Mohan Maruga Raja MK, Mishra SH. J Chin Integr Med. 2010; 8(6): 510-524. Received March 12, 2010; accepted April 28, 2010; published online June 15, 2010. Indexed/abstracted in and full-text link-out at PubMed. Journal title in PubMed: Zhong Xi Yi Jie He Xue Bao. Free full text (HTML and PDF) is available at http://www.jcimjournal.com. Forward linking and reference linking via CrossRef. DOI: 10.3736/jcim20100602
Correspondence: Muthu Kumaradoss MOHAN MARUGA RAJA; Tel: +91-265-2794051; Fax: +91-265-2423898; E-mail: email@example.com
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Ethnopharmacological knowledge, with its holistic systems approach supported by experiential base, can serve as an innovative and powerful discovery engine for newer, safer and affordable medicines［1］. In the last few decades there has been an increasing interest in the ethnopharmacological studies on medicinal plants, which is evident by numerous publications and reports. However, these reports on medicinal plants are widely scattered in journals and books pertaining to different disciplines, such as botany, chemistry, pharmacology, pharmacy and medicine. This review is an attempt to compile the exhaustive literature on Clerodendrum phlomidis, to highlight, analyze and critically assess the pharmaceutical potential of this plant that has been underestimated in a systematic way.
The genus Clerodendrum of the family Lamiaceae is a diverse genus with about 560［2］ to 580［3］ species of small trees, shrubs, lianas, or occasionally perennial herbs, mostly in the tropics and subtropics of the old world［4］. This genus was first described by Linnaeus in 1753 based on the type 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［5］. Clerodendrum displays a high degree of morphological and cytological variations, of which many species have been described by more than one author［6］. Throughout its taxonomic history Clerodendrum has been delimited in many ways, some delimitations being more inclusive than others. Clerodendrum has been divided between as many as a dozen different genera; sometimes these smaller genera were divided among different families［7, 8］. The 19th and 20th century taxonomic and phylogenetic studies did much to rectify these. Even now, especially with the development of molecular systematic methods, the delimitation of Clerodendrum continues to be modified［9］. Phenetic and cladistic studies have led to a suggestion that Clerodendrum is paraphyletic［10］ or polyphyletic［11, 12］. Parsimony analyses of 456 potentially informative characters identified four large discrete clades (Clades Ⅰ—Ⅳ) within Clerodendrum［13］. The sequence analyses of internal transcribed spacers of the nuclear ribosomal DNA concluded the genus to be polyphyletic［6］.
Clerodendrum is also a chemically diversified genus. Terpenoids are the major secondary metabolite, i.e., steroids ［14-16］, neo-clerodane diterpenes［17, 18］, triterpenes［19, 20］ and iridoids［21, 22］. Phenolic compounds have frequently been reported among which phenyl propanoids［23, 24］ and flavonoids predominate［25, 26］. A few of species have been reported to have macrocyclic alkaloids［27, 28］ and cyanogenetic glycosides［29, 30］. Clerodendrum has been found to have a number of biological activities mainly including anti-inflammatory［31, 32］, hepatoprotective［33, 34］ antihypertension［35, 36］, antioxidant［37, 38］, cytotoxicity［39］, antitumour［40］ and antifeedant activities［17］, and effects on central nervous system［41］.
Bitters are a group of botanicals predominantly bitter in taste, due to the presence of chemical constituents like alkaloids, monoterpenes (iridoid and secoiridoids), sesquiterpene lactones, diterpenes, triterpenes and rarely flavanones, acyl phloroglucides and steroids (pregnane type)［42］. In Ayurveda, for the high heat, fever and Pitta conditions, fire purging and heat dispelling herbs, i.e., bitters, are used［43］. Clerodendrum phlomidis Linn. f. (Lamiaceae) is one such traditionally recommended bitter for various ailments in India.
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1 Clerodendrum phlomidis
1.1 Taxonomical hierarchy The taxonomical hierarchy of C. phlomidis is listed in Table 1.
Table 1 Taxonomical hierarchy of C. phlomidis
1.2 Botanical and geographical sources Clerodendrum phlomidis Linn. f. (syn. Clerodendrum multiflorum (Burm.f) O. Kuntze, Volkameria multiflorum Burm. f.) belongs to the family Lamiaceae. It is commonly known as Clerodendrum or wind-killer in English and has different vernacular names in India (Table 2)［44-49］.
