Susceptibility or resistance of praziquantel in human schistosomiasis: a review
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- Wang, W., Wang, L. & Liang, Y. Parasitol Res (2012) 111: 1871. doi:10.1007/s00436-012-3151-z
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Since praziquantel was developed in 1970s, it has replaced other antischistosomal drugs to become the only drug of choice for treatment of human schistosomiases, due to high efficacy, excellent tolerability, few and transient side effects, simple administration, and competitive cost. Praziquantel-based chemotherapy has been involved in the global control strategy of the disease and led to the control strategy shifting from disease control to morbidity control, which has greatly reduced the prevalence and intensity of infections. Given that the drug has been widely used for morbidity control in endemic areas for more than three decades, the emergence of resistance of Schistosoma to praziquantel under drug selection pressure has been paid much attention. It is possible to induce resistance of Schistosoma mansoni and Schistosoma japonicum to praziquantel in mice under laboratorial conditions, and a reduced susceptibility to praziquantel in the field isolates of S. mansoni has been found in many foci. In addition, there are several schistosomiasis cases caused by Schistosoma haematobium infections in which repeated standard treatment fails to clear the infection. However, in the absence of exact mechanisms of action of praziquantel, the mechanisms of drug resistance in schistosomes remain unclear. The present review mainly demonstrates the evidence of drug resistance in the laboratory and field and the mechanism of praziquantel resistance and proposes some strategies for control of praziquantel resistance in schistosomes.
Since praziquantel, a highly effective and safe antischistosomal drug, was developed (Gönnert and Andrews 1977; Seubert et al. 1977), it has replaced all other schistosomacidal agents to become the only drug of choice for treatment against all the major species of schistosome (WHO 1993). Praziquantel makes mass chemotherapy possible as the priority control strategy in almost all countries that are endemic for schistosomiasis worldwide (WHO 1993). In sub-Saharan Africa, praziquantel-based mass chemotherapy leads to great reductions in schistosomiasis and soil-transmitted helminthes (Koukounari et al. 2007; Zhang et al. 2007; Hotez and Fenwick 2009; French et al. 2010; Leslie et al. 2011; Fenwick 2012; Hotez et al. 2012). In addition, praziquantel has been shown to exhibit anti-fibrotic activity in animal models infected with schistosome infections (Huang et al. 2011; Liang et al. 2011a, b; Abdel-Hafeez et al. 2012). It has been reported that drug resistance emerges following large-scale, repeated use of the same chemotherapeutic agent in the field (Coles 1989; Coles and Kinoti 1997; Geerts et al. 1997). Since praziquantel was introduced, it has been widely used in schistosome-endemic areas for morbidity control for more than 30 years (Harder 2002; WHO 2002; Fenwick et al. 2003; Chen 2005; Ribeiro-dos-Santos et al. 2006), and whether resistance of Schistosoma to praziquantel emerges under drug-selective pressure has been paid much attention (Cioli 2000; Doenhoff et al. 2002, 2008; Doenhoff and Pica-Mattoccia 2006; Caffrey 2007). The present review mainly demonstrates the researches regarding praziquantel resistance in the laboratory and field and the advances in mechanism of praziquantel resistance and proposes some control interventions for praziquantel resistance in schistosomes.
Experimentally induced praziquantel resistance in Schistosoma mansoni and Schistosoma japonicum
The experimentally induced resistance of S. mansoni to hycanthone and oxamniquine in 1970s (Katz et al. 1973; Campos et al. 1976; Jansma et al. 1977) stimulated a study to induce resistance to praziquantel in a Brazilian human strain of S. mansoni; however, no resistance was induced (Dias and Olivier 1986). In a study for in vitro selection of drug-resistant S. mansoni, schistosomules of S. mansoni were cultured for 3 days in the presence of schistosomicides and then inoculated intraperitoneally into mice. Comparison of drug response of the unselected and selected strains as adult worms in mice showed an increase in tolerance to amoscanate, oltipraz, and oxamniquine, but not praziquantel (Coles and Bruce 1987). In 1994, Fallon and Doenhoff (1994) firstly demonstrated that S. mansoni subjected to drug pressure may develop resistance to praziquantel over the course of relatively few subcurative multiple doses of praziquantel-treated passages of S. mansoni in mice. Ismail et al. (1994) also found that the use of praziquantel, especially in low subcurative dose, may lead to the development of resistance to therapeutic dose of the drug in following generations. Recently, a novel effective, fast, simple, and cheap method was developed to induce resistance to praziquantel in S. mansoni by using successive drug treatments of Biomphalaria glabrata snails infected with S. mansoni, which further suggests that it is possible to induce resistance of S. mansoni to praziquantel in laboratory (Couto et al. 2011).
