanadi churna

Stem bark Root

9.09

Root

1.85

Dadhika ghrita

Root

1.04

Dasamularista

Root

0.25

Kanakasava

Root

0.96

Kantakaryavaleha

Root

0.61

Madhusnuhi rasayana Mahapancagavya ghrita Mahavatagajankusa rasa Mahavishgarba taila

Root

0.24

Root

0.48

Root

7.69

Root

2.44

Mahayogaraja guggulu

Root

0.43

Dhanvantara ghrita

Root

0.08

Rodhrasava

Root

0.63

Vasacandanadi taila Root

2.65

Astangahrdaya, Cikitsasthana, Adhyaya 12:28–31 1/2 Digestive impairment, cough, asthma, discoloration, hoarseness of voice Bhaisajyaratnavali, Hikkasvasadhikara:29–34 Intermittent fever and chronic fever Sahasrayoga, Kasayaprakarana:36 Cough, dyspnea/asthma, chronic fever, urinary disorders, hemorrhoids, jaundice Bhaisajyaratnavali, Sukramehadhikara:22–24 Epilepsy, toxic conditions, dysuria, ascites, malabsorption syndrome etc. Astangahrdaya, Cikitsasthana, Adhyaya 14:13–20 1/2 Dysmenorrhea, anorexia, vomiting, cough, asthma, degenerative diseases, vata disorders, Sarngadharasamhita, piles Madhyamakhanda, Adhyaya 10:78–92 Respiratory diseases, bronchitis, Chronic obstructive pulmonary disease (COPD), cough, Bhaisajyaratnavali, hiccough and cold Hikkasvasadhikara:98–102 Sarngadharasamhita, Madhyamakhanda, Adhyaya 8:5–9 Itches, scabies, visarpa, ulcerated wounds, fistula, diabetes, leprosy and other vata, pitta Sahasrayoga, Lehaprakarana:41 and rakta related diseases Neurological and psychiatric conditions, fever, liver diseases such as jaundice Bhaisajyaratnavali, Netrarogadhikara:173–180 Vatta and Kapha related disease Rasendrasarasangraha, Vatavyadhicikitsa:13–14 Vata related disease, sciatica, tetanus/plenosthotonus, stiffness and tightness in all limbs, Bhaisajyaratnavali, lack of tactile sensation Vatavyadhyadhikara:414–423 Joint diseases, skin diseases, piles, diabetes, gout, fistula, bloating, emaciation, low Sarngadharasamhita, digestion power, asthma, cold, cough, anorexia, male and female infertility Madhyamakhanda, Adhyaya 7:56–69 1/2 Edema, abscess, hemorrhoids, anemia, toxic conditions, diabetes, diabetic carbuncle, Astangahrdaya, Cikitsasthana, gout, spleen related diseases, skin and psychotic diseases Adhyaya 12:19–23 1/2 Menorrhogia, leucorrhea, skin diseases, bleeding piles, grahani (irritable bowel Astangahrdaya, Cikitsasthana, syndrome) Adhyaya 12:24–27 1/2 Bhaisajyaratnavali, Cough, dyspnea/asthma, fever, hectic fever, bleeding disorder, anemia, jaundice, tuberculosis, chronic obstructive jaundice, chest wound/injured chest/disease of lungs, Kasadhikara:185–191 weakness, emaciation, impaired digestive fire, discoloration

a Rasayana and Churna are solid powdered formulations, Asava and Arishta are liquid fermented preparations, Avleha and Guda are semisolid preparations and Ghrita and taila are oil based liquid dosage forms of Ayurveda.



glandular swellings and hasten the wound healing whereas juice of leaves is applied on the lesions in erysipelas (Rastogi and Mehrotra, 1999; Sharma et al., 2002). Many classical preparations containing roots of C. serratum in solid, semisolid and liquid Ayurvedic dosage forms are available in Indian market indicating significance of roots compared to other plant parts (Ayurvedic Formulary of India, 2000). There are reports about utilization of this plant in many tribal communities in different states of India like Andhra Pradesh, Arunachal Pradesh, Maharashtra, Tamilnadu, Karnataka and West Bengal as highlighted in Table 2. Majority of these reports indicated usefulness of the roots and leaves of the plant for the treatment of respiratory disorders, fever, inflammation of joints and gums, liver disorders, wounds, stomachache and headache. It is noteworthy that very few reports indicated medicinal applications of other plant parts like stem, bark and seeds among tribal populations which is further reassuring the reports from Ayurvedic and traditional literature of roots being the major plant part.

5

4.2. Phenyl propanoids and flavonoids Phenolics have been reportedly present in both free as well as bound to sugar moieties in the genus Clerodendrum (Harbone, 1984; Mann et al., 1994). Many phenolic compounds have been separated from roots and leaves of plant (Table 3). Phenyl propanoids such as serratumoside-A, martynoside, myricoside and acteoside have been isolated from the aerial parts of C. serratum (Yang et al., 2000a; Fan et al., 2007). Free as well as bound flavonoid aglycones are present in different forms like catechins, leucoanthocyanidins, flavanones, flavanonols, flavones, anthocyanidins, flavonols, chalcones, aurones and isoflavones (Harbone, 1984; Mann et al., 1994). They are reported to display potent antioxidant, antimicrobial, antiasthmatic, antitumor and central nervous system (CNS) binding activities (Shrivastava and Patel, 2007b). Apigenin and luteolin glucosides have been reported from stem and leaves while a very uncommon and rare, 6-hydroxy luteolin was reportedly found present in leaves. Various flavonoids isolated from C. serratum are mentioned in Table 3.

4. Phytochemistry

5. Pharmacological investigations

Many systematic efforts have been made by various researchers to isolate and identify biologically active constituents from various plant parts (Singh et al., 2012). Research reports available on chemical constituents present in the C. serratum showed saponins, phenolics, flavonoids and carbohydrates. According to the data presented in Table 3, saponins of C. serratum contain significant amount of triterpenoids and sterols. To date, a number of reports have focused on quantification of C. serratum with respect to the content of oleanolic acid while many other reports suggested β-sitosterol as one of the chief quantifiable compound. These metabolites and their purported biological effects have been thoroughly and comprehensively covered in number of reports (Gupta et al., 1971; Gupta and Tripathi, 1973; Fuchs and Milbradt, 1993; Vidya et al., 2007). The compounds isolated from C. serratum are documented and listed in Table 3 and their structures are displayed in Fig. 2.

Most notably, roots were investigated more intensively for a range of pharmacological activities. Table 4 summarizes reported biological activities with details on study models, duration and dose range with active dose.

4.1. Terpenoids, sterols and iridoids Terpenoids have been associated with various pharmacological activities like anti-viral, anti-bacterial, anti-malarial, anti-inflammatory, inhibition of cholesterol synthesis and anti-cancer activities. Oleanolic acid, well reported for anti-inflammatory, anti-hyperlipidemic and anti-tumor effects, has been reported as the principal constituent of the triterpenoid portion of the drug (Mann et al., 1994; Liu, 1995). Oleanolic acid, queretaroic acid and serratagenic acid were reported from bark while ursolic acid was reported from stem and root of the plant. Many terpenoids isolated and identified from different parts of C. serratum are listed in Table 3. Sterols are found to be present in most of the aerial parts of this plant in free as well as in glycosidic form, β-sitosterol being the chief constituents present in stem while ɣ-sitosterol was reportedly found in roots. Many other sterols isolated from plants are listed in Table 3 (Shrivastava and Patel, 2007a). Two iridoid glucosides, serratoside A and serratoside B, were reported from the aerial parts of Clerodendrum serratum var. amplexifolium. Further 7-β-coumaroyl-oxyugandoside and 7-βcinnamoyl-oxyugandoside were also isolated from leaves of the plant (Wei et al., 2000a).

