Elsevier

Acta Tropica

Volume 96, Issues 2–3, November–December 2005, Pages 153-167
Acta Tropica

Development of antischistosomal drugs in China, with particular consideration to praziquantel and the artemisinins

https://doi.org/10.1016/j.actatropica.2005.07.010Get rights and content

Abstract

Remarkable achievements have been made in the control of schistosomiasis in China, with chemotherapy playing a seminal role. From the early 1950s through the early 1980s, Chinese scientists made considerable progress in discovery and development of compounds with antischistosomal properties, including antimonials, non-antimonials and various effective principles stemming from traditional herbs. However, only few compounds entered clinical testing, while others were abandoned mainly due to their toxicity and poor efficacy. The advent of praziquantel in the 1970s changed the landscape of research and development of drugs for treatment and morbidity control of schistosomiasis. The main Chinese contributions to enhance the understanding of the antischistosomal drug praziquantel are reviewed here, including issues of metabolism, antibody-dependency, host immune factors, stage-specific susceptibility and resistance. Over the past 25 years, researchers from China successfully developed artemether and artesunate, two derivatives from the antimalarial artemisinin, as promising drugs against Schistosoma japonicum. Laboratory investigations showed that the artemisinins display their highest activity against the juvenile stages of the parasite. These findings were consistently confirmed in randomised controlled trials; repeated oral administration of artemether or artesunate was safe and efficacious in the prevention of patent S. japonicum infections. The key findings are reviewed here, and emphasis is placed on how it stimulated research outside of China on other human schistosome species.

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.

References (122)

  • P. Andrews et al.

    Praziquantel

    Med. Res. Rev.

    (1983)
  • N. Araujo et al.

    Therapeutic evaluation of artesunate in experimental Schistosoma mansoni infection

    Rev. Soc. Bras. Med. Trop.

    (1999)
  • S. Borrmann et al.

    Artesunate and praziquantel for the treatment of Schistosoma haematobium infections: a double-blind, randomized, placebo-controlled study

    J. Infect. Dis.

    (2001)
  • C. Chen et al.

    Studies on Hemerocallis thunbergii Baker III. Isolation and characterization of active principle against schistosomiasis

    Acta Pharm. Sin.

    (1962)
  • D.J. Chen et al.

    Experimental studies on antischistosomal activity of qinghaosu

    Zhong Hui Yi Xue Zha Zhi

    (1980)
  • M.G. Chen

    Chemotherapy of schistosomiasis japonica in China

    Southeast Asian J. Trop. Med. Public Health

    (1985)
  • M.G. Chen

    Use of praziquantel for clinical treatment and morbidity control of schistosomiasis japonica in China: A review of 30 years’ experience

    Acta Trop.

    (2005)
  • X.Y. Chen et al.

    Schistosomiasis control in China: the impact of a 10-year World Bank Loan Project (1992–2001)

    Bull. World Health Organ.

    (2005)
  • H.J. Chou et al.

    All China congress on parasitic diseases

    Abstract of Papers Presented in November, 1958

    (1958)
  • D. Cioli et al.

    Praziquantel

    Parasitol. Res.

    (2003)
  • P.G. Fallon et al.

    Drug-resistant schistosomiasis: resistance to praziquantel and oxamniquine induced in Schistosoma mansoni in mice is drug specific

    Am. J. Trop. Med. Hyg.

    (1994)
  • S.D. Fang et al.

    Chemical study of Cucurbita moschata Duch. 1. The isolation and structural study of cucurbitine, a new amino acid

    Sci. Sin.

    (1961)
  • Y. Guo et al.

    Safety assessment for long-term oral treatment with artesunate in rats

    Chin. J. Schisto. Contr.

    (2000)
  • Y. Guo et al.

    Observation on the effect of artesunate on ultrastructure of schistosomula with electron microscope

    Chin. J. Schisto. Contr.

    (1997)
  • Y.X. He et al.

    Sensitivity of different isolates of Schistosoma japonicum from China to praziquantel

    Southeast Asian J. Trop. Med. Public Health

    (1992)
  • Y.X. He et al.

