Human Hepatitis B Virus HBV

Natural Synergy

Traditional Chinese Medicine

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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.

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