IJCM  Vol.5 No.3 , January 2014
Diclazuril Protects against Maternal Gastrointestinal Syndrome and Congenital Toxoplasmosis
ABSTRACT

Background: Toxoplasmosis is a common cause of foodborne, gastrointestinal and congenital syndrome with particularly severe or unknown health consequences. There is no safe and effective preventive or therapeutic modality against congenital toxoplasmosis or to eliminate the persistent chronic infection. Hypothesis: Diclazuril to be safe in pregnancy and effective against gastrointestinal toxoplasmosis. Methods: CD1 programmed pregnant mice were divided into groups and administered a diet containing diclazuril, or sham control. Treatments were initiated on Day 5 of pregnancy and continued until Day 16 when dams were euthanatized. On Day 8 of pregnancy dams were infected intraperitoneally with escalating doses of tachyzoites (0, 100, 300, 600) from Type II strain. Dams were monitored daily for distress, pain, and abortion and samples collected at the end of the experiments. Results: Infected dams developed moderate to severe Toxoplasma related complications in tachyzoites dose dependent manner. Animals became anemic and showed hydrothorax, and ascities. Diclazuril effectively protected dams from ascities and anemia (p < 0.05). Infected dams showed splenomegaly, with massive infiltration of epithelioid cells compared with the protective effect of diclazuril in treated animals. Infected dams exhibited severe hepatitis (score 0 to 4 scale = 3.5 ± 0.01) with influx of inflammatory and plasma cells, dysplastic hepatocytes, multinucleated giant cell transformation and hepatic cells necrosis. Diclazuril treatment significantly protected dams from hepatitis, also in tachyzoites dose (100, 300, 600) dependent manner (respectively infected-treated versus infected controls, p < 0.001, p < 0.01 and p < 0.05). Colonic tissues were significantly shortened in length, with infiltration of lymphocytes, and macrophages and microabscess formations in the cryptic structures, with significant improvement in diclazuril treated animals. Additionally, the number of fetuses, fetal length and fetal weight were preserved in diclazuril treated dams. Conclusions: This is the first report describing of diclazuril safety in pregnancy as well as efficacy against mild to moderate hepato-gastrointestinal syndrome in dams and fetal toxoplasmosis (Special issue, “Treatment of Liver Diseases”).


Cite this paper
H. Oz and T. Tobin, "Diclazuril Protects against Maternal Gastrointestinal Syndrome and Congenital Toxoplasmosis," International Journal of Clinical Medicine, Vol. 5 No. 3, 2014, pp. 93-101. doi: 10.4236/ijcm.2014.53017.
References
[1]   J. P. Dubey and J. L. Jones, “Toxoplasma gondii Infection in Humans and Animals in the United States,” International Journal for Parasitology, Vol. 38, No. 11, 2008, pp. 1257-1278. http://dx.doi.org/10.1016/j.ijpara.2008.03.007

[2]   J. L. Jones, D. Kruszon-Moran, M. Wilson, G. Mcquillan, T. Navin and J. B. Mcauley, “Toxoplasma gondii Infection in the United States: Seroprevalence and Risk Factors,” American Journal of Epidemiology, Vol. 154, No. 4, 2001, pp. 357-365.
http://dx.doi.org/10.1093/aje/154.4.357

[3]   D. Buxton, K. Thomson, S. Maley, S. Wright and H. J. Bos, “Vaccination of Sheep with a Live Incomplete Strain (S48) of Toxoplasma gondii and their Immunity to Challenge When Pregnant,” Veterinary Record, Vol. 129, No. 5, 1991, pp. 89-93. http://dx.doi.org/10.1136/vr.129.5.89

[4]   A. Wolf, D. Cowen and B. Paige, “Human Toxoplasmosis: Occurrence in Infants as an Encephalomyelitis Verification by Transmission to Animals,” Science, Vol. 89, No. 2306, 1939, pp. 226-227.
http://dx.doi.org/10.1126/science.89.2306.226

[5]   J. L. Jones, A. Lopez, M. Wilson, J. Schulkin and R. Gibbs, “Congenital Toxoplasmosis: A Review,” Obstetrical & Gynecological Survey, Vol. 56, No. 5, 2001, pp. 296-305. http://dx.doi.org/10.1097/00006254-200105000-00025

[6]   S. Y. Wong and J. S. Remington, “Toxoplasmosis in Pregnancy,” Clinical Infectious Diseases, Vol. 18, No. 6, 1994, pp. 853-861.
http://dx.doi.org/10.1093/clinids/18.6.853

