The antiviral activities of artemisinin and artesunate

Clinical Infectious Diseases

Volumn 47, Issue 6, 2008, Pages 804-811

  Efferth, Thomas ^a   Romero, Marta R ^c,e   Wolf, Dana G ^d   Stamminger, Thomas ^b   Marin, Jose J G ^e   Marschall, Manfred ^b  

^a GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^b UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^c IMPERIAL COLLEGE LONDON   (United Kingdom)

^d HADASSAH HEBREW UNIVERSITY MEDICAL CENTER   (Israel)

^e UNIVERSITY OF SALAMANCA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIMALARIAL AGENT; ANTIVIRUS AGENT; ARTEMETHER; ARTEMISININ; ARTEMISININ DERIVATIVE; ARTESUNATE; ARTESUNATE PLUS FERROUS IRON; CIDOFOVIR; DIHYDROARTEMISININ; FERROSANOL; FOSCARNET; GANCICLOVIR; HEMIN; INTERFERON; LAMIVUDINE; PEGINTERFERON ALPHA; QUININE; RIBAVIRIN; TRANSFERRIN; UNCLASSIFIED DRUG; VALGANCICLOVIR;

ABSENCE OF SIDE EFFECTS; ANTIMALARIAL ACTIVITY; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; ARTEMISIA ANNUA; ATAXIA; BOVINE LEUKEMIA VIRUS; CHINESE MEDICINE; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG MECHANISM; DRUG METABOLISM; ELECTROCARDIOGRAPHY; EPSTEIN BARR VIRUS; FIRST DEGREE ATRIOVENTRICULAR BLOCK; HEARING LOSS; HEMATOLOGICAL PARAMETERS; HEPATITIS B; HEPATITIS B VIRUS; HEPATITIS C; HEPATITIS C VIRUS; HERPES SIMPLEX VIRUS 1; HERPES SIMPLEX VIRUS 2; HERPES VIRUS; HUMAN; HUMAN CYTOMEGALOVIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1; MONOTHERAPY; NEUROLOGICAL COMPLICATION; NEUROTOXICITY; NEUTROPENIA; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIDE EFFECT; SINGLE DRUG DOSE; SLURRED SPEECH; UNSPECIFIED SIDE EFFECT;

ANTIVIRAL AGENTS; ARTEMISININS; CYTOMEGALOVIRUS; HEPACIVIRUS; HERPESVIRIDAE; HIV-1; HUMANS;

EID: 51549118662     PISSN: 10584838     EISSN: None     Source Type: Journal    
DOI: 10.1086/591195     Document Type: Review

References (94)

