Clofazimine, a Promising Drug for the Treatment of Babesia microti Infection in Severely Immunocompromised Hosts.

BACKGROUND: Persistent and relapsing babesiosis caused by Babesia microti often occurs in immunocompromised patients, and has been associated with resistance to antimicrobial agents such as atovaquone. Given the rising incidence of babesiosis in the United States, novel drugs are urgently needed. In the current study, we tested whether clofazimine (CFZ), an antibiotic used to treat leprosy and drug-resistant tuberculosis, is effective against B. microti. METHODS: Mice with severe combined immunodeficiency were infected with 107B. microti-infected erythrocytes. Parasites were detected by means of microscopic examination of Giemsa-stained blood smears or nested polymerase chain reaction. CFZ was administered orally. RESULTS: Uninterrupted monotherapy with CFZ curtailed the rise of parasitemia and achieved radical cure. B. microti parasites and B. microti DNA were cleared by days 10 and 50 of therapy, respectively. A 7-day administration of CFZ delayed the rise of parasitemia by 22 days. This rise was caused by B. microti isolates that did not carry mutations in the cytochrome b gene. Accordingly, a 14-day administration of CFZ was sufficient to resolve high-grade parasitemia caused by atovaquone-resistant B. microti parasites. CONCLUSIONS: Clofazimine is effective against B. microti infection in the immunocompromised host. Additional preclinical studies are required to identify the minimal dose and dosage of CFZ for babesiosis.

Age-related loss of associations between acute exercise-induced IL-6 and oxidative stress.

IL-6 mediates many aspects of the exercise-induced acute-phase response, including upregulation of antioxidant defenses. Moreover, IL-6 synthesis is regulated in part by oxidative stress. This investigation tested the hypothesis that an IL-6-mediated acute-phase response after exercise provides negative-feedback protection against exercise-induced oxidative stress. Healthy young (n = 16, 26.4 +/- 1.8 yr) and older men (n = 16, 71.1 +/- 2.0 yr) ran downhill for 45 min at 75% maximal oxygen consumption before and after a 12-wk period of supplementation with vitamin E (1,000 IU/day) or placebo. Circulating IL-6 and soluble IL-6 receptors, peripheral mononuclear cell production of IL-6, and IL-6 transcripts in muscle were measured before and within a 72-h time window after each acute exercise bout. At all time points plasma IL-6, IL-6 bioavailability, and C-reactive protein were higher in the older men; yet in response to exercise, young and older subjects experienced similar increases in these factors. Although the magnitude of postexercise changes in acute-phase variables was independent of age, correlations among plasma, mononuclear cell, and muscle IL-6 and oxidative stress were evident only in young men (R2 = 0.64, 0.35, and 0.33, respectively). These changes in circulating IL-6 were closely associated with a prooxidant state (R2 = 0.47), whereas muscle IL-6 mRNA correlated with an antioxidant state (R2 = 0.65). Supplementation with vitamin E did not affect exercise-induced responses or differences between the young and old men in a consistent manner. Therefore, oxidative stress is linked to the acute-phase response after exercise in young men, but not in older men who had elevated acute-phase reactants, suggesting that further research is warranted to determine the basis for these differences.