title: Evaluation of a cyclic GMP-dependent protein kinase inhibitor in treatment of murine toxoplasmosis: gamma interferon is required for efficacy.
abstract: The trisubstituted pyrrole 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl]pyridine (compound 1) is a potent inhibitor of cyclic GMP-dependent protein kinases from Apicomplexan protozoa and displays cytostatic activity against Toxoplasma gondii in vitro. Compound 1 has now been evaluated against T. gondii infections in the mouse and appeared to protect the animals when given intraperitoneally at 50 mg/kg twice daily for 10 days. However, samples from brain, spleen, and lung taken from infected treated mice revealed the presence of parasites after cessation of administration of compound 1, indicating that a transient asymptomatic parasite recrudescence occurs in all survivors. The ability of mice to control Toxoplasma infection after compound 1 treatment has been terminated suggested that the mouse immune system plays a synergistic role with chemotherapy in controlling the infection. To explore this possibility, gamma interferon (IFN-gamma)-knockout mice were infected with parasites and treated with compound 1, and survival was compared to that of normal mice. IFN-gamma-knockout mice were protected against T. gondii throughout the treatment phase but died during the posttreatment phase in which peak recrudescence was observed in treated immunocompetent mice. These data suggest that an IFN-gamma-dependent immune response was essential for controlling and resolving parasite recrudescence in mice treated with compound 1. In addition, when compound 1-cured immunocompetent mice were rechallenged with a lethal dose of T. gondii, all survived (n = 32). It appears that the cytostatic nature of compound 1 provides an "immunization" phase during chemotherapy which allows the mice to survive the recrudescence and any subsequent challenge with a lethal dose of T. gondii.
authors.affiliation: Department of Human and Animal Infectious Disease Research, Merck Research Laboratories, Merck and Co., Inc., Rahway, New Jersey 07076, USA. bakela_nare@merck.com
authors.forename: Bakela
authors.initials: B
authors.lastname: Nare
authors.forename: John J
authors.initials: JJ
authors.lastname: Allocco
authors.forename: Paul A
authors.initials: PA
authors.lastname: Liberator
authors.forename: Robert G K
authors.initials: RG
authors.lastname: Donald
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D007107:Immune System; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014122:Toxoplasma / Q000187:drug effects; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D016896:Treatment Outcome
chemical_list: C452660:4-(2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl)pyridine; D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D011758:Pyrroles; D007371:Interferon-gamma; D017869:Cyclic GMP-Dependent Protein Kinases