1. Tu Y. The development of new antimalarial drugs: qinghaosu and dihydro-qinghaosu. Chin Med J (Engl) 1999; 112:976-7.
2. Attaran A, Barnes KI, Curtis C, et al. WHO, the Global Fund, and medical malpractice in malaria treatment. Lancet 2004; 363:237-40.
3. Adjuik M, Agnamey P, Babiker A, et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004; 363:9-17.
4. Efferth T, Rücker G, Falkenberg M, et al. Detection of apoptosis in KG-1a leukemic cells treated with investigational drugs. Arzneimittelforschung 1996; 46:196-200.
5. Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR. The anti-malarial artesunate is also active against cancer. Int J Oncol 2001; 18:767-73.
6. Efferth T, Sauerbrey A, Olbrich A, et al. Molecular modes of action of artesunate in tumor cell lines. Mol Pharmacol 2003; 64:382-94.
7. Efferth T. Mechanistic perspectives for 1,2,4-trioxanes in anti-cancer therapy. Drug Resist Updat 2005; 8:85-97.
8. Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets 2006; 7:407-21.
9. Efferth T. Willmar Schwabe award 2006: antiplasmodial and antitumor activity of artemisinin-from bench to bedside. Planta Med 2007; 73:299-309.
10. Utzinger J, Xiao SH, Tanner M, Keiser J. Artemisinins for schistosomiasis and beyond. Curr Opin Investig Drugs 2007; 8:105-16.
11. Meshnick SR. Artemisinin: mechanisms of action, resistance and toxicity. Int J Parasitol 2002; 32:1655-60.
12. Haynes RK, Ho WY, Chan HW, et al. Highly antimalaria-active artemisinin derivatives: biological activity does not correlate with chemical reactivity. Angew Chem Int Ed Engl 2004; 43:1381-5.
13. Avery MA, Alvim-Gaston M, Rodrigues CR, et al. Structure-activity relationships of the antimalarial agent artemisinin. 6. The development of predictive in vitro potency models using CoMFA and HQSAR methodologies. J Med Chem 2002; 45:292-303.
14. Guha R, Jurs PC. Development of QSAR models to predict and interpret the biological activity of artemisinin analogues. J Chem Inf Comput Sci 2004; 44:1440-9.
15. Cardoso FJ, de Figueiredo AF, da Silva Lobato M, et al. A study on antimalarial artemisinin derivatives using MEP maps and multivariate QSAR. J Mol Model 2008; 14:39-48.
16. Zhao S. High-performance liquid chromatographic determination of artemisinine (qinghaosu) in human plasma and saliva. Analyst 1987; 112:661-4.
17. Duc DD, de Vries PJ, Nguyen XK, et al. The pharmacokinetics of a single dose of artemisinin in healthy Vietnamese subjects. Am J Trop Med Hyg 1994; 51:785-90.
18. Benakis A, Paris M, Plessas C, et al. Pharmacokinetics of sodium artesunate im and iv administration. Am J Trop Med Hyg 1993; 49(Suppl):293.
19. Batty KT, Davis TME, Thu LT, Binh TQ, Anh TK, Ilett KF. Selective high-performance liquid chromatographic determination of artesunate and a-and b-dihydroartemisinin in patients with falciparum malaria. J Chromatogr B Biomed Appl 1996; 677:345-50.
20. Teja-Isavadharm P, Watt G, Eamsila C, et al. Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. Am J Trop Med Hyg 2001; 65:717-21.
21. Barradell LB, Fitton A. Artesunate: a review of its pharmacology and therapeutic efficacy in treatment of malaria. Drugs 1995; 50:714-41.
22. Batty KT, Thu LTA, Davis TME, et al. A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria. Br J Clin Pharmacol 1998; 45:123-9.
23. Batty KT, Thu LTA, Ilett KF, et al. A pharmacokinetic and pharmacodynamic study of artesunate for vivax malaria. Am J Trop Med Hyg 1998; 59:823-7.
24. White NJ. Clinical pharmacokinetics and pharmacodynamics of artemisinin and derivatives. Trans R Soc Trop Med Hyg 1994; 88(Suppl 1):41-3.
25. Binh TQ, Ilett KF, Batty KT, et al. Oral bioavailability of dihydroartemisinin in Vietnamese volunteers and in patients with falciparum malaria. Br J Clin Pharmacol 2001; 51:541-6.
26. McGready R, Stepniewska K, Ward SA et al. Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria. Eur J Clin Pharmacol 2006; 62:367-71.
