This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Keiser, J.
Right arrow Articles by Utzinger, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Keiser, J.
Right arrow Articles by Utzinger, J.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, March 2007, p. 1096-1098, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01366-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Evaluation of the In Vivo Activity of Tribendimidine against Schistosoma mansoni, Fasciola hepatica, Clonorchis sinensis, and Opisthorchis viverrini{triangledown}

Jennifer Keiser,1* Xiao Shu-Hua,2 Jacques Chollet,1 Marcel Tanner,1 and Jürg Utzinger1

Swiss Tropical Institute, P.O. Box, CH-4002 Basel, Switzerland,1 National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Shanghai 200025, People's Republic of China2

Received 1 November 2006/ Returned for modification 10 December 2006/ Accepted 17 December 2006


arrow
ABSTRACT
 
We examined the in vivo activity of tribendimidine against selected trematodes. A single 150-mg/kg dose of tribendimidine achieved a 99.1% reduction of Clonorchis sinensis in rats. A 400-mg/kg dose of tribendimidine reduced Opisthorchis viverrini in hamsters by 95.7%. High doses of tribendimidine showed no activity against Schistosoma mansoni and Fasciola hepatica.


arrow
TEXT
 
One-quarter of a billion people are infected with parasitic trematode worms worldwide. Schistosomiasis, caused by a blood fluke of the genus Schistosoma affects an estimated 207 million people (11). Disease-associated symptoms occur in 120 million people, and 20 million people suffer from severe morbidity (2). The three most important human schistosomes are Schistosoma haematobium, Schistosoma japonicum, and Schistosoma mansoni. An estimated 40 million people are infected with food-borne trematodes, which comprise the liver flukes (Clonorchis sinensis, Fasciola spp., Opisthorchis spp.), the lung flukes (Paragonimus spp.), and the intestinal flukes (Echinostoma spp., heterophyids) (13). Food-borne trematodiasis is an emerging public health problem and is of considerable veterinary significance, but its global burden remains to be investigated (7).

Tribendimidine, a symmetrical diamidine derivative of amidantel, is a broad-spectrum anthelminthic drug, developed in China since the mid-1980s (10). The chemical structure of tribendimidine is shown in Fig. 1. Tribendimidine has recently been approved by the Chinese authorities based on the good safety and therapeutic profile against soil-transmitted helminthiasis (10, 14, 15). In a recent in vivo investigation, we have demonstrated that tribendimidine is active against an intestinal trematode, Echinostoma caproni (5). Here we extend our investigations and screen for in vivo activity of tribendimidine against a range of clinically significant trematodes, S. mansoni, Fasciola hepatica, C. sinensis, and Opisthorchis viverrini.


Figure 1
View larger version (3K):
[in this window]
[in a new window]

  		FIG. 1. Chemical structure of tribendimidine.

Animal studies were approved and carried out according to Swiss national regulations. Female NMRI mice (n = 10; age, ~5 weeks; weight, ~24 g) and female Wistar rats (n = 28; age, ~5 weeks; weight, ~100 g) were purchased from RCC (Itingen, Switzerland). Male Syrian Gold hamsters (n = 14; age, ~4 to 16 weeks; weight, ~100 to 200 g) were purchased from Charles River (Sulzfeld, Germany). Animals were kept in groups of four to five under environmentally controlled conditions, with free access to water and rodent diet.

Cercariae of S. mansoni (Liberian strain) were obtained from infected Biomphalaria glabrata following routine procedures at our laboratories. F. hepatica metacercariae (Cullompton isolate) were purchased from G. Graham (Addlestone, United Kingdom). C. sinensis and O. viverrini metacercariae were isolated from freshwater fishes caught in Guanxi province (China) and Khon Kaen province (Thailand), respectively, as described previously (4).

Tribendimidine was synthesized and provided by the National Institute of Parasitic Diseases (Shanghai, China). The drug was prepared in a suspension in 7% Tween 80 and 3% ethanol. With the exception of our adult S. mansoni screen in mice, where we routinely use a 400-mg/kg single oral dose (3), we initially used a 150-mg/kg single oral dose of tribendimidine in rats or 200 mg/kg in hamsters. Depending on the results obtained, these doses, sequentially, were lowered or increased.

Fifteen rats were infected orally with 25 metacercariae of F. hepatica. Eight weeks postinfection, five rats were treated with single 150- to 800-mg/kg oral doses of tribendimidine (only result of highest dose shown). The remaining rats were left untreated, and hence, they served as controls. One week posttreatment, rats were euthanized by CO2 and all flukes were removed from the liver and bile ducts and counted.

