journal of ethnopharmacology - dskpdfugcdskpdf.unipune.ac.in/journal/uploads/ch/ch100008-a-3.pdf ·...

R

Tp

DGa

b

c

a

ARRAA

KSSSSSBAH

C

0d

Journal of Ethnopharmacology 132 (2010) 369–383

Contents lists available at ScienceDirect

Journal of Ethnopharmacology

journa l homepage: www.e lsev ier .com/ locate / je thpharm

eview

he genus Stephania (Menispermaceae): Chemical and pharmacologicalerspectives

eepak Kumar Semwala,∗, Ruchi Badonib, Ravindra Semwalc, Sudhir Kumar Kothiyalb,ur Jas Preet Singha, Usha Rawatb

Department of Chemistry, Punjab University, Sector-14, Chandigarh 160014, Punjab, IndiaDepartment of Chemistry, University of Garhwal, Srinagar 246174, Uttarakhand, IndiaFaculty of Pharmacy, Dehradun Institute of Technology, Dehradun 248009, Uttarakhand, India

r t i c l e i n f o

rticle history:eceived 13 June 2010eceived in revised form 22 August 2010ccepted 22 August 2010vailable online 27 August 2010

ey words:

a b s t r a c t

The plants of the genus Stephania (Menispermaceae) are widely distributed, and have long been usedin folk medicine for the treatment of various ailments such as asthma, tuberculosis, dysentery, hyper-glycemia, malaria, cancer and fever. Over 150 alkaloids together with flavonoids, lignans, steroids,terpenoids and coumarins have been identified in the genus, and many of these have been evaluatedfor biological activity. This review presents comprehensive information on the chemistry and pharma-cology of the genus together with the traditional uses of many of its plants. In addition, this reviewdiscusses the structure–activity relationship of different compounds as well as recent developments and

tephania species. cepharantha. glabra. japonica. venosaerberines

the scope for future research in this aspect.© 2010 Elsevier Ireland Ltd. All rights reserved.

ntiproliferativeyperglycemia

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3702. Traditional uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3703. Chemical constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

3.1. Stephania abyssinica Walp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3713.2. Stephania aculeata F. M. Bailey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3713.3. Stephania bancroftii F. M. Bailey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3713.4. Stephania brachyandra Diels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3713.5. Stephania cepharantha Hayata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3713.6. Stephania dinklagei Diels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3723.7. Stephania delovayi Diels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3723.8. Stephania elegans Hook.f. & Thoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3723.9. Stephania erecta Craib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3733.10. Stephania excentrica H. S. Lo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3733.11. Stephania glabra (Roxb.) Miers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3733.12. Stephania hernandifolia (Willd.) Walp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
3.13. Stephania intermedia H. S. Lo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.14. Stephania japonica (Thunb.) Miers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.15. Stephania longa Lour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3.16. Stephania miyiensis S. Y. Zhao & H. S. Lo . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author. Tel.: +91 9412947995.E-mail address: dr [email protected] (D.K. Semwal).

378-8741/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.oi:10.1016/j.jep.2010.08.047

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

dx.doi.org/10.1016/j.jep.2010.08.047

http://www.sciencedirect.com/science/journal/03788741

http://www.elsevier.com/locate/jethpharm

mailto:[email protected]

dx.doi.org/10.1016/j.jep.2010.08.047

370 D.K. Semwal et al. / Journal of Ethnopharmacology 132 (2010) 369–383

3.17. Stephania pierrei Diels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3753.18. Stephania gracilenta Miers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3753.19. Stephania rotunda Lour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3753.20. Stephania sasakii Hayata . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3753.21. Stephania sinica Diels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3753.22. Stephania suberosa L. L. Forman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3753.23. Stephania succifera H. S. Lo & Y. Tsoong . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3753.24. Stephania sutchuenensis H. S. Lo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3763.25. Stephania tetrandra S. Moore . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3763.26. Stephania venosa (Blume) Spreng. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376

4. Biological activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3764.1. Anti-malarial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3764.2. Antimicrobial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3764.3. Anthelmintic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3774.4. Anti-viral activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3774.5. Anti-proliferative/anti-cancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3774.6. Antipsychotic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3774.7. Apoptosis inducing effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3774.8. Multidrug resistance reversing activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3774.9. Anti-inflammatory and analgesic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3784.10. Immunomodulating activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3784.11. Antifibrotic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3784.12. Anti-hyperglycemic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3784.13. Ca2+ channel blocking activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3784.14. Acetylcholinesterase (AChE) inhibitory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3794.15. Vasodilating and hypotensive activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3794.16. Inhibition of antinociceptive effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3794.17. Acute hemodynamic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3794.18. Histamine release inhibition activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3794.19. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3794.20. Miscellaneous uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3794.21. Toxic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

5. Future perspectives and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

. . . . . .

1

fposafutc1

wtmaoSMafita

saSi

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. Introduction

The genus Stephania belongs to family Menispermaceae, a largeamily of about 65 genera and 350 species, distributed in warmerarts of the world. The members of this family are mostly herbsr shrubs but rarely trees. The plants of the genus Stephania arelender climbers with peltate and membranous leaves. The flowersre umbelliform cymes while inflorescence are axillary and arisingrom old leafless stem. These plants have recognized medicinal val-es and traditionally have been used for the treatment of asthma,uberculosis, dysentery, hyperglycemia, cancer, fever, intestinalomplaints, sleep disturbances and inflammation (Chopra et al.,958; Gaur, 1999; Kirtikar and Basu, 2004).

Over the last five decades, an extensive amount of chemicalork has been done on many of these plants because of their tradi-

ional uses which are of interest to researchers. These plants areajor sources of bioactive alkaloids such as morphines, hasub-

nalactams, hasubanans, aporphines and berberines. The majorityf the chemical work has been reported on S. tetrandra S. Moore,. cepharantha Hayata, S. glabra (Roxb.) Miers, S. japonica (Thunb.)iers and S. venosa (Blume) Spreng, and more than 70 alkaloids

long with other minor constituents have been reported from theseve species alone. Many of these plants are known for their dis-inct biological importance including antitumor and emetine typectivity (Kuroda et al., 1976; Gupta et al., 1980).

In past decade, Chinese-herb nephropathy, a progressive inter-titial nephropathy has been observed among women in Belgiumfter the intake of weight-reducing pills containing S. tetrandra. Moore. Phytochemical analyses of these pills resulted in thedentification of aristolochic acids (responsible for nephropathy)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380

instead of tetrandrine (responsible for weight reduction), confirm-ing the replacement of S. tetrandra (han fangji) by Aristolochiafangchi (guang fangji/fangchi). These are different plants and thechemical composition also different. Similarity in the nomencla-ture of both these plants was only reason behind the substitution(Vanherweghem et al., 1993; Debelle et al., 2002; Mosihuzzamanand Choudhary, 2008).

This study is an attempt to compile an up-to-date and compre-hensive review of the genus Stephania that covers its traditionalmedicinal uses, chemistry and pharmacology. Many plants of thisgenus are pharmacologically known but chemically unknown andvice-versa. Therefore, the scope of future research in this aspect isalso discussed here.

2. Traditional uses

In traditional medicine, most of the plants of the genus Stephaniahave been used to treat a wide variety of ailments such as dysen-tery, pyrexia, tuberculosis, diarrhea, dyspepsia, urinary diseases,abdominal ills, asthma, ascariasis, dysmenorrhea, indigestion,wounds, head-ache, sore-breasts and leprosy. The rhizome extractof S. glabra (Roxb.) Miers has long been used as antidysenteric,antipyretic, antiasthamatic and antituberculosis agent (Chopra etal., 1958; Kirtikar and Basu, 2004). The aqueous concoction of thepowders of the dried rhizome of S. glabra (Roxb.) Miers and aerial
root of Trichosanthes multiloba are used as an anthelmintic againstintestinal worms in Meghalaya (Northeast India) (Das et al., 2004).S. venosa (Blume) Spreng is often used as a bitter tonic (Pharadai etal., 1985). The stems of S. dinklagei Diels possess vermifuge, aphro-disiac, analgesic and sedative effects whereas the leaves has been

nopha

urdham(P1aaareIlu

3

c2wrg

3

a

3

(

D.K. Semwal et al. / Journal of Eth

sed to treat infertility in the female and impotence in the male. Theoots of S. hernandifolia (Willd.) Walp. were used in fever, diarrhea,yspepsia and urinary diseases (Chopra et al., 1958). S. rotunda Lour.as been used to treat pulmonary consumption, dysentery, fever,bdominal ills (tubers), asthma (tubers and stems), ascariasis, dys-enorrhea (stems), indigestion, wounds, head-ache, sore-breasts

leaves) and leprosy (flowers) (Chopra et al., 1958; Burkill, 1966;haet-thanesuara, 1967; Khasiphand and Suksah, 1968; Perry,980). The root of S. tetrandra S. Moore have been used in hep-tofibrogenic disease (Chen et al., 2005), it also used as diuretic,ntiphlogistic, antirheumatic (Joshi et al., 2008), antipyretic andnalgesic in China for centuries (Achike and Kwan, 2002). S. cepha-antha Hayata has been used to treat many acute and chronic dis-ases, including venomous snakebites in Japan (Kimoto et al., 1997).n Bangladesh, the vines of S. japonica (Thunb.) Miers were used foreucorrhoea, presence of semen in urine, burning sensations duringrination by Chakma and Tonchonga tribes (Hossan et al., 2010).

. Chemical constituents

The reported data showed that alkaloids are the main andommon phytochemicals of the genus Stephania. More than00 alkaloids have been isolated from this genus togetherith flavonoids, lignans, steroids, terpenoids and coumarins. The

eported phytochemicals from different plants of the genus areiven as following.

.1. Stephania abyssinica Walp.

4′-O-methylstephavanine (1) and stephavanine (2) (Dagne etl., 1993).

.2. Stephania aculeata F. M. Bailey

7-Hydroxyaporphine, (+)-laudanidine (3) and (−)-amurine (4)Blanchfield et al., 1993, 2003).

rmacology 132 (2010) 369–383 371

3.3. Stephania bancroftii F. M. Bailey

(−)-Tetrahydropalmatine (5), (−)-stephanine (6), (−)-crebanine(7), ayuthianine (8), (+)-sebiferine and (+)-stepharine (9)(Blanchfield et al., 1993, 2003; Bartley et al., 1994).

3.4. Stephania brachyandra Diels

Sinoacutine, stephanine (6), crebanine (7) and (−)-dicentrine(10) (Shulin et al., 1992).

3.5. Stephania cepharantha Hayata

Stephaoxocanine, stephaoxocanidine, romorphinane, cepha-ranthine, cepharanoline, steponine, isotetrandrine, berbamine,stecepharine, dehydroreticuline (11), magnoflorine, menisper-ine, oblongine, cyclanoline, cis-N-methylcapaurine, sinomenine,cephamerphinanine, D-glucopyranoside, 2′-N-methylisotetran-drine, N-methyl stesakine chloride (12), stesakine 9-O-�-D-glucoside (13), N-methylasimilobine-2-O-�-D-glucopyranoside(14), cephamonine, aromoline, zippelianine, cepharamine, akna-dinine (15), aknadicine (16), cephatonine, (−)-cycleanine (28),obamegine, berbamine, isocorydine, anolobine, cotypalline,
stepharine (9), (+)-reticuline (17), obaberine, homoaromoline,fangchinoline, tetrandrine (18), cephamuline (Deng et al., 1992;Nakamura et al., 1992; Sugimoto et al., 1993, 1988; Kashiwaba etal., 1996, 1997, 2000, 1998, 1994; Nakaoji et al., 1997; Tanahashiet al., 2000), berbamine and aromorine (Akasu et al., 1976).

3 nopharmacology 132 (2010) 369–383

3

i2cd2

3

(i

3

ai

72 D.K. Semwal et al. / Journal of Eth

.6. Stephania dinklagei Diels

Liriodenine (19), dicentrinone (20), (+)-corydine (21), (+)-docorydine, (−)-roemerine, N-methylliriodendronine (22),-O,N-dimethylliriodendronine (23), aloe-emodin (24), iso-orydine, aporphines, atheroospermidine, tephalagine andehydrostephalagine (Dwuma et al., 1980; Camacho et al.,000; Goren et al., 2003).

