Recent advances in the search for new drugs for treatment of toxoplasmosis

Department of Immunology & Infectious Diseases, Research Institute, Palo Alto Medical Foundation, Palo Alto, California, USA
International Journal of Antimicrobial Agents (Impact Factor: 4.3). 02/1992; 1(4):153-164. DOI: 10.1016/0924-8579(92)90002-9


Although the combination of pyrimethamine with a sulfonamide is still very effective for treatment of toxoplasmosis the use of these two drugs immunocompromised individuals, particularly AIDS patienst, often results in a remarkable incidence of adverse reactions. There is, therefore, an urgent need for alternative drugs and newer therapeutic regimens for treatment of human toxoplasmosis. In this review, the in vitro and in vivo activities of a number of new drugs and new therapeutic regimens that have shown promising results in vartious experimental models for toxoplasmosisared discussed.

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    ABSTRACT: In conclusion, a large body of new information on the biology and immunology of T. gondii has accumulated in the past several years. Much of this is due to the advent of AIDS and the increased funding made available to researchers interested in opportunistic infections in this patient population. These scientific advances have led to a better understanding of the process by which Toxoplasma infects mammalian host cells, molecular biology and biochemistry of the parasite, antigenic structure and immune response to the infection and approaches to be adopted for drug design and therapeutic strategies. Thus, it is through such recognition of the importance of understanding the basic science of an opportunistic pathogen that such advances can be realized.
    AIDS 04/1993; 7(3):299-316. DOI:10.1097/00002030-199303000-00001 · 5.55 Impact Factor
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    ABSTRACT: The efficacy of atovaquone alone or combined with pyrimethamine, sulfadiazine, clarithromycin, and minocycline was examined in vitro and in a murine model of acute toxoplasmosis. In vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of Toxoplasma growth by an enzyme-linked immunosorbent assay. For in vivo studies, mice were acutely infected intraperitoneally with 10(4) tachyzoites of the virulent RH strain and then treated perorally for 10 days from day 1 postinfection. The following drug regimens were investigated: atovaquone at 100 and 50 mg/kg of body weight per day and the combinations of atovaquone at 50 mg/kg with sulfadiazine at 200 mg/kg, pyrimethamine at 12.5 mg/kg, clarithromycin at 200 mg/kg, or minocycline at 50 mg/kg. Efficacy was assessed by determination of survival rates and sequential determination of parasite burdens in blood, brain, and lungs. In vitro, atovaquone inhibited Toxoplasma growth at a concentration of > or = 0.02 mg/liter; the 50% inhibitory concentration was estimated to be 0.023 mg/liter. No synergistic effect was observed when it was combined with sulfadiazine, clarithromycin, or minocycline, whereas a significant antagonistic effect was noted for the combination of atovaquone with pyrimethamine. In vivo, administration of atovaquone at 100 or 50 mg/kg/day for 10 days resulted in prolonged survival compared with that in untreated mice; this survival was associated with a reduction of parasite burdens in blood and tissues during the course of treatment. The combinations of atovaquone with pyrimethamine, clarithromycin, or sulfadiazine were more efficient than each drug administered alone, in terms of survival, but parasite burdens in blood and organs were not reduced compared with those in mice treated with any of the agents alone. These experimental results confirmed the activity of atovaquone against Toxoplasma gondii, but no marked improvement in efficacy was observed in vitro and in vivo when this drug was combined with pyrimethamine, sulfadiazine, minocycline, or clarithromycin.
    Antimicrobial Agents and Chemotherapy 12/1993; 37(11):2371-8. DOI:10.1128/AAC.37.11.2371 · 4.48 Impact Factor
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    ABSTRACT: To facilitate genetic analysis of the protozoan parasite Toxoplasma gondii, sequences derived from the parasite's fused dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene have been used to produce vectors suitable for stable molecular transformation. Mutations introduced into the DHFR coding region by analogy with pyrimethamine-resistant malaria confer drug resistance to Toxoplasma, providing useful information on the structure of fused DHFR-TS enzymes and a powerful selectable marker for molecular genetic studies. Depending on the particular drug-resistance allele employed and the conditions of selection, stable resistance can be generated either by single copy nonhomologous insertion into chromosomal DNA or by massively amplified transgenes. Frequencies of integration are independent of selection, and transgenes are stable without continued selection. Cointegration of a reporter gene adjacent to the selectable marker (under the control of an independent promoter) shows no loss of the cointegrated sequences over many parasite generations. By bringing the full power of molecular genetic analysis to bear on Toxoplasma, these studies should greatly facilitate the development of a model genetic system for Apicomplexan parasites.
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