    Strain complex of Schistosoma japonicum in the mainland of China

    Southeast Asian J. Trop. Med. Public Health

    (1994)
  • S.H. Hsiao et al.

    Experimental studies on certain problems pertaining to the use of antimony compounds in schistosomiasis japonica

    Chin. Med. J.

    (1962)
  • J.K. Hsu et al.

    Preliminary trials with F30066 and F30069 in Schistosoma japonicum infections in man

    Chin. Med. J.

    (1963)
  • P.C. Inyang-Etoh et al.

    Efficacy of artesunate in the treatment of urinary schistosomiasis, in an endemic community in Nigeria

    Ann. Trop. Med. Parasitol.

    (2004)
  • M.S. Ismail et al.

    Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers

    Am. J. Trop. Med. Hyg.

    (1999)
  • D.L. Klayman

    Qinghaosu (artemisinin): an antimalarial drug from China

    Science

    (1985)
  • W.J. Le et al.

    Chemotherapeutic effect of artesunate in experimental schistosomiasis

    Acta Pharm. Sin.

    (1983)
  • W.J. Le et al.

    Studies on the efficacy of artemether in experimental schistosomiasis

    Acta Pharm. Sin.

    (1982)
  • X.H. Lei et al.

    A new class of chemotherapeutic agents orally effective against schistosomiasis japonica

    Chin. Med. J.

    (1963)
  • H.Y. Li et al.

    Observation on the prevention of schistosomiasis japonica by administration of artesunate long-term

    Chin. J. Parasitic Dis. Contr.

    (1999)
  • S.W. Li et al.

    Studies on prophylactic effect of artesunate on schistosomiasis japonica

    Chin. Med. J.

    (1996)
  • Y. Li et al.

    An over four millennium story behind qinghaosu (artemisinin)—a fantastic antimalarial drug from a traditional Chinese herb

    Curr. Med. Chem.

    (2003)
  • Y.H. Liu et al.

    Comparative efficacy of praziquantel and its optic isomers in experimental therapy of schistosomiasis japonica in rabbits

    Chin. Med. J.

    (1986)
  • G.Y. Lu et al.

    Probe on scheme with oral artesunate protecting people from infection of schistosome

    Chin. J. Parasitic Dis. Contr.

    (2000)
  • S.H. Lu et al.

    Prophylactic effect of artesunate against experimental infection of Schistosoma mansoni

    Chin. J. Parasitol. Parasitic Dis.

    (2004)
  • National Schistosomiasis Research Committee, 1959. Studies on schistosomiasis japonica in new China. Chin. Med. J. 78,...
  • National Schistosomiasis Research Committee, 1960. Studies on sodium antimonydimercaptosuccinate (Sb-58) in clinical...
  • E.K. N’Goran et al.

    Randomized, double-blind, placebo-controlled trial of oral artemether for the prevention of patent Schistosoma haematobium infections

    Am. J. Trop. Med. Hyg.

    (2003)
  • J.F. Shen et al.

    Isolation and identification of the active principle against schistosome from Dryopteris crassirhizoma

    Chin. Pharm. Bull.

    (1981)
  • M.Z. Shi et al.

    Experimental study on susceptibility of praziquantel against Schistosoma japonicum in repeated chemotherapy areas in Dongting Lake region

    Chin. J. Schisto. Contr.

    (2004)
  • S.H. Shiao et al.

    Studies on the prophylactico-therapeutic effect of cucurbitine in experimental schistosomiasis japonica in mice

    Sci. Sin.

    (1962)
  • S.H. Shiao et al.

    Studies on Hemerocallis thunbergii Baker II. Effectiveness of Hemerocallis thunbergii in oral treatment of experimental schistosomiasis in mice

    Acta Pharm. Sin.

    (1962)
  • S.H. Shiao et al.

    Studies on the effect of pumpkin seed on experimental schistosomiasis japonica

    Acta Pharm. Sin.

    (1959)
  • H.T. Song et al.

    Studies on sensitivity of Schistosoma japonicum to praziquantel—situation in low endemic areas

    Chin. J. Schisto. Contr.

    (2004)
  • Y. Song et al.

    Preventive effect of artemether on schistosome infection

    Chin. Med. J.

    (1998)
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