Novel Synergistic Protective Efficacy of Atovaquone and Diclazuril on Fetal-Maternal Toxoplasmosis
Author(s)
Helieh S. Oz*
Affiliation(s)
Department of Internal Medicine, University of Kentucky Medical Center, Lexington, KY, USA.
Department of Internal Medicine, University of Kentucky Medical Center, Lexington, KY, USA.
ABSTRACT
Over 1 billion people globally are estimated to be infected with Toxoplasma gondii with severe or unknown consequences and no safe and effective therapies are available against congenital or persistent chronic infection. We propose that atovaquone and diclazuril synergistically protect against fetal-maternal toxoplasmosis. Methods: Programmed pregnant mice were treated with atovaquone and diclazuril monotherapy, or combined (atovaquone + diclazuril) therapy and infected with tachyzoites (0, 300, 600) and the course of infection was studied. Results: Infected dams with low dose (300) developed moderate toxoplasmosis complications and treatments were similarly effective with minor differences between monotherapies. In contrast, major differences were observed amongst varied treatments during high-dose (600) infection and severe related-toxoplasmosis complications as follows. Dams developed hydrothorax, ascities and excess weight gain. Combined therapy (P < 0.01) and to a lesser extent diclazuril monotherapy (P < 0.05) protected dams from excess weight, hydrothorax, and ascities. Infected dams exhibited splenomegaly, hepatomegaly and severe hepatitis. Combined therapy synergistically normalized pathology (P < 0.001) and to a lesser degree monotherapy (diclazuril P < 0.01, and atovaquone P < 0.05) protected dams from hepatitis and splemomegaly. Additionally, behavioral response to pain stimuli and fetal weight and fetal numbers were significantly preserved in treated dams. Conclusions: This is the first report describing combined atovaquone and diclazuril therapy a) to be safe in pregnancy, b) to exert novel synergistic effects, and c) to protect dams and their nested fetuses against adverse effects of severe toxoplasmosis.
KEYWORDS
Toxoplasma, Atovaquone, Diclazuril, Synergistic, Protection, Fetal Maternal, Congenital Toxoplasmosis, Pregnancy, Gastroenteritis
Toxoplasma, Atovaquone, Diclazuril, Synergistic, Protection, Fetal Maternal, Congenital Toxoplasmosis, Pregnancy, Gastroenteritis
Cite this paper
Oz, H. (2014) Novel Synergistic Protective Efficacy of Atovaquone and Diclazuril on Fetal-Maternal Toxoplasmosis. International Journal of Clinical Medicine, 5, 921-932. doi: 10.4236/ijcm.2014.515124.
Oz, H. (2014) Novel Synergistic Protective Efficacy of Atovaquone and Diclazuril on Fetal-Maternal Toxoplasmosis. International Journal of Clinical Medicine, 5, 921-932. doi: 10.4236/ijcm.2014.515124.
References
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http://dx.doi.org/10.1007/s00436-013-3336-0
[1] Hoffmann, S., Batz, B.M. and Morris Jr., J.G. (2012) Annual Cost of Illness and Quality-Adjusted Life Year Losses in the United States Due to 14 Foodborne Pathogens. Journal of Food Protection, 75, 1292-1302.
http://dx.doi.org/10.4315/0362-028X.JFP-11-417 [2] Dubey, J.P. and Jones, J.L. (2008) Toxoplasma gondii Infection in Humans and Animals in the United States. International Journal for Parasitology, 38, 1257-1278.
http://dx.doi.org/10.1016/j.ijpara.2008.03.007 [3] Kieffer, F. and Wallon, M. (2013) Congenital Toxoplasmosis. Handbook of Clinical Neurology, 112, 1099-1101.
http://dx.doi.org/10.1016/B978-0-444-52910-7.00028-3 [4] Olariu, T.R., Remington, J.S., McLeod, R., Alam, A. and Montoya, J.G. (2011) Severe Congenital Toxoplasmosis in the United States: Clinical and Serologic Findings in Untreated Infants. Pediatric Infectious Disease Journal, 30, 1056-1061.
http://dx.doi.org/10.1097/INF.0b013e3182343096 [5] Remington, J.S., Thulliez, P. and Montoya, J.G. (2004) Recent Developments for Diagnosis of Toxoplasmosis. Journal of Clinical Microbiology, 42, 941-945.
http://dx.doi.org/10.1128/JCM.42.3.941-945.2004 [6] Wong, S.-Y. and Remington, J.S. (1994) Toxoplasmosis in Pregnancy. Clinical Infectious Diseases, 18, 853-861.
