Modulation of experimental systemic murine candidosis by intravenous pepstatin

The effect of intravenous pepstatin-A on systemic candidosis in NWNI mice was investigated. True solutions of the inhibitor proved ineffective due to a very fast clearance. Pepstatin was effective as a crystal suspension (0.69 mg in 0.1 ml saline) which produced serum inhibitory activity for greater than 29 h. From the intravenously applied suspension, pepstatin was taken up predominantly into the liver, no inhibitor being taken up by the kidneys. The suspension was protective if it was injected once before the mice were infected and repeatedly following infection. It was also effective if it was administered concomitantly with the infecting agent and thereafter. The suspension was ineffective if it was only given once before infection, and it proved to be detrimental if it was given only after infection. The results support previous findings (2), suggesting a role of fungal proteinase early in the adherence of Candida to host epithelia. Our results also suggest an inhibition of lysosomal cathepsin-D in vivo by pepstatin, which prohibits a parenteral therapeutic use of nonmodified pepstatin A.