5.1. Mast cell stabilization, anti histaminic, anti allergic and antiasthmatic activity Sachdev and group was the first group of scientists who experimentally studied the anti histaminic potential of C. serratum (Sachdev et al., 1964). A crystalline polyhydric alcoholic fraction of C. serratum root was found to cause a delayed secondary fall in blood pressure accompanied with bronchoconstriction which was inhibited with the antihistaminic drugs. The drug was found to block histamine-induced contractions of trachea preparations from guinea pig without affecting the response to acetylcholine. The anaphylactic bronchoconstrictor response in isolated guinea pig lung sensitized with compound 48/80 was found to be inhibited after continuous perfusion of fraction of C. serratum. Continuous daily administration of root extract was found to sensitize guinea pig and gradually induce protection against anaphylaxis (Gupta et al., 1967; Gupta and Gupta, 1967). Several scientists have highlighted antiallergic and antiasthmatic potential of C. serratum (Gupta, 1968; Gupta, 1971; Gupta and Tripathi, 1973; Hazekamp and Verpoorte, 2001) in the bronchial hyper-reactivity study on aqueous extract of root and stem at high (180 mg/kg) and low (90 mg/kg) doses using milk induced leucocytosis in mice and egg albumin induced asthma in guinea pigs. These studies signified the use of C. serratum roots (180 mg/kg) for antiallergic and antiinflammatory diseases like asthma (Bhangare and Ghongane, 2011; Bhangare et al., 2012). Alcoholic extract (100 and 200 mg/kg) of C. serratum roots showed potent antiasthmatic activity in ovalbumin induced experimental mice model probably acting through inhibition of inflammatory mediators like serotonin, histamine and prostaglandin due to (cyclooxygenase) COX inhibition (Thalla et al., 2012). Other investigators have also confirmed the antiasthmatic potential of C. serratum roots through several in-vivo and in-vitro screening models in guinea pig and mice (Bhujbal et al., 2009b, 2010c). Saponins isolated from roots are found to disrupt rat peritoneal mast cells and block the effect of horse serum antigen in a dose related manner (Gupta et al., 1971; Gupta and Tripathi, 1973). The



6

Table 2 Ethnomedicinal uses of C. serratum by the tribal communities in India for different diseases. Sr. Plant no. part

District/state

Local names

Ethnomedicinal uses

Method of preparation

Route of References administration

Bhilala tribals of Buldhana district, Maharashtra West Dinajpur tribals of Bengal, Purulia district tribals of West Bengal, Visakhapatnam district tribals and Western part of Andhra Pradesh Bhilala tribals of Buldhana district, Maharashtra

–

As blood purifier

Decoction

Oral

Gar khumbi

As febrifuge and in fever (in children also)

Oral (once a Powder or decoction or day for 3 days) aqueous root extract (20 g in 30 ml water) mixed with a pinch of black pepper (Piper nigrum) powder

Padal et al. (2010), Rao, et al. (2011), Dey and De (2012), Mitra and Mukherje (2013), Kalita and Khan (2013)

Bharungi, Samarkand

Decoction

Korpenwar (2012b), Sahu et al. (2013b)

4.

Boudh district of Odisha

Samarkand, Saramlatur

Used in malarial fever, nervous disorder and ophthalmic complaints Snake bite

5.

Ahmednagar district of Maharashtra

Bharangi

Applied for headache

6.

Visakhapatnam district tribals and Western part of Andhra Pradesh Khammam district of Andhra Pradesh

Barangi

Piles

Bommalamarri

Rheumatism

West Bengal Koria district of Chhattisgarh, Washim district of Maharashtra, West Godavari district of Andhra Pradesh

– As aphrodisiac Bharangi, Gunta Used for respiratory Barangi disorders, dyspepsia and asthma

10.

Raigarh area of Chhatisgarh

Guma

Liver problems

11.

Nilgiris area of Tamilnadu

–

Stomach ache caused by flatulence Administered to babies for stomachache

Visakhapatnam district of Andhra Pradesh Nasik district of Maharashtra

Porja Kothuru

To cure scabies

Dhaiti Sirtekku

Rubbed on gums for better teething in children Stimulant

Decoction

Oral

-

Pain

Powder

Oral

Peruku

Applied over the dog bite wound Stimulant

Powder

Externally

Decoction

Oral

1. Roots 2.

3.

7.

8. 9.

12.

13. 14. 15. 16. Bark 17. 18. Leaves 19.

20. 21.

Kalrayan and Kollihill area of Tamil Nadu Visakhapatnam district of Andhra Pradesh Wayanad district of Kerala state Kalrayan and Kollihill area of Tamil Nadu Manipur

North Cachar hills district of Assam Boudh district of Odisha

Sirtekku

Moirangkhanam For diabetes

Khr-khtung Samarkand –

22.

Applied to cure fever, as a febrifuge and in hiccough As a vegetable in malarial fever and nervous disorders Used in cephalagia and ophthalmia Used in jaundice

Oral

Root piece kept in a small brass container

Tied on the left Sahu et al. (2013a) arm of woman and right arm of the man Punjaji (2012) Externally Paste prepared in a cup of coconut (Cocosnucifera) oil (once a day up mixed with 1–2 tablespoon to 9–12 days) of neem (Azadirachta indica) leaves powder Powder Oral Padal, et al. (2010), Rao, et al. (2011), Kalita and Khan (2013) Paste (3 g) Oral (with one Manjula et al. (2013) glass of water twice a day for 5–7 days) – – Oudhia (2013) Powder or decoction (25 ml, Oral Anonymous (1992), twice a day) Savithramma et al. (2007), Patil et al. (2012), Kumar et al. (2012), Sinha and Sinha (2013) Decoction (half teaspoon) Oral (for three Jain and Singh (2010) days) Paste prepared with garlic Oral Hosagoudar and Henry in water (1996) Extract (2 spoonful) Oral (thrice a day for three days) Pills prepared for powder Oral Padal et al. (2013a, 2013b) Pieces – Patil (2001) Natarajan et al. (2012, 2013) Padal et al. (2010) Devi Prasad and Shyma (2013) Natarajan et al. (2012, 2013) Paochunbou (2012)

Oral (daily) Decoction prepared from fresh or dried leaves mixed with honey Paste prepared with water Externally

Sajem and Gosai (2006)

Fresh whole leaves

Orally

Sahu et al. (2013b)

Paste

Externally

Anonymous (1992)

Decoction of 4–5 leaves

Oral (twice a day)

Shankar et al. (2012), Shankar and Rawat (2013) Goswami et al. (2009), Shankar et al. (2012), Yonggam (2012), Shankar and Rawat (2013) Padal et al. (2010, 2013a, 2013b), Padal and Butchi (2013), Limcy and Sripathi (2013)

23.