Table 2 Different vernacular names of C. phlomidis in India
C. phlomidis is a common shrub of arid plains, low hills and tropical deserts. They are distributed throughout the drier parts of India (Andhra Pradesh, Uttar Pradesh, Diu Island, Delhi, Gujarat, Haryana, Karnataka, Madhya Pradesh, Maharashtra, Bihar, Orissa, Punjab, Rajasthan, Tamil Nadu, Uttar Pradesh and West Bengal), Pakistan (Sindh, Baluchistan and north-western provinces), Sri Lanka, Myanmar and south-east Asia［46, 47, 49-52］.
1.3 Controversy regarding its synonym in Ayurveda Agnimantha or Arani is an important drug of Ayurvedic system of medicine. In some Nighantus (materia medica) of Ayurveda, only one type of Agnimantha is described but in some cases, two types of Agnimantha have been mentioned, i.e. Laghu or Kshudra (Small) and Brihad (Large) which have minor differences in their medicinal properties［53-55］. Some texts refer to the source of Kshudra Agnimantha or Laghu Agnimantha as dried mature roots of C. phlomidis/C. inerme/C. nereifolium and Premna integrifolia/P. serratifolia/P. longifolia as Brihad Agnimantha［45, 55, 56］. Some consider the smaller type as P. integrifolia and the larger ones as C. phlomidis［57］. Nair［56］ quotes that P. integrifolia is used as Agnimantha in Kerala, India and both C. phlomidis and P. integrifolia may be used as Agnimantha according to availability. Some refer to Agnimantha as P. integrifolia and Arani as C. phlomidis［58］ but others quote both as Agnimantha and/or Arni［56, 59-61］. Nadkarni et al［44］ clearly mentions C. phlomidis as Agnimantha and also quotes Haines in addition who recognized two varieties, the white (Safed Tekar) and the black (Kala Tekar), the former alone being useful. In “Ayurvedic Formulary of India” the Latin name for Agnimantha is C. phlomidis and it also states that Premna sp. can be used as a substitute［62-64］. Though Tarkari is regarded as a synonym of Agnimantha, Susruta has enumerated both Agnimantha and Tarkari side by side in one group［65］, while Dravyagunavigyan (Science of treatment - Science of medicines) considers Agnimantha to be Valiya munna (P. mucronata) and Tarkari to be Ceriya munna (C. phlomidis). However throughout Kerala, India Premna sp. is used for both Agnimantha and Tarkari［62］, but Takari also refers to P. integrifolia, Sesbania aegyptiaca Pers. and Cassia tora Linn［66］.
1.4 Commerce and trade C. phlomidis is one of the highly traded medicinal plants from tropical forests, as the leaves and roots are used in folklore, Ayurveda, Siddha and Unnani medicines. The estimated consumption/trade of C. phlomidis was 306 metric tonnes for the year 2005 — 2006 and the estimated annual trade is 200 to 500 metric tonnes. It is sold under the trade name of “Arnimul” (leaf and root), the price range being 0.32 to 0.5 $ per kilogram［67］.
1.5 Anatomy, histology, microscopy and proximate analysis Anatomical, histological and powder characteristics of different parts of C. phlomidis are shown in Table 3［47, 64, 68-70］. The leaf constant values vary from those reported by Chunekar et al［70］ and Krishnamurthy et al［64］. The Ayurvedic Pharmacopoeia of India has specified the thin-layer chromatography (TLC) pattern and some parameters, viz., foreign matter (not more than 2%), total ash (not more than 6%), acid insoluble ash (not more than 1%), alcohol soluble extractive (not less than 2%) and water soluble extractive (not less than 5%) values for recognizing the identity, purity and strength of roots of C. phlomidis［47］.
