Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins
Introduction
According to the first national survey carried out in the mid 1950s, schistosomiasis due to Schistosoma japonicum was endemic in 10 provinces, one municipality and one autonomous region of China with an estimated 100 million people at risk of infection and over 10 million people infected (Zhou et al., 2005). Treatment of patients and entire communities with antischistosomal drugs has been and continues to be a cornerstone for schistosomiasis control in China (Chen, 2005, Chen et al., 2005).
In the 1950s, various antimonials were synthesized and screened with the objective to develop compounds with superiority over potassium antimony tartrate. Three compound, i.e. sodium antimony dimercaptosuccinate (Sb-58), ammonium antimony gluconate and sodium antimony subgallate (Sb-273), were selected and used for treatment of schistosomiasis (National Schistosomiasis Research Committee, 1959, National Schistosomiasis Research Committee, 1960). In the early 1960s, furapromidum was developed by Chinese scientists, which is the first non-antimonial used in the treatment of schistosomiasis (Hsiao et al., 1962, Lei et al., 1963). This compound was effective against acute schistosomiasis, but the negative conversion rate of faecal egg was low in patients with chronic schistosomiasis (Hsu et al., 1963). Until the early 1980s, other non-antimonials, such as amosconate, hexachloroparaxylene, niridazole, pararosaniline pamoate and phenithionate, were also examined for their safety and efficacy. In view of severe side effects and/or poor efficacy, these compounds were withdrawn from further clinical testing (Chen, 1985).
In the early 1970s, praziquantel was jointly discovered by Bayer and Merck in Germany (Andrews et al., 1983). In 1978, praziquantel was synthesized in China. Owing to its high efficacy against all five human schistosome species, good tolerability and ease of administration as a single oral dose, praziquantel has become the drug of choice for the treatment and morbidity control of schistosomiasis the world over (WHO, 2002, Cioli and Pica-Mattoccia, 2003, Utzinger and Keiser, 2004), including China (Chen, 2005). The large-scale application of praziquantel, which was one of the main strategies during the 10-year World Bank Loan Project (WBLP) on schistosomiasis control in China, further accelerated progress of morbidity control (Yuan et al., 2000, Chen et al., 2005).
Besides chemical compounds, efforts were also made to discover and develop antischistosomal drugs from traditional Chinese herbal medicine. An interesting finding was that pumpkin seeds exhibit antischistosomal properties, particularly against the schistosomulum (Chou et al., 1958, Shiao et al., 1959). The active ingredient isolated from pumpkin seeds was a new amino acid, i.e. curcurbitine, with a chemical structure similar to that of proline (Fang et al., 1961, Shiao et al., 1962a). Other herbs, such as hemerocalline, agrimophol and dryocrassin isolated from Hemerocallis thunbergii, Agrimonia pilosa and Dryopteris crassirhizoma, respectively, showed activity against adult schistosomes (Chen et al., 1962, Shiao et al., 1962b, Wang et al., 1979, Shen et al., 1981, Yue et al., 1985a). However, due to toxic effects, the development of these herbs was not further pursued.
The discovery of the antimalarial properties of artemisinin in the early 1970s and the successful development of its derivatives for the treatment and control of malaria is one of the most significant contributions to tropical public health in recent years (Klayman, 1985, Li and Wu, 2003, Woodrow et al., 2005). In addition to their antimalarial activity, artemisinins also exhibit antischistosomal properties (Chen et al., 1980). Most notable progress has been made with artemether (Xiao et al., 2000a, Xiao et al., 2002a, Utzinger et al., 2001a, Utzinger et al., 2001b) and artesunate (Li et al., 1996).
The purpose of this paper is to review antischistosomal drug discovery and development in China. In the next section, emphasis is placed on praziquantel, complementing Chinese scientists’ contributions, also published in this issue of Acta Tropica, on the use of praziquantel for clinical treatment and morbidity control in our country (Chen, 2005). Progress made to date with artemether and artesunate is reviewed in sections 3 Artemether, 4 Artesunate. Mention is also made how this research influenced the scientific community outside of China. Finally, a short conclusion is put forth with the aim to further stimulate research and development of antischistosomal drugs.
Section snippets
Pharmacological effect on S. japonicum
The chemical structure of praziquantel is shown in Fig. 1. It is the generic name for 2-(cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one. Praziquantel exhibits three main pharmacological effects on S. japonicum. First, it stimulates worm motor activity, which occurs promptly. Second, praziquantel induces spasmodic contraction of the musculature, which is Ca2+-dependent, and to some degree is controlled by Mg2+ (Xiao et al., 1984, Xiao and Fu, 1991). Movement of Ca
Discovery of antischistosomal properties
Artemether is the β-methyl ether derivative of dihydroartemisinin. Its chemical structure is depicted in Fig. 2a. The first report of artemether's activity against S. japonicum was published in 1982 (Le et al., 1982), just two years after the discovery of the antischistosomal properties of artemisinin (Chen et al., 1980). The initial in vivo work with artemether employed different animal models and found that 7-day-old schistosomula were particularly susceptible. In the late 1980s, activity of
Discovery of antischistosomal properties
The chemical structure of artesunate, i.e. dihydroartemisinin-10-α-succinate, is shown in Fig. 2b. One year after the discovery of the antischistosomal properties of artemether, the same group of Chinese published the first account on the activity of artesunate with an experimental focus on S. japonicum (Le et al., 1983). Administration of artesunate to mice or rabbits infected with adult schistosomes for 1–4 days resulted in moderate worm burden reductions. Meanwhile, it was found that
Conclusion
Over the past 20–25 years praziquantel-based morbidity control has been the backbone of the national schistosomiasis control programme in China (Chen, 2005). Repeated large-scale administration of this drug, combined with other control measures during the 1992–2001 WBLP for schistosomiasis proved successful in further reducing the public health significance of the disease (Chen et al., 2005). However, praziquantel fails to prevent reinfection with S. japonicum once humans contact infested water
Acknowledgements
I would like to express my deep thanks to Dr. Jürg Utzinger from the Swiss Tropical Institute for his nice and useful suggestions in completion of this paper.
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