Human Hepatitis B Virus HBV
The Hepadnaviridae family is formed by a group of highly species-specific viruses that share the presence of an endogenous DNA polymerase with reverse transcrip-tase activity [123-125] and whose genome in the mature virions is formed by a circular partially double-stranded DNA (pdsDNA) in which both strands are held together by hydrogen bonding between the 5' ends of the two strands [126]. One member of this family, the human hepatitis B virus (HBV), is characterized by its high hepatotropism. This virus belongs to the genus Orthohepadnavirus and is not cytopathic itself, although it may cause acute fulminant hepatitis [127] or chronic liver disease that may evolve into cirrhosis and, eventually, hepatocellular carcinoma [128]. In spite of the availability of an effective and safe vaccine against HBV, infection by this virus is an important worldwide health problem [129, 130]. Although several pharmacological strategies are currently being implemented to treat affected patients, no effective antiviral therapy against HBVinfection has yet been fully developed.
In a recent investigation, a group of natural products from medicinal herbs used in TCM was assayed for their anti-HBV-activity [131]. Among them, artemisinin and, in particular, its semisynthetic derivative artesunate displayed the most interesting properties. Moreover, their interest is enhanced by the existence of synergic effects with lamivudine in the absence of drug-induced toxicity in host cells, which may be an important characteristic due to the frequent problem in clinical practice of infection by lamivudine-resistant HBV strains.
The range of concentrations at which artesunate was active against HBV (> 10|M) was quite similar to that previously reported for its activity vs. human cy-tomegaloviruses [105]. Interestingly, these levels are close to the drug concentrations reached in the plasma of patients when this drug is used in antimalaria treatments (« 7|M) [132].
Similarly to artemisinin and artesunate, the model compound lamivudine induced a pronounced inhibition of HBsAg release and/or viral DNA at concentrations at which host cell viability was not affected. This effect was similar to that previously reported by other authors in HepG2 2.2.15 cells [133].
Although artesunate induced a parallel inhibition in HBsAg and HBV-DNA secretion, artemisinin-induced dose-dependent inhibition in HBsAg secretion was initially accompanied by an enhanced release of HBV-DNA (mainly rcDNA forms). This paradoxical effect was previously observed when HepG2 2.2.15 cells were treated with DNA-reactive drugs, such as Bamet-UD2 or cisplatin [134]. A similar behavior, observed under different experimental circumstances, has been suggested to be due to the inhibition of complete HBV production associated with the intra-cellular accumulation of HBV-DNA intermediates and their subsequent release into the medium [135].
11.7.3 Human Hepatitis C Virus (HCV)
Paeshuyse et al. [136] reported that the antimalarial drug artemisinin inhibits hepatitis C virus (HCV) replicon replication in a dose-dependent manner in two HCV subgenomic replicon constructs at concentrations ineffective toward Huh 5-2 host cells. Hemin, an iron donor, inhibits HCV replicon replication by inhibition of the viral polymerase [137]. The combination treatment of artemisinin and hemin caused a pronounced synergistic antiviral activity without affecting host cells.
11.7.4 Bovine Viral Diarrhea Virus (BVDV)
The Flaviviridae family includes three different genera: Pestivirus (e. g., bovine viral diarrhoea virus, BVDV); Flavivirus (e. g., Japanese encephalitis virus); and Hepacivirus (e. g., hepatitis C virus). Flaviviridae viruses constitute a major cause of disease worldwide. Thus, infection by HCV frequently causes chronic hepatitis that may progress to cirrhosis and hepatocellular carcinoma [138]. The problem is aggravated by the absence of an efficient vaccine against HCV and because currently the standard treatment, based on pegylated IFN-a and the purine nucleoside analog ribavirin (1P-,D-ribofuranosyl-1,2,4-triazole-3-carboxamide), in addition to having noxious side effects, is not efficient in approximately half of the infected patients [138]. This means that the search for more effective therapies is crucial.
Since all members of the Flaviviridae family share similarities in virion structure, genome organization, and replication machinery, some viruses, in particular BVDV, have been used as in vitro models for infection by these viruses [139]. The reason for using BVDV is that this virus is less hazardous than other members of this family because it is not infective for humans and BVDV replicates efficiently in cell culture [140]. An additional advantage is that there are two biotypes of BVDV: cytopathic and noncytopathic according to their effect on cell cultures. In contrast to infection with noncytopathic strains, infection with cytopathic BVDV leads to lysis of the host cell and hence represents a very useful tool in the investigation of the antiviral protective effect of drugs.
