Nonionic block copolymers potentiate activities of drugs for treatment of infections with Toxoplasma gondii

Abstract

We studied the interaction between drugs and the nonionic block copolymers CRL 8131 and CRL 8142 in the treatment of toxoplasmosis in murine models of the disease. Treatment of acute toxoplasmosis with copolymers alone caused slight prolongation of time to death but not survival. In contrast, significant survival occurred when mice were treated with either copolymer combined with doses of sulfadiazine, pyrimethamine, clindamycin, or atovaquone, which did not prevent mortality when used alone. Treatment with CRL 8131 plus sulfadiazine or pyrimethamine resulted in 50 or 40% survival, respectively. Treatment with the same copolymer plus a dose of clindamycin that protected 40% of the mice when used alone resulted in 100% survival. Treatment of toxoplasmic encephalitis with CRL 8131 plus an ineffective dose of atovaquone reduced the inflammation and numbers of Toxoplasma gondii cysts in the brain. Studies to investigate the drug-enhancing activity of CRL 8131 revealed that mice immunized with toxoplasma lysate plus copolymer had lymphocyte proliferation responses to T. gondii antigens significantly higher than those in mice immunized with lysate alone. Challenge of immunized mice with a lethal inoculum of T. gondii resulted in significant survival. Administration of CRL 8131 alone appeared to cause a down-regulation in the production of gamma interferon and up-regulation in the production of interleukin-2. No differences were noted in the production of tumor necrosis factor alpha between mice treated with CRL 8131 and controls.