27. Svensson US, Ashton M. Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br J Clin Pharmacol 1999; 48:528-35.
28. Sukhija M, Medhi B, Pandhi P. Effects of artemisinin, artemether, arteether on the pharmacokinetics of carbamazepine. Pharmacology 2006; 76:110-6.
29. Mihara K, Svensson US, Tybring G, Hai TN, Bertilsson L, Ashton M. Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C19. Fundam Clin Pharmacol 1999; 13:671-5.
30. Giao PT, de Vries PJ. Pharmacokinetic interactions of antimalarial agents. Clin Pharmacokinet 2001; 40:343-73.
31. Li XQ, Björkman A, Andersson TB, Gustafsson LL, Masimirembwa CM. Identification of human cytochrome P(450)s that metabolise antiparasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol 2003; 59:429-42.
32. Svensson US, Mäki-Jouppila M, Hoffmann KJ, Ashton M. Characterisation of the human liver in vitro metabolic pattern of artemisinin and auto-induction in the rat by use of nonlinear mixed effects modelling. Biopharm Drug Dispos 2003; 24:71-85.
33. Burk O, Arnold KA, Nussler AK, et al. Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 2005; 67:1954-65.
34. Simonsson US, Lindell M, Raffalli-Mathieu F, Lannerbro A, Honkakoski P, Lang MA. In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin. Eur J Clin Invest 2006; 36:647-53.
35. Bapiro TE, Andersson TB, Otter C, Hasler JA, Masimirembwa CM. Cytochrome P450 1A1/2 induction by antiparasitic drugs: dose-dependent increase in ethoxyresorufin O-deethylase activity and mRNA caused by quinine, primaquine and albendazole in HepG2 cells. Eur J Clin Pharmacol 2002; 58:537-42.
36. Bapiro TE, Sayi J, Hasler JA, et al. Artemisinin and thiabendazole are potent inhibitors of cytochrome P450 1A2 (CYP1A2) activity in humans. Eur J Clin Pharmacol 2005; 61:755-61.
37. Asimus S, Elsherbiny D, Hai TN, et al. Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects. Fundam Clin Pharmacol 2007; 21:307-16.
38. He F, Bi HC, Xie ZY, et al. Rapid determination of six metabolites from multiple cytochrome P450 probe substrates in human liver microsome by liquid chromatography/mass spectrometry: application to high-throughput inhibition screening of terpenoids. Rapid Commun Mass Spectrom 2007; 21:635-43.
39. Gordi T, Xie R, Huong NV, Huong DX, Karlsson MO, Ashton M. A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first pass hepatic extraction. Br J Clin Pharmacol 2005; 59:189-98.
40. Barradell LB, Fitton A. Artesunate: a review of its pharmacology and therapeutic efficacy in treatment of malaria. Drugs 1995; 50:714-41.
41. Ribeiro IR, Olliaro P. Safety of artemisinin and its derivatives: a review of published and unpublished clinical trials. Med Trop (Mars) 1998; 58(Suppl 3):50-3.
42. Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N. International Artemisinin Study Group. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004; 363:9-17.
43. Toovey S. Are currently deployed artemisinins neurotoxic? Toxicol Lett 2006; 166:95-104.
44. Brewer TG, Grate SJ, Peggins JO, et al. Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 1994; 51:251-9.
45. Brewer TG, Peggins JO, Grate SJ, et al. Neurotoxicity in animals due to arteether and artemether. Trans R Soc Trop Med Hyg 1994; 88(Suppl 1):S33-6.
46. Genovese RF, Newman DB, Li Q, Peggins JO, Brewer TG. Dose-dependent brainstem neuropathology following repeated arteether administration in rats. Brain Res Bull 1998; 45:199-202.
47. Genovese RF, Newman DB, Petras JM, Brewer TG. Behavioral and neural toxicity of arteether in rats. Pharmacol Biochem Behav 1998; 60:449-58.
48. Kamchonwongpaisan S, McKeever P, Hossler P, Ziffer H, Meshnick SR. Artemisinin neurotoxicity: neuropathology in rats and mechanistic studies in vitro. Am J Trop Med Hyg 1997; 56:7-12.
49. Panossian LA, Garga NI, Pelletier D. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol 2005; 58:812-3.