.7. Stephania delovayi Diels

Stephodeline (Il’inskaya et al., 1973), 16-oxodelavayineIl’inskaya et al., 1972), delavayine (25) (Fadeeva et al., 1971a) andsostephodeline (Perel’son et al., 1975).

.8. Stephania elegans Hook.f. & Thoms.

Epihernandolinol (26), N-methylcorydalmine (27), hasub-nonin, aknadinin (15), cyclanoline, magnoflorine, isotetrandrine,sochondodendrine and cycleanine (28) (Singh et al., 1981).

nopha

3

d(((T

3

dh1


.9. Stephania erecta Craib

Cepharanthine, (+)-2-N-methyltelobine (29), (+)-1,2-ehydrotelobine (30), (+)-2-nor-isotetrandrine, (+)-isotetrandrine,+)-2-nor-thalrugosine, (+)-thalrugosine, (+)-homoaromoline,+)-stephibaberine, (+)-dephnandrine, (+)-2-nor-cepharanthine,+)-nor-obaberine, (+)-obaberine (Likhitwitayawuid et al., 1993b;amez et al., 2005).

.10. Stephania excentrica H. S. Lo

Excentricine (31), N-methylexcentricine (32), roemerine, 4-emethylhasubanonine, oxoputerine, oxoanolobine, isoboldine,omoaromoline, (+)-coclaurine and sinococuline (Deng and Zhao,997; Miu et al., 1998).

rmacology 132 (2010) 369–383 373

3.11. Stephania glabra (Roxb.) Miers

(+)-Pronuciferine (33), gindarine, gindaricine, gin-darinine, hyndarine, magnoflorine, N-thyloxystephanine,N-methylhydoxystepharine, remerine, stephararine, cycleanine(28), rotundine, capaurine (34), corydalmine (35), stepholidine(36), stepharine (9), protoberberine, palmatine (37), dehydrocory-dalmine (38), jatrorrhizine (39), stepharanine (40), columbamine(41), N-desmethycycleanine (42), corynoxidine (43) (Chaudharyand Siddiqui, 1950; Chaudhary et al., 1952; Chopra et al., 1956;Cava et al., 1964, 1968; Kin et al., 1965; Robinovich et al., 1965;Shchelchkova et al., 1965; Doskotch et al., 1967; Dhar et al.,1968; Thu and Nuhn, 1971; Khanna et al., 1972; Patra et al.,1980; Bhakuni and Gupta, 1982; Bhakuni, 1984; Mahatma etal., 1987; Anonymous, 1989; Rastogi and Mehrotra, 1991; Duke,1992; Das et al., 2004), 11-hydroxypalmatine (44) (Semwal et al.,2010b), glabradine (45) and gindarudine (46) (Semwal and Rawat,2009a,b).

3.12. Stephania hernandifolia (Willd.) Walp.

(+)-3′,4′-Dihydrostephasubine (47), (+)-epistephanine (48),(+)-stephasubine (49) (Patra et al., 1988), l-quercitol, isotrilobine,�-sitosterol, aknadine, aknadinine (15), 4-demethylhasubanonine,dl-tetrandrine, fangchinoline (50), d-tetrandrine (18), d-isochondrodendrine, aknadicine (16) (Chopra et al., 1956; Moza,1960; Kupchan et al., 1961; Kunitomo et al., 1966, 1967, 1969;Moza and Basu, 1966; Moza and Bose, 1967; Kupchan et al.,
1968; Moza et al., 1968; Moza et al., 1970; Anonymous, 1994),hernandoline (Fadeeva et al., 1967), hernandine (Il’inskaya et al.,1971), hernandolinol (Fadeeva et al., 1970), methylhernandine(Fadeeva et al., 1971b), 3-O-demethylhernandifoline (51) (Fadeevaet al., 1972) and hernandifoline (Fesenko et al., 1971).

3 nopharmacology 132 (2010) 369–383

3

3

md(dhspm2toass11Y1S

(63) (Anonymous, 1999).


.13. Stephania intermedia H. S. Lo

(−)-Stepholidine (36) (Xin et al., 1992; Ellenbroek et al., 2006).

.14. Stephania japonica (Thunb.) Miers

16-Oxohasubonine, aknadicine (16), aknadine, 16-oxoproto-etaphanine, aknadinine (15), cyclanoline, cycleanine (28),

-fangchinoline (50), oxostephabenine (52), stephabenine53), lanuginosine (54), epistephanine, dehydroepistephanine,-tetrandrine (18), trilobine, epistephamiersine, insularine,asubanonine, hernandoline, obamegine, homoepistephanine,teponine, stephasunoline, oxostephasunoline (55), homoste-hanoline, hypoepistephanine, isochondrodendrine, oxostepha-iersine, isotrilobine, l-quercitol, metaphanine, n-nor-1,

-dehydroepistephanine, oxostephanine, plastoquinone, pro-ostephanaberrine, prometaphanine, stepinonine, stebisimine,xostephasunodine, stephanaberrine, stephanine (6), prostephan-berrine (56), stephamiersine, stephanoline, stepholine,tepisimine, viburnitol, protostephanine (57), oxoepistephamier-ine (58), oxostephamiersine, stephadiamine (Inubushi and Ibuka,977; Matsui and Watanabe, 1984; Matsui et al., 1984, 1973,982a,b; Matsui et al., 1975; Kondo et al., 1983; Taga et al., 1984;amamura and Matsui, 1985; Matsui and Yamamura, 1986; Duke,992; Hall and Chang, 1997) and bebeerine (59) (Hullatti andharada, 2010).

3.15. Stephania longa Lour

Longitherine (60), stephabyssine, stephaboline (Deng and Zhao,1993), isostephaboline, stephalonines A-I, norprostephabyssine(61), isoprostephabyssine (62), isoprostephabyssine and iso-longanone (Zhang and Yue, 2005).

3.16. Stephania miyiensis S. Y. Zhao & H. S. Lo

Tetrahydropalmatine (5), stepharine (9), corydalmine (35), jatr-orrhizine (39), stepharanine (40) and 4-O-demethyljatrorrhizine

nopha

3

((c(((oe

3

(

3

te1raf3a2

3.23. Stephania succifera H. S. Lo & Y. Tsoong


.17. Stephania pierrei Diels

(−)-Asimilobine (64), (−)-asimilobine 2-O-�-D-glucoside,−)-anonaine, (−)-isolaureline, (−)-xylopine, (−)-roemeroline,−)-dicentrine (10), (−)-nordicentrine, (−)-phanostenine,assythicine, magnoflorine, (−)-tetrahydropalmatine (5),−)-capaurine (34), (−)-thaicanine, (−)-corydalmine (35),−)-N-methyltetrahydropalmatine (65), (−)-xylopinine,−)-tetrahydrostephabine, (+)-reticuline (17), (+)-codamine, (±)-blongine, (−)-delavaine and (−)-salutaridine (Likhitwitayawuidt al., 1993a; Angerhofer et al., 1999).

.18. Stephania gracilenta Miers

Sinoacutine, isosinoacutine (66), magnoflorine and papaverine67) (Khosa et al., 1987).

.19. Stephania rotunda Lour.

Cepharamine (68), cycleanine (28), (+)-stepharine (9), (−)-etrahydropalmatine (5) (Chopra et al., 1958; Burkill, 1966; Tomitat al., 1966; Tomita and Kozuka, 1966, 1967; Phaet-thanesuara,967; Perry, 1980; Kozuka et al., 1985; Luger et al., 1998), coclau-ine, dehassiline, stepholidine (36), corynoxidine (43) (Thuy etl., 2006), stepharotudine (Hung et al., 2010), cepharanthine (69),angchinoline (50) (Gulcin et al., 2010), 5-hydroxy-6,7-dimethoxy-,4-dihydroisoquinolin-1(2H)-one, thaicanine 4-O-�-D-glucosidend (−)-thaicanine N-oxide (4-hydroxycorynoxidine) (Thuy et al.,005).

rmacology 132 (2010) 369–383 375

3.20. Stephania sasakii Hayata

Obaberine, thalrugosine, aknadinine (15), secocepharanthine,aknadilactam (70) and O-methylpunjabine (Moza et al., 1970;Kunitomo, 1985).

3.21. Stephania sinica Diels

Cepharanthine (69), runanine (71) and �-sitosterol (Min et al.,1985).

3.22. Stephania suberosa L. L. Forman

(+)-Cepharanthine (69), (+)-2-norcepharanthine (72),(+)-cepharanthine 2′-�-N-oxide, (+)-stephasubine, (+)-norstephasubine, stephasubimine (73) (Patra et al., 1986),(−)-tetrahydrostephabine, (−)-kikemanine, (−)-stephabinamine,tephabine, stephnubine, (−)-discretine, 8-oxypseudopalmatine,(−)-tetrahydropalmatrubine, (−)-stepholidine (36), (−)-capaurimine, pseudopalmatine, (−)-coreximine, stephaphylline(−)-ctytenchine, (−)-xylopinine and nordelavaine (Patra et al.,1987; Patra, 1987).

Cepharanone D, N-formyl-asimilobine, N-formyl-annonain(Yang et al., 2010a,b), crebanine (7), crebanine-N-oxide, dehydro-crebanine, tetrahydropalmatine (5), schefferine, asimilobine (Xueet al., 1986), 7-oxodehydrocaaverine, 7-oxocrebanine and aristolo-lactam I (Yang et al., 2010a,b).

3 nopha

3

3

cAaae2B2(

3

on(son(PLN

4

4

m


.24. Stephania sutchuenensis H. S. Lo

1-Nitroaknadinine (74) and aknadinine (15) (Wang et al., 1994).

.25. Stephania tetrandra S. Moore

Stephadione (75), oxonantenine (76), cassameridine, nantenine,assythicine, corydione, aristolochic acid I and II, fangchinoline-D (Chen and Chen, 1935; Chen et al., 1937; Si et al., 1992; Zhund Philipson, 1996; Kwan et al., 1996; Kim et al., 1997; Ogino etl., 1998b; Wong, 1998; Kim et al., 1999; Nan et al., 2000; Liangt al., 2002; Tsutsumi et al., 2003; Fang et al., 2005; Chiou et al.,006), fenfangjine A-C (Ogino et al., 1998a), stephaflavone A and(Si et al., 2001), fangchinoline (50), tetrandrine (18) (Lijin et al.,

009), 2-N-methyltetrandrine and (+)-2-N-merhylfangchinoline77) (Deng et al., 1990).

.26. Stephania venosa (Blume) Spreng.

(−)-O-acetylsukhodianine (78), kamaline, oxoaporphin,xostephanosine (79), (−)-crebanine (7), dehydrocreba-ine, (+)-N-carboxamidostepharine (80), (−)-kikemanine,−)-tetrahydropalmatine (5), (−)-stepharinosine (81), (+)-tepharine (9), liriodenine (19), (−)-O-methylstepharinosine,xocrebanine, dehydrostephanine, (−)-ushinsunine, oxostepha-ine, (−)-sukhodiamine, (−)-sukhodianine-�-N-oxide,−)-stephadiolamine-�-N-oxide (Guinaudeau et al., 1981, 1982;haradai et al., 1985; Charles et al., 1987; Banerji et al., 1994;ikhitwitayawuid et al., 1999), stepharanine, cyclanoline and-methyl stepholidine (Ingkaninan et al., 2006).

