title: In vitro and in vivo studies of the utility of dimethyl and diethyl carbaporphyrin ketals in treatment of cutaneous leishmaniasis.
abstract: Carbaporphyrin ketals are porphyrinoid compounds in which a pyrrole ring of a typical porphyrin macrocycle has been replaced by a ketal-substituted indene ring. It was recently demonstrated that these compounds are effective in vitro against Leishmania tarentolae. Their in vitro effectiveness is increased when they are exposed to visible light; they act as photosensitizers capable of mediating the production of reactive oxygen species (ROS). Following on this evidence, the effectiveness and cytotoxicity of the dimethyl and diethyl carbaporphyrin ketals (CKOMe and CKOEt, respectively) were determined in vitro using pathogenic Leishmania species with and without exposure to visible light (2 and 4 h). The effectiveness against various pathogenic Leishmania species was determined to be in a micromolar range. Additionally, the effect of encapsulating the carbaporphyrin ketals in liposome formulations was tested. Liposomal delivery diminished their toxicity, while the effectiveness was enhanced upon exposure to visible light (photodynamic effect). The cytotoxicity levels for human U937 cells and hamster peritoneal macrophages were in the ranges of 0.3 to 9 μM and 7 to 330 μM, respectively. When tested in vivo, using a hamster (Mesocricetus auratus) model of cutaneous leishmaniasis, CKOMe was active even in the dark, suggesting that the compound, once metabolized in the animal tissue, produces an active ingredient that does not seem to be photosensitive. Reduction in lesion size, histopathologic analyses, and smears confirmed the in vivo effectiveness of the compound, since the parasitic load was diminished without noticeable toxic effects.
authors.affiliation: PECET, School of Medicine, Universidad de Antioquia, Carrera 53 No. 61-30, Medellín, Colombia.
authors.forename: Viviana M
authors.initials: VM
authors.lastname: Taylor
authors.forename: David L
authors.initials: DL
authors.lastname: Cedeño
authors.forename: Diana L
authors.initials: DL
authors.lastname: Muñoz
authors.forename: Marjorie A
authors.initials: MA
authors.lastname: Jones
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Lash
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Young
authors.forename: Manuel H
authors.initials: MH
authors.lastname: Constantino
authors.forename: Nicholas
authors.initials: N
authors.lastname: Esposito
authors.forename: Iván D
authors.initials: ID
authors.lastname: Vélez
authors.forename: Sara M
authors.initials: SM
authors.lastname: Robledo
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002478:Cells, Cultured; D006224:Cricetinae; D006801:Humans; D007891:Leishmania / Q000187:drug effects*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology; D008027:Light; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000187:drug effects; D059208:Parasite Load; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011166:Porphyrins / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D008081:Liposomes; D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species