Clinically Available Medicines Demonstrating Anti-Toxoplasma Activity

ABSTRACT Toxoplasma gondii is an apicomplexan parasite of humans and other mammals, including livestock and companion animals. While chemotherapeutic regimens, including pyrimethamine and sulfadiazine regimens, ameliorate acute or recrudescent disease such as toxoplasmic encephalitis or ocular toxoplasmosis, these drugs are often toxic to the host. Moreover, no approved options are available to treat infected women who are pregnant. Lastly, no drug regimen has shown the ability to eradicate the chronic stage of infection, which is characterized by chemoresistant intracellular cysts that persist for the life of the host. In an effort to promote additional chemotherapeutic options, we now evaluate clinically available drugs that have shown efficacy in disease models but which lack clinical case reports. Ideally, less-toxic treatments for the acute disease can be identified and developed, with an additional goal of cyst clearance from human and animal hosts.

[1]  S. Costa,et al.  Current Therapy of Acquired Ocular Toxoplasmosis: A Review , 2015 .

[2]  L. Younis,et al.  Could miltefosine be used as a therapy for toxoplasmosis? , 2015, Experimental parasitology.

[3]  M. Leboyer,et al.  Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta‐analysis , 2015, Acta psychiatrica Scandinavica.

[4]  M. Hakimi,et al.  Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis. , 2015, Structure.

[5]  Scott Emrich,et al.  A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria , 2015, Nature.

[6]  H. Ramadan,et al.  Triclosan and triclosan-loaded liposomal nanoparticles in the treatment of acute experimental toxoplasmosis. , 2015, Experimental parasitology.

[7]  R. Y. Othman,et al.  Recent Advances in Toxoplasma gondii Immunotherapeutics , 2014, The Korean journal of parasitology.

[8]  L. A. Veloza,et al.  Anti-Toxoplasma activity of natural products: a review. , 2014, Recent patents on anti-infective drug discovery.

[9]  J. E. Bennett,et al.  Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases , 2014 .

[10]  Zhaoshou Yang,et al.  Gefitinib Inhibits the Growth of Toxoplasma gondii in HeLa Cells , 2014, The Korean journal of parasitology.

[11]  Juan D. Chaparro,et al.  Auranofin Is Highly Efficacious against Toxoplasma gondii In Vitro and in an In Vivo Experimental Model of Acute Toxoplasmosis , 2014, PLoS neglected tropical diseases.

[12]  K. Andrews,et al.  Drug repurposing and human parasitic protozoan diseases , 2014, International journal for parasitology. Drugs and drug resistance.

[13]  M. Leboyer,et al.  Comparative analysis of anti-toxoplasmic activity of antipsychotic drugs and valproate , 2014, European Archives of Psychiatry and Clinical Neuroscience.

[14]  L. Knoll,et al.  Fusidic acid is an effective treatment against Toxoplasma gondii and Listeria monocytogenes in vitro, but not in mice , 2013, Parasitology Research.

[15]  D. Rice,et al.  Modification of Triclosan Scaffold in Search of Improved Inhibitors for Enoyl‐Acyl Carrier Protein (ACP) Reductase in Toxoplasma gondii , 2013, ChemMedChem.

[16]  J. Flegr How and why Toxoplasma makes us crazy. , 2013, Trends in parasitology.

[17]  H. Atmaca,et al.  In-vivo efficacy of toltrazuril on experimentally induced Toxoplasma gondii tissue cysts in lambs: a novel strategy for prevention of human exposure to meat-borne toxoplasmosis. , 2013, Research in veterinary science.

[18]  W. de Souza,et al.  Toxoplasma gondii: the effect of fluconazole combined with sulfadiazine and pyrimethamine against acute toxoplasmosis in murine model. , 2013, Experimental parasitology.

[19]  Y. Alfonso,et al.  Antiretroviral activity of protease inhibitors against Toxoplasma gondii. , 2013, Revista do Instituto de Medicina Tropical de Sao Paulo.