. Biological activities

.1. Anti-malarial activity

Four major alkaloids dehydroroemerine (DN), tetrahydropal-atine (TN) (5), xylopinine (XN) and cepharanthine (CN) (69) as

rmacology 132 (2010) 369–383

well as aqueous extract (SA) and dichloromethane extracts (SD1and SD2) from S. rotunda Lour. were tested against Plasmodium falci-parum W2 in vitro. DN, CN and SD1 were the most active against W2with IC50 values of 0.36, 0.61 �M and 0.7 �g/mL, respectively. TheirIC50 values on human monocytic THP1 cells were 10.8, 10.3 �Mand >250 �g/mL, respectively. CN, SD1 and SA were selected for invivo antimalarial testing against Plasmodium berghei in mice. Theresults of SD1 and SA at a dose of 150 mg/kg showed a decrease of89 and 74% of parasitaemia by intra-peritoneal injection and 62.5and 46.5% of parasitaemia by oral administration, respectively. Theresults for CN at a dose of 10 mg/kg showed a decrease of 47% ofparasitaemia by intra-peritoneal injection and 50% of parasitaemiaby oral administration. Drug interaction of chloroquine (CL) andmajor alkaloids indicates that CN–CL and TN–XN associationsare synergistic (Chea et al., 2007). The bisbenzylisoquinolinealkaloids from S. erecta Craib and tetrahydroprotoberberine alka-loids from S. pierrei Diels showed anti-malarial activity againstthe D6 (ED, 1540 ng/mL) and W2 (ED, 3130 ng/mL) strains ofPlasmodium falciparm having ED values of 950 and 470 ng/mLin the D6 and W2 strains, respectively. The antimalarial activityof S. pierrei Diels was attributed to the nonquaternary apor-phine alkaloids and the tetrahydroprotoberberines possessing aphenolic functionality. None of the isolates showed a degree ofselectivity comparable to that of antimalarial drugs such as chloro-quine, quinine, mefloquine, and artemisinin (Likhitwitayawuidet al., 1993a,b). Six compounds from S. dinklagei Diels

including, two zwitterionic oxoaporphine alkaloids [N-methylliriodendronine (22) and 2-O,N-dimethylliriodendronine(23)], two oxoaporphine alkaloids [liriodenine (19) and dicen-trinone (20)], one aporphine alkaloid [corydine (21)] and oneanthraquinone [aloe-emodine (24)] were tested for antiprotozoaland cytotoxic activity in vitro. N-methylliriodendronine was mostactive against Leishmania donovani amastigotes (IC50 = 36.1 �M).Liriodenine showed the highest activity against L. donovani, andP. falciparum with IC50 values of 26.16 and 15 �M, respectively.Aloe-emodin (24) was the only compound active (IC50 = 14 �M)against T.b. brucei (Camacho et al., 2000). The aqueous extract ofleaves of S. abyssinica Walp. showed significant anti-plasmodialactivity in vitro against chloroquine sensitive and resistant labora-tory adapted strains of P. falciparum with IC50 values >30 �g mL−1

(Muregi et al., 2004).

4.2. Antimicrobial activity

A hasubanalactam alkaloid, glabradine (45) isolated from thetubers of S. glabra (Roxb.) Miers was evaluated for antimicro-bial activity against Staphylococcus aureus, S. mutans, Microsporumgypseum, M. canis and Trichophyton rubrum and displayed potentantimicrobial activity superior to those of novobiocin and ery-thromycin with IZD values of 19–27 cm (Semwal and Rawat,
2009a,b). An ethanolic extract was also evaluated for its antimi-crobial activity against five bacterial species (S. aureus, S. mutans, S.epidermidis, Escherichia coli and Klebsiella pneumonia) and six fungalspecies (Aspergillus niger, A. fumigatus, Penicillum citranum, M. gyp-seum, M. canis and T. rubrum) and found to be active against most

nopha

o((CCla

4

M(A(ic7ngr

4

Hac1dtlmaome

4

aWotirShscfiAolaettidwb1s


f the tested microorganisms with MIC range of 50–100 �g/mLSemwal et al., 2009). The methanolic root extract of S. japonicaThunb.) Miers showed significant in vitro activity together withissampelos pareira and Cyclea peltata (Hullatti and Sharada, 2007).epharanone D, N-formyl-asimilobine and N-formylannonain iso-

ated from S. succifera H. S. Lo & Y. Tsoong showed significantntimicrobial activity in vitro (Yang et al., 2010a,b).

.3. Anthelmintic activity

The alcoholic extract of the dried rhizome of S. glabra (Roxb.)iers was tested against various helminth parasites, i.e. nematode

Heterakis gallinarum, Ascaridia galli, Ancylostoma ceylanicum andscaris suum), cestode (Raillietina echinobothrida) and trematodeFasciolopsis buski) in dosages ranging between 25 and 100 mg/mLn 0.9% phosphate buffered saline (PBS, pH 7.2) at 38 ± 1 ◦C. Theontrols, kept in PBS, survived for an average 22 h (trematode),2 h (cestode) and 55 > 380 h (nematodes). The results showed pro-ounced effect on the cestode and trematode, i.e. a dose-dependentradual decline in physical motility was observed in R. echinoboth-ida and F. buski (Das et al., 2004).

.4. Anti-viral activity

The antiviral activity of methanolic extract of S. cepharanthaayata tubers, its chloroform soluble fraction (alkaloid fraction)nd the major alkaloid FK-3000 were investigated in BALB/c miceutaneously infected with HSV-1 strain 7401H. At oral doses of25 and 250 mg/kg body weight, the methanol extract significantlyelayed skin lesions on score 2 (vesicles in the local region), limitedhe development of further lesions on score 6 (mild zosteriformesion) and prolonged the mean survival time of HSV-1 infected

ice. After administration of the alkaloid fraction at doses of 25nd 50 mg/kg or FK-3000 at 10 and 25 mg/kg, similar results werebtained. Although the alkaloid improved the survival of infectedice, it had a narrow therapeutic index (Nawawi et al., 2001; Liu

t al., 2004; Zhang et al., 2005).

.5. Anti-proliferative/anti-cancer activity

Four alkaloids (dl-tetrandrine, fangchinoline (50), d-tetrandrinend d-isochondrodendrine) isolated from S. hernandifolia (Willd.)alp. showed significant cytotoxicity against human carcinoma

f the nasopharynx carried in tissue culture (KB), and that dl-etradrine and d-tetrandrine showed significant inhibitory activityn vivo against the Walker 256 intramuscular carcinosarcoma in theat (Kupchan et al., 1968). Ethanolic extract of S. venosa (Blume)preng. bulb was tested for antiproliferative activity against SKBR3uman breast adenocarcinoma cell line using MTT assay andhowed activity in potential range for further investigation on can-er cells (Moongkarndi et al., 2004). Aporphine alkaloid isolatedrom S. venosa (Blume) Spreng. exhibited antiproliferation activ-ty on SKOV3 human ovarian cancer cell line using MTT assay.porphine showed strong inhibition activity with an ED50 valuef 6 �g/mL (Montririttigri et al., 2008). Four bisbenzylisoquino-ine alkaloids (cepharanthine (69), cepharanoline, isotetrandrinend berbamine) from S. cepharantha Hayata showed significantffects on proliferation of culture cell from the murine skin inhe range of 0.01–0.1 �g/mL (Nakaoji et al., 1997). Cepharan-hine (CN) inhibits tumor promotion after topical applicationn two-stage carcinogenesis in mouse skin. Epidermal ornithine
ecarboxylase activities inhibited by topical application of CN,ith 5 mg/mouse) and mezerein (5 mg/mouse) were found to
e inhibited by topical application of CN, with a ED50 values of.2 mM and 1.4 mM, respectively. A diet containing 0.005% CNlightly suppressed the two-stage promotion of skin tumors by

rmacology 132 (2010) 369–383 377

twice-weekly applications of 2.5 Mg TPA for 2 weeks (first stage)followed by twice-weekly applications of 2.5 Mg mezerein for23 weeks (second stage) in ICR mice following initiation by 50Mg 7,12-dimethylbenz[a]anthracene. Oral administration of CNinhibits the tumor promotion in two-stage carcinogenesis in mouseskin (Yasukawa et al., 1991). S. tetrandra S. Moore demonstratedantiproliferative and proapoptotic activities in a rat hepatic stel-late cell line, HSC-T6 (Chor et al., 2005). The extract, as well astwo aporphine alkaloids, (−)-asimilobine-2-O-�-D-glucoside and(−)-nordicentrine from S. pierrei Diels, and (+)-2-N-methyltelobinefrom S. errecta Craib showed potent cytotoxic activity againstthe KB (ED50 3.6 �g/mL) and P-388 (ED50 0.8 �g/mL) cell sys-tems. It was found that the cytotoxicity of S. pierrei Diels wasmainly due to the presence of the aporphine alkaloids containingthe 1,2-methylenedioxy group (Likhitwitayawuid et al., 1993a,b;Angerhofer et al., 1999). Five compounds (7-oxodehydrocaaverine,7-oxocrebanine, dehydrocrebanine, crebanine and aristololactamI) from the tuber of S. succifera H. S. Lo & Y. Tsoong were evalu-ated for their cytotoxic activity by MTT assay. Dehydrocrebanineand crebanine showed inhibitory activity towards chronic myel-ogenous leukemia (K562), human gastric carcinoma (SGC-7901)and human hepatoma (SMMC-7721) cell lines (Yang et al., 2010a,b).Aqueous extract of S. venosa (Blume) Spreng. tubers was studied forcytotoxic activity on human peripheral blood mononuclear cells(PBMCs) and showed activity with IC50 value of 300 mg/mL. Theeffect of the extract on apoptotic induction was also evaluated at theconcentration of 300 mg/mL on PMBCs from healthy subjects andfrom cervical cancer patients and significantly induced apoptosis ofthe PBMCs from both healthy subjects and from the patients. Theantiproliferative effect was also evaluated on the cells from healthysubjects and demonstrated activity with IC50 value of 40 mg/mL(Sueblinvong et al., 2007).

4.6. Antipsychotic activity

(−)-Stepholidine (SPD) isolated from S. intermedia H. S. Lo, whichbinds to the dopamine D1 and D2 like receptors has been evalu-ated for its antipsychotic effects in animal models. The effects ofSPD, clozapine and haloperidol in increasing forelimb and hindlimbretraction time in the paw test and in reversing the apomorphineand MK801-induced disruption of prepulse inhibition was investi-gated. In the paw test, clozapine and SPD increased the hind limbretraction time. In the prepulse inhibition paradigm, all three drugsreverse the apomorphine-induced disruption in prepulse inhibi-tion, while none of the drugs could reverse the MK801-induceddisruption. SPD even slightly, but significantly potentiated theeffects of MK801 (Ellenbroek et al., 2006).

4.7. Apoptosis inducing effect

Apoptosis inducing effect of tetrandrine (TN), a bisbenzyliso-quinoline alkaloid derived from S. tetrandra S. Moore on activatedhepatic stellate cells of rat has been examined. The hepatic stel-late cells transformed by Simian virus 4 (T-HSC/CL-6) to overcomethe limitations inherent in studying primary cultures of hep-atic stellate cells. TN treatment at doses of 25 and 50 �g/mL for12 h induced apoptosis as confirmed by DNA fragmentation andincreased sub-G1 DNA content. TN also induced the activationof capase-3 protease and subsequent proteolytic cleavage of poly(ADP-ribose) polymerase (Zhao et al., 2004).

4.8. Multidrug resistance reversing activity

An alkaloidal extract of the vines of S. japonica (Thunb.) Miersshowed multidrug resistance reversing activity as demonstratedby the bicinchoninic acid assay. Insotrilobine and trilobine from

3 nopha

ti(toapastata

4

SImwiasciusadtrhifagp1(wga

4

dtaratnc1eseiapdtmr


he plant were shown to be as active as verapamil (standard)n reversing doxorubicin resistance in human breast cancer cellsMCF-7 cells). Isotrilobine has MDR-reversing activity comparableo verapamil at concentrations less than the ED20 of isotrilobinen MCF-7/ADR cells. Trilobine has low activity with a slope of 28s compared with slopes of 211 and 232 for isotrilobine and vera-amil, respectively. The greater efficacy of isotrilobine to trilobineppears to be a result of the methyl group at N-2′. This is the onlytructural difference between the two compounds and suggestshat a tertiary amine is preferred at this position to a secondarymine. The slightly increased lipophilicity induced by the addi-ion of another methyl group may also contribute to the increasedctivity (Hall and Chang, 1997).