Aizawl and Mamit districts of Mizoram

Phuihnamshak

24.

Aizawl and Mamit districts of Mizoram, East siang district and Tagin tribe of Arunachal Pradesh Rayagadda district of Odisha, Visakhapatnam district of Andhra Pradesh, Attappady and Vakkodan hill regions of Kerala

Pakkomleyo, Tapin

To reduce blood pressure

Fresh or steamed leaves or decoction

Oral

Seethachettu, Cheruthekku, Angaravallari

Applied on the forehead to treat headache

Juice mixed with equal quantities of gingelly oil and butter or paste

Externally

25.

Korpenwar (2012b)



7

Table 2 (continued ) Sr. Plant no. part

District/state

Local names

Ethnomedicinal uses

Method of preparation

26.

Nilgiris region of Tamilnadu, Buldhana district of Maharashtra, Konkan region

Bharungi, Bharangi

Applied on cuts, itching, rashes lesions in erysipelas and wounds to mitigate the glandular swellings and hasten the wound healing

Externally Paste (prepared with calcium powder) or juice or pulp

27.

Coastal Karnataka

Baarengi

Used for herpes

–

–

28. Stem 29. Seeds 30. Shoots and flowers 31. Herb 32.

China and Thailand Lob yung – – Poba reserved forest region of Otioyi’ng Assam

Cancer Dropsy For stomach disorder and diarrhea

Tea – Oral

Nagas region of India

Astringent Applied to kill parasites and remove dandruff Used for irregular menstruation Cough, asthma, bronchitis, hiccough, chronic skin diseases, headache and fevers Spermicidal

Decoction – Tender shoots and flowers (cooked with pork and taken as curry) Paste Juice extract

Oral External

Decoction

Oral

Powder

Oral

Kumari et al. (2012)

–

–

Pokharkar et al. (2010), Pradhan et al. (2012)

Atsuksuba

33. 34.

Himalayan region of India

–

35. Whole plant except root

Western Ghat area of Maharashtra

–

Route of References administration Hosagoudar and Henry (1996), Rastogi and Mehrotra (1999), Sharma et al. (2002), Korpenwar (2012b), Korpenwar (2012a) Bhandary and Chandrashekhar (2011) Inta et al. (2008) Anonymous (1992) Pegu et al. (2013)

Changkija (1999)

Table 3 Chemical constituents isolated from various parts of C. serratum. Class

Chemical constituents

Origins

Reference

Terpenoids

Oleanolic acid (1), Queretaroic acid (2) and Serratagenic acid (3)

Bark

Ursolic acid (4) Icosahydropicenic acid (5) Bauer-9-en-3-one (6) Se-saponin A (7) Serratin (8), Lupeol (9) β-sitosterol ɣ-sitosterol Spinasterol (10), Spinasteryl-β-D-glucopyranoside (11) α-spinasterol (12) Stigmasterol (13), Bis(2-ethylhexyl) phthalate (14) and Serratumin A (15) 7-β-coumaroyl-oxyugandoside (16) and 7-β-cinnamoyl-oxyugandoside (17) Serratoside A (18) and Serratoside B (19) ( þ )-catechin (20), Caffeic acid (21) and Ferulic acid (22) Serratumoside-A (23) and Myricoside (24) Acteoside (25) and Martynoside (26)

Root and stem Root Twigs and stems Aerial parts Leaves Stem Root Twigs and stems Leaves Aerial parts Leaves Aerial parts Leaves Aerial parts Aerial parts and Leaves

Apigenin-7-glucoside (27) Luteoline 7–0-β-D-glucuronide (28), Luteolin (29), Scutellarein (30), Apigenin (31), 6-hydroxy luteolin (32) (An uncommon 6-oxygenated flavones) and Baicalein (33) 5-hydroxy-7,4-dimethoxy flavones (34) 40 ,5,7-trihydroxy-flavone (35) Glucose and D-mannitol Sucrose (disaccharide)

Root Leaves

Banerjee et al. (1969), Rangaswami and Sarangan (1969), Fan et al. (2007) Ganapty et al. (1997), Vidya et al. (2007) Bhujbal et al. (2010b) Boonsri (2003) Yang et al. (2000b) Raju et al. (2008) Ganapty et al. (1997) Banerjee et al. (1969) Boonsri (2003) Nair et al. (1976) Fan et al. (2007) Wei et al. (2000a) Yang et al. (2000c) Nair et al. (1976) Yang et al. (2000a) Yang et al. (2000a), Fan et al. (2007), Wei et al. (2000a) Bhujbal et al. (2010d) Nair et al. (1976)

Stem Aerial parts Root Twigs and stems

Ganapty et al. (1997) Fan et al. (2007) Garg and Verma (1966) Boonsri (2003)

Sterols

Iridoids Phenyl propanoids

Flavonoids

Carbohydrate

protective effect of C. serratum saponins was found to be associated with the augmentation of antiallergic activity in the lung tissues of treated animals through inhibition of histamine and slow reacting substance of anaphylaxis (SRS-A) responses on guinea pig ileum to a greater extent and for longer period as compared to the untreated control animals (Gupta, 1968, 1994; Gupta et al., 1968). The study proved bronchodilatory effect of roots and validated its traditional use in asthma which was further

supported by the reports on anti-asthmatic effects of saponins isolated from C. serratum by offering protection to sensitized guinea pigs against micro-aerosol of histamine as well as egg albumin (antigen). In another study reported by Bhujbal et al. (2010a) potent antihistaminic and antiallergic properties of icosahydropicenic acid (IHPA), isolated from the ethanolic extract of the roots of C. serratum was reported in isolated goat tracheal chain


8


Fig. 2. Selected compounds isolated from C. serratum.



Fig. 2. (continued)


9


10

Table 4 Summary of pharmacological studies of C. serratum. Pharmacological activity

Tested substance Study model (type of study, duration of study, standard control)

Dose range (route of administration)

Anti-allergic activity

Aqueous extract of roots and stems

Milk induced leukocytosis in mice (in vivo, 14 days, Dexamethasone (0.5 mg/kg)) Bronchial hyper reactivity (egg albumin aerosol induced bronchospasm (anaphylactic micro shock) in guinea pigs) (in vivo, 21 days, dexamethasone (0.31 mg/kg)) Alcoholic extract Ovalbumin induced experimental mice model (24 days, of roots ovalbumin (in vivo, 50 μl of 1.5%)) Ethanolic extract Isolated goat tracheal chain preparation (in vitro, 1 h, of roots histamine (50 μg/ml)) Clonidine induced catalepsy in mice (in vivo, 3 h, chlorpheniramine maleate (10 mg/kg)) Milk induced leucocytosis and eosinophilia studies in mice (in vivo, 24 h, milk (4 ml/kg)) Guinea pigs model (in vivo)

Low dose (90 mg/kg) and 180 mg/kg high dose (180 mg/kg) of 90 mg/kg of roots roots and stems (i.p.) and 180 mg/kg of stem 100 and 200 mg/kg (i.p.) 100 and 200 mg/kg

Anti-asthmatic activity

Wound healing activity

Ethanolic extract Excision and incision model (in vivo, 14 days) of leaves and Dead space wound models (in vivo, 10 days) roots

