sm-8668 and Blastomycosis

The purpose of this study was to determine if there is a correlation between production of certain lymphokines in progressive blastomycosis in untreated mice, resistance to infection in immunized mice, and cure in antifungal triazole (SCH 39304)-treated mice. Infection was measured by colony-forming units of Blastomyces dermatitidis in lungs. Serum level of IgE was used as a marker for in vivo IL-4 activity. Serum IgE levels rose in untreated mice from 6 micrograms/ml at 3 weeks to 24 micrograms/ml by the fourth week as their infection progressed. This corresponded to a peak in vitro production of IL-4 (147 pg/ml) by antigen-stimulated spleen cells at Week 4. By contrast, there was an inverse relationship between serum IgE- and antigen-stimulated production of IFN-gamma in vitro, e.g., 80 U/ml at the third week and 4 U/ml at Week 4. In mice undergoing cure with SCH 39304, serum IgE decreased from 12 micrograms/ml at the third week to 2 micrograms/ml at Week 4. This correlated with a drop in IL-4 and an increase in IFN-gamma production in in vitro assays. As cure proceeded over the next 4 weeks, IgE and IFN-gamma measurements were near background levels. In immunized mice a low-grade chronic blastomycosis emerged after 3 weeks of infection. Chronic infection was associated with inverse cycles of elevated IgE in serum and IFN-gamma production as assayed in vitro. IL-4 production cycled directly with increased IgE levels in serum. Although spleen cells from untreated mice produced IFN-gamma and IL-4 when stimulated with antigen, they did not mount significant proliferative responses. By contrast, spleen cells and lymph node cells from immunized and SCH 39304-treated mice made good proliferative responses to antigen and this correlated with resistance and clearing of the infection, respectively. These data indicate that in pulmonary blastomycosis, serum IgE levels correlate directly with IL-4 and inversely with IFN-gamma production. Clearing of the infection by the antifungal agent SCH 39304 reduces lymphokine production to background levels but sensitizes lymphocytes for proliferative responses to antigen.

Topics: Animals; Antifungal Agents; Antigens, Surface; Blastomycosis; Cells, Cultured; Disease Models, Animal; Immunization; Immunoglobulin E; Interferons; Interleukin-4; Lung; Lymph Nodes; Lymphocytes; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Spleen; Thy-1 Antigens; Triazoles

SCH 39304 was tested for treatment of acute or established murine pulmonary blastomycosis and was compared with ketoconazole and fluconazole in a model of acute infection. Only SCH 39304 at 25 or 50 mg/kg of body weight per day produced 100% survival for 30 days after the 20-day treatment, although only 33% of the mice were cleared of infection. SCH 39304 at 2 mg/kg/day was similar to ketoconazole at 100 mg/kg/day and to fluconazole at 10 mg/kg/day. In a model of established blastomycosis, used to evaluate long-term treatment of very sick or moribund mice, SCH 39304 at 50 mg/kg/day protected against death with a 96% cumulative 8-week survival. SCH 39304 was clearly superior on a milligram-per-kilogram basis in acute blastomycosis, and long-term treatment of more severe blastomycosis was curative.

Topics: Animals; Antifungal Agents; Blastomycosis; Fluconazole; Ketoconazole; Lung Diseases; Mice; Mice, Inbred BALB C; Triazoles

SCH 39304, a broad-spectrum azole derivative, was evaluated in an experimental mouse model of blastomycosis pneumonia. Five days after being inoculated with Blastomyces dermatitidis, infected mice were treated with either oral SCH 39304, fluconazole, or intraperitoneal amphotericin B. A dose response protective effect was observed with SCH 39304 at 5 to 100 mg/kg of body weight per day, with 5 mg of SCH 39304 per kg per day providing activity similar to that of 100 mg of fluconazole per kg per day. Colony counts of yeasts in the lungs of mice sacrificed while on therapy with SCH 39304 were consistently below those of controls, and several lungs were sterile. We conclude that SCH 39304 is effective in murine blastomycosis treatment and deserves to be evaluated in the treatment of human blastomycosis.

Topics: Amphotericin B; Animals; Antifungal Agents; Blastomycosis; Fluconazole; Lung; Lung Diseases, Fungal; Male; Mice; Mice, Inbred BALB C; Triazoles