The findings of a recent study suggest that artemisinin is an inhibitor of the production of Flaviviridae viruses and that its effect is additive to those of IFN-a and ribavirin. The pharmacological interest of artemisinin and its derivatives for the treatment of infections by these viruses is enhanced by the facts that a large proportion of people infected with HCV do not respond to available pharmacological regimes (ranging from 20% of patients infected with genotype 3 to 80% of those infected with genotype 1b) [141].
Owing to the fact that the mechanisms of action of IFN-a [142,143] and ribavirin [143, 144] against Flaviviridae viruses are probably different from those described for artemisinin [145], there exists the possibility of additive effects of these drugs, which, indeed, were observed in the study of Romero et al. [146]. IFN binds to cell surface receptors and stimulates signal pathways that lead to the activation of cellular enzymes that repress viral replication [143], whereas ribavirin, in addition to its immunomodulatory properties, has direct antiviral activities that can be ascribed to several possible mechanisms. These include the inhibition of the HCV RNA-dependent RNA polymerase NS5B and the recently described activity as an RNA mutagen able to impair viral replication [147].
11.7.5 Other Viruses
Disbrow et al. [89] reported that dihydroartemisinin inhibited papillomavirus-induced tumor formation in vivo. Human papillomavirus-16 (HPV-16) is causatively linked with carcinogenesis [148]. This raises the question of whether dihydroarte-misinin acts on HPV-16, thereby preventing tumor development. Although dogs topically treated with dihydroartemisinin did not develop mucosal tumors, they developed antibodies against the viral L1 capsid protein, suggesting that dihy-droartemisinin had inhibited tumor growth but not early rounds of papillomavirus replication [89].
Other authors reported that artemisinins are inactive against human herpes simplex virus-6 (HHV-6), which is causatively related to the development of Kaposi's sarcoma in immunodeficiency diseases such as AIDS [149]. Artesunate was very active against human simplex virus-1 (HSV-1), weakly active against human immunodeficiency virus-1 (HIV-1), but inactive against influenza A viruses [105].
11.8 Side Effects of Artemisinin
A clinical-safety review of 108 clinical studies enrolling 9241 patients provided ample evidence that artemisinins are safe and without serious adverse events or severe significant toxicity and especially without neurotoxicity [53].
Neurotoxic effects have been repeatedly reported in experiments with mice rats, and dogs, as recently reviewed by Toovey [150]. Affected areas in the brain stem are the reticular system with autonomic control, the vestibular system, the auditory system (trapezoid nucleus), and the red nucleus, which is important for coordination [151-157]. Longer exposure times with lower peak blood concentrations are more neurotoxic than shorter durations of exposure and higher peak blood levels [158]. These animal experiments give rise to concerns about the safety of artemisinin and its derivatives in human beings.
However, few reports point to neurotoxic effects of artemether in clinical application. Van Hensbroek et al. [159] observed delayed coma recovery times (CRT) under treatment with intramuscular artemether vs. intravenous quinine in Gambian children suffering from malaria. Due to these conflicting results, Stepniewska et al.
[160] performed a meta-analysis of seven studies with 1919 malaria patients. Applying a uniform CRT definition, no significant different in CRT between artemether and quinine was found. Furthermore, no statistically significant difference with regard to neurological sequalae was observed. In a recent study by Dondorp et al.
[161], malaria patients treated with artesunate were compared with quinine-treated patients. The authors did not find significant differences of neutoxic symptoms (in terms of times to speak, eat, and sit) between both treatment groups. Neurological sequelae did not occur after treatment. Interestingly, malaria patients who developed late-onset hypoglycemia had a higher incidence of death than artesunate-treated patients without hypoglycaemia. This may be an issue that deserves further investigation in the future.