.9. Anti-inflammatory and analgesic activity

To investigate the anti-inflammatory effects of S. tetrandra. Moore in vitro and in vivo, its effects on the production ofL-6 and inflammatory mediators were analyzed. When human

onocytes/macrophages (stimulated with silica) were treatedith 0.1–10 �g/mL the plant, the production of IL-6 was inhib-

ted up to 50%. It also suppressed the production of IL-6 bylveolar macrophages. In addition, it inhibited the release ofuperoxide anion and hydrogen peroxide from human mono-ytes/macrophages. To assess the anti-fibrosis effects of S. tetrandra,ts effects on in vivo experimental inflammatory models were eval-ated. In the experimental silicosis model, IL-6 activities in theera and in the culture supernatants of pulmonary fibroblasts werelso inhibited by it. In vitro and in vivo treatment with S. tetran-ra reduced collagen production by rat lung fibroblasts and lungissue. It also reduced the levels of serum GOT and GPT in theat cirrhosis model induced by CCl4, and was effective in reducingepatic fibrosis and nodular formation (Kang et al., 1996). The anti-

nflammatory constituents, tetrandrine (18) and fangchinoline (50)rom S. tetrandra have been shown to decrease IL-1beta, IL-6, IL-8nd TNF-alpha as well as decrease leukotriene and prostaglandineneration. Furthermore, tetrandrine has been shown to inhibit theroduction of TNF-alpha and IL-6 by microglial cells (Teh et al.,990; Xue et al., 2008). The combined analgesic effect of aconitumAc) and S. tetrandra (St) was found superior to that of Ac and Sthen used alone. The combined Ac-St showed remarkable anal-

esic activity within 3 h (p < 0.01) in rabbits and mice models (Li etl., 2000).

.10. Immunomodulating activity

S. tetrandra S. Moore has been used to treat autoimmuneiseases such as rheumatoid arthritis and systemic lupus ery-he matosus. Tetrandrine (18) has potential immunomodulatingnd anti-inflammatory effects. T-lymphocytes play a criticalole as autoactive and pathogenic population in autoimmunend inflammatory diseases. Some experimental data showedhat, through down-regulating the protein kinase C (PKC) sig-aling, interleukin-2 secretion and the expression of the Tell activation antigen (CD71), tetrandrine inhibited phorbol2-myristate 13-acetate (PMA)+ionomycin-induced T cell prolif-ration dependent on interleukin-2 receptor � chain and CD69,uch an action was unrelated to Ca2+ channel blockade (Hot al., 1999). Tetrandrine (0.1–10 �ML−1) significantly inhib-ted neutrophil-monocyte chemotactic factor-1 upregulation anddhesion to fibrinogen induced by N-formyl-methionyl-leucyl-
henylalanine and PMA. Tetrandrine at 0.1–100 �ML−1 causedose and time-dependent loss of cell viability of mouse peri-oneal macrophages, guinea-pig alveolar macrophages and mouse
acrophage-like J774 cells, reduced production of oxygen freeadical, down-regulated synthesis and release of some pro-

rmacology 132 (2010) 369–383

inflammatory cytokines (Pang and Hoult, 1997; Shen et al.,1999).

4.11. Antifibrotic effect

Antifibrotic effect of a methanol extract from S. tetrandra S.Moore on experimental liver fibrosis has been investigated. Liverfibrosis was induced by bile duct ligation and scission (BDL/S) inrats. In BDL/S rats, activity levels of aspirate transaminase, ala-nine transaminase, alkaline phosphatase, concentration of totalbilirubin in serum, and 100 mg/kg/day or 200 mg/kg/day, (p.o. for4 weeks) in BDL/S rats reduced the serum aspirate transaminase,alanine transaminase, alkaline phosphatase activity levels signifi-cantly (p < 0.01) (Nan et al., 2000).

4.12. Anti-hyperglycemic effect

The ethanolic extract of the tubers of S. glabra (Roxb.) Mierswas evaluated for its hyperglycemic effects against alloxan-induceddiabetic and significantly decreased the blood sugar level in exper-imental animals (Semwal et al., 2010a). A palmatine derivative,11-hydroxypalmatine (44) isolated from this plant was also evalu-ated for its anti-hyperglycemic activity. The test compound wasadministered at doses of 25, 50, and 100 mg/kg, p.o., 36 h afteralloxan injection (60 mg/kg, i.v.). The alloxan-induced diabetic miceshowed significant reduction in blood glucose after treatment withthe test compound by 52% as compared to the positive controlglibenclamide (54%) and the diabetic control (27%) (Semwal et al.,2010b). S. tetrandra S. Moore roots increases the blood insulin leveland reduces the blood glucose level in streptozotocin diabetic mice.Actions of bisbenzylisoquinoline alkaloids isolated from the plantwere investigated in the hyperglycemia of diabetic mice. A mainbisbenzylisoquinoline alkaloid fangchinolin (0.3–3 mg/kg) signifi-cantly reduced blood glucose level of the diabetic mice. The effectof fangchinoline was 3.9 fold greater than that of water extract(Tsutsumi et al., 2003). S. tetrandra has a direct effect on the retinalcapillary of posterior ocular region and suppressed neovascular-ization of retinal capillary in streptozotocin diabetic rats throughthe activation of tetrandrine (Liang et al., 2002). The oral adminis-tration of ethanol and aqueous extract (400 mg/kg body weight) ofpowdered corm of S. hernandifolia significantly (p < 0.05) decreasedthe blood glucose of normal and Streptozotocin-induced diabeticrats up to 12 h. Glibenclamide was used as a standard drug at a doseof 0.25 mg/kg (Sharma et al., 2010).

4.13. Ca2+ channel blocking activity

Abnormal Ca2+ signaling and elevated concentration of intra-cellular free Ca2+ are the basic pathophysiological events involvedin various diseases. As a Ca2+ antagonist, tetrandrine (S. tetrandra)can inhibit extracellular Ca2+ entry, int ervene in the distributionof intracellular Ca2+, maintain intracellular Ca2+ homeostasis, andthen disrupt the pathological processes. As shown in whole cellpatch-clamp recordings, tetrandrine blocked bovine chromaffincells voltage-operated Ca2+ channel current in a time and con-centration dependently manner. In rat phaeochromocytoma PC 12cells, 100 �mol L−1 tetrandrine abolished high K+ (30 mmol L−1)-induced sustained increase in cytoplasmic Ca2+ concentration,inhibited bombesin-induced inositol triphosphate accumulation inNIH/3T3 fibroblast and abolished Ca2+ entry (Takemura et al., 1996).Tetrandrine can affect cardiovascular electrophysiologic proper-
ties by inhibit the contractility, ±dt/dpmax, and automaticity ofmyocardium, prolong the FRP, and exert concentration-dependentnegative inotropic and chronotropic effects without altering car-diac excitability. Tetrandrine directly blocks both T-type and L-typecalcium current in ventricular cells and vascular smooth muscle

nopha

cemtCma

4

cSu(ppttna-aane

4

ftiopsvrif3(lhscbnrFcp

4

tiad6pwbds


ells, but it does not shift the I–V relationship curve of ICa. All itsffects would be beneficial in the treatment of angina, arrhyth-ias, and other cardiovascular disorders. It also directly inhibits

he activity of BKCa channel in endothelial cell line and also inhibitsa2+-release-activated channels in vessel endothelial cells, whichight significantly contribute to the change of endothelial cell

ctivity (Qian, 2002; Yao and Jiang, 2002).

.14. Acetylcholinesterase (AChE) inhibitory activity

Three quaternary protoberberine alkaloids, stepharanine,yclanoline and N-methyl stepholidine from S. venosa (Blume)preng. tuber expressed inhibitory activity on AChE with IC50 val-es of 14.10, 9.23 and 31.30 �M, respectively. The AChE inhibitorypotential drugs for Alzheimer’s disease) activity of these com-ounds was compared with those of the related compounds,almatine, jatrorrhizine and berberine, as well as with tertiary pro-oberberine alkaloids, stepholidine and corydalmine isolated fromhe same plant. The results suggest that the positive charge at theitrogen of the tetrahydroisoquinoline portion, steric substitutiont the nitrogen, planarity of the molecule or substitutions at C-2,3, -9, and -10 affect the AChE inhibitory activity of protoberberinelkaloids (Ingkaninan et al., 2006). The ethanolic extract of rootslong with the alkaloids isolated from S. rotunda Lour. showed sig-ificant AChE inhibitory activity (in vitro) using a rat cortex AChEnzyme (Hung et al., 2010).

.15. Vasodilating and hypotensive activities

Comparative studies of the effects of tetrandrine (TN) andangchinoline (FN), two major components of the Radix of S.etrandra S. Moore, on vasodilations and on calcium movementn vascular smooth muscle, and studies of hypotensive effectsn stroke-prone spontaneously hypertensive rats (SHRSP) wereerformed. TN and FN inhibited high K+ (65.4 mM) and inducedustained contraction in the rat aorta smooth muscle strips. IC50alues for TN and FN were 0.27 ± 0.05 �M and 9.53 ± 1.57 �m,espectively, and this inhibition was antagonized by increas-ng the Ca2+ concentration in the medium. The IC50 of TNor norepinephrine (NE)-induced contraction (0.86 ± 0.04 g) was.08 ± 0.05 �m, and the IC50 of FN for NE-induced contraction0.88 ± 0.07 g) was 14.20 ± 0.40 �M. At the molecular level, radio-abelled 45Ca2+ uptake tests revealed that TN and FN also inhibitedigh K+ (65.4 mM) and 1 �M NE-stimulated Ca2+ influx in rat aortatrips at the maximal concentration was needed to inhibit theontraction. TN (3 mg/kg) and FN (30 mg/kg) administered by i.v.olus injection also lowered the mean arterial pressure (MAP) sig-ificantly during the period of observation in conscious SHRSP,espectively. These results showed that TN was more potent thanN in blocking calcium channels and antihypertensive activity. Theompounds were also shown to have hypotensive effects on strokerone spontaneously hypertensive rats (Kim et al., 1997).

.16. Inhibition of antinociceptive effect

Fangchinoline (FN), a non-specific calcium antagonist, from S.etrandra S. Moore showed antagonistic activity on morphine-nduced antinociception in mice. It has been found that FN (IP)ttenuated morphine (SC)-induced antinociception in a dose-ependent manner with significant effect at doses of 30 and0 mg/kg body wt (IP) in the tail-flick test but not the tail-
inch tests. This antagonism was abolished by pretreatmentith a serotonin precursor, 5-hydroxytryptophan (5-HTP, IP),
ut not by pretreatment with a noradrenaline precursor, L-ihydroxyphenylalanine (L-DOPA, IP) in the tail-flick test. Theerotonergic pathway may be involved in the antagonism of

rmacology 132 (2010) 369–383 379

morphine-induced antinociception by FN and, in agreement withother reports, also indicates the possible dissociation of the mor-phine analgesic effect from its tolerance-development mechanism(Fang et al., 2005).

4.17. Acute hemodynamic effect

Acute hemodynamic effect of tetrandrine, isolated from S.tetrandra was assessed in anesthetized cirrhotic rats. Tetrandrinedecreases of PVP and MAP, the maximum percentage reduction ofPVP after drug was 5.4 ± 1.0%, 9.2 ± 0.8% and 23.7 ± 1.2% of baseline, respectively, for the doses given 2.0, 6.6 and 20.0 mg/kg. Totalperipheral resistance was also reduced by the drug (Huang et al.,1999).

4.18. Histamine release inhibition activity

Bisbenzylisoquinoline alkaloids from S. cepharantha Hayataroots and tubers were tested for histamine release inhibitionassay. The order of the potency of inhibitory effect was rankedas homoaromoline, aromoline, isotetrandrine, cepharanthine (69),fangchinoline (50), obaberine and tetrandrine (Nakamura et al.,1992).

4.19. Antioxidant activity

Fangchinoline (50) and cepharanthine (69) isolated from S.rotunda Lour. performing different in vitro antioxidant assays,including 1,1-diphenyl-2-picryl-hydrazyl (DPPH) free radicalscavenging, 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)(ABTS) radical scavenging, N,N-dimethyl-p-phenylenediaminedihydrochloride (DMPD) radical scavenging, superoxide anion(O2

•−) radical scavenging, hydrogen peroxide scavenging, totalantioxidant activity, reducing power, and ferrous ion (Fe2+) chelat-ing activities. Cepharanthine and fangchinoline showed 94.6 and93.3% inhibition on lipid peroxidation of linoleic acid emul-sion at 30 �g/mL concentration, respectively. On the other hand,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),�-tocopherol, and trolox indicated inhibitions of 83.3, 92.2, 72.4,and 81.3% on peroxidation of linoleic acid emulsion at the sameconcentration (30 �g/mL), respectively (Gulcin et al., 2010). Theethanol and aqueous extracts (400 mg/kg body weight) of pow-dered corm of S. hernandifolia (Willd.) Walp. strongly scavengedDPPH radicals with IC50 values of 265.33 and 217.90 �g/mL, respec-tively in vitro whereas the superoxide radical were scavenged withIC50 values of 526.87 and 440.89 �g/mL, respectively. Ascorbic acid,a natural antioxidant, was used as positive control (Sharma et al.,2010).