[20]  P. Khanna,et al.  Development of Toxoplasma gondii vaccine , 2012, Human vaccines & immunotherapeutics.

[21]  C. Roberts,et al.  Salicylanilide inhibitors of Toxoplasma gondii. , 2012, Journal of medicinal chemistry.

[22]  N. M. Silva,et al.  Enrofloxacin is able to control Toxoplasma gondii infection in both in vitro and in vivo experimental models. , 2012, Veterinary parasitology.

[23]  J. Haagsma,et al.  Disease burden of foodborne pathogens in the Netherlands, 2009. , 2012, International journal of food microbiology.

[24]  P. Davis,et al.  Toxoplasma on the Brain: Understanding Host-Pathogen Interactions in Chronic CNS Infection , 2012, Journal of parasitology research.

[25]  Leann Tilley,et al.  Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion , 2011, Proceedings of the National Academy of Sciences.

[26]  D. Lindsay,et al.  Evaluation of Five Antischizophrenic Agents Against Toxoplasma gondii in Human Cell Cultures , 2011, The Journal of parasitology.

[27]  M. Widdowson,et al.  Foodborne Illness Acquired in the United States—Major Pathogens , 2011, Emerging infectious diseases.

[28]  F. Sörgel,et al.  Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections , 2010, Clinical Microbiology Reviews.

[29]  D. Rice,et al.  Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase. , 2010, Journal of medicinal chemistry.

[30]  D. Roos,et al.  Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses. , 2010, Cell host & microbe.

[31]  R. Yolken,et al.  Thiazole, oxadiazole, and carboxamide derivatives of artemisinin are highly selective and potent inhibitors of Toxoplasma gondii. , 2010, Journal of medicinal chemistry.

[32]  Anang A. Shelat,et al.  Chemical genetics of Plasmodium falciparum , 2010, Nature.

[33]  W. de Souza,et al.  Toxoplasma gondii: fluconazole and itraconazole activity against toxoplasmosis in a murine model. , 2010, Experimental parasitology.

[34]  L. Sibley,et al.  Artemisone and Artemiside Control Acute and Reactivated Toxoplasmosis in a Murine Model , 2009, Antimicrobial Agents and Chemotherapy.

[35]  A. Teixeira-Carvalho,et al.  Innate immunity and regulatory T-cells in human Chagas disease: what must be understood? , 2009, Memorias do Instituto Oswaldo Cruz.

[36]  D. Roos,et al.  Apicomplexan Parasites Co-Opt Host Calpains to Facilitate Their Escape from Infected Cells , 2009, Science.

[37]  G. Toffoli,et al.  C677T and A1298C MTHFR polymorphisms, a challenge for antifolate and fluoropyrimidine-based therapy personalisation. , 2009, European journal of cancer.

[38]  D. Buxton,et al.  Veterinary vaccines against Toxoplasma gondii. , 2009, Memorias do Instituto Oswaldo Cruz.

[39]  J. Dubey The History of Toxoplasma gondii—The First 100 Years , 2008, The Journal of eukaryotic microbiology.

[40]  W. de Souza,et al.  Itraconazole affects Toxoplasma gondii endodyogeny. , 2008, FEMS microbiology letters.

[41]  Mark Noble,et al.  Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system , 2008, Journal of biology.

[42]  R. Yolken,et al.  Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. , 2007, Schizophrenia bulletin.

[43]  M. E. Kouni Adenosine Metabolism in Toxoplasma gondii: Potential Targets for Chemotherapy , 2007 .

[44]  R. Yolken,et al.  In Vitro Inhibition of Toxoplasma gondii by Four New Derivatives of Artemisinin , 2006, Antimicrobial Agents and Chemotherapy.

[45]  Joseph L. DeRisi,et al.  Tetracyclines Specifically Target the Apicoplast of the Malaria Parasite Plasmodium falciparum , 2006, Antimicrobial Agents and Chemotherapy.

[46]  H. Flynn,et al.  In Vitro Antifungal Activity of the Fourth Generation Fluoroquinolones Against Candida Isolates from Human Ocular Infections , 2006, Ocular immunology and inflammation.

