Natural Product Radiance, Vol. 8(5), 2009, pp.549-554 Review Paper

A phyto-pharmacological overview on Adhatoda zeylanica Medic. syn. A. vasica (Linn.) Nees

Sayeed Ahmad*, Madhukar Garg, Maksood Ali, Mhaveer Singh, Md Tanwir Athar and Shahid Husain Ansari Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy Jamia Hamdard, Hamdard Nagar, New Delhi -110 062, *Correspondent author, E-mail: [email protected]; Phone no. +91-9891374647 Received 25 August 2008; Accepted 1December 2008 Abstract Germany10. Leaves are simple, petiolate, Adhatoda zeylanica Medic. syn A. vasica (Linn.) Nees (Vasaka), a popular ex-stipulate, 10-20 cm long and 3-10 cm Indian medicinal , has long been used commonly in Ayurvedic system of medicine. The plant broad, lanceolate to ovate lanceolate has been found to possess diverse number of pharmacological activities. The present paper gives having crenate margin, tapering base and an account of updated information on its phytochemical and pharmacological activities. The an acuminate apex with characteristic review reveals that wide range of phytochemical constituents have been isolated from the plant and it possesses important activities like antitussive, antibacterial, abortifacient, anti-inflammatory and odor and bitter taste. Transverse section antiulcer. Various other activities like radiomodulation, hypoglycaemic, cardiovascular protection, of the leaves showed two layers of palisade antitubercular, antiviral, hepatoprotective, antimutagenic and antioxidant have also been reported. cells with diacytic stomata. Glandular and These reports are very encouraging and indicate that herb should be studied more extensively for non glandular trichomes are present on its therapeutic benefits. Clinical trials using vasaka for a variety of combinations in different both the surfaces of the leaf. Elongated formulations should also be conducted. cystoliths, acicular and prismatic form of Keywords: Adhatoda vasica, Adhatoda zeylanica, Arusa, Malabar Nut, Vasaka, calcium oxalate crystals are present in the Vasicine, Phytoconstituents, Pharmacological activities. mesophyll. The midrib region composed IPC code; Int. cl.8 — A61K 36/00, A61K 127/00, A61P 11/00, A61P 31/00 of 4-6 layers of collenchyma just below the epidermis and 3-5 vascular bundles, Introduction of numerous popular formulations central one being largest12. Adulteration Adhatoda zeylanica Medic. including cough syrups used in of leaves with A. beddomei Clarke, (Family — ) syn. A. vasica combination with ginger and tulsi where Ailanthus altissima (Mill.) Swingle (Linn.) Nees and adhatoda it exerts its action as an expectorant and (syn. A. glandulosa Desf.) and Linn. It is commonly known as Basak antispasmodic4. Bisolvon, a branded drug A. excelsa Roxb. leaves is very common (Bengali); Aradusi, adusa (Gujrati); containing Vasaka as an ingredient is and can be distinguished from the genuine Arusa, baansa, adulsa (Hindi); used to clear the airways by decreasing drug by their characteristic macroscopic 12 Bansa, basuti, bhekkar (Punjabi), and the mucus secretions and opening the air and microscopic features . shwetavasa, vasa, vasaka (Sanskrit) passages5. There are various herbal and Malabar nut (English) in different formulations, viz. Kada, Fermiforte, Phytochemical studies languages and regions of India1-3. It has Spirote available for the treatment of A. zeylanica mainly consists of been used in Ayurvedic system of various kinds of respiratory disorders6-9. pyrroquinazoline alkaloids (Fig. 1 a-k), medicine for the treatment of various It is an evergreen, gregarious, viz. vasicine, vasicol, vasicinone, peganine ailments of respiratory tract in both perennial , 1-2.5 m in height, having along with other minor constituents. children and adults. All the parts of the opposite ascending branches1. The plant Vasicine is a major bioactive plant have been used for their therapeutic is distributed throughout India up to an pyrroquinazoline alkaloid of vasaka beneficiary effect from ancient times4. It altitude of 1300 m and mainly found in present in the concentration of 1.3%. is also used for the treatment of bleeding sub-Himalayan regions; also found in Minor alkaloids include adhatonine, piles3. The plant is used as an ingredient , Pakistan, Myanamar and vasicinol and vasicinolone. Flowers mainly