Immunomodulatory activity

Aqueous extract of roots

Reported dose

Reference

Bhangare and Ghongane (2011); Bhangare et al. (2012)

Thalla et al. (2012) 80 μg/ml 80 μg/ml Bhujbal et al. (2009b) 50, 100, 200 mg/kg (i.p.) 50, 100, 200 mg/kg Bhujbal et al. (2009b)

50, 100, 200 mg/kg

50, 100, 200 mg/kg Bhujbal et al. (2010c) 5% w/w ointment gel, 5% w/w ointment Vidya et al. Topical gel (2005b) 20 mg/kg ointment gel, 20 mg/kg Oral ointment gel 100 and 200 mg/kg, p.o. 100 and 200 mg/kg Juvekar et al. (2006)

Phagocytic and proliferation assays in mice peritoneal macrophages (in vitro, 14 days, cyclophosphamide) Humoral antibody titer and delayed type hypersensitivity (DTH) reactions in mice (in vivo, 14 days, ovalbumin) Hepatoprotective Alcoholic extract Carbon tetrachloride (CCl4) induced hepatotoxicity in rats 10 & 20 mg/kg, p.o. activity of roots (in vivo, 14 days, silymarin (100 mg/kg/day)) Rifampicin induced hepatotoxicity in rats (in vivo, 200 mg/kg, p.o. Alcoholic and aqueous extracts 10 days, silymarin (25 mg/kg)) of leaves Anti-oxidant activity Petroleum ether Free radical scavenging activity using DPPH (in vitro, 1 h, 0.1 mg/ml/d Ascorbic acid, butylated hydroxytoluene and quercetin) and chloroform 0.5 mg /ml/d extracts of leaves Trolox equivalent antioxidant capacity using ABTS (in vitro, 16 h, Ascorbic acid, butylated hydroxytoluene and quercetin) Free radical scavenging activity using DPPH (in vitro, 1 h, 0.1 mg/ml/d Methanolic and water extracts of Ascorbic acid, butylated hydroxytoluene and quercetin) 0.5 mg/ml/d leaves Trolox equivalent antioxidant capacity using ABTS (in vitro, 16 h, ascorbic acid, butylated hydroxytoluene and quercetin) 7.812, 15.625, 31.25, 62.5, Ethanolic extract Free radical scavenging activity using DPPH (1 h) and nitric oxide assay (3 h), (in vitro, ascorbic acid and rutin) 125, 250, 500 and of aerial parts 1000 mg/ml and roots Ethanolic extract Free radical scavenging activity using DPPH assay 50–250 mg/ml of roots (in vitro, 1 h, ascorbic acid) Water extract of Free radical scavenging activity using FRAP assay and 20–120 mg/ml roots hydrogen peroxide assay (in vitro, 1 h, ascorbic acid) 200 to 1000 μg/ml Methanolic Free radical scavenging activity using DPPH, reducing extract of leaves power and total antioxidant activity assay (in vitro, 1 h, ascorbic acid) Anti-bacterial activity Defatted ethanol Disc diffusion method (in vitro, 24 h, streptomycin 2.5, 5 & 7.5 mg/disc extract of roots (10 μg/disc)) Ethanolic extract Serial dilution method (in vitro, 3 days, ampicillin and 500 mg/ml of roots tetracycline) 20,40 and 80 mg/ml Anti-viral activity Alcoholic extract Direct inoculation method (in vitro, 5 days) of plant excluding root part Anti-inflammatory Aqueous extract Rats granuloma pouch method (in vivo, 10 days, Low dose (90 mg/kg) and activity of roots dexamethasone (0.36 mg/kg)) high dose (180 mg/kg), i.p. 50, 100 and 200 mg/kg, Alcoholic extract Carrageenan induced hind paws edema (4 h) and cotton p.o. of roots pellet granuloma models (8 h) in rats (in vivo, phenylbutazone (100 mg/kg)) Analgesic activity Ethanolic extract Tail flick test (in vivo, 7 days, diclofenac sodium 250 and 500 mg/kg of leaves (3 mg/kg)) Ethanolic extract Acetic acid induced writhing test (in vivo, 30 min, 250 and 500 mg/kg of leaves Diclofenac sodium (3 mg/kg)) Anti-nociceptive Alcoholic extract Hot plate method (in vitro, 3 h, morphine sulfate 50, 100 and 200 mg/kg, activity of roots (5 mg/kg)) Oral Acetic acid induced writhing (in vivo, 15 min, morphine sulfate (5 mg/kg)) Anti-pyretic activity Alcoholic extract Rabbits (by measuring reduction in pyrexia) 50, 100 and 200 mg/kg, of roots (in vivo, 3 h, paracetamol (100 mg/kg)) Oral

20 mg/kg

Vidya et al. (2007)

200 mg/kg

Agrawal et al. (2013)

Not effective

Mohamed et al. (2012)

Not effective

0.1 mg/ml/d 0.5 mg/ml/d

7.812, 15.625, 31.25, Ismail and 62.5, 125, 250, 500 Leelavathi (2011) and 1000 mg/ml 150 mg/ml Bhujbal et al. (2009b) 60 mg/ml Bhujbal et al. (2009b) 200 to 1000 μg/ml Prasad et al. (2012) 7.5 mg/disc

Vidya et al. (2010)

500 mg/ml

Narayanan et al. (2004) Aswal et al. (1996)

Not effective

180 mg/kg

Bhangare et al. (2012)

100 and 200 mg/kg Narayanan et al. (1999) 500 mg/kg

Saha et al. (2012)

500 mg/kg

Saha et al. (2012)

100 and 200 mg/kg Narayanan et al. (1999) 200 mg/kg 100 and 200 mg/kg Narayanan et al. (1999)



11

Table 4 (continued ) Pharmacological activity

Tested substance Study model (type of study, duration of study, standard control)

Dose range (route of administration)

Reported dose

Reference

Vascular activities

Petroleum ether extract of leaves Chloroform extract of leaves Water extract of leaves Methanolic extract of leaves Methanolic extract of leaves Aqueous extract of roots Methanolic extract of roots Methanolic extract of leaves

0.12, 0.25, 0.5 and 1.0 mg/ml

Not effective

Mohamed et al. (2012)

Anti-cancer activity

Alpha-glucosidase inhibitory activity

Methanolic extract of leaves Aqueous extract of leaves Methanolic extract of root

Anti-angiogenic effect using rat aortic model (in vitro, 5 days, suramin)

0.5 and 1.0 mg/ ml 1.0 mg/ml

Vasorelaxant effect using rat aortic ring assay (in vitro, 1 h, verapamil (1.0 and 2.0 μM)) Dalton's ascetic lymphoma cell model in mice (in vivo, 14 days, cyclophosphamide (25 mg/kg/day))

0.12, 0.25, 0.5 and 1.0 mg/ml 400, 200, 100, 50, 25 and 27.93 μg/ml 12.5 μg/ml 100 and 200 mg/kg/day, Not effective i.p. 200 mg/kg