11.9 Conclusion and Perspectives
After being used in TCM for two millennia, one of the "gems" of TCM's treasure box has been rediscovered in recent years. Artemisinin is certainly one of the most promising natural products of the past two decades. With respect to malaria, it has great potential to contribute to a change in the desperate situation that the world faces. Fortunately, the value of this molecule is not limited to the treatment of malaria, and a wealth of papers has been published demonstrating the activity of artemisinin and its derivatives against cancer cells, schistosomiasis, and various viral diseases. Even more, the bioactivity of artemisinin and its derivatives is much broader (Fig. 11.2). An enlarged bioactivity profile of artemisinin and its derivatives may include the inhibition of
• Protozoans in addition to the Plasmodium or Schistosoma genus, i.e., Toxoplasma gondii [162-169], Leishmania major and L. donovani [170-173]; Trypanosoma cruzi and T. brucei rhodesiense [174], Neospora caninum [175], and Eimeria tenella [176];
• Trematodes such as Echinostoma caproni [177];
• Fungi as exemplified by Pneumocystis carinii [178], Candida albicans [179], and Cryptoccocus neoformans [180];
• Yeast (Saccharomyces cerevisiae) [65, 181]; and
• Bacteria, i.e., Leptospira serovars [182] and some anaerobic bacteria [183].
Ironically, in an age when many scientists are searching for compounds with increased specificity to their molecular and cellular targets, artemisinin is coming up
- Fig. 11.2 Bioactivity of artemisinins
with its own multifunctionality. This class of compounds seems to have many different targets against different diseases. Conceptually, modern concepts in molecular pharmacology aim to increase treatment efficacy and to decrease unwanted side effects by developing compounds that attack disease-related target molecules with high affinity. It is quite obvious that the natural evolution of pharmacologically active compounds in plants took a different path. Natural products have evolved into plants as chemical weapons to protect from infections with bacteria, viruses, and other microorganisms as well as herbivores such as insects, worms, humans, etc. It comes as no surprise that multifunctional molecules might be more versatile and, hence, more successful than mono-specific ones in protecting plants from environmental harm. In the case of artemisinin, it has been shown to be active against various plant pathogenic fungi (Gaeumannomyces graminis var. tritici, Rhizoctonia cerealis, Gerlachia nivalis, and Verticillium dahliae) [179], supporting a role of artemisinin as protective agent for plants.
References
1. Efferth T, Miyachi H, Bartsch H (2007a) Cancer Genom Proteom 4:81-91
2. Efferth T, Li PC, Konkimalla VS, Kaina B (2007b) Trends Mol Med 13:353-361
3. Efferth T, Fu YJ, Zu YG, Schwarz G, Konkimalla VS, Wink M (2007c) Curr Med Chem 14:2024-2032
4. Efferth T, Rücker G, Falkenberg M, Manns D, Olbrich A, Fabry U, Osieka R (1996) Arzneimittelforschung 46:196-200
5. Efferth T, Kaina B (2004) Cancer Genom Proteom 1:363-370