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simple rapid and a reproducible method Escherichia coli, whereas water extract for quantization of vasicine and vasicinone, showed activity against S. aureus only 24. the peak purity can be determined for the extraction of compounds using photodiode Anticholinesterase array detector for the separation of two Vasicinone obtained from the using acetonitrile phosphate buffer roots produced transient hypotension in (pH 3.9) and a hibar merck made up of cats, contraction of isolated intestine and 21 depression of isolated heart in guinea pigs, C18 column . Reverse HPLC can be used for the exact determination of vasicine thus showing good anticholinesterase using 100mM heptane sulfonic acid and activity25.

methanol as the mobile phase, in C18 column and UV-visible detector. Method Wound healing was validated for the determination of The rate of healing was found to accuracy, precision by carrying out be higher in the plant extract treated linearity/recovery experiment. It was wounds in buffaloes as compared to 26 Adhatoda zeylanica suggested that method can be applied for pancreatic tissue extracts . the routine quality control of vasicine from consist of kaempferol and quercetin13. herbal preparations22. Hypoglycaemic A new moiety 2′-4-dihydroxy chalcone- HPTLC method has been Ethanolic extract of the leaves 4-glucoside has been identified in the developed for the determination of exhibited hypoglycaemic activity in the 27 flowers14. Four quinazoline alkaloids: pharmacologically important quinazoline rats . Modak and Rao found that when vasicoline, adhatodine, vasicolinone and alkaloids vasicine and vasicinone in non-nitrogenous principle of the leaves in anisotine have been obtained from the Vasaka. The assay combines the suspension form administrated orally at leaves and vasicinone, vasicol have been separation and quantification of analytes the dose of 25 mg/kg, lowered the blood sugar level of rabbits for a short period of isolated from the inflorescence15. on silica gel 60 GF254 HPTLC plates with time28. Sitosterol, β-glucoside-galactose and visualization under UV light and scanning deoxy vasicine have been isolated from the at 270-281nm23. Abortifacient/Oxytocic roots of the plant6. Vasicine possesses uterine Phytochemical investigations of Pharmacological activities stimulating and oxytocic activity and leaves also yielded a quinazoline alkaloid Water and alcoholic extracts of causes abortifacient effect by the release identified as 1,2,3,9-tetrahydro-5- Vasaka exerts significant of prostaglandins under the influence of methoxypyrrolo[2,1-b] quinazoline-3-ol17. pharmacological actions due to the oestrogens. The activity was found almost Addition of 2-aminobenzylamine to the presence of active constituents like similar to oxytocin29. vicinyl vicinal tricarbonyl reagent leads to vasicine and vasicinone. The In a study conducted on rats, 18 the short synthesis of vasicine . Vasicinone pharmacological activities of vasicine rabbits, hamsters and guinea pigs it was and vasicine has been determined by HPLC and vasicinone are much more as found that vasicine has uterotonic and method and studies on stability of vasicine compared to their racemic forms4. Various abortifacient effects possibly by enhancing and vasicinone in solutions and plant activities reported are: the synthesis and release of prostaglandins. 19 extracts have also been reported . The In this study dose dependent effect was treatment of vasaka cells with Antibacterial observed with effective doses ranging Chloramphenicol (100-200mg/l) Alcoholic extract of leaves between 2.5-10 mg/kg. However, antibiotic doubled the production of and roots showed antibacterial activity administration of estradiol dipropionate quinazoline alkaloids20. HPLC provides a against Staphylococcus aureus and potentiated the abortifacient effect in

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Vasicinone (a) 6-Hydroxy peganine (b) Vasicine (c)

Adhavasinone (d) Adhavasine (e) Vasicol (f)