50. Petras JM, Kyle DE, Gettayacamin M, et al. Arteether: risks of 2-week administration in Macaca mulatta. Am J Trop Med Hyg 1997; 56:390-6.
51. Petras JM, Young GD, Bauman RA, et al. Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: the lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei. Anat Embryol 2000; 201:383-97.
52. Li QC, Mog SR, Si YZ, Kyle DE, Gettayacamin M, Milhous WK. Neurotoxicity and efficacy of arteether related to its exposure times and exposure levels in rodents. Am J Trop Med Hyg 2002; 66:516-25.
53. Davies TME, Karunajeewa HA, Ilett KF. Artemisinin-based combination therapies for uncomplicated malaria. Med J Aust 2005; 182:181-5.
54. van Hensbroek MB, Onyiorah E, Jaffar S, et al. A trial of artemether or quinine in children with cerebral malaria. N Engl J Med 1996; 335:69-75.
55. Stepniewska K, Day N, Babiker A, et al. A meta-analysis using individual patient data of trials comparing artemether with quinine in the treatment of severe falciparum malaria. Trans R Soc Trop Med Hyg 2001; 95:637-50.
56. Dondorp A, Nosten F, Stepniewska K, Day N, White N; South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) Group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366:717-25.
57. Qian RS, Li ZL, Yu JL, Ma DJ. The immunologic and antiviral effect of qinghaosu. J Tradit Chin Med 1982; 2:271-6.
58. Kaptein SJ, Efferth T, Leis M, et al. The anti-malaria drug artesunate inhibits replication of cytomegalovirus in vitro and in vivo. Antiviral Res 2006; 69:60-9.
59. Efferth T, Marschall M, Wang X, et al. Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses. J Mol Med 2002; 80:233-42.
60. Shapira MY, Resnick IB, Chou S, et al. Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplant. Clin Infect Dis 2008; 46:1455-7.
61. Marschall M, Freitag M, Weiler S, Sorg G, Stamminger T. Recombinant GFP-expressing human cytomegalovirus as a tool for screening of antiviral agents. Antimicrob Agents Chemother 2000; 44:1588-97.
62. Mocarski ES Jr, Shenk T, Pass RF. Cytomegalovirus. In: Fields BN, Knipe DM, Howley PM, eds. Fields virology. 5th ed. Philadelphia: Lippincott-Raven, 2007:2701-72.
63. Yurochko AD, Kowalik TF, Huong SM, Huang ES. Human cytomegalovirus upregulates NF-κB activity by transactivating the NF-κB p105/p50 and p65 promoters. J Virol 1995; 69:5391-400.
64. Yurochko AD, Mayo MW, Poma EE, Baldwin AS Jr, Huang ES. Induction of the transcription factor Sp1 during human cytomegalovirus infection mediates upregulation of the p65 and p105/p50 NF-κB promoters. J Virol 1997; 71:4638-48.
65. Bork PM, Schmitz ML, Kuhnt M, Escher C, Heinrich M. Sesquterpene lactone containing Mexican Indian medicinal plants and pure sesquiterpene lactones as potent inhibitors of transcription factor NF-κB. FEBS Lett 1997; 402:85-90.
66. Siedle B, Garcia-Pineres AJ, Murillo R, et al. Quantitative structure-activity relationship of sesquiterpene lactones as inhibitors of the transcription factor NF-kappaB. J Med Chem 2004; 47:6042-54.
67. Johnson RA, Wang X, Ma X-L, Huong S-M, Huang E-S. Human cytomegalovirus up-regulates the phosphotidylinositol 3-kinase (PI3-K) pathway: inhibition of PI3-K activity inhibits viral replication and virus-induced signaling. J Virol 2001; 75:6022-32.
68. Ghazal P, Lubon H, Fleckenstein B, Henninghausen L. Binding of transcription factors and creation of a large nucleoprotein complex on the human cytomegalovirus enhancer. Proc Natl Acad Sci USA 1987;84:3658-62.
69. Prösch S, Wuttke R, Krüger DH, Volk HD. NF-kappaB - a potential therapeutic target for inhibition of human cytomegalovirus (re)activation? Biol Chem 2002; 383:1601-9.
70. Marchini A, Liu H, Zhu H. Human cytomegalovirus with IE-2 (UL122) deleted fails to express early lytic genes. J Virol 2001; 75:1870-8.