6. Efferth T, Olbrich A, Sauerbrey A, Ross DD, Gebhart E, Neugebauer M (2002a) Anticancer Res 22:4221-4224
7. Efferth T, Olbrich A, Bauer R (2002b) Biochem Pharmacol 64:617-623
8. Efferth T, Sauerbrey A, Halatsch ME, Ross DD, Gebhart E (2003a) Naunyn Schmiedebergs Arch Pharmacol 367:56-67
9. Efferth T, Rauh R, Kahl S, Tomicic M, Boechzelt H, Tome ME, Briehl MM, Bauer R, Kaina B (2005a) Biochem Pharmacol 69:811-818
10. Efferth T, Chen T, Kaina B, Wang G (2005b) Cancer Genomics Proteomics 2:115-124
11. Efferth T (2005) Oncol Rep 13:459-463
12. Rinner B, Siegl V, Pürstner P, Efferth T, Brem B, Greger H, Pfragner R (2004) Anticancer Res 24:495-500
13. Adams M, Efferth T, Bauer R (2006) Planta Med 72:862-864
14. Adams M, Mahringer A, Bauer R, Fricker G, Efferth T (2007a) Planta Med 73:1475-1478
15. Adams M, Mahringer A, Fricker G, Efferth T, Bauer R (2007b) Planta Med 73:1154-1157
16. Konkimalla VB, Efferth T (2008) Anti-cancer natural product library from traditional Chinese medicine. Combinat Chem High Throughput Screening 11:7-15
17. Konkimalla VB, Suhas VL, Chandra NR, Gebhart E, Efferth T (2007) Expert Rev Anticancer Ther 7:317-329
18. Rauh R, Kahl S, Boechzelt H, Bauer R, Kaina B, Efferth T (2007) Chin Med 2:8
19. Romero MR, Serrano MA, Efferth T, Alvarez M, Marin JJ (2007) Planta Med 73:552-558
20. Wang J, Zheng Y, Efferth T, Wang R, Shen Y, Hao X (2005) Phytochemistry 66:697-701
21. Wang YF, Cao JX, Efferth T, Lai GF, Luo SD (2006a) Chem Biodivers 3:646-653
22. Wang YF, Lai GF, Efferth T, Cao JX, Luo SD (2006b) Chem Biodivers 3:1023-1030
23. Hsu E (2006) Br J Clin Pharmacol 61:666-670
24. Klayman DL (1985) Science 228:1049-1055
25. Li Y, Wu YL (1998) Med Trop 58 Suppl 3:9S-12S
26. Yeung S, Pongtavornpinyo W, Hastings IM, Mills AJ, White NJ (2004) Am J Trop Med Hyg 71(2 Suppl):179-186
27. Semenov A, Olson JE, Rosenthal PJ (1998) Antimicrob Agents Chemother 42:2554-2558
28. Shenai BR, Sijwali PS, Singh A, Rosenthal PJ (2000) J Biol Chem 275:29000-29010
29. Berman PA, Adams PA (1997) Free Radic Biol Med 22:1283-1288
30. O'Neill PM, Posner GH (2004) J Med Chem 47:2945-2964
31. Posner GH, Oh CH (1992) J Am Chem Soc 114:8328-8329
32. Meshnick SR, Yang YZ, Lima V, Kuypers F, Kamchonwongpaisan S, Yuthavong Y (1993) Antimicrob Agents Chemother 37:1108-1114
33. Butler AR, Gilbert BC, Hulme P, Irvine LR, Renton L, Whitwood AC (1998) Free Radic Res 28:471-476
34. Shterman N, Kupfer B, Moroz C (1991) Pathobiology 59:19-25
35. Payne AG (2003) Med Hypotheses 61:206-209
36. Moore JC, Lai H, Li JR, Ren RL, McDougall JA, Singh NP, Chou CK (1995) Cancer Lett 98:83-87
37. Efferth T, Benakis A, Romero MR, Tomicic M, Rauh R, Steinbach D, Hafer R, Stamminger T, Oesch F, Kaina B, Marschall M (2004a) Free Radic Biol Med 37:998-1009
38. Aulbert E, Disselhoff W, Sorje H, Schulz E, Gericke D (1980) Eur J Cancer 16:1217-1232
39. Gatter KC, Brown G, Trowbridge IS, Woolston RE, Mason DY (1983) J Clin Pathol 36:539-545
40. Judd W, Poodry CA, Strominger JL (1980) J Exp Med 152:1430-1435
41. Trowbridge IS, Omary MB (1981) Proc Natl Acad Sci USA 78:3039-3043
42. Sutherland R, Delia D, Schneider C, Newman R, Kemshead J, Greaves M (1981) Proc Natl Acad Sci USA 78:4515-4519