http://dx.doi.org/10.1093/clinids/18.6.853 [7] Mead, P.S., Slutsker, L., Dietz, V., et al. (1999) Food-Related Illness and Death in the United States. Emerging Infectious Diseases, 5, 607-625.
http://dx.doi.org/10.3201/eid0505.990502 [8] Pereira, K.S., Franco, R.M.B. and Leal, D.A.G. (2010) Transmission of Toxoplasmosis (Toxoplasma gondii) by Foods. Advances in Food and Nutrition Research, 60, 1043-4526.
http://dx.doi.org/10.1016/S1043-4526(10)60001-0 [9] Jones, J.L., Kruszon-Moran, D., Wilson, M., McQuillan, G., Navin, T. and McAuley, J.B. (2001) Toxoplasma gondii Infection in the United States: Seroprevalence and Risk Factors. The American Journal of Epidemiology, 154, 4, 357-365.
http://dx.doi.org/10.1093/aje/154.4.357 [10] Brown, A.S., Schaefer, C.A., Quesenberry Jr., C.P., Liu, L., Babulas, V.P. and Susser, E.S. (2005) Maternal Exposure to Toxoplasmosis and Risk of Schizophrenia in Adult Offspring. The American Journal of Psychiatry, 162, 767-773.
http://dx.doi.org/10.1176/appi.ajp.162.4.767 [11] Bachmann, S., Schroder, J., Bottmer, C., Torrey, E.F. and Yolken, R.H. (2005) Psychopathology in First-Episode Schizophrenia and Antibodies to Toxoplasma gondii. Psychopathology, 38, 87-90.
http://dx.doi.org/10.1159/000085349 [12] Wang, H.L., Wang, G.H., Li, Q.Y., Shu, C., Jiang, M.S. and Guo, Y. (2006) Prevalence of Toxoplasma Infection in First-Episode Schizophrenia and Comparison between Toxoplasma-Seropositive and Toxoplasma-Seronegative Schizophrenia. Acta Psychiatrica Scandinavica, 114, 40-48.
http://dx.doi.org/10.1111/j.1600-0447.2006.00780.x [13] Cortina-Borja, M., Tan, H.K., Wallon, M., Paul, M., Prusa, A., Buffolano, W., et al. (2010) Prenatal Treatment for Serious Neurological Sequelae of Congenital Toxoplasmosis: An Observational Prospective Cohort Study. PLoS Medicine, 7, Article ID: e1000351.
http://dx.doi.org/10.1371/journal.pmed.1000351 [14] Berrebi, A., Assouline, C., Bessieres, M.H., Lathière, M., Cassaing, S., Minville, V. and Ayoubi, J.M. (2010) Long-Term Outcome of Children with Congenital Toxoplasmosis. The American Journal of Obstetrics and Gynecology, 203, 552.e1-552.e6.
http://dx.doi.org/10.1016/j.ajog.2010.06.002 [15] Habib, F.A. (2008) Post-Treatment Assessment of Acute Toxoplasma Infection during Pregnancy. Journal of Obstetrics and Gynaecology, 28, 593-595.
http://dx.doi.org/10.1080/01443610802344332 [16] Julliac, B., Theophile, H., Begorre, M., Richez, B. and Haramburu, F. (2010) Side Effects of Spiramycin Masquerading as Local Anesthetic Toxicity during Labor Epidural Analgesia. International Journal of Obstetric Anesthesia, 19, 331-332.
http://dx.doi.org/10.1016/j.ijoa.2010.03.002 [17] Petersen, E. and Schmidt, D.R. (2003) Sulfadiazine and Pyrimethamine in the Postnatal Treatment of Congenital Toxoplasmosis: What Are the Options? Expert Review of Anti-Infective Therapy, 1, 175-182.
http://dx.doi.org/10.1586/14787210.1.1.175 [18] Bessieres, M.H., Berrebi, A., Cassaing, S., Fillaux, J., Cambus, J.P., Berry, A., Assouline, C., Ayoubi, J.M. and Magnaval, J.F. (2009) Diagnosis of Congenital Toxoplasmosis: Prenatal and Neonatal Evaluation of Methods Used in Toulouse University Hospital and Incidence of Congenital Toxoplasmosis. Memorias do Instituto Oswaldo Cruz, 104, 389-392.
http://dx.doi.org/10.1590/S0074-02762009000200038 [19] Oz, H.S. and Tobin, T. (2012) Atovaquone Ameliorates Gastrointestinal Toxoplasmosis Complications in a Pregnancy Model. Medical Science Monitor, 18, 337-345.