[47]  D. Peyramond,et al.  Prevalence of toxoplasma encephalitis in AIDS patients treated with Didanosine hospitalised in a French infectious service. , 2004, Current HIV research.

[48]  D. Lindsay,et al.  EFFICACY OF PONAZURIL IN VITRO AND IN PREVENTING AND TREATING TOXOPLASMA GONDII INFECTIONS IN MICE , 2004, The Journal of parasitology.

[49]  R. Yolken,et al.  Drugs used in the treatment of schizophrenia and bipolar disorder inhibit the replication of Toxoplasma gondii , 2003, Schizophrenia Research.

[50]  K. Fujisaki,et al.  Growth inhibitory effect of triclosan on equine and bovine Babesia parasites. , 2003, The American journal of tropical medicine and hygiene.

[51]  N. Walchshofer,et al.  Quinonic derivatives active against Toxoplasma gondii , 2002, Parasitology Research.

[52]  J. Boothroyd,et al.  An rRNA mutation identifies the apicoplast as the target for clindamycin in Toxoplasma gondii , 2002, Molecular microbiology.

[53]  J. E. Hyde,et al.  Pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: what next? , 2001, Trends in parasitology.

[54]  J. Havlíček,et al.  Decrease of psychomotor performance in subjects with latent ‘asymptomatic’ toxoplasmosis , 2001, Parasitology.

[55]  R. Lyons,et al.  Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of apicomplexan Fab I. , 2001, International journal for parasitology.

[56]  J. Remington,et al.  Activity of Gatifloxacin Alone or in Combination with Pyrimethamine or Gamma Interferon against Toxoplasma gondii , 2001, Antimicrobial Agents and Chemotherapy.

[57]  L. Weiss,et al.  Toxoplasma gondii: from animals to humans. , 2000, International journal for parasitology.

[58]  J. Boothroyd,et al.  Characterization of cytochrome b from Toxoplasma gondii and Q(o) domain mutations as a mechanism of atovaquone-resistance. , 2000, Molecular and biochemical parasitology.

[59]  F. Peyron,et al.  Toxoplasma encephalitis: influence of the vehicle on the efficacy of different doses of 2',3'-dideoxyinosine in mice. , 2000, Parasite.

[60]  D. Roos,et al.  Recombinant expression, purification, and characterization of Toxoplasma gondii adenosine kinase. , 1999, Molecular and biochemical parasitology.

[61]  G. Pizzolato,et al.  Evaluation of trimethoprim and sulphamethoxazole as monotherapy or in combination in the management of toxoplasmosis in murine models. , 1999, International journal of antimicrobial agents.

[62]  J. Remington,et al.  Quinupristin-Dalfopristin Is Active againstToxoplasma gondii , 1999, Antimicrobial Agents and Chemotherapy.

[63]  F. Peyron,et al.  Alterations of Toxoplasma gondii induced by 2',3'-dideoxyinosine in vitro. , 1998, The Journal of parasitology.

[64]  T. Slifer,et al.  The ketolide antibiotics HMR 3647 and HMR 3004 are active against Toxoplasma gondii in vitro and in murine models of infection , 1997, Antimicrobial agents and chemotherapy.

[65]  K. Joiner,et al.  Characterization of anti-Toxoplasma activity of SDZ 215-918, a cyclosporin derivative lacking immunosuppressive and peptidyl-prolyl-isomerase-inhibiting activity: possible role of a P glycoprotein in Toxoplasma physiology , 1997, Antimicrobial agents and chemotherapy.

[66]  F. Peyron,et al.  Effects of 2',3'-dideoxyinosine on Toxoplasma gondii cysts in mice , 1997, Antimicrobial agents and chemotherapy.

[67]  T. Slifer,et al.  Activity of trovafloxacin in combination with other drugs for treatment of acute murine toxoplasmosis , 1997, Antimicrobial agents and chemotherapy.

[68]  H. B. Fung,et al.  Treatment regimens for patients with toxoplasmic encephalitis. , 1996, Clinical therapeutics.

