HEALTH EFFECTS

IV. HEALTH EFFECTS

A detailed clinical trial took place in 1998 with use of crude extract prepared from whole herb of B. hancei against chronic hepatitis (67). A total of 174 patients with chronic hepatitis B were treated thrice daily with 5 g of the extract at Yunnan Nanjiang Hospital, Yunnan Province, China. All patients were diagnosed with chronic hepatitis B based on the clinical criteria. Of 174 patients aged 7–65 years, 116, 73, and 29 patients have had the disease for 6–

12, 18–24, and more than 24 months, respectively. A total of 146 patients were successfully treated (67%), 70 felt better, but 2 showed no therapeutic effect. It was demonstrated that the extract could significantly inhibit HBV replica- tion and decrease HBsAg, HBeAg, HBV DNA, and IgM anti-HBc levels by 32.6%, 38.5%, 61.0%, and 48.4%, respectively. The extract also significantly reduced SGPT and modulated the immunological function of the treated patients. Moreover, the extract was confirmed to have anti-inflammatory, anti-infective, immunomodulatory, and antivirus activities in animal models. No toxic effect was observed in the patients and animals treated with the B. hancei extract at the same doses.

V. CONCLUSION AND COMMENT Modern physical and chemical analyses as well as in vitro and in vivo

bioassays provide powerful tools for a better understanding of the chemical and biological aspects of B. hancei. Phenylpropanoid glycosides are the major constituents of B. hancei and are believed to be responsible for the various actions of this herbal medicine. Although acteoside is a representative main constituent of the phenylethanoids present in the species, the efficacy of B. hancei is ascribable to a complex mixture of phytochemicals in the herb.

In follow-up biomedical research of B. hancei aimed at finding new drug(s), the following fundamental issues must be considered:

1. Source materials: Each batch of B. hancei must be properly iden- tified by botanically well-trained personnel; it is important to set up quality standards for the herb including morphological in- spection, microscopic examination, chemical and physical analyses

698 Tan and Kong

as well as quantification of major and preferably activity-related component(s).

2. Standardization: B. hancei contains many phytochemicals, some of which such as phenylpropanoid glycosides are known to be associated with activities of the herb extract. However, some minor constituents of the species remain to be characterized. It is thus recommended that the levels of active or key components such as acteoside, preferably along with a chemical fingerprint, be used as indicators of the herb extract for quality and consistency controls.

3. Biological assays: The chemical profile derived from the species by itself is insufficient for the understanding of its efficacy. This is where biochemistry, molecular biology, and cell biology are invalu- able in establishing quantifiable and reproducible assays. Moreover, the chemical fingerprint is important to link these biological assays and provide assurance of efficacy and consistency. In addition, it must be kept in mind that the in vitro and in vivo assays may not be consistent with the clinical results.

4. Clinical studies: It is important that clinical trials for the herb be designed in a manner that reflects the above requirements. The acceptable standard for clinical tests recommends a randomized and double-blind placebo trial with clinical indicators showing statistically significant differences between treatment and placebo groups.

REFERENCES 1. Kunming Department of Health. Yunnan Zhongcaoyao Xuan, Kunming:

Kunming Press, 1970:659–660. 2. Jiangsu College of New Medicine. The Dictionary of the Traditional Chinese Medicine. 1st ed. Shanghai: Shanghai Press of Science & Technology, 1977: 2204–2205. 3. He ZD, Wang DZ, Yang CR. Phenylpropanoid glycosides from Brandisia hancei . Acta Botan Yunnan 1990; 12:439–446. 4. He ZD, Yang CR. Brandioside, a phenylpropanoid glycoside from Brandisia hancei . Phytochemistry 1991; 30:701–702. 5. Kong LD, Wolfender JL, Cheng CH, Hostettmann K, Tan RX. Xanthine oxidase inhibitors from Brandisia hancei. Planta Med 1999; 65:744–746. 6. Zhou YC, Zheng RL. Phenolic compounds and an analog as superoxide anion scavengers and antioxidants. Biochem Pharmacol 1991; 42:1177–1179. 7. Shi Y, Wang W, Fan B, Jia Z, Yao S, Zheng R. Fast repair of dAMP radical anions by phenylpropanoid glycosides and their analogs. Biochim Biophys Acta 2000; 1474:383–389.