In S. japonicum, Yue and colleagues (1990) carried out a set of animal experiments to explore the possibility of inducing resistance of S. japonicum to praziquantel; however, analysis of total and female worm burden reductions indicated that there was no significant difference between the sensitivity to praziquantel of F1 and F2 progenies of S. japonicum and the parent worms. However, it has been recently proved that S. japonicum (strain of Mainland China) is able to develop resistance to praziquantel under continuous drug pressure (Liang et al. 2011a, b), and the drug resistance could exhibit in the stages of adult worms, cercariae, and miracidia (Li et al. 2011). There is no knowledge about experimental induction of praziquantel resistance in Schistosoma haematobium reported till now.
Praziquantel resistance: evidence from the field
Currently, the majority of field surveys of praziquantel resistance focus on S. mansoni. Although few praziquantel-resistant isolates are detected in the field, a reduced susceptibility of the drug in S. mansoni has been widely found in many endemic foci, notably in African countries like Egypt and Senegal (Fallon et al. 1994; Ismail et al. 1996; Bonesso-Sabadini and de Souza Dias 2002; Danso-Appiah and De Vlas 2002; Lawn et al. 2003; Melman et al. 2009). There is currently no direct evidence for the development of resistance of S. haematobium to praziquantel; however, it has been reported that repeated standard treatment fails to clear the infection in schistosomiasis cases caused by infection of S. haematobium (Herwaldt et al. 1995; Silva et al. 2005, 2008; Alonso et al. 2006).
Since 1992, the World Bank Loan Project for Schistosomiasis Control was initiated in China, and a praziquantel-based chemotherapy has been involved in the national schistosomiasis control program (Xianyi et al. 2005). It is estimated that more than 50 million individuals have received praziquantel treatment for morbidity control in the endemic areas (Chen 2005; Xiao et al. 2010). The emergence of resistance of S. japonicum to praziquantel has received much attention (Zhai et al. 1999; Wang and Liang 2007; Wu et al. 2011). Praziquantel at a single oral dose of 40 mg/kg was given to S. japonicum-infected cases detected in the field endemic foci with high, moderate, or low endemicities in China, so as to assess the current efficacy of the drug following large-scale, expanded, and repeated use, and the results indicated that the current efficacy of praziquantel against S. japonicum was still high and has not changed after more than three decades of repeated, expanded chemotherapy in the main endemic areas of China (Liang et al. 2001a; Wang et al. 2010, 2012). It is suggested that no evidence of tolerance or resistance to praziquantel in S. japonicum was detected in China. Another study was designed to evaluate the efficacy of praziquantel against S. japonicum in an area with repeated chemotherapy compared with a newly identified endemic focus in Hunan Province, China, and no significant difference was found in cure rates between the two areas (89.7 vs. 90.3 %) following treatment with praziquantel at single oral dose of 40 mg/kg. The results suggested that the efficacy of the drug in the area with repeated chemotherapy was not significantly different from that in the newly identified endemic focus (Yu et al. 2001). In addition, a cross-sectional survey was conducted in 33 villages in Sichuan Province to evaluate the efficacy of praziquantel for the treatment of S. japonicum in humans. After treating infected persons (185 cases) two times with 40-mg/kg doses of praziquantel, only one remained infected, suggesting that in the near term, praziquantel remains effective in treating human S. japonicum infection in China (Seto et al. 2011).