NHCH3

N(CH3)2 N(CH ) 3 2 NHCOOCH3

Vasicolinone (g) Vasicoline (h) Adhatodine (i)

Anisotine (j) Vasicinolone (k)

Fig. 1(a-k): Quinazoline ring containing constituents of Adhatoda zeylanica

Vol 8(5) September-October 2009 551 Review Paper guinea pigs whereas treatment with aspirin chorioallantoic membrane showing ability to concentrate in the macrophages inhibited the abortifacient activity due to potent activity at a dose of 50 µg/pellet and enhance the level of lysozyme in inhibition of release of prostaglandins30. equivalent to that of hydrocortisone bronchial secretions along with level of whereas methanolic extract showed lesser Rifampicin in the lung tissue and sputum, Antitussive activity34. acting as adjunctive for the therapy of Vasicine and vasicinone showed tuberculosis39. bronchodilatory activity in vitro and Hepatoprotective bronchoconstrictory activity in vivo, The leaves showed significant Toxicity studies however, combination of both the hepatoprotective effect at a dose of Vasicine hydrochloride was alkaloids (1:1) showed bronchodilatory 50-100 mg/kg on the liver damage subjected to chronic toxicity studies in activity in vivo as well as in vitro4. induced by d-galactosamine in rats35. rats and monkeys for six months, where Evaluation of antitussive effect of the mortality and body weight of treated vasaka on anesthetized guinea pigs and Antiulcer animals were found comparable to rabbits was confirmed electrically and Leaf powder of this plant showed control. Hematological and biochemical mechanically and found to be 1/20th and considerable antiulcer activity in parameters were with in the normal 1/40th as active as codeine intravenously experimental rats in ethanol induced physiological range. No abnormality was and almost similar in activity as by oral ulceration model36. found in the major organs while carrying administration31. Kanjang, a fixed out their autopsy and histopathological combination of A. zeylanica, Antimutagenic examination indicating the relatively non Echinacea purpurea (Linn.) Antimutagenic and antioxidant toxic nature of vasicine hydrochloride40. Moench. and Eleuthrococcus status have also been attributed for senticosus Maxim. showed a significant A. zeylanica. It exerts antioxidant effect Conclusion efficacy in acute upper respiratory against lipid peroxide and xanthine The literature survey revealed that infections32. oxidase induced oxidation37. A. zeylanica is an important source of many pharmacologically and medicinally Digestive Radiomodulation important chemicals such as vasicine, Decoction of the leaves activated Leaf extract showed a vasicinone, vasicolone and other various the trypsin enzyme in in vitro studies and radiomodulatory influence against useful minor alkaloids. The thus stimulated the digestion process33. radiation induced hematological pyrroquinazoline group of alkaloids is the alterations in the peripheral blood of swiss most searched chemical constituents of Cardioprotective albino mice. A significant increase in it. The plant has been widely studied for In combination of vasicine and serum alkaline phosphatase activity and its pharmacological activities and regarded vasicinone, a significant reduction in decrease in acid phosphatase activity was as universal panacea in Ayurvedic cardiac depressant effect was observed. No observed in leaf extract pretreated medicines and finds its position as a effect was shown by vasicinone (dl-form), irradiated animals during the entire period versatile plant having a wide spectrum of however l-form was found to be weakly of study38. medicinal activities. As the global scenario effective in stimulating cardiac muscles4. is now changing towards the use of non Antituberculer toxic plant products, development of Anti-inflammatory Growth of Mycobacterium modern drugs from Vasaka should be Anti-inflammatory activity of tuberculosis was found to be inhibited emphasized. Clinical trials should be methanolic extracts (a non alkaloid by benzyl amine, ambroxol, bromhexine conducted to support its therapeutic use. fraction, saponins and the alkaloids) were (semisynthetic derivatives of vasicine) due It is also important to recognize that its evaluated by using modified hens egg to their mucolytic action. These have extracts may be effective not only in the

