A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans

Wei, Haixia; Wei, Shanshan; Lindsay, David S.; Peng, Hong‐Juan

doi:10.1371/journal.pone.0138204

Cited by 117 publications

(101 citation statements)

References 46 publications

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“…10 However, this therapeutic regimen requires long dosing periods and can be limited by rash, leukopenia, nephrotoxicity, teratogenicity, and kernicterus in newborns. 11 There is a longstanding need for better toxoplasmosis drugs, especially therapeutic agents that are non-toxic, nonteratogenic, and with simple dosing profiles.…”

Section: Introductionmentioning

confidence: 99%

Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis

et al. 2016

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New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses anti-toxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human Ether-à-go-go-Related Gene (hERG) inhibitory activity, associated with long Q-T syndrome, and, consequently, presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new anti-toxoplasmosis therapy.

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Section: Introductionmentioning

confidence: 99%

Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis

et al. 2016

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“…In summary, there is a compelling need for safe and effective treatments for toxoplasmosis (7,8). A comprehensive analysis of the present stage of toxoplasmosis treatments has recently been published (5,9).…”

mentioning

confidence: 99%

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

Szajnman

et al. 2017

Antimicrob Agents Chemother

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Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as Toxoplasma gondii, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfurcontaining linear bisphosphonates against T. gondii, we investigated the potential synergistic interaction between one of these derivatives, 1-[(n-heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG-CoA reductase). C7S showed high activity against the T. gondii bifunctional farnesyl diphosphate (FPP)/geranylgeranyl diphosphate (GGPP) synthase (TgFPPS), which catalyzes the formation of FPP and GGPP (50% inhibitory concentration [IC 50 ] ϭ 31 Ϯ 0.01 nM [mean Ϯ standard deviation]), and modest effect against the human FPPS (IC 50 ϭ 1.3 Ϯ 0.5 M). We tested combinations of C7S with statins against the in vitro replication of T. gondii. We also treated mice infected with a lethal dose of T. gondii with similar combinations. We found strong synergistic activities when using low doses of C7S, which were stronger in vivo than when tested in vitro. We also investigated the synergism of several commercially available bisphosphonates with statins both in vitro and in vivo. Our results provide evidence that it is possible to develop drug combinations that act synergistically by inhibiting host and parasite enzymes in vitro and in vivo.

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“…In fact, drugs used to treat toxoplasmosis are largely active during the tachyzoite replication phase, and their effectiveness against bradyzoites in tissue cysts is drastically reduced once chronic infection by T. gondii is established [102].…”

Section: Studies On Behavioral Disorders In Animals and Humansmentioning

confidence: 99%

Toxoplasma gondii and Schizophrenia: A Relationship That Is Not Ruled Out

Sorlózano-Puerto¹,

Gutiérrez‐Fernández²

2016

Schizophrenia Treatment - The New Facets

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Over recent years, it has been proposed that some diseases of unknown origin, such as schizophrenia, may be caused by persistent chronic infections coupled with a genetic component and may be perpetuated by the immune system. This hypothesis is supported by epidemiological and biological evidence on the exposure of schizophrenics to infectious diseases during prenatal or postnatal periods, including Toxoplasma gondii, chlamydia, human herpes virus, human endogenous retroviruses, parvovirus B19, mumps, and flu viruses. This growing list of microbes will undoubtedly continue to increase in the future. Linking infection to schizophrenia is a complex challenge that requires further experimental and epidemiological research. T. gondii is the infectious agent that has most frequently been related to neuropsychiatric disorders, including schizophrenia, and it is considered to represent a highly useful model to analyze the influence of a microorganism on human behavior and the development of psychiatric disease. It may also help to detect patient subpopulations susceptible to treatment with specific antimicrobials by improving definition of the differential phenotype of the disease, and it offers the possibility of a preventive approach.

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A Systematic Review and Meta-Analysis of the Efficacy of Anti-Toxoplasma gondii Medicines in Humans

Cited by 117 publications

References 46 publications

Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis

Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis

Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis

Toxoplasma gondii and Schizophrenia: A Relationship That Is Not Ruled Out

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