Mechanism of praziquantel resistance
In the absence of exact mechanisms of action of praziquantel, the mechanisms of drug resistance in schistosomes remain unclear. A confounding factor regarding praziquantel resistance which should be noted is that immature schistosomes are “resistant” (less susceptible) to the drug and the low cure rates achieved may thus be due to the presence of immature worms in the patients at the time of treatment (Renganathan and Cioli 1998; Gryseels et al. 2001). Such a hypothesis is supported by the higher cumulative cure rates achieved by two treatments a few weeks apart (Picquet et al. 1998; Utzinger et al. 2000; N’Goran et al. 2003). However, Danso-Appiah and De Vlas (2002) performed an innovative meta-analysis which compared the praziquantel efficacy in Senegal and other areas and concluded that the reported poor cure rates from Senegal were atypical. The discovery that the structurally unusual S. mansoni beta subunit of voltage-gated Ca2+ channels SmCavbeta1 is involved in praziquantel activity and is consistent with the known pharmacological effects of the drug stimulated a study to investigate whether low sensitivity to praziquantel in S. mansoni was due to mutation in the gene coding for the beta subunit (Kohn et al. 2003; Greenberg 2005; Jeziorski and Greenberg 2006; Valle et al. 2003). After sequencing the cDNAs coding for SmCavbeta1 and SmCavbeta2 subunits of the praziquantel-susceptible and praziquantel-resistant strains of S. mansoni, no significant difference was detected. Northern blotting analysis of different strains and various developmental stages revealed no major quantitative differences in the expression of the beta subunits (Valle et al. 2003). The hypothesis that Ca2+ channel is responsible for praziquantel resistance is therefore denied.
It is hypothesized that the changes in the biological characteristics of schistosomes associated with the development of praziquantel resistance could affect the transmission and pathology of the diseases they cause. To test this hypothesis, the host–parasite relationships of five praziquantel-resistant and five praziquantel-susceptible isolates of S. mansoni were compared in B. glabrata snails and outbred mice. The rate (19.8 %) of B. glabrata infected with praziquantel-resistant isolates was significantly higher than that (8.9 %) with praziquantel-susceptible isolates (P = 0.006), and such a change between the drug-susceptible and drug-resistant isolates was considered to be associated with the presence of resistance to praziquantel (Liang et al. 2001b). Liang et al. (2010) demonstrated that the male cercariae of praziquantel-susceptible isolates of S. mansoni had significantly higher tail-shedding rates than that of female cercariae when exposed to the same concentration of praziquantel (all P values <0.05), while the phenomenon was not observed in praziquantel-resistant isolates. It is thought that this sexual differential resistance phenomenon of S. mansoni suggests that resistance to praziquantel is induced by reducing the praziquantel susceptibility of male worms.
ATP-binding cassette (ABC) transport proteins are a large family of membrane proteins that have many cellular functions in animals, plants, and bacteria including the transport of diverse compounds such as peptides, hormones, cholesterol, and iron (Glavinas et al. 2004; Geisler and Murphy 2006). It is indicated that the chemotherapy failure in the treatment of bacteria and cancer is correlated with the ABC transport proteins (Gatti et al. 2011; Wawrzycka 2011; Lewis et al. 2012; Rodrigues et al. 2012). In addition, several members of this family like P-glycoprotein and multidrug resistance-associated proteins (MRPs) may be involved in the drug resistance in parasites (Blackhall et al. 1998, 2008; Lespine et al. 2008). There are two ABC transport protein homologues identified in S. mansoni, SmMRP1, a S. mansoni orthologue of MRP1, and SMDR2, a S. mansoni orthologue of P-glycoprotein (Bosch et al. 1994). Higher levels of SMDR2 RNA are expressed in female parasites than in males, while higher SmMRP1 RNA levels are observed in males than in females (Kasinathan et al. 2010a). Notably, the adult worms of S. mansoni upregulate the expression of both of these transporters in response to praziquantel (Messerli et al. 2009; Kasinathan et al. 2010a). It has been reported that, although SMDR2 is expressed in S. mansoni, there is no increase in mRNA levels of SMDR2 in drug-resistant parasites (Bosch et al. 1994). Messerli et al. (2009) examined the relationship between praziquantel and P-glycoprotein expression in S. mansoni, and the results demonstrated significant increased SMDR2 RNA levels and anti-P-glycoprotein immunoreactive protein expression following exposure to sublethal concentrations of praziquantel. In addition, praziquantel-resistant isolate had significantly increased levels of SMDR2 RNA and anti-P-glycoprotein immunoreactive protein compared with praziquantel-susceptible isolates. The findings perhaps indicate a role for multidrug-resistant proteins in the development or maintenance of praziquantel resistance. Furthermore, it has been reported that SMDR2 is modulated by praziquantel and, importantly, the transport of a fluorescent analogue of praziquantel suggests that praziquantel is also a substrate for SMDR2 (Kasinathan et al. 2010b). It is therefore possible that ABC transport proteins are involved in praziquantel resistance in schistosomes.