552 Natural Product Radiance Review Paper isolation, but may actually have a 10. Text book of Pharmacognosy, by M Ali (Ed), and vasicinone in Adhatoda vasica with modulating effect when given in CBS Publishers, New Delhi, 2nd Edn, 1998, Photo Diode Array Detection, J Liquid combination with other drugs. p. 355. Chromatogr Related Technol, 2001, 24(2), 153-159. 11. Indian Herbal Pharmacopoeia, RRL, Jammu References and IDMA, Mumbai, 1998, Vol. I, pp.1-9. 22. Francis M, Sane RT and Tipnis S, Simultaneous 1. Medicinal and Poisonous of Pakistan HPLC method for determination of by SR Baquar, Karachi Publisher, Karachi, 12. Satakopan S and Thomas PJ, Note on vasicine and glycyrrhizin from herbal Pakistan, Ist Edn, 1989, p. 95-96. adulterant of Vasaka, Indian J Pharm, preparations, Indian Drugs, 2003, 40(12), 1970, 32 (3), 66-67. 712-715. 2. Anjaria J and Bhatt G, A Glossary of Selected Indigenous of India, Nature 13. Rawat MS, Pant S, Badoni YS and Negi, 23. Das C, Poi R and Chowdhury A, HPTLC Heals, SRISTI, Ahmedabad, 1995, p. 11. Biochemical investigation of some wild fruits determination of vasicine and vasicinone in of Garhwal Himalayas, Prog Hortic, 1994, Adhatoda vasica, Phytochem Anal, 3. The Wealth of India, A Dictionary of Indian 26(1-2), 35-40. 2005, 16(2), 90-92. Raw Materials and Industrial Products — Raw 14. Bhartiya HP and Gupta PC, A chalcone 24. George M, Venkatraman PR and Pandalai KM, Materials Series, Publications & Information glycoside from the flowers of Adhatoda Directorate, Council of Scientific and Investigations on plant antibiotics, part II, A vasica, Phytochemistry, 1982, 21(1), search for antibiotic substances in some Indian Industrial Research, New Delhi, 1948, pp. 247. 31-32; Revised Edn, 1985, Vol. 1 (A), pp. medicinal plants, J Sci Ind Res, 1947, 6 B, 76-79; First Supplement series, Vol. 1 (A-Ci), 15. Singh A, Theraputic monograph- Adhatoda 42-46. 2000, p. 24. vasica, Ind-Swift Ltd, Mohali, Chandigarh, 1997, pp. 25-45. 25. Lahiri PK and Pradhan SN, Pharmacological 4. Atal CK, Chemistry and Pharmacology of investigation of vasicinol-an alkaloid from Vasicine - A new oxytocic and abortifacient, 16. Jain MP, Koul SK, Dhar KL and Atal CK, Novel Adhatoda vasica Nees, Indian J Exp Indian Drugs, 1980, 15(2), 15-18. nor-harmal alkaloid from Adhatoda Biol, 1964, 2, 219-222. vasica, Phytochemistry, 1980, 19, 5. Racle JP, Clinical and anatomopathological 1880-1882. 26. Zama MMS, Singh HP and Kumar A, Comparative studies on Adhatoda vasica effect of Bisolvon in respiratory resuscitation, 17. Chowdhury BK and Bhattacharyya AU, A Ann Anesth Francaise, 1976, 17(1), 51-58. and pancreatic tissue extract on wound further quinazoline alkaloid from Adhatoda healings in buffaloes, Indian Vet J, 1991, 6. Iyengar MA, Jambaiah KM, Kamath MS and vasica, Phytochemistry, 1985, 24, 68, 864-866. Rao GO, Studies on an antiasthma Kada, a 3080-3082. proprietary herbal combination, Part I. 18. Wasserman H and Kuo GH, The chemistry of 27. Dhar ML, Dhar MM, Dhawan BN, Mehrotra Clinical study, Indian Drugs, 1994, vicinal tricarbonyls, an efficient synthesis of BN and Ray C, Screening of Indian plants for 31,183-186. (±)-vasicine, Tetrahedron Lett, 1991, biological activity part 1, Indian J Exp Biol, 1968, 6, 232-247. 7. Shete AB, Femiforte, indigenous herbomineral 32(48), 7131-7132. formulation in the management of non- 19. Brain R and Bhupendra B, High-performance 28. Modak AT and Rao R, Hypoglycemic activity specific leucorrhoea, Doctor’s News, 1993, liquid chromatographic determination of of non-nitrogenous principle from the leaves 5, 13-14. vasicine and vasicinone in Adhatoda of Adhatoda vasica Nees, Indian J 8. Doshi MM, Vasavada SA, Joshi MD and vasica Nees, J Chromatogr, 1983, Pharm, 1996, 28, 105-106. Mody SB, Herbal cough formulations and 258(4), 183-188. process for the preparation thereof, 29. Gupta OP, Anand KK, Ghatak BJR and Atal CK, 20. Rajni M and Bhavsar GC, Adhatoda vasica Vasicine, alkaloid of Adhatoda vasica, A US Patent – 20030228383, 2003 (http:// Nees, Effect of chloramphenicol on total www.freepatentsonline.com/y2003/ promising uterotonic abortifacient, Indian alkaloids, Indian Drugs, 1993, 30, J Exp Biol, 1978, 16, 1075-1077. 0228383.html). 87-88. 9. Farnlof A, Naturlakemedel och Naturmedel, 30. Chandhoke N, Vasicine, The alkaloid of Halsokostra dets Forlag, Stockholm, 1998, 21. Srivastava S, Verma KR, Gupta MR, Singh CS Adhatoda vasica, Indian Drugs, 1982, 109, 132. and Kumar S, HPLC determination of vasicine 24(9), 425-426.