4.20. Miscellaneous uses

Tetrandrine (TN) from the root of S. tetrandra S Moore has beenused to treat silicosis. Except for its antiinflammatory, antifibro-genetic, immunomodulating effects and antioxidant effects, TNshows antiallergic effects, inhibitory effects on pulmonary vesselsand airway smooth muscle contraction, and platelet aggregationvia its nonspecific calcium channel antagonism that suggested itspotential in the treatment of asthma, pulmonary hypertension andchronic obstructive pulmonary disease (Xie et al., 2002). TN hasbeen used to treat silicosis, autoimmune disorders, and hyper-tension in Mainland China for decades. The accumulated studies
both in vitro and in vivo reveal that it preserves a wide vari-ety of immunosuppressive effects. Importantly, the TN-mediatedimmunosuppressive mechanisms are evidently different fromsome known DMARDs. The synergistic effects have also beendemonstrated between TN and other DMARDs like FK506 and

3 nopha

corHgiidst4wcomrmsleaadfrloofsvcati2

4

Soovchs2

5

oaSSrcaatittt


yclosporin. TN is a very potential candidate to be considered as onef DMARDs in the treatment of autoimmune diseases, especiallyheumatoid arthritis (Lai, 2002). The stem extract of S. cepharanthaayata (SC) was evaluated for its toxicity, bacteriostatic, antiphlo-istic and antalgic activity. For toxicity, SC administered to mice by.v. and i.p. routes in solution in physiological serum (water contain-ng 9 g/L of NaCl) is well tolerated and LD0 (maximum non-lethalose) was found higher than 500 mg/kg. SC exhibits a bacterio-tatic activity against Gram (+) and Gram (−) bacteria. For instancehe MIC values are 2 mg/mL on Staphylococcus aureus London and4 mg/mL on a strain of Proteus. The antiphlogistic activity of SCas studied on female rats by using phenylbutazone as a positive

ontrol and inhibits in a statistically significant manner the devel-pment of the carrageen oedema at 100 mg/kg, the action beingaximum 3 h after administration. The antalgic activity was car-

ied out by i.p. administration of SC and aspirin (standard) to maleice of 0.2 mL of an aqueous solution of acetic acid (30 g/L) and

howed significant results (Debat et al., 1980). Two aporphine alka-oids, corydine (21) and atherospermidine isolated from ethanolicxtract of the stems of S. dinklagei Diels showed DNA damagingctivity (Goren et al., 2003). Levo-tetrahydropalmatine (l-THP), anlkaloid constituent found in many plants of genus Stephania pro-uced a rightward and downward shift in the dose–response curveor cocaine self-administration and attenuated cocaine-inducedeinstatement. l-THP also reduced food-reinforced responding andocomotor activity (Mantsch et al., 2007). The effects of a leaf extractf S. hernandifolia on testicular activities in albino rats at the dosef 2 g or 4 g of leaves/mL distilled water/100 g body weight/dayor 28 days was studied. Treatment with both doses resulted inignificant reduction in relative weight in the testis, the seminalesicles, the prostate, and the epididymis without any significanthange in the liver and kidney weight. The extract reduced thectivities of testicular androgenic key enzymes and plasma level ofestosterone along with inhibition of spermatogenesis without anynduction of hepatic and renal toxicity (Ghosh et al., 2002; Jana et al.,003).

.21. Toxic effects

Apart from various medicinal uses, rare plants of the genustephania have been reported for their acute toxic effects. Theral administration of aqueous extract of wet and dry root tuberf Stephania cepharantha Hayata showed acute toxicity with LD50alue of 41.4 g/kg and 22.9 g/kg, respectively (Chen et al., 1999). S.ephalantha Hayata (root tubers) and S. epigaea H.S. Lo (root tubers)ave been recognized as toxic plants in China (Huai et al., 2010). S.inica (an shu ling) was shown to have hepatotoxicity (Haller et al.,002).

. Future perspectives and conclusion

Although, an extensive amount of research work has been donen some plants of this genus to date, but a large number of speciesre still chemically and/or pharmacologically unknown such as. brevipes Craib, S. tomentella Forman, S. glandulifera Miers and. capitata (Blume) Spreng. Consequently, a broad field of futureesearch remains possible in which the isolation of new active prin-iples from these species would be of great scientific merit. Thelkaloids are of particular interest as many are highly potent bio-ctives and perhaps responsible for most of activities shown by
he plants of this genus. However, the mechanism of their actions still unknown. Hence, a detailed study is required to understandhe structure–activity relationship of these constituents. As litera-ure showed, many plant extracts having cytotoxic activity, hence,he particular constituent responsible for the activity may be iso-
rmacology 132 (2010) 369–383

lated for further process. In addition, some plant extracts were onlyscreened for their preliminary in vitro activities, so, the advanceclinical trial of them deserves to be further investigated. Herein,we described the possible applications in clinical research but fur-ther investigations on phytochemical discovery and subsequentscreening are needed for opening new opportunities to developpharmaceuticals based on Stephania constituents.

Acknowledgements

This work was financially supported by UGC New Delhi underthe Dr. D.S. Kothari Post Doctoral Fellowship Scheme. The authorspay their sincere thanks to editor and referees of the journal, fortheir valuable suggestions to improve this article.

References

Achike, F.I., Kwan, C.Y., 2002. Characterization of a novel tetrandrine-induced con-traction in rat tail artery. Acta Pharmacologica Sinica 23, 698–704.

Akasu, M., Itokawa, H., Fujita, M., 1976. Biscoclaurine alkaloids in callus tissues ofStephania cepharantha. Phytochemistry 15, 471–473.

Angerhofer, C.K., Guinaudeau, H., Wongpanich, V., Pezzuto, J.M., Cordell, G.A., 1999.Antiplasmodial and cytotoxic activity of natural bisbenzylisoquinoline alkaloids.Journal of Natural Products 62, 59–66.

Anonymous, 1989. The Wealth of India, Row Materials vol. X (Sp-W), Publicationand Information Directorate CSIR, New Delhi, India, p. 41.

Anonymous, 1994. Indian Medicinal Plants, vol. 2, Arya Vaidya Sala, Orient Longman,India, p. 280.

Anonymous, 1999. Zhongcaoyao, 30, 250.Banerji, J., Chatterjee, A., Patra, A., Bose, P., Das, R., Das, B., Shamma, M., Tantisewie,

B., 1994. Kamaline, an unusual aporphine alkaloid, from Stephania venosa. Phy-tochemistry 36, 1053–1056.

Bartley, J.P., Baker, L.T., Carvalho, C.F., 1994. Alkaloids of Stephania bancroftii. Phyto-chemistry 36, 1327–1331.

Bhakuni, D.S., 1984. Some aspects of protoberberine alkaloids. Journal of the IndianChemical Society 61, 1016–1022.

Bhakuni, D.S., Gupta, S., 1982. The alkaloids of Stephania glabra. Journal of NaturalProducts 45, 407–411.

Blanchfield, J.T., Kitching, W., Sands, D.P.A., Thong, Y.H., Kennard, C.H.L., Byriel, K.A.,1993. Alkaloids from some Australian Stephania (Menispermaceae) species. Nat-ural Product Letters 3, 305–312.

Blanchfield, J.T., Sands, D.P.A., Kennard, C.H.L., Byriel, K.A., Kitching, W., 2003.Charecterisation of alkaloids from some Australian Stephania (Menispermaceae)species. Phytochemistry 63, 711–720.

Burkill, I.H., 1966. A Dictionary of the Economic Products of the Malay Peninsula,Kuala Lumpur. The Ministry of Agriculture and Co-operatives, Malaysia, p. 2113.

Camacho, M.R., Kirby, G.C., Warhurst, D.C., Croft, S.L., Phillipson, J.D., 2000. Oxoa-porphine alkaloids and quinines from Stephania dinklagei and evalution of theirantiprotozoal activity. Planta Medica 66, 478–480.

Cava, M.P., Nomura, K., Schlessinger, R.H., Buck, K.T., Douglas, B., Raffauf, R.F.,Weisbach, J.A., 1964. Chemical determination of the absolute configuration ofaporphines-reductive cleavage of proaporphines. Chemistry and Industry (Lon-don), 282–283.

Cava, M.P., Nomura, K., Talapatra, S.K., Mitchell, M.J., Schlessinger, R.H., Buck, K.T.,Beal, J.L., Douglas, B., Raffauf, R.F., Weisbach, J.A., 1968. Alkaloids of Stepha-nia glabra. Direct chemical correlation of the absolute configuration of somebenzyltetrahydroisoquinoline, proaporphine, and aporphine alkaloids, Newprotoberberine alkaloid. Journal of Organic Chemistry 33, 2785–2788.

Charles, B., Bruneton, J., Pharadai, K., Tantisewie, B., Guinaudeau, H., Shamma, M.,1987. Some unusual proaporphine and aporphine alkaloids from Stephaniavenosa. Journal of Natural Products 50, 1113–1117.

Chaudhary, G.R., Sharma, V.N., Dhar, M.L., 1952. The alkaloid of Stephania glabraMiers. Identity of aindarine and gindarimine with tetrahydropalmatine (5) andpalmatine respectively. Journal of Scientific and Industrial Research B 11, 337.

Chaudhary, G.R., Siddiqui, S., 1950. The alkaloids of Indian Stephanias. Pt. I. Isolationof three crystalline alkaloids from the tubers of Stephania glabra Miers. Journalof Scientific and Industrial Research B 9, 79.

Chea, A., Hout, S., Bun, S.S., Tabatadze, N., Gasquet, M., Azas, N., Elias, R., 2007.Antimalarial activity of alkaloids isolated from Stephania rotunda. Journal ofEthnopharmacology 102, 132–137.

Chen, J., Tong, Y., Zhang, X., Tian, H., Chang, Z., 1999. Acute toxicity of Stephaniacepharantha. Journal of Chinese Medicinal Materials 22, 468–469.

Chen, K., Chen, A., 1935. The alkaloids of han-fang-chi. The Journal of BiologicalChemistry 109, 681–685.

Chen, K., Chen, A., Anderson, R., Rose, C., 1937. The pharmacological action of tetran-drine, an alkaloid of han-fang-chi. Chinese Journal of Physiology 11, 13–34.

Chen, Y.W., Li, D.G., Wu, Z.X., Chen, Y.W., Lu, H.M., 2005. Tetrandrine inhibitsactivation of rat hepatic stellate cells stimulated by transforming growth factor-beta in-vitro via up-regulation of Smad 7. Journal of Ethnopharmacology 100,299–305.

nopha

C

C

C

C

D

D

D

D

D

D

D

D

D

D

D

D

E

F

F

F

F

F

F

F

G

G

G

G

G

G

G

H

H


hiou, W.F., Lee, W.S., Yeh, P.H., 2006. Tetrandrine selectively protects againstamyloid-�-protein but not against MPTP-induced cytotoxicity in SK-N-SH neu-roblastoma cells. Planta Medica 72, 1300–1304.

hopra, R.N., Chopra, I.C., Handa, K.L., Kapur, L.D., 1958. Chopra’s Indigenous Drugsof India, 2nd ed. Char UN and Sons, Ltd., Calcutta, India, p. 412.

hopra, R.N., Nayar, S.L., Chopra, I.C., 1956. Supplementary to Glossary of IndianMedicinal Plants. PID, New Delhi, India.

hor, S.Y., Hui, A.Y., To, K.F., 2005. Antiproliferative and proapoptotic effects of herbalmedicine on hepatic stellate cells. Journal of Ethanapharmacology 100, 180–186.

agne, E., Gunatilaka, A.A.L., Kingston, D.G.I., Alemu, M., 1993. 4′-O-Methylstephavanine from Stephania abyssinica. Journal of Natural Products 56,2022–2025.

as, B., Pal, P., Tandon, V., Lyndem, L.M., Kar, P.K., Rao, H.S.P., 2004. Anthelminticefficacy of extract of Stephania glabra and aerial root extract of Trichosanthesmultiloba in vitro: two indigenous plants in Shillong, India. Journal of ParasiticDiseases 28, 37–44.