Thirteen rats were infected orally with 40 C. sinensis metacercariae. Four weeks postinfection, two groups of four rats each were given a single 75- or 150-mg/kg oral dose of tribendimidine. The remaining rats served as controls. Killing and dissection of rats was done as described above.

Fourteen hamsters were infected orally with 45 O. viverrini metacercariae. Four weeks postinfection, four hamsters each were treated orally with a single 200- or 400-mg/kg dose of tribendimidine. The remaining hamsters served as controls. Hamsters were killed and dissected 1 week posttreatment, and O. viverrini flukes were removed from the liver, gall bladder, and bile ducts and counted.

Ten mice were infected subcutaneously with 80 S. mansoni cercariae. Seven weeks postinfection, half of the mice were treated with a single 400-mg/kg oral dose of tribendimidine. The remaining mice served as controls. Twenty-eight days posttreatment, animals were killed by blood letting, and S. mansoni flukes were removed from the liver and mesenteric veins, sexed, and counted.

Mean worm burdens in the different treatment and control groups were calculated. Statistical analyses were done in version 2.4.5 Statsdirect (Statsdirect Ltd., Cheshire, United Kingdom). Differences in the median of the responses between the treatment and the respective control groups were examined with the Kruskal-Wallis (KW) test. A difference in median was considered to be significant at a level of 5%.

We observed high in vivo activities of tribendimidine against C. sinensis and O. viverrini. A 99.1% worm burden reduction was achieved with 150 mg/kg tribendimidine administered to C. sinensis-infected rats. At half this dose, the worm burden reduction was still significant (68.9%; KW = 5.46; P = 0.019; Table 1). A single 400-mg/kg oral dose of tribendimidine given to hamsters infected with adult O. viverrini reduced the worm burden by 95.7%. At half this dose, a worm burden reduction of 61.4% was obtained, which was significant (Table 2).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Effect of single oral doses of tribendimidine against adult C. sinensis flukes harbored in rats


View this table:
[in this window]
[in a new window]

  		TABLE 2. Effect of single oral doses of tribendimidine against O. viverrini harbored in hamsters

On the other hand, tribendimidine lacked in vivo efficacy against adult S. mansoni and adult F. hepatica flukes; high doses showed no worm burden reduction at all (Tables 3 and 4).


View this table:
[in this window]
[in a new window]

  		TABLE 3. Effect of a single oral dose of tribendimidine against adult F. hepatica harbored in rats


View this table:
[in this window]
[in a new window]

  		TABLE 4. Effect of single oral dose of tribendimidine against adult S. mansoni harbored in mice

We were somewhat surprised that the four biologically-related trematodes examined, which in the adult stage are all harbored in the liver, either in the veins (S. mansoni) or the tissue and bile ducts (C. sinensis, F. hepatica, and O. viverrini), differ greatly in their susceptibility to tribendimidine in rodents. Elucidations on the mechanism of action of tribendimidine might help to clarify why S. mansoni and F. hepatica flukes, harbored in mice and rats, respectively, are not susceptible to tribendimidine. Pharmacokinetics and the choice of the host model might also play a role in the differential activities of tribendimdine observed.

For over two decades, treatment of opisthorchiasis and clonorchiasis has relied on praziquantel (6). Fortunately, parasite resistance to praziquantel has not been a major public health issue thus far. However, low cure rates have already been reported after administration of praziquantel to clonorchiasis patients in Vietnam (12). Hence, the development of new, orally active, single-dose trematocidal drugs—in the period while praziquantel remains effective—would be an important step forward. Since tribendimidine is a safe and highly efficacious drug for treatment of soil-transmitted helminth infections (15), a phase II clinical trial could be initiated with an emphasis on opisthorchiasis or clonorchiasis. In addition, it is important to note that the latter two diseases often geographically overlap with soil-transmitted helminthiasis (1, 8, 9). Consequently, the effect of tribendimidine on concurrent infections with soil-transmitted helminths and either C. sinensis or O. viverrini should be assessed.


arrow
ACKNOWLEDGMENTS
 
We are grateful to T. Smarn for his help in obtaining the metacercariae of O. viverrini.

