Novel Synergistic Protective Efficacy of Atovaquone and Diclazuril on Fetal-Maternal Toxoplasmosis

Abstract

Over 1 billion people globally are estimated to be infected with Toxoplasma gondii with severe or unknown consequences and no safe and effective therapies are available against congenital or persistent chronic infection. We propose that atovaquone and diclazuril synergistically protect against fetal-maternal toxoplasmosis. Methods Programmed pregnant mice were treated with atovaquone and diclazuril monotherapy, or combined (atovaquone + diclazuril) therapy and infected with tachyzoites (0, 300, 600) and the course of infection was studied. Results Infected dams with low dose (300) developed moderate toxoplasmosis complications and treatments were similarly effective with minor differences between monotherapies. In contrast, major differences were observed amongst varied treatments during high-dose (600) infection and severe related- toxoplasmosis complications as follows. Dams developed hydrothorax, ascities and excess weight gain. Combined therapy (P < 0.01) and to a lesser extent diclazuril monotherapy (P < 0.05) protected dams from excess weight, hydrothorax, and ascities. Infected dams exhibited splenomegaly, hepatomegaly and severe hepatitis. Combined therapy synergistically normalized pathology (P < 0.001) and to a lesser degree monotherapy (diclazuril P < 0.01, and atovaquone P < 0.05) protected dams from hepatitis and splemomegaly. Additionally, behavioral response to pain stimuli and fetal weight and fetal numbers were significantly preserved in treated dams Conclusions This is the first report describing combined atovaquone and diclazuril therapy (a) to be safe in pregnancy, (b) to exert novel synergistic effects, and (c) to protect dams and their nested fetuses against adverse effects of severe toxoplasmosis.

Evaluation of Propranolol Effect on Experimental Acute and Chronic Toxoplasmosis Using Quantitative PCR

“…Murphy et al showed that erythrocyte G proteins are functional and that propranolol, as an antagonist of G protein-coupled b-adrenergic receptors, inhibits G protein activity in erythrocytes. They also discovered that like other b 2 antagonists, propranolol inhibited blood-stage parasite growth, such that propranolol used in combination with existing antimalarial agents in cell culture reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum and was also effective in reducing drug doses in animal models of infection (33).…”

“…Spiramycin monotherapy can be effective during the early stage of pregnancy to prevent prenatal transmission. More than 50% of patients treated with spiramycin retained T. gondii DNA in blood and remained infected (2). So, for prevention/eradication of the chronic infection or protection against congenital toxoplasmosis, current chemotherapy is not safe or effective.…”

“…Recently, infections with T. gondii have also been linked to possible increased risk for autism and early onset of schizophrenia (2,5). In addition, toxoplasmosis is considered the third most common nosocomially acquired foodborne disease and can lead to death if it is not treated (2).…”

“…Toxoplasma is classified by the National Institutes of Health and Centers for Disease Control (CDC) as a category B human-infectious pathogen. Over 1 billion people are estimated to be infected with T. gondii globally (2). Toxoplasmosis in immunocompetent people is usually asymptomatic or appears as flulike symptoms, swollen lymph glands, muscle aches, and pain that may last from a few days to several weeks (3).…”

“…So, for prevention/eradication of the chronic infection or protection against congenital toxoplasmosis, current chemotherapy is not safe or effective. Therefore, it is necessary to investigate new and more-effective therapeutic agents with low toxicity to treat this disease (2,7,11).…”