DMBA induced skin carcinogenicity in liver and kidney of 300, 600 and 900 mg/kg, 900 mg/kg mice (in vivo, 45 days, 7, 12- dimethylbenz[a]anthracene Oral (DMBA) (25 μl)) Dalton's ascetic lymphoma cell in mice 300 mg/kg, Oral Not effective (in vivo, 14 days, 5-fluorouracil (200 mg/kg)) 300 mg/kg Kinetic end point assay (enzyme assay) (in vitro, 1 h, voglibose)

preparation and clonidine induced mast cell degranulation (at a dose of 100 mg/kg, p.o.) in rats. These effects might be observed due to stabilization of mast cell membrane or inhibition of antigen-induced histamine release (Bhujbal et al., 2010a) by the compound. A composition containing ethanolic extract of C. serratum roots was found to produce significant reduction in the mortality of rats subjected to triple antigen-induced anaphylactic shock and also found to represent marked protection of rat mesenteric mast cells from disruption by compound 48/80 in dose dependent manner when investigated for mast cell stabilizing and antianaphylactic property in rats (Gohil and Mehta, 2011). An oral aerosol spray of polyherbal formulation containing ethanolic extracts of Adhatoda vasica leaf, C. serratum root, Curcuma longa rhizome, Solanum xanthocarpum fruit and Piper longum fruit demonstrated significant anti-inflammatory and bronchodilatory activity as compared to polyherbal extract when investigated against allergen-induced bronchospasm using guinea pigs and carrageenan induced paw edema model in rats and acetic acid induced vascular permeability model in mice (Mehta et al., 2011). A composition containing C. serratum (ROUTACK) was found to offer significant protective effects against anaphylaxis (Gandhi and Balaraman, 2011) and a hydro-alcoholic extract of a polyherbal composition containing C. serratum roots has claimed antiasthmatic property in a dose dependent prophylaxis manner in comparison with salbutamol. These compositions were found to relax bronchial muscles and to reduce inflammation probably acting through free radical scavenging, expectorant and antihistaminic mechanisms which was further supported by lung tissue histology studies (Tulsiani, 2012). Antiasthmatic evaluation of hydro alcoholic extract of an Ayurvedic Bharangyadi preparation (C. serratum root, Hedychium spicatum rhizome and Inula racemosa root in equal proportions) showed potent histamine antagonism property (50 mg/kg) with significant mast cell stabilizing (500 and 1000 μg/ml) and spasmolytic activity (200 mg/kg and 500 mg/kg) in various in-vitro and in-vivo experimental models (Kajaria et al., 2012c). C. serratum roots in combination with other herbal drugs have been included in some recent patent applications for treatment of chronic respiratory disorders like cough, cold, allergic asthma, seasonal allergic rhinitis, pharyngitis, laryngitis and inflammation

100 mg/ml

Not effective

Zalke et al. (2010)

Chinchali et al. (2011, 2012) Nagdeva et al. (2012)

Bachhawat et al. (2011)

(Doshi et al., 2003, 2006). However, in depth investigations on bioactivity guided fractionation and marker identification from roots, are need of time to explore the ethnomedicinal uses of the drug and to elucidate exact mechanism for mast cell stabilization and anti-asthmatic effects of roots. 5.2. Wound healing activity In a comparative wound healing study in excision, incision and dead space wound models in albino rats, ethanolic extract of roots and leaves showed protective effects when assessed by rate of wound contraction, period of epithelialization, skin breaking strength, granulation tissue dry weight, tensile strength of granulation tissue and histopathology (Vidya et al., 2005b). Wound healing potential of roots could be attributed to a wide antibacterial spectrum of root extractives; however elucidation of protective mechanisms and responsible bioactives for the wound healing activity will require more detailed investigation on the root extracts. 5.3. Effects on immune system The aqueous extract of C. serratum roots (100 and 200 mg/kg, p.o.) showed an improvement of innate immunity attributed to the ability to stimulate both adaptive and innate immune response either through stimulation of macrophages or through stimulated release of factors involved in proliferation of bone marrow cells in mice. An increased acid phosphatase and myeloperoxidase activity as well as significant increase in the production of nitric oxide (NO), hydrogen peroxide (H2O2) and oxygen (O2) was observed in macrophages treated with the extract (Juvekar et al., 2006). These findings are further reinforced by reports on immunomodulatory activity of ethanolic extract of Bharangyadi preparation (500 mg/kg body weight orally) with pronounced immune-protective activity against cyclophosphamide induced immunosuppression model in albino mice (Kajaria et al., 2013b). Immunostimulant property of a polyherbal formulation RV08, was also reported through specific immunological responses, serum antibody titer and footpad thickness tests. The effect of RV08 on humoral response and cell mediated response showed significant increase in the peritoneal


12


macrophage count and rise in blood lymphocyte and spleen lymphocyte count in experimental animals which strongly suggested conceivable involvement of RV08 composition as first line of defense through immunomodulation of lymphoid cells (Babu et al., 2001). 5.4. Hepatoprotective activity Administration of an alcoholic extract of C. serratum roots (20 mg/kg) for two weeks has significantly reduced the level of serum bilirubin and liver function marker enzymes in carbon tetrachloride (CCl4) induced wistar rats indicating its potential as a hepatoprotective agent possibly due to the radical scavenging activity of the flavonoids present in the drug (Vidya et al., 2007). The alcoholic (200 mg/kg. p.o.) and aqueous extract (200 mg/kg. p.o.) of leaves of C. serratum were also found to possess significant hepatoprotective effects when assessed in rifampicin induced hepatotoxicity by analyzing SGOT, SGPT, ALP, total bilirubin, direct bilirubin, GGTP increase in the total proteins levels in the groups treated with extracts. Both the extracts restored the normal level of aspartate transaminase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) with significant reduction in liver weight indicating the stabilization of plasma membrane as well as repair of hepatic tissue due to damage caused by rifampicin (Agrawal et al., 2013). Reports on the biomarker ursolic acid, isolated from alcoholic root extract suggested restorative effects on the levels of AST, ALT and ALP towards respective normal value, to stabilize the plasma membranes as well as to repair hepatic tissue damage caused by CCl4. Ursolic acid was found to normalize the disturbed antioxidant status by maintaining the levels of glutathione and by inhibiting the production of malondialdehyde or may be due to the inhibition of toxicant activation and the enhancement of body defense system. The hydroalcoholic extract of the polyherbal composition containing C. serratum root bark showed significant protection against acetaminophen-induced hepatotoxicity in rats probably due to a free radical scavenging activity as assessed by DPPH free radical scavenging activity (Tulsiani et al., 2009). These findings provided scientific evidence to the ethnomedicinal reports of C. serratum in treating acute jaundice; however investigations are still required to fully explicate the exact mechanisms behind the protection (Vidya et al., 2007). 5.5. Antioxidant activity Bhujbal et al. (2009b) have demonstrated in-vitro antioxidant effects of ethanolic root extract (50–250 mg/ml) at various concentrations in the DPPH (1,1-diphenyl-2-picryl-hydrazyl) radical scavenging assay (IC50 value 175 mg/ml); FRAP (ferric reducing antioxidant power) assay and hydrogen peroxide radical scavenging assay (IC50 85 mg/ml) and suggested the role of polyphenols and flavonoids for the observed antioxidant effects in the extract (Bhujbal et al., 2009b). The antioxidant potential of methanolic extract of leaves was found more potent (EC50 value 0.51 μg/ml) due to higher polyphenolic content than other extracts (petroleum ether, chloroform and water) when evaluated in trolox equivalent antioxidant capacity (TEAC) in DPPH and 2,20 -azinobis-(3-ethylbenzothiazoneline-6-sulfonic acid) diammonium salt (ABTS) assays (Mohamed et al., 2012). Antioxidant potential of methanolic extract (200–1000 μg/ml) of leaves was further supported by additional reports on DPPH assay, reducing power assay and total antioxidant activity assay (Prasad et al., 2012). The antioxidant potential of aerial parts and roots of C. serratum has been further explored in ameliorating rheumatism, using DPPH and nitric oxide assay. The ethanolic extract of aerial parts showed good antioxidant properties against DPPH (IC50 values