43. Butler D (1997) Nature 386:535-541
44. WHO (2000) Trans R Soc Trop Med Hyg 94:S1-S75
45. White NJ (2004) J Clin Invest 113:1084-1092
46. Silachamroon U, Krudsood S, Phophak N, Looareesuwan S (2002) Korean J Parasitol 40:1-7
47. Mutabingwa TK (2005) Acta Trop 95:305-315
48. White N (1999) Philos Trans R Soc London B Biol Sci 354:739-749
49. Mishra SK, Asthana OP, Mohanty S, Patnaik JK, Das BS, Srivastava JS, Satpathy SK, Dash S, Rath PK, Varghese K (1995) Trans R Soc Trop Med Hyg 89:299-302
50. Mohanty S, Mishra SK, Satpathy SK, Satpathy S, Patnaik JK (1997) Trans R Soc Trop Med Hyg 91:328-330
51. Price R, van Vugt M, Nosten F, Luxemburger C, Brockman A, Phaipun L, Chongsupha-jaisiddhi T, White N (1998) Am J Trop Med Hyg 59:883-888
52. Mohanty S, Patel DK, Pati SS, Mishra SK (2006) Indian J Med Res 124:245-260
53. Ribeiro IR, Olliaro P (1998) Med Trop (Mars) 58:50-53
54. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N (2004) Lancet 363:9-17
55. Davies TME, Karunajeewa HA, Ilett KF (2005) Med J Aust 182:181-185
56. Bar-Zeev N, White N (2006) J Trop Pediatr 52:78-82
57. Bakshi R, Hermeling-Fritz I, Gathmann I, Alteri E (2000) Trans R Soc Trop Med Hyg 94:419-424
58. Omari AA, Gamble C, Garner P (2005) Cochrane Database Syst Rev 19:CD005564
59. Bukirwa H, Critchley J (2006) Cochrane Database Syst Rev 25:CD004966
60. Obonyo CO, Juma EA, Ogutu BR, Vulule JM, Lau J (2007) Trans R Soc Trop Med Hyg 101:117-126
61. Efferth T (2005a) Drug Resist Updat 8:85-97
62. Efferth T (2006) Curr Drug Targets 7:407-421
63. Efferth T (2007) Planta Med 73:299-309
64. Efferth T, Oesch F (2004) Biochem Pharmacol 68:3-10
65. Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR (2001) Int J Oncol 18:767-773
66. Efferth T, Davey M, Olbrich A, Rücker G, Gebhart E, Davey R (2002b) Blood Cells Mol Dis 28:160-168
67. Efferth T, Ramirez T, Gebhart E, Halatsch ME (2004b) Biochem Pharmacol 67:1689-1700
68. Efferth T, Briehl MM, Tome ME (2003b) Int J Oncol 23:1231-1235
69. Efferth T, Saüerbrey A, Olbrich A, Gebhart E, Rauch P, Weber HO, Hengstler JG, Halatsch ME, Volm M, Tew KD, Ross DD, Fünk JO (2003c) Mol Pharmacol 64:382-394
70. Efferth T, Volm M (2005) In Vivo 19:225-232
71. Aisen P (2004) Int J Biochem Cell Biol 36:2137-2143
72. Kelter G, Steinbach D, Konkimalla VB, Tahara T, Taketani S, Fiebig HH, Efferth T (2007) PLoS ONE 2:e798
74. Lai H, Sasaki T, Singh NP, Messay A (2005) Life Sci 76:1267-1279
75. Folkman J (1992) Semin Cancer Biol 3:65-71
76. Kerbel R, Folkman J (2002) Nat Rev Cancer 2:727-739
77. Chen HH, Zhoü HJ, Fang X (2003) Pharmacol Res 48:231-236
78. Chen HH, Zhou HJ, Wang WQ, Wü GD (2004a) Cancer Chemother Pharmacol 53:423-432
79. Chen HH, Zhou HJ, Wü GD, Loü XE (2004b) Pharmacology 71:1-9.
80. Dell'Eva R, Pfeffer U, Vene R, Anfosso L, Forlani A, Albini A, Efferth T (2004) Biochem Pharmacol 68:2359-2366
81. Hüan-hüan C, Li-Li Y, Shang-Bin L (2004) Cancer Lett 211:163-173
82. Anfosso L, Efferth T, Albini A, Pfeffer U (2006) Pharmacogenomics J 6:269-278
83. Li Y, Shan F, Wü JM, Wü GS, Ding J, Xiao D, Yang WY, Atassi G, Leonce S, Caignard DH, Renard P (2001) Bioorg Med Chem Lett 11:5-8
