Brigitte Leclef

Activity of ketoconazole derivatives against Leishmania mexicana amazonensis within mouse peritoneal macrophages.

Imidazoles such as ketoconazole have proven antileishmanial activity, both in vitro and in vivo. New derivatives of ketoconazole have been synthesized in order to improve the therapeutic index and antileishmanial activity as assessed by mouse peritoneal macrophages infected with Leishmania mexicana amazonesis. Amino-acid derivatives of ketoconazole are at least 10 times more effective than ketoconazole in vitro, and the best effect is observed using the phenylalanyl-ketoconazole. Fatty acid derivatives, such as oleoyl-ketoconazole, also possess a greater therapeutic activity but to a lesser extent than amino-acid derivatives. Moreover, oleoyl-ketoconazole showed a remarkable property in terms of effective dose. Our results demonstrate the potential antileishmanial efficacy of some ketoconazole derivatives, and suggest that phenylalanyl-ketoconazole should be considered for experimental evaluation in animal models.

Acetylated Low-density-lipoprotein As a Vehicle for Antiinfectious Drugs - Preparation and Antileishmanial Activity of Ac-ldl Containing Ketoconazole-oleate

Previous studies have demonstrated that mouse peritoneal macrophages take up low-density lipoproteins (LDL) which have been chemically modified by the acetylation of lysine residues (Ac-LDL). This uptake is mediated through a specific receptor known as the scavenger receptor. Ac-LDL therefore appear to have excellent potential for antiinfectious drug targeting. We have developed a new method to incorporate ketoconazole-oleate, a lipophilic derivative of ketoconazole, into Ac-LDL. The method involves solubilization of LDL in the presence of Na deoxycholate, the addition of a micellar solution of the drug to be incorporated, and the subsequent removal of the detergent leading to the formation of reconstituted LDL (referred to as LDL-KOL). The LDL-KOL contain 200 drug molecules per LDL particle and compete for the binding of native 125I-LDL on human skin fibroblast monolayers. Furthermore, reconstituted LDL-KOL are indistinguishable from native LDL with regard to lipid composition and electrophoretic mobility. LDL-KOL, when acetylated, are recognized by the scavenger receptor. Acetylated LDL-KOL show antileishmanial activity when tested on infected macrophages. The activity appears to be mediated through the scavenger-cell pathway, as LDL-KOL are inactive under the same conditions. Moreover, acetylated LDL-KOL are selectively accumulated within infected macrophages rather than in normal cells. This may be of value in the treatment of intracellular infections.