13.0770.34 μg/ml) and nitric oxide radical assay (IC50 values 142.30 73.06 μg/ml) whereas extract of roots showed satisfactory antioxidant properties against DPPH with IC50 value of 25.8070.89 μg/ml when compared to other extracts under test (Ismail and Leelavathi, 2011). The potential antioxidant effects of the drug can be extrapolated if antioxidant constituents from the plant can be isolated and characterized for prevention of diseases like rheumatism, cancer and many more involving oxidative damage as one of the underlying factors. 5.6. Antiinfective activity Defatted ethanol extract of C. serratum roots showed an obvious dose dependent antimicrobial activity against gram positive bacteria (Bacillus cereus, Bacillus subtilis, Staphylococcus aureus and Pseudomonas aeruginosa) and gram negative bacteria (Enterobacter aerogenes, Escherichia coli, Proteus vulgaris and Alcaligenes faecalis) when evaluated by disc diffusion method. The results showed remarkable anti-bacterial activity of extract against Enterobacter aerogenes, Pseudomonas aeruginosa and Bacillus subtilis while it was found less active against Escherichia coli when compared to reference standard streptomycin (Vidya et al., 2010) may be due to synergistic or individual effect of the flavonoids, saponins, sterols and triterpenoids present in the drug. This study validates the ethnomedical use of this plant by the tribal group of Western Ghats of India for wound healing. Similarly, hydroalcoholic extract of Bharangyadi composition have also demonstrated antibacterial and antifungal activities in support with the earlier findings (Kajaria et al., 2012a). The alcoholic extract of C. serratum plant has not showed significant inhibition of viral cytopathic effect or reduction in number of plaques against Semliki forest virus, Encephalomyocarditis virus and Japanese B Encephalitis virus (Aswal et al., 1996). 5.7. Antiinflammatory, antinociceptive, antipyretic and analgesic activity Many studies have provided data on antiinflammatory effects of C. serratum extracts of aerial parts, roots and stems. An aqueous extract of roots reported significant anti-inflammatory effects at high dose (180 mg/kg, p.o.) in granuloma pouch model in rats. Roots in low dose (90 mg/kg, p.o.) and stems in high dose (180 mg/ kg, p.o.) showed significant preventive effects in comparison with dexamethasone (a standard antiinflammatory agent). Thus, it can be postulated that roots are more effective than stems and it would be useful as antiallergic and antiinflammatory drug for disease like asthma (Bhangare and Ghongane, 2011; Bhangare et al., 2012). Methanolic extract of the aerial parts of C. serratum demonstrated dual inhibitory effect on arachidonic acid metabolism or an inhibitor of phospholipase A2 when studied in ethyl phenylpropiolate-induced ear edema and in carrageenan and arachidonic acid induced hind paw edema in rats. The extract exerted an inhibitory activity on the acute phase of inflammation due to an inhibition of synthesis and/or release of inflammatory mediators through cyclooxygenase and lipoxygenase pathways (Phacharoen, 2007), whereas an alcoholic root extract of C. serratum showed a potent antiinflammatory effect by reducing paw edema (acute) and cotton-pellet granuloma (chronic) in inflammation models (Narayanan et al., 1999). Apigenin-7glucoside isolated from C. serratum roots has been demonstrated for anti-inflammatory effects in rats (Fuchs and Milbradt, 1993). The hydro-alcoholic extract (50, 200 and 500 mg/kg dose) of Bharangyadi preparation showed inhibition of carrageenan induced inflammation due to the inhibition of the enzyme cyclooxygenase and subsequent inhibition of prostaglandin synthesis which rationalizes traditional use of this plant in bronchial



asthma and related inflammatory conditions (Kajaria et al., 2012b). This antiinflammatory effect of C. serratum might be observed due to flavonoids and saponins, but other active substances might also be responsible leading to synergistic effects. Narayanan et al. (1999) studied antinociceptive effects of an alcoholic extract of C. serratum roots (50, 100 and 200 mg/kg) in acetic acid induced writhing (200 mg/kg) and hot plate method (100 and 200 mg/kg) (Narayanan et al., 1999). A reduction in the number of abdominal constrictions in acetic acid induced writhing in mice indicated the antinociceptive effect of C. serratum which has further been supported by the findings of hot plate method where a significant increase in area under curve was observed. However, the response was much less when compared to morphine and exact mechanism remains to be investigated in detail. The authors have also indicated significant antipyretic activity of alcoholic extract (100 and 200 mg/kg) of C. serratum roots in rabbit model through a dose dependent reduction in pyrexia after administration of C. serratum (Narayanan et al., 1999). The combination of antinociceptive, antiinflammatory and antipyretic effects of C. serratum indicated a prospect of intervention with prostaglandin synthesis, as prostaglandins have been established as a common mediator in all these responses. However, this possibility remains to be investigated thoroughly. The ethanolic extract of C. serratum leaves has been found to produce considerable centrally acting analgesic activity in tail flick test at 250 mg/kg dose and peripherally acting analgesic activity in acetic acid induced writhing test at 500 mg/kg dose which was found comparable with diclofenac sodium. Blockade of capillary permeability or release of endogenous substances like prostaglandins might be a postulated mechanism (Saha et al., 2012). In another study, the author has established a potent analgesic effect of methanolic extract of the aerial parts of C. serratum when injected subcutaneously into the right dorsal hind paw of the mice via an inhibition of peripherally and centrally mediated nociception in early as well as in late phase (Phacharoen, 2007). Advanced studies can be undertaken in the direction of purification of the chemical constituents of the leaves and investigation of the biochemical pathways for the development of a potent analgesic agent with a low toxicity and better therapeutic index. 5.8. Vascular activity Antiangiogenic and vasorelaxant evaluation of methanolic extract of C. serratum leaves exhibited protective effects in rat aortic ring assay (Mohamed et al., 2012). The investigators have demonstrated role of nitric oxide (NO) signaling pathway in endothelium dependent relaxation effect attributed to polyphenolics rich composition. Therefore, antioxidants and antiinflammatory agents that may enhance either NO activity or reduce tissue angiotensin-II, might be considered as a therapeutic approach for cardiovascular disease. This study also pointed out the inhibitory effects of selective and/or nonselective cycloxygenase-2 inhibitors (COX-2), lipoxygenases inhibitors and cytochrome P450 epoxygenases inhibitors during the blood vessels formation and proangiogenic factors secretion. In contrast to the earlier report, another study highlighted the vasoconstrictive effect of methanolic extract of the aerial part of C. serratum on the isolated human umbilical vein (Phacharoen, 2007). 5.9. Anticancer activity Administration of methanolic extract of C. serratum leaves has significantly reduced tumor development in 7,12-dimethylbenz[α] anthracene (DMBA) induced skin carcinogenicity in testis, liver and kidney of mice (Chinchali et al., 2011, 2012). Rapid recovery was observed in the treated mice due to anti lipidperoxidative and antioxidant functions of extract during papilloma genesis

