Influence of the immunostimulating substance tiprotimod on Candida albicans infection in relation to activation of macrophages.
In an experimental model of persistent systemic candidiasis the effect of the thiazole compound Tiprotimod was examined. Balb/c mice infected intravenously with Candida albicans developed a fungal colonization of the kidneys with peak levels of about 10(6) colony forming units (cfu)/organ after 3 weeks of infection paralleled by the formation of necrotic alterations of the organs. Infected animals were treated with the immunostimulator Tiprotimod after the fungal colonization of kidney was manifested (3 days post infection). The treatment resulted in a decrease of the infectious load, abscess formation in kidney, as well as a reduction of Candida in the urine. The optimal dose in this model was in the range of 2 mg/kg, higher and lower doses appeared to be less effective, thus indicating a bell-shaped curve of response. By examining the time course of induction of protection by the drug it was noticed that protection does not occur before 10 days after infection. We therefore examined during the course of infection the phagocytic capacity and the production of O2- -radicals (chemiluminescence) of macrophages in Tiprotimod-treated animals. Activation of O2- -radical generation was stimulated rapidly (peak level at day 6) in the drug-treated animals, whereas stimulation of the phagocytic capacity was not observed until two weeks after infection. Activation of macrophage phagocytosis thus paralleled the reduction of the infectious load by Tiprotimod. Combination therapy with the antifungal agent ketoconazole resulted in at least additive decrease of mortality resulting from C. albicans infection.
Dickneite
G
G
Research Laboratories, Behringwerke AG, Marburg/Lahn, Federal Republic of Germany.
Schorlemmer
H U
HU
Sedlacek
H H
HH
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002177:Candidiasis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016264:Dextran Sulfate; D003911:Dextrans / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D005609:Free Radicals; D007654:Ketoconazole / Q000008:administration & dosage; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013481:Superoxides / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D003911:Dextrans; D005609:Free Radicals; D013844:Thiazoles; D013481:Superoxides; D016264:Dextran Sulfate; C061180:tiprotimod; D007654:Ketoconazole