ebat, J., Lemoine, J., Gabillault, F.L., 1980. Stephania cepharantha extract, its methodof preparation and its use as pharmaceutical. United States Patent 4235890.

ebelle, F.D., Nortier, J.L., De Prez, E.G., Garbar, C.H., Vienne, A.R., Salmon, I.J.,Deschodt-Lanckman, M.M., Vanherweghem, J.L., 2002. Aristolochic acids inducechronic renal failure with interstitial fibrosis in salt-depleted rats. Journal of theAmerican Society of Nephrology 13, 431–436.

eng, J.Z., Zhao, S.X., 1993. Alkaloids from aerial parts of Stephania longa. Phyto-chemistry 33, 941–942.

eng, J.Z., Zhao, S.X., 1997. 2-N-methylexcentricine, a new alkaloid from root ofStephania excentrica. Journal of Natural Products 60, 294–295.

eng, J.Z, Zhao, S.X., Lou, F., 1990. A new monoquaternqry bisbenzylisoquinolinealkakoid from Stephania testrandra. Journal of Natural Products 53, 993–994.

eng, J.Z., Zhao, S.X., Miu, Z.C., 1992. Morphinane alkaloid from roots of Stephaniacepharantha. Phytochemistry 31, 1448–1450.

har, M.L., Dhar, M.M., Dhawan, B.N., Ray, C., 1968. Screening of Indian plants forbiological activity: Part I. Indian Journal of Experimental Biology 6, 232–247.

oskotch, R.W., Malik, M.Y., Beal, J.L., 1967. The identification of dehydrocory-dalmine and a new protoberberine alkaloid, Stepharanine, in Stephnnia glabratubers. Journal of Organic Chemistry 32, 3253.

uke, J.A, 1992. Handbook of Phytochemical Constituents of GRAS Herbs and OtherEconomic Plants. CRC Press, Boca Raton, FL, USA.

wuma, B.D., Ayim, J.S.K., Withers, S.F., Agyemang, N.O., Ateya, A.M., El-Azizi, M.M.,Knapp, J.E., Slatkin, D.J., Schiff, P.L., 1980. Constituents of West African MedicinalPlants. XXVII. Alkaloids of Rhigiocarya racemifera and Stephania dinklagei. Journalof Natural Products 43, 123–129.

llenbroek, B.A., Zhang, X.X., Jin, G.Z., 2006. Effects of (−)stepholidine in animalmodels for schizophrenia. Acta Pharmacologica Sinica 27, 1111–1118.

adeeva, I.I., Fesenko, D.A., II’inskaya, T.N., Perel’son, M.E., Tolkachev, O.N., 1971b.Alkaloids of Stephania hernandifolia VIII. Methylhernandine. Chemistry of Natu-ral Compounds 7, 432–434.

adeeva, I.I., Il’inskaya, T.N., Perel’son, M.E., 1970. Alkaloids of Stephania hernandifoliaV. Structure of hernandolinol. Chemistry of Natural Compounds 6, 516.

adeeva, I.I., Il’inskaya, T.N., Perel’son, M.E., Kuzovkov, A.D., 1971a. The structureof delavayine. An alkaloid from Stephania delovayi. Chemistry of Natural Com-pounds 7, 756–761.

adeeva, I.I., Kuzovkov, A.D., Il’inskaya, T.N., 1967. Alkaloids of Stephania hernandi-folia III. Chemistry of Natural Compounds 3, 88–89.

adeeva, I.I., Perel’son, M.E., Tolkachev, O.N., 1972. Alkaloids of Stephania hernan-difolia IX. 3-O-demethylhernandifoline. Chemistry of Natural Compounds 8,136–137.

ang, L.H., Zhang, Y.H., Ku, B.S., 2005. Fangchinoline inhibited the antinociceptiveeffect of morphine in mice. Phytomedicine 12, 183–188.

esenko, D.A., Fadeeva, I.I., Il’inskaya, T.N., Perel’son, M.E., Tolkachev, O.M., 1971.Alkaloids of Stephania hernandifolia VI. Hernandifoline. Chemistry of NaturalCompounds 7, 150–154.

aur, R.D., 1999. Flora of District Garhwal North West Himalaya (With ethno botan-ical notes), 1st ed. TransMedia Srinagar Garhwal, India, pp. 76–77.

hosh, D., Jana, D., Debnath, J.M., 2002. Effects of leaf extract of Stephania her-nandifolia on testicular gametogenesis and androgenesis in albino rats: adose-dependent response study. Contraception 65, 379–384.

oren, A.C., Zhou, B.N., Kingston, D.G.I., 2003. Cytotoxic and DNA damaging activ-ity of some aporphine alkaloids from Stephania dinklagei. Planta Medica 69,867–868.

uinaudeau, H., Shamma, M., Tantisewie, B., Pharadai, K., 1981. 4,5,6,6a-Tetradehydro-N-methyl-7-oxoaporphinium salts. Journal of the ChemicalSociety, Chemical Communications, 1118.

uinaudeau, H., Shamma, M., Tantisewie, B., Pharadai, K., 1982. Aporphine alkaloidsoxygenated at C-7. Journal of Natural Products 45, 355–357.

ulcin, I., Elias, R., Gepdiremen, A., Chea, A., Topal, F., 2010. Antioxidant activ-ity of bisbenzylisoquinoline alkaloids from Stephania rotunda: cepharanthineand fangchinoline. Journal of Enzyme Inhibition and Medicinal Chemistry 25,44–53.

upta, R.S., Krepinsky, J.J., Siminovitch, L., 1980. Structural determinants respon-sible for the biological activity of (−)-emetine (−)-crytopleurine, and
(−)-tylocrebrine: structure-activity relationship among related compounds.Molecular Pharmacology 18, 136.
all, A.M., Chang, C.J., 1997. Multidrug resistance modulators from Stephania japon-ica. Journal of Natural Products 60, 1193–1195.

aller, C.A., Dyer, J.E., Ko, R.J., Olson, K.R., 2002. Making a diagnosis of herbal-relatedtoxic hepatitis. The Western Journal of Medicine 176, 39–44.

rmacology 132 (2010) 369–383 381

Ho, L.J., Chang, D.M., Lee, T.C., Chang, M.L., Lai, J.H., 1999. Plant alkaloid tetran-drine down reg ulates protein kinase C-dependent signaling pathway in T cells.European Journal of Pharmacology 367, 389–398.

Hossan, M.S., Hanif, A., Agarwala, B., Sarwar, M.S., Karim, M., Rahman, M.T., Jahan,R., Rahmatullah, M., 2010. Traditional use of medicinal plants in Bangladesh totreat urinary tract infections and sexually transmitted diseases. EthnobotanyResearch & Applications 8, 61–74.

Huai, H., Dong, Q., Liu, A., 2010. Ethnomedicinal analysis of toxic plants from fiveethnic groups in China. Ethnobotany Research & Applications 8, 169–179.

Huang, Y.T., Chang, F.C., Chen, K.J., Hong, C.Y., 1999. Acute hemodynamic effectsof tetramethylpyrazine and tetrandrine on Cirrhotic rats. Planta Medica 65,130–134.

Hullatti, K.K., Sharada, M.S., 2007. Antimicrobial activity of Cissampelos pareira.Cyclea peltata and Stephania japonica methanolic root extracts. Advances inPharmacology and Toxicology 8, 105–108.

Hullatti, K.K., Sharada, M.S., 2010. Comparative phytochemical investigation of thesources of ayurvedic drug Patha: a chromatographic fingerprinting analysis.Indian Journal of Pharmaceutical Sciences 72, 39–45.

Hung, T.M., Dang, N.H., Kim, J.C., Jang, H.S., Ryoo, S.W., Lee, J.H., Choi, J.S., Bae, K., Min,B.S. 2010. Alkaloids from roots of Stephania rotunda and their cholinesteraseinhibitory activity. Planta Medica. PMID: 20391319, in press.

Il’inskaya, T.N., Perel’son, M.E., Fadeeva, I.I., Fesenko, D.A., Tolkachev, O.N., 1972.Alkaloids of Stephania delovayi II. 16-Oxodelavayine. Chemistry of Natural Com-pounds 8, 134–135.

Il’inskaya, T.N., Perel’son, M.E., Fesenko, D.A., Tolkachev, O.N., 1973. Alkaloidsof Stephania delovayi III. Stephodeline. Chemistry of Natural Compounds 9,613–615.

Il’inskaya, T.N., Fesenko, D.A., Fadeeva, I.I., Perel’son, M.E., Tolkachev, O.N., 1971.Alkaloids of Stephania hernandifolia VII. Hernandine. Chemistry of Natural Com-pounds 7, 171–174.

Ingkaninan, K., Phengpa, P., Yuenyongsawad, S., Khorana, N., 2006. Acetyl-cholinesterase inhibitors from Stephania venosa tuber. The Journal of Pharmacyand Pharmacology 58, 695–700.

Inubushi, Y., Ibuka, T., 1977. In: Manske, R.H.F. (Ed.), The Alkaloids, vol. 16. AcademicPress, New York, USA, pp. 393–430.

Jana, D., Maiti, R., Gosh, D., 2003. Effects of Stephania hernandifolia leaf extract ontesticular activity in rats. Asian Journal of Andrology 5, 125–129.

Joshi, V.C., Avula, B., Khan, I.A., 2008. Authentication of Stephania tetrandra S. Moore(Fang Ji) and differentiation of its common adulterants using microscopy andHPLC analysis. Journal of Natural Medicines 62, 117–121.

Kang, H.S., Kim, Y.H., Lee, C.S., Lee, J.J., Choi, I., Pyun, K.H., 1996. Anti-inflammatoryeffects of Stephania tetrandra S. Moore on interleukin-6 production andexperimental inflammatory disease models. Mediators of Inflammation 5,280–291.

Kashiwaba, N., Morooka, S., Kimura, M., Murakoshi, Y., Toda, J., Sano, T., 1994. Twonew morphinane alkaloids from Stephania cepharantha Hayata (Menisperma-ceae). Chemical and Pharmaceutical Bulletin 42, 2452–2454.

Kashiwaba, N., Morooka, S., Kimura, M., Ono, M., 1996. Stephaoxocanine, a nobledihydroisoquinoline alkaloid from Stephania cepharantha. Journal of NaturalProducts 59, 803–805.

Kashiwaba, N, Morooka, S., Kimura, M., Ono, M., 1997. Stephaoxocanidine, a newisoquinolin alkaloid from Stephania cepharantha. Natural Products Letters 9,177–180.

Kashiwaba, N., Ono, M., Toda, J., Suzuki, H., Sano, T., 1998. Alkaloidal constituents ofvines of Stephania cepharantha. Natural Medicines 52, 541.

Kashiwaba, N., Ono, M., Toda, J., Suzuki, H., Sano, T., 2000. Aporphine glycosides fromStephania cepharantha seeds. Journal of Natural Products 63, 477–479.

Khanna, N.K., Madan, B.R., Mahatma, O.P., Surana, S.C., 1972. Some psychopharma-cological actions of Stephania glabra (Roxb) Miers: an Indian indigenous herb.Indian Journal of Medical Research 60, 472–480.

Khasiphand, C., Suksah, T.P., 1968. Textbook of Medicinal Education, Thonburi. Min-istry of Public Health, Nakornthon Phaesat, Thailand, p. 239.

Khosa, R.L., Mohan, Y., Wahi, A.K., 1987. Chemical studies on roots of Stephaniagracilenta. Indian Journal of Natural Products 3, 8–9.

Kim, H.S., Zhang, Y.H., Fang, L.H., Yun, Y.P., Lee, H.K., 1999. Effect of tetrandrine andfangchinoline on human platelet aggregation and thromboxane B2 formation.Journal of Ethnopharmacology 66, 241–246.

Kim, H.S., Zhang, Y.H., Oh, K.W., Ahn, H.Y., 1997. Vasodilating and hypotensive effectsof fangchinoline and tetrandrine on the rat aorta and the stroke prone sponta-neously hypertensive rat. Journal of Ethnopharmacology 58, 117–123.

Kimoto, T., Suemitsu, K., Nakayama, H., Komori, E., Ohtani, M., Ando, S., 1997. Ther-apeutic experience of venomous snakebites by the Japanese viper (Agkistrodonhalys blomhoffii) with low dose of antivenin: report of 43 consecutive cases.Nippon Geka Hokan [Archiv f r japanische Chirurgie] 66, 71–77.