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(a pre-cancer condition which precedes development of carcinomas). The researchers have further demonstrated the functional action of components like flavonoids and phenolics in mediating varied pathways including activation of detoxification and prevention of cellular damage, inhibition of cell proliferation and induction of apoptosis. In line with the observation that flavonoids and phenolics can effectively reduce the incidence and multiplicity of skin papilloma, many investigators have confirmed anti-cancer property of C. serratum by various in-vivo and in-vitro studies (Zalke et al., 2010; Nagdeva et al., 2012). 5.10. Alpha glucosidase inhibitory activity Methanolic extract of C. serratum roots (100 mg/ml) was evaluated for alpha-glucosidase inhibitory activity using enzyme assay. The extract was not found significantly effective (32.3% inhibition with IC50 value 265 79 mg/ml) and may require higher dose to produce the effect (Bachhawat et al., 2011). 5.11. Clinical studies Many clinical reports on a classical Ayurvedic formula “Bharangyadi” containing C. serratum as a major ingredient showed remarkable antiasthmatic effects. The antiasthmatic effect of Bharangyadi preparation (3 ml bd for 15 days in moderate asthmatic patients) was assessed directly on respiratory parameter using MATLABs lung mechanics modeling considering lung volume, airways resistance and lung compliance parameters. Significant increase in lung volume and compliance with decrease in airways resistance justified the traditional claim of drug in asthma (Kajaria et al., 2013a). The efficacy of Bharangyadi yoga (30 ml bd with honey for 30 days in 30 clinically diagnosed bronchial asthmatic patients) and its nebulizer (2.5 ml bd for 15 days in 30 clinically diagnosed bronchial asthmatic patients) has been successfully evaluated for the management of chronic persistent asthma as well as acute attack of asthma (Kajaria and Bhalerao, 2012). To determine the effective route of administration, drug was given orally and inhalation through nebulizer to ascertain the added effect of inhalation. Inhalation of aqueous extract of Bharangi through nebulizer during attack along with Bharangi churna (3 g tid for 30 days with lukewarm water (225 mg/kg/day in divided dose in children)) showed good bronchodilatation and expectoration effects in clinical studies (Madhu, 2012). Kajaria et al. (2011) have developed nebulization therapy for administration of Bharangyadi preparation through inhalation route and commendably tested for its effectiveness in asthmatic patients. Bharangyadi Avleha, as described in Sahastra Yogam, Shwasa roga Chikitsa (Sharma and Sharma, 2004) was found to be effective in clinical study for the Samprapti of Tamaka Shwasa (bronchial asthma); however, the results were statistically not so encouraging for the patients having Vata Pradhana Samprapti and Kapha Pradhana Samprapti both (Gohel et al., 2011). The efficacy and tolerability of Khasceeze-SF cough syrup was successfully tested using 50 patients of either sex (age 15–65 years) for cough and related symptoms such as sore throat, sneezing, breathlessness and fever. Khasceeze-SF cough syrup includes Vasaka (Adhatoda vasica leaves), Basil (Ocimum sanctum leaves), Liquorice (Glycyrrhiza glabra roots and rhizomes), Beleric myrobalan (Terminalia bellerica fruits), Spiked Ginger Lily (Hedychium spicatum rootstock), Bharangi (C. serratum roots) and Long pepper (Piper longum fruits), however the original report has not indicated authentication of individual herb in the composition. This study suggested that the composition facilitated healing of the diseased bronchial tree and alleviated cough of any etiology without any feeling of drowsiness, irritability or dryness in mouth (Satam et al., 2011).


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6. Toxicological information The systemic toxicity and safety evaluation reports of C. serratum and its formulation are still found inadequate to postulate the safety aspects of the drug. According to the records of Ayurvedic Pharmacopoeia of India (2001), the daily clinical dose recommended for adult, ranges from 3–6 g of root powder and about 10–20 g of kwatha churna (Ayurvedic Pharmacopoeia of India, 2001). There are limited reports available to assess toxic effects of the extracts and formulations of C. serratum and one of the studies has reported LD50 value of ursolic acid isolated from the drug as 100 mg/kg body weight. According to one more report, acute treatment of mice with the standardized ethanolic extract of C. serratum root bark produced toxicity at 1.57 g/kg dose (Wahyono et al., 2007). The administration of 90% alcoholic extract of C. serratum root (at doses of 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00 and 2.50 g/kg) to mice was not found to produce any significant change in the autonomic or behavioral responses during the observation period. The oral LD50 value of an alcoholic extract of roots in mice calculated graphically was found to be 1.8 g/kg (Narayanan et al., 1999) while the ethanolic extract of C. serratum leaves was found nontoxic with starting dose of 2000 mg/kg when given for 14 days (Saha et al., 2012). In contrast, the LD50 value of 70% alcoholic root extract and ursolic acid isolated from the extract was found to be 200 and 100 mg/kg body weight respectively in albino rats by the staircase method (Vidya et al., 2007). The contrasting values of the LD50 are probably due to the presence of different components with varied concentrations found in the plant. The acute and sub chronic toxicity of Bharangyadi preparation was found to be nontoxic at the dose of 2–20 g/kg in rodents but long term use of the preparation especially at higher than the reported dose may require critical care during administration (Kajaria et al., 2012d). In general administration of C. serratum at the recommended daily clinical dose usually does not cause any significant adverse effects in humans. However, additional toxicology studies including long-term toxicity, genotoxicity, teratogenic and reproductive studies and large scale clinical trials are necessary to assess the potential of C. serratum as an alternative for treating respiratory diseases. Further the toxicity studies designed with the lower doses can provide more physiologically meaningful data. Any report on contraindications with the use of C. serratum and its formulations have not been recorded till date.

7. Quality control aspects There are certain controversies regarding the identification and authentication of C. serratum (Bharangi). The genuineness of drug has been disputed and pharmacists are skeptical over its identity. This situation arose due to availability of many other drugs in the market as Bharangi. Plants from many taxa other than Clerodendrum, but belonging to family Verbenaceae and few other plants from different families have been sold in the market under the common name Bharangi. Roots of C. serratum are often found adulterated with roots of many plant from Verbenaceae, Rubiaceae and Simaroubaceae families. Clerodendrum indicum (L.) Kuntze, Gmelina arborea Roxb., Premna obtusifolia R. Br. and P. herbacea Roxb. of the family Verbenaceae, Gardenia latifolia Aiton, G. resinifera Roth, and G. turgida Roxb. of the family Rubiaceae and Picrasma quassioides (D.Don) Benn. from Simaroubaceae family are most common adulterants of Bharangi. A plant species can be easily identified by taxonomists in flowering stage (Narayanan et al., 2002) but the identification of leaves and roots seems much more challenging, especially in the processed plant material (e.g. powdered). Detailed phytochemical analysis and