Table 3 Anatomical, histological and powder characteristics of different parts of C. phlomidis
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2 Ethnomedical uses
Indian system of medicines particularly Ayurveda and Siddha uses C. phlomidis as a single drug or in combination with other drugs. It was found that, a village nearby Pondicherry, India is called after the Tamil name, Thalludhalai［71］. The Ayurvedic properties of C. phlomidis are: Rasa (taste) — Tikta (bitter), Katu (pungent/acrid), Kashaaya (astringent), and Madhura (sweet); Guna (quality) — Rooksha (non-unctuous), and Laghu (light); Veerya (potency) — Ushna (heat); Vipaka (transformation with digestion) — Katu (pungent)［47］. Due to its bitter and pungent nature C. phlomidis is considered to normalize the vitiated Kapha and Vata dosa［55］. It is constituted as a number of Ayurvedic formulations indicated for digestive disorders, acidity, gas, diarrhoea, laxative, liver tonic and general health tonic［72］. The roots are used in different Ayurvedic formulations such as Ayushyavardhaak tel, Bhratpanchamula, Chandraprabha vati, Lavanbhasker churna, Abhayarisht, Chavanprasha, Dasamularista, Ashwagandharishta, Mritasanjivani, Dasamula Kvatha Churna, Haritakiavleh, Indukanta Ghrta, Dhanvantara Ghrta, Gorocanadi Vati, Narayana Taila, Ras pitari, Vrahat Panchamuli［44, 47, 55, 63, 72, 73］ and Muthu Marunthu (a Siddha polyherbal formulation). C. phlomidis is also an ingredient of many stress/pain relief massage oil blends and many polyherbal formulations that are used as rejuvenation tonic. Though root is considered to be the authentic drug it is the leaf that finds application in folklore medicines［64］. The ethnomedical uses of different parts of C. phlomidis are given in Table 4.
Table 4 Ethnomedical uses of different parts of C. phlomidis
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3 Veterinary uses
C. phlomidis finds a lot of applications in Indian traditional veterinary practices［91］. The tribals Santals feed C. phlomidis to their cattle for diarrhea and worms or when the stomach swells［46, 50, 81］. Extracts of leaves are applied on body of domestic animals to kill lice. Leaves are good fodders especially for goats［92］. Leaf paste is applied to infested hooves to give a relief for the animals and reportedly cures foot and mouth diseases and secondary infections［93］. Fresh leaf extracts are pasted on animals with skin problems［94］ and used for hypothermia or shivering in cattle［95］. In Chittoor, Ananthapur districts of Andhra Pradesh and Southern India C. phlomidis is used for alleviating diseases of livestock by the local traditional herbal practitioners. Leaves are given orally twice daily to cure convulsive seizures and trypanosomosis infection until cured［96］.
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4 Utilization in agriculture
In Surapala’s Vrkshayurveda (a 1 000 AD text), root of C. phlomidis is mentioned in the application of various tree disorders［97］. C. multiflorum is used as a herbal pesticide particularly for insect pest like aphids and red hairy caterpillar［98-101］. Leaf extracts are also used for preserving grains［102］ and to control green worms (Heliothis sp.)［103］. Jowar (sorghum) seeds are treated at the spike forming stage with leaf juice of C. multiflorum to protect from fungal infections (Sporisorium sp.)［104］.
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A crystalline non-glucoside bitter principle (C17H16O6, melting point (m.p.) 213 ℃), ceryl alcohol, β-sitosterol, γ-sitosterol, palmitic acid, cerotic acid and an unidentified sterol (C28H48O, m.p. 155 ℃) have been isolated from the leaf［105］ and identified as pectolinaringenin as well by Subramanian et al［106］, and was earlier reported by Bhakuni et al［105］. The water extracts were found to contain glucose, arabinose and potassium nitrate［105］. Two compounds (C14H28O2, m.p. 67 ℃ and C31H64O2, m.p. 93 ℃) and a bitter resinous substance reported［105］ are yet to be characterized. D-mannitol, β-D-glucoside of β-sitosterol, β-sitosterol and ceryl alcohol were also isolated from the stem［107］. The stem, leaf and flower parts were reported positive for alkaloids and negative for saponins and tannins［108］. Scutellarein (5,6,7,4′-tetrahydroxy flavones), pectolinaringenin (6,4′-dimethoxy scutellarein) and a flavanone have been isolated from the leaf［106］. A chemotaxonomic marker of the genus, (24S)-ethylcholesta-5,22,25-triene-3β-ol (C29H46O, m.p. 151— 153 ℃) was isolated from the leaf［14］. β-sitosterol, γ-sitosterol, ceryl alcohol, clerodin (C24H34O7), clerosterol (C29H48O) and clerodendrin-A (C27H26O17) were also isolated from the root［109］. Seth et al［110］ reported 6,4′-dimethyl-7-acetoxyscutellarein, pectolinarigenin, hispidulin, apigenin and luteolin isolated from the flower. Chalcone glycoside (4,2′,4′-trihydroxy-6′-methoxychalcone-4,4′α-D-diglucoside, m.p. 186— 188 ℃, C28H34O15), pectolinarigenin, 7-hydroxy flavone and 7-hydroxy flavanone 7-O-glucoside were reported isolated from the flower and the leaf［111, 112］. α-L-rhamnopyranosyl-(1→2)-α-D-glucopyranosyl-7-O-naringin-4′-O-α-D-glucopyranoside-5-methyl ether (C34 H44 O19) was reported isolated from the root by Anam［112］.