Kin, F.K., Fadeeva, I.I., Il’inskaya, T.N., 1965. A study of the alkaloids of plants ofthe genus Stephania II. The alkaloids of Stephania glabra. Chemistry of NaturalCompounds 1, 308–309.

Kirtikar, K.R., Basu, B.D., 2004. Indian Medicinal Plants, vol. 1., 2nd ed. L. M. Basu,Allahabad, India, p. 94.

Kondo, S., Matsui, M., Watanabe, Y., 1983. Alkaloids from the Fruits of Stephania
japonica MIERS. I. Structure of stephabenine: a new hasubanan ester-ketal alka-loid. Chemical and Pharmaceutical Bulletin 31, 2574–2577.
Kozuka, M., Miyaji, K., Sawada, T., Tomita, M., 1985. A major alkaloid of the leavesand stems of Stephania rotunda. Journal of Natural Products 48, 341–342.

Kunitomo, J., 1985. O-methyl deoxopunjabin, a secobisbenzylisoquinoline alkaloidbearing and aryl methyl group and three other secobisbenzylisoquinoline alka-

3 nopha

K

K

K

K

K

K

K

L

L

L

L

L

L

L

L

L

M

M

M

M

M

M

M

M

M

M

M

M


loids O-methylpunjabin secocepharanthine and dihydrosecocepharanthine.Chemical and Pharmaceutical Bulletin 33, 135–143.

unitomo, J., Nagai, Y., Yuge, E., 1967. Studies on the Alkaloids of Menisperma-ceous Plants. CCXXXIV: Alkaloids of Stephania sasakii Hayata 7, Isolation of watersoluble quaternary base, Steponine. Yakugaku Zasshi 87, 1010–1011.

unitomo, J., Okamoto, Y., Yuge, E., Nagai, Y., 1969. The characterization andstructures of aknadilactam and steporphine from Stephania sasakii, Hayata.Tetrahedron Letters 10, 3287–3289.

unitomo, J., Yuge, E., Nagai, Y., 1966. Studies on the alkaloids of Menisperma-ceous plants. CCXXII: Alkaloids of Stephania sasakii Hayata 6, isolation ofN-methylpapaveraldinium (N-methylxanthalinium), a new water soluble qua-ternary base. Yakugaku Zasshi 86, 456–460.

upchan, S.M., Asbun, W.L., Thyagarajan, B.S., 1961. Menispermaceae alkaloids III.Alkaloids of Stephania hernandifolia. Journal of Pharmaceutical Sciences 50,819–822.

upchan, S.M., Suffness, M.I., White, D.N.J., McPhail, A.T., Sim, G.A., 1968. Isolationand structural elucidation of 4-demethylhasubanonine, a new alkaloid fromStephania hernandifolia. Journal of Organic Chemistry 33, 4529–4531.

uroda, H, Nakazawa, S., Katagiri, K., Shiratori, O., Konuka, M., Fujitani, K., Tomita, M.,1976. Antitumor effect of bisbenzylisoquinoline alkaloids. Chemical and Phar-maceutical Bulletin 24, 2413–2420.

wan, C.Y., Chen, Y.Y., Ma, M.F., Daniel, E.E., Hui, S.C., 1996. Tetrandrine, a cal-cium antagonist of Chinese herbal origin, interacts with vescular muscles�-adrenoceptor. Life Sciences 59, 359–364.

ai, J.H., 2002. Immunomodulatory effects and mechanisms of plant alkaloid tetran-drine in autoimmune diseases. Acta Pharmacologica Sinica 23, 1093–1101.

i, X., Zhang, S., Qin, L., Song, Z., Mao, C., Zhang, Q., 2000. Experimental study ofanalgesic effect of combined aconitum and Stephania tetrandra. Chinese Journalof Integrative Medicine 6, 111.

iang, X.C., Hagino, N., Guo, S.S., Tsutsumi, T., Kobayashi, S., 2002. Therapeuticefficacy of Stephania tetrandra S. Moore for treatment of neovascularizationof retinal capillary (retinopathy) in diabetes-in-vitro study. Phytomedicine 9,377–384.

ijin, Z., Xiao, W., Jianhua, L., Wenjuan, D., Daijie, W., Yanling, G., 2009. Use ofpH-zone refining countercurrent chromatography for preparative separation offangchinoline and tetrandrine from Stephania tetrandra. Chromatographia 69,959–962.

ikhitwitayawuid, K., Angerhofer, C.K., Chai, H., Pezzuto, J.M., Cordell, G.A., 1993a.Cytotoxic and antimalarial alkaloids from the tubers of Stephania pierrei. Journalof Natural Products 56, 1468–1478.

ikhitwitayawuid, K., Angerhofer, C.K., Cordell, G.A., Pezzuto, J.M., Ruangrungsi, N.,1993b. Cytotoxic and antimalarial bisbenzylisoquinoline alkaloids from Stepha-nia errecta. Journal of Natural Products 56, 30–38.

ikhitwitayawuid, K., Dej-ajisai, S., Jong-bunprasert, V., 1999. Antimalarials fromStephania venosa, Prismatomeris sessiliflora Diospyros montana and Murraya sia-mensis. Planta Medica 65, 754–756.

iu, X.J., Wang, Y.F., Zhang, M.Y., 2004. Study on the inhibitory effect of cepharanthineon herpes simplex type 1 virus (HSV-1) in vitro. Journal of Chinese MedicinalMaterials (Chin) 27, 107–110.

uger, P., Weber, M., Dung, N.X., Moi, L.D., Khoi, T.T., Phuong, D.L., 1998. (−)-Tetrahydropalmatine monohydrate. Acta Crystallographica C 54, 1977–1980.

ahatma, O.P., Rathore, D.S., Pancholi, N.S., 1987. Further studies on some pharma-cological action of gindarin hydrochloride, an alkaloid of Stephania glabra (Rox.)Miers. Indian Drugs 24, 537–541.

antsch, J.R., Li, S.J., Risinger, R., Awad, S., Katz, E., Baker, D.A., Yang, Z., 2007.Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement in rats. Psychopharmacology 192, 581–591.

atsui, M., Kabashima, T., Ishida, K., Takebayashi, T., Watanabe, Y., 1982a. Alka-loids of the leaves of Stephania japonica. Journal of Natural Products 45,497–500.

atsui, M., Watanabe, Y., 1984. Structure of Oxostephasunoline, a new hasubanalac-tam alkaloid from Stephania japonica. Journal of Natural Products 47, 465–469.

atsui, M, Watanabe, Y., Hinomoto, T., 1982b. Carbon-13 NMR spectra of somehasubanan alkaloids. Journal of Natural Products 45, 247–251.

atsui, M., Watanabe, Y., Ibuka, T., Tanaka, K., 1975. Constitution of four new hasub-anan alkaloids from Stephania japonica Miers. Chemical and PharmaceuticalBulletin 23, 1323–1335.

atsui, M., Watanabe, Y., Ibuka, T., Tanaka, K., 1973. Constitution of four newhasubanan alkaloids from Stephania Japonica Miers. Tetrahedron Letters 14,4263–4266.

atsui, M., Yamamura, Y., 1986. Alkaloids from the Fruits of Stephania japonica.3. Structures of prostephanaberrine and stephanaberrine, two new hasubananalkaloids. Journal of Natural Products 49, 588–592.

atsui, M., Yamamura, Y., Takebayashi, T., Iwaki, K., Takami, Y., Kunitake, K., Koga,F., Urasaki, S., Watanabe, Y., 1984. Oxoepistephamiersine, a new hasbanalactamalkaloid from Stephania japonica. Journal of Natural Products 47, 858–861.

in, Z.D, Lin, G., Xu, G.X., Munekazu, I., Toshiyuki, T., Mizuo, M., 1985. Alkaloids ofStephania sinica. Phytochemistry 24, 3084–3085.

iu, Z.C., Deng, J.H., Zhao, S.X., Feng, R., Du, Z., 1998. Structural determination andspectral assignment of an alkaloid with a novel skeleton by selective long-range
DEPT and 1D multiple relay Cosy NMR techniques. Chinese Journal of OrganicChemistry 18, 243–245.
ontririttigri, K., Moongkarndi, P., Joongsomboonkusol, S., Chitkul, B., Pattana-panyasat, K., 2008. Apoptotic activity of aporphine from Stephania venosa onhuman ovarian cancer cells. Mahidol University Journal of Pharmaceutical Sci-ences 35, 52–56.

rmacology 132 (2010) 369–383

Moongkarndi, P., Kosem, N., Luanratana, O., Jongsomboonkusol, S., Pongpan, N.,2004. Antiproliferative activity of Thai medicinal plant extracts on human breastadenocarcinoma cell line. Fitoterapia 75, 375–377.

Mosihuzzaman, M., Choudhary, M.I., 2008. Protocols on safety, efficacy, standard-ization, and documentation of herbal medicine. Pure and Applied Chemistry 80,2195–2230.

Moza, B.K., 1960. Investigations on Stephania hernandifolia. Indian Journal of Phar-macy 22, 63–65.

Moza, B.K., Basu, D.K., 1966. Investigations on Stephania hernandifolia. Indian Journalof Pharmacy 28, 338.

Moza, B.K., Bhaduri, B., Basu, D.K., Kunitomo, J., Okamoto, Y., Yuge, E.,Nagai, Y., Ibuka, T., 1970. Constitution of three new alkaloids, aknadinine(4-demethylhasubanonine), aknadicine (4-demethylnorhasubanonine), andaknadilactam (4-demethyl-16-oxohasubanonine). Tetrahedron 26, 427–433.

Moza, B.K., Bose, A.K., 1967. Investigations on Stephania hernandifolia. Indian Journalof Pharmacy 29, 342.

Moza, B.K., Bose, A.N., Chaudhry, P.K., 1968. Investigations on Stephania hernandifo-lia. Indian Journal of Pharmacy 30, 179.

Muregi, F.W., Chhabra, S.C., Njagi, E.N.M., Lang‘at-Thoruwa, C.C., Njue, W.M.,Orago, A.S.S., 2004. Anti-plasmodial activity of some Kenyan medicinal plantextracts singly and in combination with chloroquine. Phytotherapy Research18, 379–384.

Nakamura, K., Tsuchiya, S., Sugimoto, Y., Sugimura, Y., Yamada, Y., 1992. Histaminerelease inhibition activity of bisbenzylisoquinoline alkaloids. Planta Medica 58,505–508.

Nakaoji, K., Nayeshiro, H., Tanahashi, T., Su, Y., Nagakura, N., 1997. Bisben-zylisoquinoline alkaloid from Stephania cepharantha and their effects onproliferation of culture cell from the Murine hair apparatus. Planta Medica 63,425–428.

Nan, J.X., Park, E.J., Lee, S.H., Park, P.H., Kim, J.Y., Ko, G., Sohn, D.H., 2000. Antifi-brotic effect of Stephania tetrandra on experimental liver fibrosis induced bybile duct ligation and scission in rats. Archives of Pharmacal Research 23,501–506.

Nawawi, A., Nakamura, N., Meselhy, M.R., Hattori, M., Kurokawa, M., Shiraki,K., Kashiwaba, N., Ono, M., 2001. In vivo antiviral activity of Stephaniacepharantha against herpes simplex virus type-1. Phytotherapy Research 15,497–500.

Ogino, T., Sato, T., Sasaki, H., Okada, M., Maruno, M., 1998b. Studies on the crude drugcontaining angiotensin I converting enzyme inhibitors (III). On the activity ofprinciple in Stephania tetrandra S. moor and their derivatives. Natural Medicines52, 172–178.

Ogino, T., Sato, T., Sasaki, H., Sugama, K., Okada, M., 1998a. Four new bisbenzyliso-quinoline alkaloids from roots of Stephania tetrandra. Natural Medicines 52,124–129.

Pang, L., Hoult, J.R., 1997. Cytotoxicity to macrophages of tetrandrine, an antisilicosis alkaloid, accompanied by an overproduction of prostaglandins. Biochem-ical Pharmacology 53, 773–782.

Patra, A., 1987. Promorphinane and hasubanane alkaloids of Stephania suberosa.Phytochemistry 26, 2391–2395.