[69]  F. Derouin,et al.  In vitro and in vivo effects of rifabutin alone or combined with atovaquone against Toxoplasma gondii , 1996, Antimicrobial agents and chemotherapy.

[70]  J. Remington,et al.  Trovafloxacin is active against Toxoplasma gondii , 1996, Antimicrobial agents and chemotherapy.

[71]  W. Melchers,et al.  Anti-toxoplasma effect of pyrimethamine, trimethoprim and sulphonamides alone and in combination: implications for therapy. , 1996, The Journal of antimicrobial chemotherapy.

[72]  J. Remington,et al.  Rifapentine is active in vitro and in vivo against Toxoplasma gondii , 1996, Antimicrobial agents and chemotherapy.

[73]  S. Queener,et al.  Lipophilic antifolates as agents against opportunistic infections. 1. Agents superior to trimetrexate and piritrexim against Toxoplasma gondii and Pneumocystis carinii in in vitro evaluations. , 1996, Journal of medicinal chemistry.

[74]  D. Roos,et al.  In vitro assays elucidate peculiar kinetics of clindamycin action against Toxoplasma gondii , 1995, Antimicrobial agents and chemotherapy.

[75]  D. Lindsay,et al.  Treatment of acute Toxoplasma gondii infections in mice with diclazuril or a combination of diclazuril and pyrimethamine. , 1995, The Journal of parasitology.

[76]  J. Alder,et al.  Treatment of experimental Toxoplasma gondii infection by clarithromycin-based combination therapy with minocycline or pyrimethamine. , 1994, Journal of acquired immune deficiency syndromes.

[77]  C. Tinelli,et al.  In-vitro and in-vivo activity of rifabutin against Toxoplasma gondii. , 1994, The Journal of antimicrobial chemotherapy.

[78]  H. R. Chang,et al.  Activity of epiroprim (Ro 11-8958), a dihydrofolate reductase inhibitor, alone and in combination with dapsone against Toxoplasma gondii , 1994, Antimicrobial Agents and Chemotherapy.

[79]  D. Lindsay,et al.  Activity of diclazuril against Toxoplasma gondii in cultured cells and mice. , 1994, American journal of veterinary research.

[80]  T. Slifer,et al.  Rifabutin is active in murine models of toxoplasmosis , 1994, Antimicrobial Agents and Chemotherapy.

[81]  E. Pfefferkorn,et al.  Toxoplasma gondii: susceptibility and development of resistance to anticoccidial drugs in vitro , 1993, Antimicrobial Agents and Chemotherapy.

[82]  J. Remington,et al.  In vivo activity of the macrolide antibiotics azithromycin, roxithromycin and spiramycin againstToxoplasma gondii , 1991, European Journal of Clinical Microbiology and Infectious Diseases.

[83]  H. Kirst,et al.  Comparative activity of macrolides against Toxoplasma gondii demonstrating utility of an in vitro microassay , 1991, Antimicrobial Agents and Chemotherapy.

[84]  C. Chastang,et al.  Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine , 1991, Antimicrobial Agents and Chemotherapy.

[85]  F. Derouin,et al.  In vivo assessment of antimicrobial agents against Toxoplasma gondii by quantification of parasites in the blood, lungs, and brain of infected mice , 1990, Antimicrobial Agents and Chemotherapy.

[86]  H. R. Chang,et al.  In vitro and in vivo effects of doxycycline on Toxoplasma gondii , 1990, Antimicrobial Agents and Chemotherapy.

[87]  J. Kovacs,et al.  Interaction of sulfonamide and sulfone compounds with Toxoplasma gondii dihydropteroate synthase. , 1990, The Journal of clinical investigation.

[88]  J. Kovacs,et al.  Potent antipneumocystis and antitoxoplasma activities of piritrexim, a lipid-soluble antifolate , 1988, Antimicrobial Agents and Chemotherapy.