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31. Dhuley JN, Antitussive effect of Adhatoda 34. Chakraborty A and Brantner AH, Study of mice, Biol Trace Elem Res, 2006, 111 vasica extract on mechanical or alkaloids from Adhatoda vasica Nees on (1-3), 217-228. chemical stimulation-induced coughing in their antiinflammatory activity, Phytother animals, J Ethnopharmacol, 1999, 67, Res, 2001, 15(6), 532-534. 38. Kumar A, Ram J, Samarth RM and Kumar M, 361-365. Modulatory influence of Adhatoda vasica 35. Bhattacharya D, Pandit S, Jana U, Sen S Nees leaf extract against gamma irradiation in 32. Narimanian M, Badalyan M, Panosyan V, and Sur TK, Hepatoprotective activity of Swiss albino mice, Phytomedicine, 2005, Gabrielyan E, Panossian A, Wikman G and Adhatoda vasica aqueous leaf extract on 12 (4), 285-293. Wagner H, Randomized trial of a fixed d-galactosamine induced liver damage, combination (KanJang®) of herbal extracts Fitoterapia, 2005, 76, 223-225. 39. John M and Snell JC, Activity of bromhexine containing Adhatoda vasica, Echinacea and ambroxol, semisynthetic derivatives of purpurea and Eleutherococcus 36. Shrivastava N, Srivastava A, Banarjee A and vasicine from the Indian shrub Adhatoda senticosus in patients with upper respiratory Nivsarkar M, Antiulcer activity of Adhatoda vasica, against Mycobacterium tract infections, Phytomedicine, 2005, 12, vasica Nees, J Herb Pharmacother, tuberculosis in vitro, J 539-547. 2006, 6(2), 43-49. Ethnopharmacol, 1996, 50, 49-53.

33. Vijaya S and Vasudevan TN, The effect of some 37. Jahangir T, Khan TH, Prasad L and Sultana S, 40. Pahwa GS, Zutshi U and Atal CK, Chronic medicinal plants on activity of digestive Reversal of cadmium chloride-induced toxicity studies with vasicine from Adhatoda enzymes, Indian Drugs, 1994, 31, oxidative stress and genotoxicity by vasica Nees in rats and monkeys, Indian J 215-217. Adhatoda vasica extract in Swiss albino Exp Biol, 1987, 25, 467-470.

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