Brandisia hancei 699 8. Li YM, Han ZH, Jiang SH, Jiang Y, Yao SD, Zhu DY. Fast repairing of oxidized

OH radical adducts of dAMP and dGMP by phenylpropanoid glycosides from Scrophularia ningpoensis Hemsl. Acta Pharmacol Sin 2000; 21:1125–1128. 9. Li W, Zheng R, Su B, Jia Z, Li H, Jiang Y, Yao S, Lin N. Repair of dGMP hydroxyl radical adducts by verbascoside via electron transfer: a pulse radiolysis study. Int J Radiat Biol 1996; 69:481–485. 10. Li J, Wang PF, Zheng R, Liu ZM, Jia Z. Protection of phenylpropanoid glycosides from Pedicularis against oxidative hemolysis in vitro. Planta Med 1993; 59:315–317. 11. Braca A, De Tommasi N, Di Bari L, Pizza C, Politi M, Morelli I. Antioxidant principles from Bauhinia tarapotensis. J Nat Prod 2001; 64:892–895. 12. Harput US, Saracoglu I, Inoue M, Ogihara Y. Phenylethanoid and iridoid glycosides from Veronica persica. Chem Pharm Bull (Tokyo) 2002; 50:869–871. 13. Li J, Ge RC, Zheng RL, Liu ZM, Jia ZJ. Antioxidative and chelating activities of phenylpropanoid glycosides from Pedicularis striata. Zhongguo Yaoli Xuebao 1997; 18:77–80. 14. He ZD, Lau KM, Xu HX, Li PC, Pui-Hay But P. Antioxidant activity of phenylethanoid glycosides from Brandisia hancei. J Ethnopharmacol 2000; 71:483–486. 15. Xiong Q, Kadota S, Tani T, Namba T. Antioxidative effects of phenylethanoids from Cistanche deserticola. Biol Pharm Bull 1996; 19:1580–1585. 16. Wong IY, He ZD, Huang Y, Chen ZY. Antioxidative activities of phenyl- ethanoid glycosides from Ligustrum purpurascens. J Agric Food Chem 2001; 49:3113–3119. 17. Li JX, Xin D, Li H, Lu JF, Tong CW, Gao JN, Chan KM. Effect of verbascoside on decreasing concentration of oxygen free radicals and lipid peroxidation in skeletal muscle. Zhongguo Yaoli Xuebao 1999; 20:126–130. 18. Liao F, Zheng RL, Gao JJ, Jia ZJ. Retardation of skeletal muscle fatigue by the two phenylpropanoid glycosides: verbascoside and martynoside from Pedicu- laris plicata maxim. Phytother Res 1999; 13:621–623. 19. Murai M, Tamayama Y, Nishibe S. Phenylethanoids in the herb of Plantago lanceolata and inhibitory effect on arachidonic acid-induced mouse ear edema. Planta Med 1995; 61:479–480. 20. Schapoval EE, Vargas MR, Chaves CG, Bridi R, Zuanazzi JA, Henriques AT. Antiinflammatory and antinociceptive activities of extracts and isolated compounds from Stachytarpheta cayennensis. J Ethnopharmacol 1998; 60:53–59. 21. Vane JR. Nature 1994; 367:215. 22. Sahpaz S, Garbacki N, Tits M, Bailleul F. Isolation and pharmacological activity of phenylpropanoid esters from Marrubium vulgare. J Ethnopharmacol 2002; 79:389–392. 23. Xiong Q, Tezuka Y, Kaneko T, Li H, Tran LQ, Hase K, Namba T, Kadota S. Inhibition of nitric oxide by phenylethanoids in activated macrophages. Eur J Pharmacol 2000; 400:137–144. 24. Inoue M, Ueda M, Ogihara Y, Saracoglu I. Induction of cytokines by a phenylpropanoid glycoside acteoside. Biol Pharm Bull 1998; 21:1394–1395.