Lup-20(29)-en-3-triacontanoate (C60H108O2), tetratriacontanol and 24β-ethylcholesta-5,22E,25-triene-3β-ol were reported isolated from aerial parts［49］. Shanker et al［113］ reported a new validated TLC method for the quantification of a marker sterol, 24β-ethylcholesta-5,22E,25-triene-3β-ol with chloroform-methanol (98.5∶1.5) (Rf 0.54±0.05) and densitometric evaluation at 650 nm after anisaldehyde-sulphuric acid derivatization. The amounts quantified in different solvent extracts were hexane 0.055 2, chloroform 0.054 7, ethanol (95%) 0.033 8, methanol 0.092 7 and ethyl acetate 0.104 7% w/w. Figure 1 and 2 show the chemical structures of some isolated compounds from C. phlomidis.
Figure 1 Chemical structures of some isolated compounds from C. phlomidis (Ⅰ)
Figure 2 Chemical structures of some isolated compounds from C. phlomidis (Ⅱ)
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6 Non-clinical investigations
Many studies have reported the diversified biological activities of C. phlomidis which are described in details as followed.
6.1 Analgesic activity An ethanolic extract of leaves (150 and 300 mg/kg, i.p.) was evaluated for analgesic activity in albino mice (either sex, 20 to 25 g) by Eddy’s hot plate method. The extract at 300 mg/kg showed significant activity, supporting the folklore claim as analgesic［114］.
6.2 Anti-amnesic activity An aqueous extract of bark (yield 2% w/w) at 100 and 200 mg/kg, p.o. was evaluated for anti-amnesic activity in young Swiss mice (8 weeks, either sex) and old Swiss mice (28 weeks, either sex). Acute toxicity studies showed hypersensitivity, grooming, convulsions, sedation, hypothermia, ptosis and mortality at dose of above 1 000 mg/kg. The dose at 200 mg/kg more significantly enhanced the learning and memory of aged animals rather than the young ones. The extract profoundly increased step-down latency (SDL) indicating improvement in the memory of younger mice and significantly inhibited the acetylcholinesterase (AchE) activity indicating its potential in the attenuation of learning and memory deficits especially in aged mice［115］. The study concluded C. phlomidis as a potential nootropic and anti-cholinesterase agent［115］.
6.3 Anti-asthmatic activity An aqueous extract (yield 7.9% w/w) of leaves was studied for anti-asthmatic activity in male albino mice (Swiss strain, 22 to 25 g). The effect of extract (2, 4, 10 mg/mL) on goat tracheal chain was also studied, indicating a significant activity at 4 and 10 mg/mL with the relaxant effect (depression of histamine receptor 1). The extract at dose levels of 25, 50 and 100 mg/kg, i.p. in milk-induced eosinophilia showed significantly at 100 mg/kg the antagonizing effect. In three-day treatment by the aqueous extract (25, 50 and 100 mg/kg, i.p.), the 100 mg/kg dose showed 73.25% protection of mast cell degranulation. The aqueous extract, when studied for capillary permeability (25, 50 and 100 mg/kg, i.p.), at 100 mg/kg dose level significantly decreased transmittance, indicating its effect on optical density of the eye. The overall study lends credence to the beneficial use of aqueous extract in the treatment of asthma and related conditions［116］. The authors have quoted a back reference regarding the anti-ulcerogenic activity of C. phlomidis, which is misleading. In fact, C. splendens was screened for anti-ulcerogenic activity in the mentioned reference［117］.
6.4 Antidiarrhoeal activity A successive methanolic extract (yield 7.5% w/w) of leaves showed no mortality till an oral dose of 1 g/kg. The methanolic extract at doses of 200, 400, 600 and 800 mg/kg was evaluated for castor oil-induced diarrhea, gastrointestinal motility and prostaglandin E2-induced enteropooling in albino rats (Wistar strain, 180 to 200 g, either sex). The methanolic extract at 600 and 800 mg/kg showed significant inhibition of defecation frequency and decrease in propulsion of the charcoal meal through gastrointestinal tract. The extract also significantly inhibited prostaglandin E2-induced enteropooling in almost all the dose levels. The mechanism appears to be spasmolytic and anti-enteropooling［118］. Although the extract has shown only the presence of steroids, alkaloids and flavonoids, the authors concluded that the activities of the extract might be due to tannins, which is controversial.