J. Keiser (project no. PMPDB-114358) and J. Utzinger (project no. PPOOB-102883) are grateful to the Swiss National Science Foundation for sustained financial support.


arrow
FOOTNOTES
 
* Corresponding author. Mailing address: Swiss Tropical Institute, P.O. Box, CH-4002 Basel, Switzerland. Phone: 41 61 284-8218. Fax: 41 61 284-8105. E-mail: jennifer.keiser{at}unibas.ch. Back

{triangledown} Published ahead of print on 28 December 2006. Back


arrow
REFERENCES
 
    1
  1. Chai, J. Y., and B. Hongvanthong. 1998. A small-scale survey of intestinal helminthic infections among the residents near Pakse, Laos. Korean J. Parasitol. 36:55-58.[Medline]
    2. 2
  2. Chitsulo, L., D. Engels, D. Montresor, and L. Savioli. 2000. The global status of schistosomiasis and its control. Acta Trop. 23:41-51.
    3. 3
  3. Keiser, J., N. A. El Ela, E. El Komy, N. El Lakkany, T. Diab, J. Chollet, J. Utzinger, and R. Barakat. 2006. Triclabendazole and its two main metabolites lack activity against Schistosoma mansoni in the mouse model. Am. J. Trop. Med. Hyg. 75:287-291.[Abstract/Free Full Text]
    4. 4
  4. Keiser, J., S. H. Xiao, J. Xue, Z. S. Chang, P. Odermatt, S. Tesana, M. Tanner, and J. Utzinger. 2006. Effect of artesunate and artemether against Clonorchis sinensis and Opisthorchis viverrini in rodent models. Int. J. Antimicrob. Agents 28:370-373.[CrossRef][Medline]
    5. 5
  5. Keiser, J., S. H. Xiao, and J. Utzinger. 2006. Effect of tribendimidine on adult Echinostoma caproni harbored in mice, including scanning electron microscopic observations. J. Parasitol. 92:858-962.[CrossRef][Medline]
    6. 6
  6. Keiser, J., and J. Utzinger. 2004. Chemotherapy for major food-borne trematodes: a review. Expert Opin. Pharmacother. 5:1711-1726.[CrossRef][Medline]
    7. 7
  7. Keiser, J., and J. Utzinger. 2005. Emerging foodborne trematodiasis. Emerg. Infect. Dis. 11:1507-1514.[Medline]
    8. 8
  8. Kim, C. H., Y. E. Na, N. M. Kim, D. W. Shin, and D. Y. Chang. 1994. Intestinal parasite and Clonorchis sinensis infection among the inhabitants in the upper stream of Taechong Dam, Kumgang (River). Korean J. Parasitol. 32:207-214.[Medline]
    9. 9
  9. Nontasut, P., T. V. Thong, J. Waikagul, M. T. Anantaphruti, W. Fungladda, N. Imamee, and N. V. De. 2003. Social and behavioral factors associated with Clonorchis infection in one commune located in the Red River Delta of Vietnam. Southeast Asian J. Trop. Med. Public Health 34:269-273.[Medline]
    10. 10
  10. Ren, H. N., B. Z. Cheng, and Z. N. Zhuang. 1987. Experimental therapeutic efficacy of a new anti-hookworm drug, tribendimidin. Chin. J. Parasitol. Parasit. Dis. 5:262-264.
    11. 11
  11. Steinmann, P., J. Keiser, R. Bos, M. Tanner, and J. Utzinger. 2006. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect. Dis. 6:411-425.[CrossRef][Medline]
    12. 12
  12. Tinga, N., N. De, H. V. Vien, L. Chau, N. D. Toan, P. A. Kager, and P. J. Vries. 1999. Little effect of praziquantel or artemisinin on clonorchiasis in Northern Vietnam. A pilot study. Trop. Med. Int. Health 4:814-818.[CrossRef][Medline]
    13. 13
  13. World Health Organization. 1995. Control of foodborne trematode infections. Report of a WHO study group. WHO Technical Report Series 849. World Health Organization, Geneva, Switzerland.
    14. 14
  14. Wu, Z. X., Y. Y. Fang, and Y. S. Liu. 2006. Effect of a novel drug—enteric coated tribendimidine in the treatment of intestinal nematode infections. Chin. J. Parasitol. Parasit. Dis. 24:23-26.
    15. 15
  15. Xiao, S. H., H. M. Wu, M. Tanner, J. Utzinger, and C. Wang. 2005. Tribendimidine: a promising, safe and broad-spectrum anthelmintic agent from China. Acta Trop. 94:1-14.[CrossRef][Medline]

Antimicrobial Agents and Chemotherapy, March 2007, p. 1096-1098, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01366-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • White, N. J. (2008). Qinghaosu (Artemisinin): The Price of Success. Science 320: 330-334 [Abstract] [Full Text]  

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Keiser, J.
Right arrow Articles by Utzinger, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Keiser, J.
Right arrow Articles by Utzinger, J.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»