evaluation of quality parameters serve as major tool to confirm the identity of the material. Ayurvedic Pharmacopoeia of India has specified certain limits for foreign matter (not more than 2%), total ash (NMT 11%), acid-insoluble ash (NMT 1%), alcohol soluble extractive (NLT 6%) and water soluble extractive (NLT 12%) as quality parameters for roots (Ayurvedic Pharmacopoeia of India, 2001) for ease of its identification and authentication. Plant anatomy and phytochemistry have been used for many years by pharmacognosists as tools to authenticate plant material. Nayar et al. (1976) had studied the anatomical features of Premna herbacea and described certain diagnostic features to distinguish C. serratum from P. herbacea (Nayar et al., 1976) while other investigators have reported complete pharmacognostical features including gross anatomical features, cellular composition, tissue organization and cellular inclusions of roots of C. serratum to differentiate it from the common adulterants (Narayanan et al., 2002; Babu et al., 2010). Roots of C. indicum can be differentiated from that of C. serratum by presence of well-developed periderm. The phellogen of C. indicum root is reported to be pericyclic in origin, so that the cortex is lost during the process of periderm development whereas, in C. serratum young roots show 450– 500 mm wide cortical zone in the radial plane with the inner boundary being marked by isolated small groups of fibers. The secondary xylem of the roots of C. serratum exhibits distinct growth rings marked by the occurrence of boundary parenchyma and isolated nests of vascular tracheids not shared by the roots of Premna and Gardenia as a distinct feature. Further, the type of sclerenchyma in the root barks of Clerodendrum, Premna and Gardenia offer easy accessible evidence to confirm their identity. Presence of group of scattered brachysclereids in the secondary phloem in bark of C. serratum is distinguished by the presence of libriform fibers in the sclerenchymatous elements of the Premna and Gardenia bark. Other microscopic features to distinguish P. herbacea from C. serratum include nodulated roots, compound starch grains in the bark tissue and absence of stone cells in the cortex. As far as the analytical reports for the quantification of secondary metabolites in the drug are concerned, very few studies showing estimation of oleanolic acid and stigmasterol have been reported in roots (Gupta et al., 2005; Gokani et al., 2007; Gantait et al., 2010; Jayaprakasam et al., 2013). Recent reports on quantification analysis of stigmasterol in C. serratum roots using high performance thin layer chromatography (HPTLC) with mobile system chloroform:methanol (9:0.5) gave good separation with symmetric peaks at Rf value 0.80 70.02 at a selected wavelength of 366 nm in roots as well as in formulation containing C. serratum roots (Jayaprakasam et al., 2013). The presence of oleanolic acid in hydrolyzed methanolic extract has been reported in 0.0093– 0.020%w/w using mobile phase system toluene:ethyl acetate: formic acid (7:3:0.3) (Gupta et al., 2005). In spite of well reported phytochemical profiling of the plant, only very few analytical studies are reported suggesting wide scope for development of reliable and sensitive methods, such as liquid chromatography, high performance liquid chromatography, reversed phase high performance liquid chromatography and liquid chromatography coupled with hyphenated techniques for the determination and quantification of bioactives of C. serratum. Molecular characterization of Clerodendrum species can be exploited for plant breeding activities, DNA sequencing analysis and for conservation of genetic resources also.

8. Conclusion In present review, we have summarized multifaceted uses and recent findings on phytochemistry, pharmacology and toxicity



studies of different extracts, polyherbal and Ayurvedic formulations containing C. serratum to provide bridge between the ongoing scientific research on the drug and traditional and ethno medicinal reports. Pharmacological studies of fresh or dried materials, crude extracts and isolated components of C. serratum provide a pragmatic support for its numerous traditional and popular uses. Recent reports have focused on evaluating the anti-asthmatic, anti-inflammatory, hepatoprotective, anticancer, antioxidant and antibacterial activities of mostly roots and leaves of the plant, which can be explained by the presence of various flavonoids, phenolics and saponins in roots. Most of the mentioned pharmacological studies have provided some level of scientific evidence for its traditional usages in asthma, inflammatory and infectious disorders. However no experimental evidence is available substantiating its traditional use in rheumatism, ulcer, cholera, tuberculosis and ophthalmic disorders, which can be explored further. C. serratum roots and leaves exert beneficial effects in the treatment of asthma, allergy and inflammation when evaluated in various animal models but extensive studies are necessary to address issues regarding composition of the extract, explicability of preclinical experiments, lack of transformation of the preclinical results to clinical efficacy, accuracy of clinical trials data, safety confirmation and drug interaction. Furthermore, phytochemistry of this plant has not been fully researched and there is a paucity of information on the additive or synergistic effects of chief compounds present in the drug which might be responsible in therapeutic outcome of the treatment. There is a necessity to examine the biochemical and physiological mechanisms behind potential anti-asthmatic and anti-inflammatory activities offered by roots of the plant. This study along with some of the clinical observations of formulations containing C. serratum strongly recommends need of further investigations on standardized extracts and bioactives of C. serratum for evaluation of antiinflammatory and anti-asthmatic effects to ensure the prominent role of triterpenoids and flavonoids in the prevention of a wide variety of inflammatory diseases. Additionally it is required to establish mechanisms of action of possible markers and to explore the structure activity relationships among the constituents present in roots with specific reference to its anti-asthmatic and anti allergic activity. In addition, the observed chemoprotective and cytotoxic properties needs to be explored for the potential benefits of C. serratum as an adjuvant therapy for various types of cancers. Most of the pharmacological studies have been reported for uncharacterized crude extracts of the plant and it is difficult to reproduce the results of these studies and pinpoint the active metabolite down the offered protection. Hence, our study strongly recommends the need for phytochemical standardization and bioactivity guided identification of active metabolites particularly from roots. However, the vast traditional uses and pronounce pharmacological activities of C. serratum pointing towards an immense scope for phytochemical and therapeutic exploration of the drug for treatment of many disorders. Attempts should also be made to determine modes of action, bioavailability, pharmacokinetics and physiological pathways for specific bio actives of C. serratum roots which might be responsible behind the protective effects offered by extracts rich in flavonoids and triterpenoids in many pharmacological studies. Some findings depicted interesting biological activities for example; hepatoprotective activity of ursolic acid was found significant and similar to silymarin, which can be further explored to fill the gaps for development of a drug as a potent antiasthmatic agent. However, from a clinical perspective, efforts are required for developing clinical studies focusing on antiasthmatic potential of C. serratum to meet the Western standards of evidence-based medicine.

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Natural population of the plant species is diminishing owing to habitat destruction, over exploitation along with poor seed setting and germination. As C. serratum is categorized under nearly threatened species by IUCN (International Union for the Conservation of Nature and Natural Resources) (Singh and Singh, 2009; Kumari et al., 2012), effective preventive measures must be taken to preserve natural populations of this plant in India. Callus induction through an auxin-cytokinin combination has been reported for C. serratum with increased length of leaves and shoots of the plant according to some plant biotechnology reports (Vidya et al., 2005a; Srinivas and Bellary, 2012). Immense intervention is required from the biotechnology field at this junction for cultivation techniques developed for preservation of natural source of C. serratum and development of tissue culture techniques for rapid clonal multiplication and essentially to provide uniform raw material for medicinal uses as well as for commercialization of this drug.

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