6.5 Anti-inflammatory activity The aqueous and alcoholic leaf extract-treated group showed general decrease in the size of the swelling following certain initial fluctuations and reduction in suppuration especially in speed of general drying up of the pus［64］. No details were found regarding the dose of the extract administered.
6.6 Antimicrobial studies Twenty microliters of defatted methanolic (yield 4.4% w/w) and acetone (yield 1.7% w/w) extracts of stems and leaves (combined) were screened for five Gram-positive bacteria, seven Gram-negative bacteria and three fungi species by an agar diffusion method, respectively. Acetone extract was not active while the methanolic extract showed inhibition against Citrobacter freundii and Staphylococcus epidermidis［119］. The preliminary phytochemical analysis of C. phlomidis extracts was not clear whether it is for methanolic or acetone extract. Furthermore, it was astonishing to note that although the data indicated the absence of alkaloids, tannins, cardiac glycosides, steroids, flavonoids and saponins, the authors concluded that the antimicrobial activity might be attributed to various active constituents present in either mono or combined way of them.
Ethyl acetate and hexane extracts of leaves (yield 8.4% and 1.1% w/w) and stems (yield 3.21% and 0.52% w/w) at concentration of 1 mg/ml were screened for human pathogens and plant pathogens by poison plate technique, respectively. The leaf extract (particularly hexane extract) was more active than stem extract on both pathogens. However, the stem extract was only inhibitory to plant pathogens. The study revealed that both extracts were more effective in controlling plant pathogens than human pathogens and could be utilized in pesticide formulations［120］. Antifungal activity of two flavones, flavonone glucoside and one chalcone glucoside isolated from C. phlomidis were studied. Chalcone glucoside was highly promising followed by pectolinaringenin, flavonone glucoside and flavones［121］.
6.7 Antiplasmodial activity An ethanolic leaf extract showed 96% inhibition at 100 μg/mL and a 50% inhibitory concentration (IC50) value of 25 μg/mL against Plasmodium falciparum. The study concluded that the activity might be due to the presence of iridoids［122］ but no iridoids have been reported yet from C. phlomidis.
6.8 Antiviral studies An ethanolic extract of leaves was evaluated for antiviral activity against sunnhemp rosette virus (SRV) on Cyamopsis tetragonoloba. The virus inhibitory activity was 29% with no significant antiviral response［123］.
6.9 Brine shrimp lethality study Both biological activity and toxicity of a root aqueous extract using Artemia salina (Brine shrimp test) were studied. The extract with a median lethal concentration (LC50) value of 3,750 μg/mL showed no brine shrimp lethality［124］.
6.10 Hypoglycemic activity Chaturvedi et al［55］ studied the effect of decoction and alcoholic extract of C. phlomidis on adrenaline-induced hyperglycemia and alloxan-induced diabetics in rats, in which the alcoholic extract had a more significant inhibitory effect. Both decoction and alcoholic extract brought down the blood sugar levels effectively and exhibited the same degree of action in alloxan-induced diabetic rats. In a comparative study between the immediate effect (hourly basis) and long term effect (30 days) of decoction in normal rats, C. phlomidis produced comparable fall in blood sugar both on immediate as well as on long term use.
A defatted ethanol extract of leaves was screened for hypoglycemic activity in alloxan-induced diabetic rats at two dose levels, 100 and 200 mg/kg. The extract at 200 mg/kg exhibited significant hypoglycemic activity and also correction of altered cholesterol and triglycerides levels. In the histopathological studies more prominent islet cells were seen in both metformin and ethanol extract (200 mg/kg) treated groups［187］.
6.11 Immunomodulatory activity A methanolic extract of roots was evaluated for specific immune response (antihyaluronidase titer, plaque forming cell assay and delayed-type hypersensitivity test) and non-specific immune response (carbon clearance and E. coli-induced abdominal sepsis). The specific immune response was studied in BLAB/c albino mice (either sex, 22 to 25 g) for 7 days. The extract at 300 mg/kg showed significance in antihyaluronidase titre, plaque forming cell assay and delayed-type hypersensitivity test. In carbon clearance test (5-day treatment) and E. coli-induced abdominal sepsis (15-day treatment) the extract showed increased phagocytic index, significant clearance of carbon particles and only 20% mortality in 24 h particularly without any symptoms of peritonitis in surviving animals. The study concluded that the methanolic extract exhibited a high response in most of the studied models and the chemical constituents diterpenoids and flavonoids might contribute to the immunomodulatory activity［125］.