84. Sadava D, Phillips T, Lin C, Kane SE (2002) Cancer Lett 179:151-156
85. Wang Q, Wü LM, Zhao Y, Zhang XL, Wang NP (2002) Yao Xüe Xüe Bao 37:477-478
86. Singh NP, Lai HC (2004) Anticancer Res 24:2277-2280
87. Yamachika E, Habte T, Oda D (2004) Anticancer Res 24:2153-2160
88. Efferth T, Giaisi M, Merling A, Krammer PH, Li-Weber M (2007d) PLoS ONE 2:e693
89. Disbrow GL, Baege AC, Kierpiec KA, Yüan H, Centeno JA, Thibodeaüx CA, Hartmann D, Schlegel R (2005) Cancer Res 65:10854-10861
90. Lai H, Singh NP (2006) Cancer Lett 231:43-48
91. Berger TG, Dieckmann D, Efferth T, Schültz ES, Fünk JO, Baür A, Schüler G (2005) Oncol Rep 14:1599-1603
92. Singh N, Verma K (2002) Arch Oncol 10:279-280
93. Singh NP, Panwar VK (2006) Integr Cancer Ther 5:391-394
94. Ross AGP, Bartley PM, Sleigh AC, Olds GR, Li YS, Williams GM, McManüs DP (2002) N Engl J Med 346:1212-1220
95. Gryseels B, Polman K, Clerinx J, Kestens L (2006) Lancet 368:1106-1118
96. Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J (2006) Lancet Infect Dis 6:411-425
97. Engels D, Chitsülo L, Montresor A, Savioli L (2002) Acta Trop 82:139-146
99. Chen DJ, Fü LF, Shao PP, Wü FZ, Fan CZ, Shü H, Ren CX, Sheng XL (1980) Zhong Hüi Yi Xüe Zha Zhi 60:422-425
100. Utzinger J, Xiao SH, Tanner M, Keiser J (2007) Cürr Opin Investig Drugs 8:105-116
101. Utzinger J, Xiao SH, Keiser J, Chen MG, Zheng J, Tanner M (2001) Cürr Med Chem 8:1841-1860
102. Utzinger J, Keiser J, Xiao SH, Tanner M, Singer BH (2003) Antimicrob Agents Chemother 47:1487-1495
103. Utzinger J, Zhoü XN, Chen MG, Bergqüist R (2005) Acta Trop 96:69-96
104. Xiao SH (2005) Acta Trop 96:153-167
105. Efferth T, Marschall M, Wang X, Hüong SM, Haüber I, Olbrich A, Kronschnabl M, Stamminger T, Hüang ES (2002c) J Mol Med 80:233-242
106. Britt WJ, Alford CA (1996) Cytomegalovirüs. In: Fields BN, Knipe DM, Howley PM (eds) Fields Virology, 3rd edn. Lippincott-Raven, Philadelphia, pp 2493-2523
107. Stratta RJ, Shaeffer MS, Markin RS, Wood RP, Langnas AN, Reed EC, Doonovan JP, Woods GL, Bradshaw KA, Pillen TJ, Shaw BW Jr (1992) Dig Dis Sci 37:673-688
108. Shen CY, Ho MS, Chang SF, Yen MS, Ng HAT, Huang ES, Wu CW (1993) J Infect Dis 168:449-452
109. Crumpacker CS (1996) N Engl J Med 355:721-729
110. Chrisp P, Clissold SP (1991) Drugs 41:104-129
111. Hitchcock MJM, Jaffe HS, Martin JC, Stagg RJ (1996) Antimicrob Agents Chemother 7:115-127
112. Polis MA, Spooner KM, Baird BFM, Manischewitz JF, Jaffe HS, Fisher PE, Fallon J, Davey RT Jr, Kovacs JA, Walker RE, Whitcup SM, Nussenblatt RB, Lane HC, Masur H (1995 Antimicrob Agents Chemother 39:882-886
113. Erice A (1999) Clin Microbiol Rev 12:286-297
114. Marchini A, Liu H, Zhu H (2001) J Virol 75:1870-1878
115. Ghazal P, Lubon H, Fleckenstein B, Henninghausen L (1987) Proc Natl Acad Sci USA 84:3658-3662
116. Yurochko AD, Kowalik TF, Huong SM, Huang ES (1995) J Virol 69:5391-5400
117. Yurochko AD, Mayo MW, Poma EE, Baldwin AS Jr, Huang ES (1997) J Virol 71:4638-4648
118. Johnson RA, Wang X, Ma X-L, Huong S-M, Huang E-S (2001) J Virol 75:6022-6032
119. Chou S, Marousek G, Guentzel S, Follansbee SE, Poscher ME, Lalezari JP, Miner RC, Drew WL (1997) J Infect Dis 176:786-789