Patra, A., Freyer, A.J., Guinaudeau, H., Shamma, M., Tantisewie, B., Pharadai, K., 1986.The bisbenzylisoquinoline alkaloids of Stephania Suberosa. Journal of NaturalProducts 49, 424–427.

Patra, A., Ghosh, A., Mitra, A.K., 1980. Alkaloids of Stephania glabra. Planta Medica40, 333–336.

Patra, A., Montgomery, C.T., Freyer, A.J., Guinaudeau, H., Shamma, M., Tantisewie,B., Pharadai, K., 1987. The protoberberine alkaloids of Stephania suberosa. Phy-tochemistry 26, 547–549.

Patra, M., Mandal, T.K., Mukhopadhyay, P.K., Ranu, B.C., 1988. (+)-3′ ,4′-dihydrostephasubine, a bisbenzylisoquinoline alkaloid from Stephania hernan-difolia. Phytochemistry 27, 653–655.

Perel’son, M.E., Fadeeva, I.I., Il’inskaya, T.N., 1975. Alkaloids of Stephania delavayi IV.Isostephodeline 11, 197–201.

Perry, L.M., 1980. Medicinal Plants of East and Southeast Asia. MIT Press, Cambridge,UK, p. 267.

Phaet-thanesuara, P., 1967. Pramua Sapphakhun Ya Thai, (Medicinal Uses of ThaiDrugs), vol. 2, Samakhon Rongrien Phaet Phaen Boran, Bangkok, Thailand, p.208.

Pharadai, K., Pharadai, T., Tantisewie, B., Guinaudeau, H., 1985. (−)-O-Acetylsukhodianine and oxostephanosine: two new aporphinoids fromStephania venosa. Journal of Natural Products 48, 658–659.

Qian, J.Q., 2002. Cardiovascular pharmacological effects of bisbenzylisoquinolinealkaloid derivatives. Acta Pharmacologica Sinica 23, 1086–1092.

Rastogi, R.P., Mehrotra, B.N., 1991. Compendium of Indian Medicinal Plants, vol. 1.CDRI Lucknow and PID New Delhi, India, pp. 387–390.

Robinovich, I.M., Kibalchich, P.N., Fadeeva, I.I., 1965. Stephania plants as a source ofnew drugs. Aptechn Delo 14, 19–23.

Semwal, D.K., Rawat, U., 2009a. Antimicrobial hasubanalactam alkaloid from Stepha-nia glabra. Planta Medica 75, 378–380.

Semwal, D.K., Rawat, U., 2009b. Gindarudine, a novel morphine alkaloid from Stepha-nia glabra. Chinese Chemical Letters 20, 823–826.

Semwal, D.K., Rawat, U., Badoni, R., Semwal, R., Singh, R., 2010a. Anti-hyperglycemicactivity of Stephania glabra tubers in alloxan induced diabetic mice. Journal ofMedicine 11, 17–19.

Semwal, D.K., Rawat, U., Bamola, A., Semwal, R., 2009. Antimicrobial activity ofPhoebe lanceolata and Stephania glabra; preliminary screening studies. Journalof Scientific Research 1, 662–666.

nopha

S

S

S

S

S

S

S

S

S

S

S

T

T

T

T

T

T

T

T

T


emwal, D.K., Rawat, U., Semwal, R., Singh, R., Singh, G.J.P., 2010b. Anti-hyperglycemic effect of 11-hydroxypalmatine, a palmatine derivative fromStephania glabra tubers. Journal of Asian Natural Products Research 12, 99–105.

harma, U, Sahu, R.K., Roy, A., Golwala, D.K., 2010. In vivo antidiabetic and antiox-idant potential of Stephania hernandifolia in streptozotocin-induced-diabeticrats. Journal of Young Pharmacists 2, 255–260.

hchelchkova, I.I., Ilinskaya, T.N., Kuzovkov, A.D., 1965. The alkaloids of Stephaniaglabra. Chemistry of Natural Compounds 1, 210–212.

hen, Y.C., Chen, C.F., Wang, S.Y., Sung, Y.J., 1999. Impediment to calcium influx andreactive oxygen production accounts for the inhibition of neutrophil Mac-1 Up-regulat ion and adhesion by tetrandrine. Molecular Pharmacology 55, 186–193.

hulin, P., Lei, C., Guolin, Z., 1992. Studies on medicinal isoquinoline alkaloids III:alkaloids of Stephania brachyandra. Natural Product Research and Development4, 11–15.

i, D., Zhong, D., Sha, Y., Li, W., 2001. Two biflavonoids from the aerial part of Stepha-nia tetrandra. Phytochemistry 58, 563–566.

i, D.Y., Zhao, S.X., Deng, J.Z., 1992. A 4,5-dioxoaporphine from the aerial parts ofStephania tetrandra. Journal of Natural Products 55, 828–829.

ingh, R.S., Kumar, P., Bhakuni, D.S., 1981. The Alkaloids of Stephania elegans. Journalof Natural Products 44, 664–667.

ueblinvong, T., Plumchai, T., Leewanich, P., Limpanasithikul, W., 2007. Cytotoxiceffects of water extract from Stephania venosa tubers. Thai Pharmaceutical andHealth Science Journal 2, 203–208.

ugimoto, Y., Kawaminami, S., Yamada, Y., 1993. Biosynthetic relationship of aromo-line and berbamine in cultured roots of Stephania cepharantha. PhytochemicalAnalysis 4, 100–102.

ugimoto, Y., Sugimura, Y., Yamada, Y., 1988. Production of bisbenzylisoquino-line alkaloid in cultured roots of Stephania cepharantha. Phytochemistry 27,1379–1381.

aga, T., Akimoto, N., Ibuka, T., 1984. Stephadiamine, a new skeletal alkaloid fromStephania japonica, the first example of a C-norhasubanan alkaloid. Chemicaland Pharmaceutical Bulletin 32, 4223–4226.

akemura, H., Imoto, K., Ohshika, H., Kwan, C.Y., 1996. Tetrandrine as a cal-cium antagonist. Clinical and Experimental Pharmacology and Physiology 23,751–753.

amez, P.A., Lantvit, D., Lim, E., Pezzuto, J.M., 2005. Chemosensitizing action ofcepharenthine against drug-resistant human malaria, Plasmodium falciparum.Journal of Ethnopharmacology 98, 137–142.

anahashi, T., Su, Y.S., Nagakura, N., Nayeshiro, H., 2000. Quaternary isoquinolinealkaloids from Stephania cepharantha. Chemical and Pharmaceutical Bulletin 48,370–373.

eh, B.S., Seow, W.K., Li, S.Y., Thong, Y.H., 1990. Inhibition of prostaglandin andleukotriene generation by the plant alkaloids tetrandrine and berbamine. Inter-national Journal of Immunopharmacology 12, 321–326.

hu, N.V., Nuhn, P., 1971. Studies of alkaloids of Stephania glabra (Roxb.) Miers.Pharmazie 26, 504–505.

huy, T.T., Porzel, A., Franke, K., Wessjohann, L., Sung, T.V., 2005. Isoquinolone andprotoberberine alkaloids from Stephania rotunda. Pharmazie 60, 701–704.

huy, T.T., Sung, T.V., Franke, K., Wessjohann, L., 2006. Benzyl isoquinoline andtetrahydroprotoberberine alkaloids from Stephania rotunda Lour. Journal ofChemistry 44, 372–376.

omita, M., Kozuka, M., 1966. Studies on the Alkaloids of MenispermaceousPlants, CCXXVII.: Alkakloids of Stephania rotunda Loureiro. Yakugaku Zasshi 86,871–873.

rmacology 132 (2010) 369–383 383

Tomita, M., Kozuka, M., 1967. Studies on the Alkaloids of Menispermaceous Plants.CCXLV: alkaloids of Stephania cepharantha Hayata 7. Structure of Cepharamine.Yakugaku Zasshi 87, 1203–1208.

Tomita, M., Kozuka, M., Uyeo, S., 1966. Studies on the alkaloids of Menispermaceousplants. CCXXIII: Alkaloids of Stephania rotunda Loureiro. Yakugaku Zasshi 86,460–466.

Tsutsumi, T., Kobayashi, S., Liu, Y.Y., 2003. Anti-hyperglycemic effect of fangchi-noline isolated from Stephania tetrandra Radix in streptozotocin-diabetic mice.Biological and Pharmaceutical Bulletin 26, 313–317.

Vanherweghem, J.L., Depierreux, M., Tielemans, C., Abramowicz, D., Drawta, M.,Jadoul, M., Richard, C., Vendervelde, D., Verbeelen, D., Vanhaelen-Fastre, R.,Vanhaelen, M., 1993. Rapidly progressive interstitial renal fibrosis in youngwomen: association with slimming regimen including Chinese herbs. Lancet341, 387–391.

Wang, X.K., Zhao, Y.R., Zhao, T.F., Lai, S., Che, C.T., 1994. 1-Nitroaknadinine fromStephania sutchuenensis. Phytochemistry 35, 263–265.

Wong, K.K., 1998. Differential effect of tetrandrine on aortic relaxation and chrono-topic activity in rat isolated aorta and atria. Planta Medica 64, 663–665.

Xie, Q.M., Tang, H.F., Chen, J.Q., Bian, R.L., 2002. Pharmacological actions of tetran-drine in inflammatory pulmonary diseases. Acta Pharmacologica Sinica 23,1107–1113.

Xin, G., Li-Juan, C., Buda, M., Guo-Zhang, J., 1992. Effects of l-stepholidine on tyro-sine hydroxylase activity in rat corpus striatum. Acta Pharmacologica Sinica 13,289–292.

Xue, Y., Wang, Y., Feng, D.C., Xiao, B.G., Xu, L.Y., 2008. Tetrandrine suppresseslipopolysaccharide induced microglial activation by inhibiting NF-kappaB path-way. Acta Pharmacologica Sinica 29, 245–251.

Xue, Z., Zhang, P.L., Ma, J.M., 1986. Alkaloids from Stephania succifera H.S. Lo et Y-Tsoong. Acta Pharmacologica Sinica 21, 223–225.

Yamamura, Y., Matsui, M., 1985. Alkaloids from the fruits of Stephania japonica 2.Structure of oxospephabenine and N,O-dimethyloxostephine. Journal of NaturalProducts 48, 746–750.

Yang, D.L., Mei, W.L., Dai, H.F., 2010a. Cytotoxic alkaloids from the tuber of Stephaniasuccifera. Chinese Journal of Medicinal Chemistry 20, 206–210.

Yang, D.L., Mei, W.L., Wang, H., Dai, H.F., 2010b. Antimicrobial alkaloids from thetubers of Stephania succifera. Zeitschrift für Naturforschung B 65, 757–761.

Yao, W.X., Jiang, M.X., 2002. Effects of tetrandrine on cardiovascular electrophysio-logic properties. Acta Pharmacologica Sinica 23, 1069–1074.

Yasukawa, K., Takido, M., Takeuchi, M., Akasu, M., Nakagawa, S., 1991. Cepha-ranthine inhibits two-stage tumor promotion by 12-O-tetradecanoylphorbol13-acetate and mezerein on skin tumor formation in mice initiated with 7, 12-dimethylbenz[a]anthracene. Journal of Cancer Research and Clinical Oncology117, 421–424.

Zhang, C., Wang, Y., Liu, X., Lu, J., Qian, C.W., Wan, Z., Yan, X., Zheng, H., Zhang, M.,Xiong, S., Li, J., Qi, S., 2005. Antiviral activity of cepharanthine against severeacute respiratory syndrome coronavirus in vitro. Chinese Medical Journal 118,493–496.

Zhang, H., Yue, J.M., 2005. Hasubanan type alkaloids from Stephania longa. Journal
of Natural Products 68, 1201–1207.
Zhao, Y.Z., Kim, J.Y., Park, E.J., Lee, S.H., Woo, S.W., Ko, G., Sohn, D.H., 2004. Tetrandrineinduces apoptosis in hepatic stellate cells. Phytotherapy Research 18, 306–309.

Zhu, M., Philipson, J.D., 1996. Hong Kong samples of the traditional Chinese medicineFang Ji contain aristolochic acid toxins. International Journal Pharmacognosy 34,283–289.

journal of ethnopharmacology - dskpdfugcdskpdf.unipune.ac.in/journal/uploads/ch/ch100008-a-3.pdf ·...

Documents