Interventions to control resistance
Interventions to control praziquantel resistance in schistosomes
• Avoiding treatment with subcurative doses of praziquantel. It has been proved that following treatment with subcurative doses resistance to praziquantel is possible to be experimentally induced in S. japonicum and S. mansoni (Fallon and Doenhoff 1994; Liang et al. 2011a, b). Standard treatment protocol should be implemented and subcurative treatment (total dose of less than 40 mg/kg) should be avoided to be employed for treatment of human schistosome infections.
• Decrease of treatment frequency. It has been indicated that high-frequency treatment has a higher possibility for inducing drug resistance than that of low-frequency treatment (Martin et al. 1982, 1984). Therefore, the frequency of praziquantel-based chemotherapy in high-risk populations should be decreased, while other control strategies like snail control, health education, improving sanitation by supplying tap water, and building lavatories and latrines should be emphasized (Wang et al. 2009a, b; Hong et al. 2011; Sun et al. 2011).
• Strengthening monitoring of drug quality. In order to ensure the effectiveness of praziquantel, the monitoring of praziquantel quality should be strengthened, and the monitoring parameters include quantitative analysis, purity, and bioavailability of the active component of the drug (Botros et al. 2011).
• Enhancement of praziquantel resistance detection and monitoring. There is no cross-resistance between praziquantel and other antischistosomal drugs detected till now. It has been proved both in laboratory and in field that the praziquantel-resistant isolates of S. mansoni remain susceptible to oxamniquine (Drescher et al. 1993; Fallon and Doenhoff 1994; Stelma et al. 1997). Therefore, detection of praziquantel resistance should be strengthened to detect cases infected with praziquantel-resistant strains of schistosomes as early as possible. And then other antischistosomal drugs like oxamniquine and mefloquine (Xiao et al. 2009, 2011, 2012), as alternatives of praziquantel, are employed for treatment of human infections, which can effectively cure cases timely. On other hand, such a replacement could rapidly remove the resistant strains from the schistosome populations in a certain area, which would effectively control the spread of drug resistance-related genes in the endemic foci.
Praziquantel, as the first drug of choice for treatment of human schistosomiases, has been widely used in the field for more than three decades (WHO 2002; Fenwick et al. 2003; Chen 2005; Ribeiro-dos-Santos et al. 2006). Given that, reduced sensitivity of praziquantel has been detected in S. mansoni in endemic foci (Fallon et al. 1994; Ismail et al. 1996; Bonesso-Sabadini and de Souza Dias 2002; Danso-Appiah and De Vlas 2002; Lawn et al. 2003; Melman et al. 2009), and there are some cases wherein there is failure to clear the infections of S. haematobium following standard treatment with praziquantel (Herwaldt et al. 1995; Silva et al. 2005, 2008; Alonso et al. 2006). In addition, it is possible to induce praziquantel resistance in S. mansoni and S. japonicum (Fallon and Doenhoff 1994; Liang et al. 2011a, b). It is therefore, of great importance to strengthen the monitoring of praziquantel sensitivity and detection of praziquantel resistance in schistosomes, and development of effective and rapid detection techniques is urgently needed. In areas where mass chemotherapy with praziquantel is implemented, the development and spread of drug resistance should be avoided and slowed as far as possible. In addition, once resistant strains are detected, some interventions should be quickly carried out to prevent the spread of drug-resistant genes in schistosome-endemic regions.
This study was supported by grants from the National Science and Technology Pillar Program of China (2009BAI78B06), Jiangsu Department of Health (X200901, X200912, and X201111), Jiangsu Provincial Scientific Foundation of Preventive Medicine (Y201031), and Jiangsu Provincial Scholarship.