[7]   M. Cortina-Borja, H. K. Tan, M. Wallon, M. Paul, A. Prusa, W. Buffolano, G Malm, A. Salt, K. Freeman, E. Petersen and R. E. Gilbert, “European Multicentre Study on Congenital Toxoplasmosis (EMSCOT). Prenatal Treatment for Serious Neurological Sequelae of Congenital Toxoplasmosis: An Observational Prospective Cohort Study,” PLOS Medicine, Vol. 7, No. 10, 2010, pp. 1-10.
http://dx.doi.org/10.1371/journal.pmed.1000351

[8]   A. Berrébi, C. Assouline, M. H. Bessières, M. Lathière, S. Cassaing, V. Minville and J. M. Ayoubi, “Long-Term Outcome of Children with Congenital Toxoplasmosis,” American Journal of Obstetrics & Gynecology, Vol. 203, No. 6, 2010, pp. 552-558.
http://dx.doi.org/10.1016/j.ajog.2010.06.002

[9]   F. A. Habib, “Post-Treatment Assessment of Acute Toxoplasma Infection during Pregnancy,” Journal of Obstetrics & Gynaecology, Vol. 28, No. 6, 2008, pp. 593-595. http://dx.doi.org/10.1080/01443610802344332

[10]   B. Julliac B, H. Théophile, M. Begorre, B. Richez and F. Haramburu, “Side effects of Spiramycin Masquerading as Local Anesthetic Toxicity during Labor Epidural Analgesia,” International Journal of Obstetric Anesthesia, Vol. 19, No. 3, 2010, pp. 331-332.
http://dx.doi.org/10.1016/j.ijoa.2010.03.002

[11]   H. S. Oz and T. Tobin, “Atovaquone Ameliorates Gastrointestinal Toxoplasmosis Complications in a Pregnancy model,” Medical Science Monitor, Vol. 18, No. 9, 2012, pp. BR337-BR345.
http://dx.doi.org/10.12659/MSM.883342

[12]   D. E. Granstrom and T. Tobin, “Treatment of EPM Formulations and Methods to Treat and Prevent Equine Protozoal Myeloencephalitis,” US Patent No. 5,883,095, 1999.

[13]   R. C. L. Assis, F. D. Luns, M. E. Beletti, R. L. Assis, N. M. Nasser, E. S. M. Faria and M. C. Cury, “Histomorphometry and Macroscopic Intestinal Lesions in Broilers Infected with Eimeria Acervulina,” Veterinary Parasitology, Vol. 168, No. 3-4, 2010, pp. 185-189.
http://dx.doi.org/10.1016/j.vetpar.2009.11.017

[14]   J. H. Hackstein, U. Mackenstedt, H. Mehlhorn, J. P. Meijerink, H. Schubert and J. A. Leunissen, “Parasitic Apicomplexans Harbor a Chlorophyll a-D1 Complex, the Potential Target for Therapeutic Triazines,” Parasitology Research, Vol. 81, No. 3, 1995, pp. 207-216.

[15]   D. Ajzenberg, N. Cogne, L. Paris, M. H. Bessieres, P. Thulliez and P. Filisetti, “Genotype of 86 Toxoplasma gondii Isolates Associated with Human Congenital Toxoplasmosis, and Correlation with Clinical Findings,” The Journal of Infectious Diseases, Vol. 186, No. 5, 2002, pp. 684-689. http://dx.doi.org/10.1086/342663

[16]   D. K. Howe, S. Honore, F. Derouin and L. D. Sibley, “Determination of Genotypes of Toxoplasma gondii Strains Isolated from Patients with Toxoplasmosis,” Journal of Clinical Microbiology, Vol. 35, No. 6, 1997, pp. 1411-1414.

[17]   H. S. Oz, J. Ebersole and W. J. de Villiers, “The Macrophage Pattern Recognition Scavenger Receptors SR-A and CD36 Protect against Microbial Induced Pregnancy Loss,” Inflammation Research, Vol. 60, No. 1, 2011, pp. 93-97. http://dx.doi.org/10.1007/s00011-010-0241-1

[18]   H. S. Oz, T. Chen T, W. J. de Villiers and C. McClain, “Glutathione Enhancing Agents Protect against Steatohepatitis in a Model,” Journal of Biochemical and Molecular Toxicology, Vol. 20, No. 1, 2006, pp. 39-47.
http://dx.doi.org/10.1002/jbt.20109

[19]   H. S. Oz, T. Chen and H. Nagasawa, “Comparative Efficacies of Two Cysteine Prodrugs and a Glutathione Delivery Agent in a Colitis Model,” Translational Research, Vol. 150, No. 2, 2007, pp. 122-129.
http://dx.doi.org/10.1016/j.trsl.2006.12.010

[20]   H. S. Oz, T. Chen and W. J. S. de Villiers, “Green Tea Polyphenols and Sulfasalazine have Parallel Anti-inflammatory Properties in Colitis Models,” Frontiers in Immunology, Vol. 4, Article. 132, 2013, pp. 1-10.