6.12 Nematicidal activity An aqueous leaf extract showed a moderate nematicidal activity against larvae of root-knot nematode Meloidogyne incognita and antifungal effect (43.58% inhibition) against Fusarium oxysporum f. sp. Cumini［126］.
6.13 Psychopharmacological activity A successive methanolic leaf extract (yield, 7.5% w/w) was studied in Swiss albino mice (either sex, 20 to 25 g) for phenobarbitone sodium-induced sleep, general behavior test, muscle relaxant activity and exploratory behavior (rat model) at doses of 200, 400 and 600 mg/kg, respectively. The dose at 400 and 600 mg/kg, i.p. significantly lengthened the phenobarbitone sodium-induced sleep time in mice. The same dose levels produced slight/moderate spontaneous, sound, pain and touch responses. The studies at all dose levels showed significant losses of motor coordination and tone of muscles. A significant decrease was shown by all three dose levels in the extraploratory behavior of rats in Y-maze test and in head dips responses in mice. The study concluded that the extract possessed most of the pharmacological activities of minor tranquilizers［90］. The authors have quoted that the extract is non-toxic and causes no death even up to an oral dose of 3.2 mg/kg while the doses selected for the study was 200, 400 and 600 mg/kg, i.p. which is contradictory.
6.14 Pharmacological effects of pure compounds The isolated compound 7-hydroxy flavone acts on targets like aromatase, alcohol dehydrogenase, 17β hydroxyl steroid oxydoreductase, multidrug resistance transporter (MDR-TR)- P-glycoprotein transporter (PGP-TR) and 3,5- cyclic nucleotide phosphodiesterase. This flavone also exerts in vivo antinociceptive activity［127］ and is active towards fatty acid amide hydrolase (FAAH) with an IC50 value of 0.5 to 1 μmol/L. Furthermore, it was reported that it also reduced the FAAH-dependent uptake of anandamide and its metabolism in intact RBL2H3 basophilic leukaemia cells［128］.
6.15 Studies on formulation containing C. phlomidis A 50% ethanolic extract of Chyavanprasha showed a nitric oxide scavenging activity［129］. A defatted 50% ethanolic extract of Chyavanprasha showed a radioprotective effect in mice exposed to lethal dose of γ-radiation［130］. Muthu Marunthu showed a very good controlling capacity on the biochemical events during tumor progression without producing any toxic effects［131］. The aqueous and alcoholic extracts of Amrit nectar tablets and the herbal Ayurvedic food supplement M-4 (Maharishi-4) reduced toxicities induced by Adriamycin and Cisplatin［132］, showing antineoplastic activities［133-137］. The studies with formulations containing C. phlomidis were not emphasized much as it would be unscientific to attribute the overall activities of the formulation to a single plant.
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7 Clinical investigations
In a clinical study, a 22% reduction of blood sugar was observed when 8 pills with an alcoholic extract were administered to 10 normal and 33 maturity-onset diabetic patients［138］. Effects of age, sex and complications on the results were not considered in this study.
A case report stated that a 70 year male patient with complaints of polyuria, polydypsia, constipation, loss of vision, tingling, and numbness in extremities for the duration of 10 years and complicated with pulmonary tuberculosis responded well without any adverse effect, when administered with C. phlomidis decoction daily in 4 divided doses for three weeks along with anti-tubercular treatment simultaneously. Significant lowering of fasting blood sugar and improvement of polydypsia and polyuria were reported［55］. In another clinical claim reported of 23 patients, 46% treated with C. phlomidis (a 1:4 decoction prepared from 15 to 30 g in daily divided doses for 5 weeks) showed 7.1% mean fall of blood sugar and 18.2% fall in urine sugar with no side effects［55］. But the report did not contain sufficient data for re-analysis as well as statistical analysis, e.g., no means, no standard deviations. The small number of patients in the multiple arms of the study made generalization difficult. However the authors still assumes that C. phlomidis might be a good oral hypoglycemic agent.