http://dx.doi.org/10.12659/MSM.883342 [20] Oz, H.S., Hughes, W.T. and Rehg, J.E. (1999) Rat Model for Dual Opportunistic Pathogen Prophylaxis: Cryptosporidium Parvum and Pneumocystis carinii. Laboratory Animal Science, 49, 331-334. [21] Hudson, A.T., Dickins, M., Ginger, C.D., Gutteridge, W.E., Holdich, T., Hutchinson, D.B., Pudney, M., Randall, A.W. and Latter, V.S. (1991) 566C80: A Potent Broad Spectrum Anti-Infective Agent with Activity against Malaria and Opportunistic Infections in AIDS Patients. Drugs under Experimental and Clinical Research, 17, 427-435. [22] Hughes, W.T. and Oz, H.S. (1995) Successful Prevention and Treatment of Babesiosis with Atovaquone. Journal of Infectious Diseases, 172, 1042-1046.
http://dx.doi.org/10.1093/infdis/172.4.1042 [23] Oz, H.S. and Westlund, H.K. (2012) Human Babesiosis: An Emerging Transfusion Dilemma. International Journal of Hepatology, 2012, Article ID: 431761.
http://dx.doi.org/10.1155/2012/431761 [24] Assis, R.C.L., Luns, F.D., Beletti, M.E., Assis, R.L., Nasser, N.M., Faria, E.S.M. and Cury, M.C. (2010) Histomorphometry and Macroscopic Intestinal Lesions in Broilers Infected with Eimeria acervulina. Veterinary Parasitology, 168, 185-189.
http://dx.doi.org/10.1016/j.vetpar.2009.11.017 [25] Granstrom, D.E. and Tobin, T. (1999) Treatment of EPM Formulations and Methods to Treat and Prevent Equine Protozoal Myeloencephalitis. US Patent No. 5883095. [26] Dirikolu, L., Lehner, F., Nattrass, C., et al. (1999) Diclazuril in the Horse: Its Identification and Detection and Preliminary Pharmacokinetics. Journal of Veterinary Pharmacology and Therapeutics, 22, 374-379.
http://dx.doi.org/10.1046/j.1365-2885.1999.00232.x [27] Hackstein, J.H.P., Mackenstedt, U., Mehlhorn, H., Meijerink, J.P.P., Schubert, H. and Leunissen, J.A.M. (1995) Parasitic Apicomplexans Harbor a Chlorophyll a-D1 Complex, the Potential Target for Therapeutic Triazines. Parasitology Research, 81, 207-216. [28] Oz, H.S. and Tobin, T. (2014) Diclazuril Protects against Maternal Gastrointestinal Syndrome and Congenital Toxoplasmosis. International Journal of Clinical Medicine, 5, 93-101.
http://dx.doi.org/10.4236/ijcm.2014.53017 [29] Ajzenberg, D., Cogne, N., Paris, L., Bessières, M.H., Thulliez, P., Filisetti, D., Pelloux, H., Marty, P. and Dardé, M.L. (2002) Genotype of Toxoplasma gondii Isolates Associated with Human Congenital Toxoplasmosis, and Correlation with Clinical Findings. Journal of Infectious Diseases, 186, 684-689.
http://dx.doi.org/10.1086/342663 [30] Howe, D.K., Honore, S., Derouin, F. and Sibley, L.D. (1997) Determination of Genotypes of Toxoplasma gondii Strains Isolated from Patients with Toxoplasmosis. Journal of Clinical Microbiology, 35, 1411-1414. [31] Oz, H.S., Ebersole, J.L. and de Villiers, W.J.S. (2011) The Macrophage Pattern Recognition Scavenger Receptors SR-A and CD36 Protect against Microbial Induced Pregnancy Loss. Inflammation Research, 60, 93-97.
http://dx.doi.org/10.1007/s00011-010-0241-1 [32] Oz, H.S., Chen, T.S. and Nagasawa, H. (2007) Comparative Efficacies of 2 Cysteine Prodrugs and a Glutathione Delivery Agent in a Colitis Model. Translational Research, 150, 122-129.
http://dx.doi.org/10.1016/j.trsl.2006.12.010 [33] Oz, H.S., Chen, T. and de Villiers, W.J.S. (2013) Green Tea Polyphenols and Sulfasalazine Have Parallel Anti-Inflammatory Properties in Colitis Models. Frontiers in Immunology, 132, 1-103.
http://dx.doi.org/10.3389/fimmu.2013.00132 [34] Oz, H.S., Im, H.J., Chen, T.S., de Villiers, W.J.S. and McClain, C.J. (2006) Glutathione-Enhancing Agents Protect against Steatohepatitis in a Dietary Model. Journal of Biochemical and Molecular Toxicology, 20, 39-47.
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