700 Tan and Kong 25. Pettit GR, Numata A, Takemura T, Ode RH, Narula AS, Schmidt JM, Cragg

GM, Pase CP. Antineoplastic agents. 107. Isolation of acteoside and isoacteoside from Castilleja linariaefolia. J Nat Prod 1990; 53:456–458. 26. Saracoglu I, Inoue M, Cali I, Ogihara Y. Studies on constituents with cytotoxic and cytostatic activity of two Turkish medicinal plants Phlomis armeniaca and Scutellaria salviifolia . Biol Pharm Bull 1995; 18:1396–1400. 27. Nagao T, Abe F, Okabe H. Antiproliferative constituents in the plants. 7. Leaves of Clerodendron bungei and leaves and bark of C trichotomum. Biol Pharm Bull 2001; 24:1338–1341. 28. Li J, Zheng Y, Zhou H, Su B, Zheng R. Differentiation of human gastric adenocarcinoma cell line MGc80-3 induced by verbascoside. Planta Med 1997; 63:499–502. 29. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part I). J Natl Cancer Inst 1998; 90:1529–1536. 30. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part II). J Natl Cancer Inst 1998; 90:1609–1620. 31. Ohno T, Inoue M, Ogihara Y, Saracoglu I. Antimetastatic activity of acteoside, a phenylethanoid glycoside. Biol Pharm Bull 2002; 25:666–668. 32. Inoue M, Sakuma Z, Ogihara Y, Saracoglu I. Induction of apoptotic cell death in HL-60 cells by acteoside, a phenylpropanoid glycoside. Biol Pharm Bull 1998; 21:81–83. 33. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992; 258:607–614. 34. Jaken S. Protein kinase C and tumor promoters. Curr Opin Cell Biol 1990; 2:192– 197. 35. Kiley SC, Clark KJ, Duddy SK, Welch DR, Jaken S. Increased protein kinase C in mammary tumor cells: relationship to transformation and metastatic progression. Oncogene 1999; 18:6748–6757. 36. Liu B, Honn KV. Protein kinase C inhibitor calphostin C inhibitor B16 melanoma metastasis. Int J Cancer Res 1992; 52:147–153. 37. Boscoboinik D, Szewczyk A, Hensey C, Azzi A. Inhibition of cell proliferation by a-tocopherol: role of protein kinase C. J Biol Chem 1991; 266:6188–6194. 38. Herbert JM, Maffrand JP, Taoubi K, Augereau JM, Fouraste I, Gleye J. Verbascoside isolated from Lantana camara, an inhibitor of protein kinase C. J Nat Prod 1991; 54:1595–1600. 39. Zhou BN, Bahler BD, Hofmann GA, Mattern MR, Johnson RK, Kingston DG. Phenylethanoid glycosides from Digitalis purpurea and Penstemon linarioides with PKCalpha-inhibitory activity. J Nat Prod 1998; 61:1410–1412. 40. Daels-Rakotoarison DA, Seidel V, Gressier B, Brunet C, Tillequin F, Bailleul F, Luyckx M, Dine T, Cazin M, Cazin JC. Neurosedative and antioxidant activ- ities of phenylpropanoids from Ballota nigra. Arzneimittelforschung 2000; 50:16–23. 41. Zhang F, Jia Z, Deng Z, Wei Y, Zheng R, Yu L. In vitro modulation of telomerase activity, telomere length and cell cycle in MKN45 cells by verbasco- side. Planta Med 2002; 68:115–118.

Brandisia hancei 701 42. Xiong Q, Hase K, Tezuka Y, Tani T, Namba T, Kadota S. Hepatoprotective acti

vity of phenylethanoids from Cistanche deserticola. Planta Med 1998; 64: 120–125. 43. Xiong Q, Has K, Tezuka Y, Namba T, Kadota S. Acteoside inhibits apoptosis in

D -galactosamine and lipopolysaccharide-induced liver injury. Life Sci 1999; 65:421–430. 44. Hayashi K, Nagamatsu T, Ito M, Hattori T, Suzuki Y. Acteoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent. 2. Effect of acteoside on leukocyte accumulation in the glomeruli of nephritic rats. Jpn J Pharmacol 1994; 66:47–52. 45. Hayashi K, Nagamatsu T, Ito M, Hattori T, Suzuki Y. Acetoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent: effect of acteoside on crescentic-type anti-GBM nephritis in rats. Jpn J Pharmacol 1994; 65:143–151. 46. Hayashi K, Nagamatsu T, Ito M, Yagita H, Suzuki Y. Acteoside, a component of Stachys sieboldii MIQ, may be a promising antinephritic agent. 3. Effect of aceteoside on expression of intercellular adhesion molecule-1 in experimental nephritic glomeruli in rats and cultured endothelial cells. Jpn J Pharmacol 1996; 70:157–168. 47. Hattori T, Fujitsuka N, Shindo S. Effect of acteoside on mesangial proliferation in rat anti-Thy 1 nephritis. Nippon Jinzo Gakkai Shi 1996; 38:202–212. 48. Pennacchio M, Alexander E, Chisalberti EL, Richmond GS. Cardioactive effects of Eremophila alternifolia extracts. J Ethnopharmacol 1995; 47:91–95. 49. Ahmad M, Rizwni GH, Aftab K, Ahmad VU, Gilani AH, Ahmad SP. Acteoside:

a new antihypertensive. Phytother Res 1995; 9:525–527. 50. Pennacchio M, Syah YM, Ghisalberti EL, Alexander E. Cardioactive compounds from Eremophila species. J Ethnopharmacol 1996; 53:21–27. 51. Pennacchio M, Alexander E, Syah YM, Ghisalberti EL. The effect of

verbascoside on cyclic 3V,5V-adenosine monophosphate levels in isolated rat heart. Eur J Pharmacol 1996; 305:169–171. 52. Pennacchio M, Syah YM, Alexander E, Ghisalberti EL. Mechanism of action of verbascoside on the isolated rat heart: increases in level of prostacyclin. Phytother Res 1999; 13:254–255. 53. He ZD, Huang Y, Yao X, Lau CW, Law WI, Chen ZY. Purification of phenylethanoids from Brandisia hancei and the antiproliferative effects on aortic smooth muscle. Planta Med 2001; 67:520–522. 54. Wong IY, Huang Y, He ZD, Lau CW, Chen ZY. Relaxing effects of Ligstrum purpurascens extract and purified acteoside in rat aortic rings. Planta Med 2001; 67:317–321. 55. Molnar J, Gunics G, Musci I, Koltai M, Petri I, Shoyama Y, Matsumoto M, Nishioka I. Antimicrobial and immunomodulating effects of some phenolic glycosides. Acta Microbiol Hung 1989; 36:425–432. 56. Li J, Zhao Y, Wang B, Cui J. Phenylethanoid glucosides from flos Buddlejae. Zhongguo Zhongyao Zazhi 1997; 22:613–615, 640. 57. Pardo F, Perich F, Villarroel L, Torres R. Isolation of verbascoside, an

702 Tan and Kong antimicrobial constituent of Buddleja globosa leaves. J Ethnopharmacol 1993;

39:221–222. 58. Didry N, Seidel V, Dubreuil L, Tillequin F, Bailleul F. Isolation and antibacterial activity of phenylpropanoid derivatives from Ballota nigra. J Ethnopharmacol 1999; 67:197–202. 59. Arciniegas A, Avendan˜o A, Pe´rez-Castorena AL, Romo de Vivar A. Flavonoids from Buddleja pariflora. Biochem Syst Ecol 1997; 25:185–186. 60. Avila JG, de Liverant JG, Martinez A, Martinez G, Munoz JL, Arciniegas A, Romo de Vivar A. Mode of action of Buddleja cordata verbascoside against Staphylococcus aureus . J Ethnopharmacol 1999; 66:75–78. 61. Kim HJ, Woo ER, Shin CG, Hwang DJ, Park H, Lee YS. HIV-1 integrase inhibitory phenylpropanoid glycosides from Clerodendron trichotomum. Arch Pharm Res 2001; 24:286–291. 62. Bermejo P, Abad MJ, Diaz AM, Fernandez L, Santos JD, Sanchez S, Villa- escusa L, Carrasco L, Irurzun A. Antiviral activity of seven iridoids, three saiko- saponins and one phenylpropanoid glycoside extracted from Bupleurum rigidum and Scrophularia scorodonia. Planta Med 2002; 68:106–110. 63. Yamahara J, Kitani T, Kobayashi H, Kawahara Y. Studies on Stachys sieboldii MIQ II: anti-anoxia action and the active constituents. Yakugaku Zasshi 1990; 110:932–935. 64. Kohda H, Tanaka S, Yamaoka Y, Yahara S, Nohara T, Tanimoto T, Tanaka A. Studies on lens-aldose-reductase inhibitor in medicinal plants. II Active constituents of Monochasma savatierii Franch. et Maxim. Chem Pharm Bull (Tokyo) 1989; 37:3153–3154. 65. Daels-Rakotoarison DA, Seidel V, Gressier B, Brunet C, Tillequin F, Bailleul F, Luyckx M, Dine T, Cazin M, Cazin JC. Neurosedative and antioxidant activities of phenylpropanoids from Ballota nigra. Arzneimittelforschung 2000; 50:16–23. 66. Seidel V, Bailleul F, Tillequin F. Diterpene and phenylpropanoid heteroside esters from Ballota nigra L. Ann Pharm Fr 1998; 56:31–35. 67. Huang CG, Shi TR. Efficacy of Baogan Keli (the extract of Brandisia hancei) observed in 218 patients with HBV. Zhongguo Minzu Minjian Zazhi 1998; 34:19–20.