120. Scott GM, Weinberg A, Rawlinson WD, Chou S (2007) Antimicrob Agents Chemother 51:89-94
121. Kaptein SJ, Efferth T, Leis M, Rechter S, Auerochs S, Kalmer M, Bruggeman CA, Vink C, Stamminger T, Marschall M (2006) Antiviral Res 69:60-69
122. Alejo E (1999) Clin Microbiol Rev 12:286-297
123. Fang CT, Nath N, Pielech M, Dodd RY (1981) J Virol Methods 2:349-356
124. Lien J, Petcu DJ, Aldrich CE, Mason WS (1987) J Virol 61:3832-3840
125. Wang GH, Seeger C (1993) J Virol 67:6507-6512
126. Molnar-Kimber KL, Summers JW, Mason WS (1984) J Virol 51:181-191
127. Bartholomeusz A, Locarnini S (2001) Hepatology 34:432-435
128. Iino S (2002) Oncology 62 (Suppl 1):18-23
129. Beasley RP, Hwang LY (1991) Overview on the epidemiology of hepatocellular carcinoma. In: Hollinger FB, Lemon SM, Margolis M (eds) Viral Hepatitis and Liver Disease. Williams and Willkins, Baltimore, pp. 532-535
130. EASL Jury (2003) J Hepatol 38:533-540
131. Romero MR, Efferth T, Serrano MA, Castano B, Macias RI, Briz O, Marin JJ (2005) Antiviral Res 68:75-83
132. Batty KT, Davis TM, Thu LT, Binh TQ, Anh TK, Ilett KF (1996) J Chromatogr B Biomed Appl 677:345-350
133. Placidi L, Faraj A, Loi AG, Pierra C, Egron D, Cretton-Scott E, Gosselin G, Perigaud C, Martin LT, Schinazi RF, Imbach JL, el Kouni MH, Bryant ML, Sommadossi JP (2001) An-tivir Chem Chemother 12:99-108
134. Romero MR, Martinez-Diez MC, Larena MG, Macias RIR, Dominguez M, Garcia-Monzon C, Serrano MA, Marin JJG (2002) Antivir Chem Chemother 13:371-380
135. Chouteau P, Le Seyec J, Saulier-Le Drean B, Cannie I, Brissot P, Lescoat G, Guguen-Guillouzo C, Gripon P (2001) J Hepatol 34:108-113
136. Paeshuyse J, Coelmont L, Vliegen I, Van Hemel J, Vandenkerckhove J, Peys E, Sas B, De Clercq E, Neyts J (2006) Biochem Biophys Res Commun 348:139-144
137. Fillebeen C, Rivas-Estilla AM, Bisaillon M, Ponka P, Muckenthaler M, Hentze MW, Ko-romilas AE, Pantopoulos K (2005) J Biol Chem 280:9049-9057
138. Tanikawa K (2004) Hepatobiliary Pancreat Dis Int 3:17-20
139. Buckwold VE, Beer BE, Donis RO (2003) Antiviral Res 60:1-15
140. Behrens SE, Grassmann CW, Thiel HJ, Meyers G, Tautz N (1998) J Virol 72:2364-2372
141. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, Goodman ZD, Ling MH, Cort S, Albrecht JK (1998) N Engl J Med 339:1485-1492
142. Samuel CE (2001) Clin Microbiol Rev 14:778-809
143. Durantel D, Carrouee-Durantel S, Branza-Nichita N, Dwek RA, Zitzmann N (2004) Antimi-crob Agents Chemother 48:497-504
144. Lau JY, Tam RC, Liang TJ, Hong Z (2002) Hepatology 35:1002-1009
145. Yang YZ, Little B, Meshnick SR (1994) Biochem Pharmacol 48:569-573
146. Romero MR, Serrano MA, Vallejo M, Efferth T, Alvarez M, Marin JJ (2006) Planta Med 72:1169-1174
147. Tam RC, Lau JY, Hong Z (2001) Antivir Chem Chemother 12:261-272
148. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S (2007) Lancet 370:890-907
149. Naesens L, Bonnafous P, Agut H, De Clercq E (2006) J Clin Virol 37(Suppl 1):S69-75
150. Toovey S (2006) Toxicol Lett 166:95-104
151. Brewer TG, Grate SJ, Peggins JO, Weina PJ, Petras JM, Levine BS, Heiffer MH, Schuster BG (1994a) Am J Trop Med Hyg 51:251-259