[21]   K. N. Westlund, L. Zhang, F. Ma and H. S.Oz, “Chronic Inflammation and Pain in a Tumor Necrosis Factor Receptor (TNFR) (p55/p75-/-) Dual Deficient Murine Model,” Translational Research, Vol. 160, No. 1, 2012, pp. 84-94. http://dx.doi.org/10.1016/j.trsl.2011.10.003

[22]   R. Thiébaut, S. Leproust, G. Chêne and R. Gilbert, “Effectiveness of Prenatal Treatment for Congenital Toxoplasmosis: A Meta-Analysis of Individual Patients’ Data SYROCOT (Systematic Review on Congenital Toxoplasmosis) Study Group,” The Lancet, Vol. 369, No. 9556, 2007, pp. 115-122.
http://dx.doi.org/10.1016/S0140-6736(07)60072-5

[23]   P. S. Mead, L. Slutsker, V. Dietz, L. F. McCaig, J. S. Bresee, C. Shapiro, P. M. Griffin and R. V. Tauxe, “Food-Related Illness and Death in the United States,” Emerging Infectious Diseases, Vol. 5, No. 5, 1999, pp. 606-625.

[24]   L. J. Robertson, J. W. van der Giessen, M. B. Batz, M. Kojima and S. Cahill, “Have Foodborne Parasites Finally Become a Global Concern?” Trends in Parasitology, Vol. 29, No. 3, 2013, pp. 101-103.
http://dx.doi.org/10.1016/j.pt.2012.12.004

[25]   M. H. Bessières, A. Berrebi, S. Cassaing, J. Fillaux, J. P. Cambus, A. Berry, C. Assouline, J. M. Ayoubi and J. F. Magnaval, “Diagnosis of Congenital Toxoplasmosis: Prenatal and Neonatal Evaluation of Methods Used in Toulouse University Hospital and Incidence of Congenital Toxoplasmosis,” Memórias do Instituto Oswaldo Cruz, Vol. 104, No. 2, 2009, pp. 389-392.
http://dx.doi.org/10.1590/S0074-02762009000200038

[26]   L. Dirikolu, A. F. Lehner, C. Nattrass, B. G. Bentz, W. E. Woods, W. G. Carter, W. Karpiesiuk, J. Jacobs, J. Boyles, J. D. Harkins, D. E. Granstrom and T. Tobin, “Diclazuril in the Horse: Its Identification and Detection and Preliminary Pharmacokinetics,” Journal of Veterinary Pharmacology and Therapeutics, Vol. 22, No. 6, 1999, pp. 374-379. http://dx.doi.org/10.1046/j.1365-2885.1999.00232.x

[27]   L. Dirikolu, J. H. Foreman and T. Tobin, “Current Therapeutic Approaches to Equine Protozoal Myeloencephalitis,” Journal of the American Veterinary Medical Association, Vol. 242, No. 4, 2013, pp. 482-491.
http://dx.doi.org/10.2460/javma.242.4.482

[28]   D. S. Lindsay and J. P. Dubey, “Determination of the Activity of Diclazuril against Sarcocystis Neurona and Sarcocystis Falcatula in Cell Cultures,” Journal of Parasitology, Vol. 86, No. 1, 2000, pp. 164-166.

[29]   D. S. Lindsay and B. L. Blagburn, “Activity of Diclazuril against Toxoplasma gondii in Cultured Cells and Mice,” American Journal of Veterinary Research, Vol. 55, No. 4, 1994, pp. 530-533.

[30]   T. M. Work, G. Massey, B. A. Rideout, C. H. Gardiner, D. B. Ledig, O. C. H. Kwok and J. P. Dubey, “Fatal Toxoplasmosis in Fee-Ranging Endangered ‘ALALA’ from Hawaii,” Journal of wildlife diseases, Vol. 36, No. 2, 2000, pp. 205-212.
http://dx.doi.org/10.7589/0090-3558-36.2.205

[31]   B. H. Zhou, H. W. Wang, Z. S. Zhao, M. Liu, W. C. Yan, J. Zhao, Z. Zhang and F. Q. Xue, “A Novel Serine/ Threonine Protein Phosphatase Type 5 from Second-Generation Merozoite of Eimeria Tenella Is Associated with Diclazuril-Induced Apoptosis,” Parasitology Research, Vol. 112, No. 4, 2013, pp. 1771-1780.
http://dx.doi.org/10.1007/s00436-013-3336-0

 
 
Top