Bisphosphonate inhibitors of Toxoplasma gondi growth: in vitro, QSAR, and in vivo investigations.

We have investigated the activity of 60 bisphosphonates against the replication of Toxoplasma gondii in vitro and of three of the most active compounds, in vivo. The two most active compounds found were n-alkyl bisphosphonates containing long (n = 9 or 10) hydrocarbon chains, not the nitrogen-containing species used in bone resorption therapy. The target of all of the most active bisphosphonates appears to be the isoprene biosynthesis pathway enzyme farnesyl pyrophosphate synthase (FPPS), as indicated by the correlations between T.

Different strains of Toxoplasma gondii induce different cytokine responses in CBA/Ca mice.

To investigate the role that cytokines may have in the development of toxoplasmic encephalitis (TE), the levels of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin-12 (IL-12 ]p40[), IL-10, IL-6, IL-4, and IL-2 in serum were examined in CBA/Ca mice infected with a type II strain (ME49 or FORT) of Toxoplasma gondii. These strains caused severe (ME49) or mild (FORT) TE in CBA/Ca mice. From weeks 1 to 8 of infection, the levels of IL-6, IL-10, IL-12, IFN-gamma, and TNF-alpha in serum were significantly higher in the ME49-infected mice than in the FORT-infected mice, suggesting a role for these cytokines in the severity of TE in CBA/Ca mice.

Inhibition of secretion of interleukin-1alpha and tumor necrosis factor alpha by the ketolide antibiotic telithromycin.

The antibiotic telithromycin was examined for its effect on secretion of interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, IL-10, and tumor necrosis factor alpha (TNF-alpha) by lipopolysaccharide (LPS)-stimulated monocytes of eight human donors. Secretion of each cytokine was significantly increased by LPS alone, whereas treatment with telithromycin significantly inhibited secretion of IL-1alpha and TNF-alpha but not secretion of IL-1beta, IL-6, and IL-10. Telithromycin had immunomodulatory effects as a result of alteration of secretion of IL-1alpha and TNF-alpha by monocytes.

In vivo activities of farnesyl pyrophosphate synthase inhibitors against Leishmania donovani and Toxoplasma gondii.

The in vivo activities of three bisphosphonates were determined against Leishmania donovani and Toxoplasma gondii. Alendronate was essentially inactive against both parasites. Pamidronate was active against L.