152. Brewer TG, Peggins JO, Grate SJ, Petras JM, Levine BS, Weina PJ, Swearengen J, Heiffer MH, Schuster BG (1994b) Trans R Soc Trop Med Hyg 88 (Suppl 1):S33-S36
153. Kamchonwongpaisan S, McKeever P, Hossler P, Ziffer H, Meshnick SR (1997) Am J Trop Med Hyg 56:7-12
154. Genovese RF, Newman DB, Li Q, Peggins JO, Brewer TG (1998a) Brain Res Bull 45:199-202
155. Jones-Brando L, D'Angelo J, Posner GH, Yolken R (2006) Antimicrob Agents Chemother 50:4206-4208
156. Panossian LA, Garga NI, Pelletier D (2005) Ann Neurol 58:812-813
157. Petras JM, Young GD, Bauman RA, Kyle DE, Gettayacamin M, Webster HK, Corcoran KD, Peggins JO, Vane MA, Brewer TG (2000) Anat Embryol 201:383-397
158. Li QC, Mog SR, Si YZ, Kyle DE, Gettayacamin M, Milhous WK (2002) Am J Trop Med Hyg 66:516-525
159. van Hensbroek MB, Onyiorah E, Jaffar S, Schneider G, Palmer A, Frenkel J, Enwere G, Forck S, Nusmeijer A, Bennett S, Greenwood B, Kwiatkowski D (1996) N Engl J Med 335:69-75
160. Stepniewska K, Day N, Babiker A, Lalloo D, Warrell D, Olliaro P, White N (2001) Trans R Soc Trop Med Hyg 95:637-650
161. Dondorp A, Nosten F, Stepniewska K, Day N, White N (2005) Lancet 366:717-725
162. Chang HR, Pechere JC (1988) Trans R Soc Trop Med Hyg 82:867
163. Ke OY, Krug EC, Marr JJ, Berens RL (1990) Antimicrob Agents Chemother 34:1961-1965
164. Genovese RF, Newman DB, Petras JM, Brewer TG (1998b) Pharmacol Biochem Behav 60:449-458
165. Berens RL, Krug EC, Nash PB, Curiel TJ (1998) J Infect Dis 177:1128-1131
166. Son ES, Song KJ, Shin JC, Nam HW (2001) Korean J Parasitol 39:133-141
167. Holfels E, McAuley J, Mack D, Milhous WK, McLeod R (1994) Antimicrob Agents Chemother 38:1392-1396
168. Nagamune K, Beatty WL, Sibley LD (2007a) Epub ahead of print
169. Nagamune K, Moreno SN, Sibley LD (2007b) Epub ahead of print
170. Yang DM, Liew FY (1993) Parasitology 106 (Pt 1):7-11
171. Avery MA, Muraleedharan KM, Desai PV, Bandyopadhyaya AK, Furtado MM, Tekwani BL (2003) J Med Chem 46:4244-4258
172. Menon RB, Kannoth MM, Tekwani BL, Gut J, Rosenthal PJ, Avery MA (2006) Comb Chem High Throughput Screen 9:729-741
173. Sen R, Bandyopadhyay S, Dutta A, Mandal G, Ganguly S, Saha P, Chatterjee M (2007) J Med Microbiol 56(Pt 9):1213-1218
174. Mishina YV, Krishna S, Haynes RK, Meade JC (2007) Antimicrob Agents Chemother 51:1852-1854
175. Kim JT, Park JY, Seo HS, Oh HG, Noh JW, Kim JH, Kim DY, Youn HJ (2002) Vet Parasitol 103:53-63
176. Allen PC, Danforth HD, Augustine PC (1998) Int J Parasitol 28:1131-1140
177. Keiser J, Brun R, Fried B, Utzinger J (2006) Antimicrob Agents Chemother 50:803-805
178. Merali S, Meshnick SR (1991) Antimicrob Agents Chemother 35:1225-1227
179. Tang HQ, Hu J, Yang L, Tan RX (2000) Planta Med 66:391-393
180. Galal AM, Ross SA, Jacob M, ElSohly MA (2005) J Nat Prod 68:1274-1276
181. Li W, Mo W, Shen D, Sun L, Wang J, Lu S, Gitschier JM, Zhou B (2005) PLoS Genet 1:e36
182. Murray CK, Ellis MW, Hospenthal DR (2004) Am J Trop Med Hyg 71:685-686
183. Shoeb HA, Tawfik AF, Shibl AM, el-Feraly FS (1990) J Chemother 2:362-367
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