71. Eickhoff J, Hanke M, Stein-Gerlach M, et al. RICK activates an NFkB dependent anti-HCMV response. J Biol Chem 2004; 279:9642-52.
72. Naesens L, Bonnafous P, Agut H, De Clercq E. Antiviral activity of diverse classes of broad-acting agents and natural compounts in HHV-6-infected lymphoblasts. J Clin Virol 2006; 37(Suppl 1):S69-75.
73. Fang CT, Nath N, Pielech M, Dodd RY. A modified technique for the detection of hepatitis B virus-specific DNA polymerase. J Virol Methods 1981; 2:349-56.
74. Lien J, Petcu DJ, Aldrich CE, Mason WS. Initiation of termination of duck hepatitis B virus DNA synthesis during virus maturation. J Virol 1987; 61:3832-40.
75. Wang GH, Seeger C. Novel mechanism for reverse transcription in hepatitis B viruses. J Virol 1993; 67:6507-12.
76. Bartholomeusz A, Locarnini S. Hepatitis B virus mutants and fulminant hepatitis B: fitness plus phenotype. Hepatology 2001; 34:432-5.
77. Iino S. Natural history of hepatitis B and C virus infections. Oncology 2002; 62(Suppl 1):18-23.
78. Beasley RP, Hwang LY. Overview on the epidemiology of hepatocellular carcinoma. In: Hollinger FB, Lemon SM, Margolis M, eds. Viral hepatitis and liver disease. Baltimore: Williams & Willkins, 1991:532-5.
79. The EASL jury. EASL International Consensus Conference on Hepatitis B. J Hepatol 2003; 38:533-40.
80. Romero MR, Efferth T, Serrano MA, et al. Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an "in vitro" replicative system. Antiviral Res 2005; 68:75-83.
81. Batty KT, Davis TM, Thu LT, Binh TQ, Anh T, Ilett KF. Selective high-performance liquid chromatographic determination of artesunate and alpha- and beta-dihydroartemisinin in patients with falciparum malaria. J Chromatogr B Biomed Appl 1996; 677:345-50.
82. Placidi L, Faraj A, Loi AG, et al. Antiviral activity and intracellular metabolism of bis(tButylSATE) phosphotriester of beta-l-2′,3′- dideoxyadenosine, a potent inhibitor of HIV and HBV replication. Antivir Chem Chemother 2001; 12:99-108.
83. Tanikawa K. Pathogenesis and treatment of hepatitis C virus-related liver diseases. Hepatobiliary Pancreat Dis Int 2004; 3:17-20.
84. Buckwold VE, Beer BE, Donis RO. Bovine viral diarrhea virus as a surrogate model of hepatitis C virus for the evaluation of antiviral agents. Antiviral Res 2003; 60:1-15.
85. Samuel CE. Antiviral actions of interferons. Clin Microbiol Rev 2001; 14:778-809.
86. Durantel D, Carrouee-Durantel S, Branza-Nichita N, Dwek RA, Zitzmann N. Effects of interferon, ribavirin, and iminosugar derivatives on cells persistently infected with noncytopathic bovine viral diarrhea virus. Antimicrob Agents Chemother 2004; 48:497-504.
87. Lau JY, Tam RC, Liang TJ, Hong Z. Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 2002; 35:1002-9.
88. Yang YZ, Little B, Meshnick SR. Alkylation of proteins by artemisinin: effects of heme, pH and drug structure. Biochem Pharmacol 1994; 48:569-73.
89. Romero MR, Serrano MA, Vallejo M, et al. Antiviral effect of artemisinin from Artemisia annua against a model member of the Flaviviridae family, the bovine viral diarrhoea virus (BVDV). Planta Med 2006; 72:1169-74.
90. Tam RC, Lau JY, Hong Z. Mechanisms of action of ribavirin in antiviral therapies. Antivir Chem Chemother 2001; 12:261-72.
91. Paeshuyse J, Coelmont L, Vliegen I, et al. Hemin potentiates the antihepatitis C virus activity of the antimalarial drug artemisinin. Biochem Biophys Res Commun 2006; 348:139-44.
92. Fillebeen C, Rivas-Estilla AM, Bisaillon M, et al. Iron inactivates the RNA polymerase NS5B and suppresses subgenomic replication of hepatitis C virus. J Biol Chem 2005; 280:9049-57.
93. Birku Y, Mekonnen E, Bjorkman A, Wolday D. Delayed clearance of Plasmodium falciparum in patients with human immunodeficiency virus co-infection treated with artemisinin. Ethiop Med J 2002; 40:17-26.
94. Tang HQ, Hu J, Yang L, Tan RX. Terpenoids and flavonoids from Artemisia species. Planta Med 2000; 66:391-3.