Namboodari et al［139］ reported that the combination of Dasmularista, Pippalyasava and Vettumaran Gutika was effective in the 90-day treatment of acute rheumatoid arthritis. Park et al［140］ have evaluated the methodological quality of all randomized controlled trials (RCTs) on the effectiveness of Ayurvedic medicine for rheumatoid arthritis (RA). The Jadad score assigned for the study by Namboodari et al［139］ was 2 due to poor study design and the inability to draw any meaningful conclusions.
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8 Concluding remarks and future potential
Regarding the controversy if Agnimantha/Arani is C. phlomidis or P. integrifolia, it is difficult to judge as neither the Nighantus nor any classical texts has referred to a morphological character. It is quite likely that both plants might have been actually used for the same purposes, since they were well known for their ethnomedical values. There is a discrepancy in pharmacognostical parameters reported by different authors. However the anatomical and histological studies will provide with evidence for establishing the identity and the degree of purity.
Currently, sterols, flavones, flavanones, chalcone, triterpene and neo-clerodane diterpenoids have been reported from different parts of C. phlomidis. The compounds C14H28O2 and C31H64O2 reported by Bhakuni et al［105］ are still unidentified. Pectolinaringenin along with resinous substances might be responsible for the bitterness of the herbal agent. Only a few of bitter flavonoid glycosides have been reported earlier, e.g., naringin and neo-hesperidin. Pectolinaringenin is considered as a bitter principle of rare non-glucosidal flavone. Different extracts have shown the presence of tannins, flavonoids, terpenoids, steroids, phenolics, saponins and alkaloids. But there is difference of opinions by studies regarding the presence and absence of some secondary metabolites, such as saponins and tannins. Many authors have mentioned the presence of alkaloids in C. phlomidis but none of them have reported about their chemical group. A question would then be if this is apparent mutual exclusiveness between classes of secondary metabolites just a delusion resultant of insufficient studies or a reality. Relationships among the occurrences of classes of secondary metabolites would be a point deserving consideration, because it may end up useful in future prospects of pharmacological substances. Phenyl propanoids, abietane diterpenoids and lectins isolated from other Clerodendrum species are reported for HIV-1 integrase inhibition［24］, angiotensin converting enzyme (ACE) inhibition［141］, histamine and arachidonic acid release inhibition［142］, cytotoxicity［143］ and immunosuppressive activity［144］. The future phytochemical investigation should be focused on identification of these bio-active moieties from C. phlomidis.
The ethnomedical uses give a clue that how people treat different health problems with C. phlomidis parts. In the view of the magnitude of its use, the more studies to be conducted seem essential. The overall pharmacological studies indicated that the alcoholic leaf extract was analgesic, antidiarrhoeal, antiplasmodial, hypoglycemic and minor tranquilizers, while the aqueous extract was anti-asthmatic, hypoglycemic, antifungal, nematicidal, anti-amnestic and anti-arthritic. The hexane soluble constituents of leaves were potent antimicrobials. The root aqueous extract was anti-inflammatory while the root methanolic extract exhibited an immunomodulatory activity. The bitter constituents might be responsible for hypoglycemic, immunomodulatory and psychopharmacological activities, since these bitter principles were found to have effects in blood sugar regulation, reducing anxiety and regenerating nervous system. Conversely, many of the pharmacological studies were experimentally poor. Very high (non-physiological) concentrations were used in both in vivo and in vitro studies before a biological response was seen. For example, in the psychopharmacological activity, the administered dose of 600 mg/kg i.p would be toxic. However there is a good coincidence of the traditional uses with analgesic, anti-asthmatic, anti-inflammatory, anti-diarrhoeal, and hypoglycemic effects experimentally observed, which was in harmony with Farnsworth’s observation［145］. It is evident from the reference list of the present works that extracts have been objectives of most investigations whilst fractions of extract/pure compounds tracked to their bioactivities have been paid little attentions by phytochemists and pharmacologists. It is suggested that the future pharmacological investigations should focus on unexplored traditional uses of C. phlomidis. In a sense, the experimental works should explore potential uses of C. phlomidis with no records in the list of popular uses. A few of examples are the antimicrobial, anti-oxidant, and nematicidal effects. In the light of two clinical observations with no convincible data conducted at extract level in 1975 and 1983, it is evident to have a well-designed clinical study to confirm the hypoglycemic effectiveness of the species. It is believable that many novelties about C. phlomidis may disclose the relationships of their constituents to the corresponding pharmacological effects.
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