[89]  E. Pfefferkorn,et al.  Toxoplasma gondii: in vivo and in vitro studies of a mutant resistant to arprinocid-N-oxide. , 1988, Experimental parasitology.

[90]  J. Kovacs,et al.  Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate. , 1987, The Journal of clinical investigation.

[91]  B. Luft Potent in vivo activity of arprinocid, a purine analogue, against murine toxoplasmosis. , 1986, The Journal of infectious diseases.

[92]  B. Luft,et al.  Activity of roxithromycin (RU 28965), a macrolide, against Toxoplasma gondii infection in mice , 1986, Antimicrobial Agents and Chemotherapy.

[93]  B. Luft,et al.  The effects of cyclosporine on Toxoplasma gondii in vivo and in vitro. , 1986, Transplantation.

[94]  R. McLeod,et al.  New micromethod to study the effect of antimicrobial agents on Toxoplasma gondii: comparison of sulfadoxine and sulfadiazine individually and in combination with pyrimethamine and study of clindamycin, metronidazole, and cyclosporin A , 1984, Antimicrobial Agents and Chemotherapy.

[95]  E. Hewlett,et al.  Antileishmanial activity of chlorpromazine , 1984, Antimicrobial Agents and Chemotherapy.

[96]  G. Piekarski Behavioral alterations caused by parasitic infection in case of latent toxoplasma infection. , 1981, Zentralblatt fur Bakteriologie, Mikrobiologie und Hygiene. 1. Abt. Originale A, Medizinische Mikrobiologie, Infektionskrankheiten und Parasitologie = International journal of microbiology and hygiene. A, Medical microbiology, infectious....

[97]  J. Remington,et al.  The effect of trimethoprim and sulfamethoxazole on Toxoplasma gondii in vitro and in vivo. , 1979, The American journal of tropical medicine and hygiene.

[98]  J. Remington,et al.  Effect of Clindamycin on Acute and Chronic Toxoplasmosis in Mice , 1974, Antimicrobial Agents and Chemotherapy.

[99]  W. Robinson,et al.  The Effect of Rifampin on Toxoplasma gondii 1 , 1970, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[100]  M. Hokelek,et al.  In Vivo Efficacy of Drugs against Toxoplasma gondii Combined with Immunomodulators. , 2016, Japanese journal of infectious diseases.

[101]  H. Ramadan,et al.  Preventive prospective of triclosan and triclosan-liposomal nanoparticles against experimental infection with a cystogenic ME49 strain of Toxoplasma gondii. , 2015, Acta tropica.

[102]  P. G. Saraiva,et al.  Current Therapy of Acquired Ocular Toxoplasmosis: A Review. , 2015, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[103]  M. H. el Kouni Adenosine metabolism in Toxoplasma gondii: potential targets for chemotherapy. , 2007, Current pharmaceutical design.

[104]  J. Maertens,et al.  History of the development of azole derivatives. , 2004, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[105]  Ph.D. Joseph Heitman M.D.,et al.  Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases , 2004, Mycopathologia.

[106]  F. Peyron,et al.  Effects of artesunate, dihydroartemisinin, and an artesunate-dihydroartemisinin combination against Toxoplasma gondii. , 2000, The American journal of tropical medicine and hygiene.

[107]  J. Buzby,et al.  Economic costs and trade impacts of microbial foodborne illness. , 1997, World health statistics quarterly. Rapport trimestriel de statistiques sanitaires mondiales.

[108]  F. Derouin,et al.  Effect of immunosuppressive drug regimens on acute and chronic murine toxoplasmosis , 1996, Parasitology Research.

[109]  H. Tanowitz,et al.  In vitro assessment of antimicrobial agents against Toxoplasma gondii. , 1988, The Journal of infectious diseases.

[110]  B. Luft In vivo and in vitro activity of roxithromycin against Toxoplasma gondii in mice. , 1987, European journal of clinical microbiology.

[111]  C. M. Fraser The Merck veterinary manual. , 1986 .

[112]  John E. Bennett,et al.  Principles and practice of infectious diseases. Vols 1 and 2. , 1979 .