title: Topical treatment of L. major infected BALB/c mice with a novel diselenide chitosan hydrogel formulation.
abstract: Topical therapy is the ideal outpatient treatment of cutaneous leishmaniasis (CL) because of the ease of administration and lower cost. It could be suitable as monotherapy for localized cutaneous leishmaniasis (LCL) or in combination with systemic therapies for more severe forms of the disease. Although paromomycin (PM) ointment can be recommended for the treatment of LCL caused by Leishmaniamajor, a more effective topical treatment should be achieved regarding the physicochemical properties of this aminoglucoside and its rather poor intrinsic antileishmanial activity, that hampers the accumulation of enough amount of drug in the dermis (where the infected macrophages home) to exert its activity. In this work, we determined a 50% effective dose of 5.6 μM for a novel compound, bis-4-aminophenyldiselenide, against L. major intracellular amastigotes. This compound and PM were formulated in chitosan hydrogels and ex vivo permeation and retention studies in the different skin layers were performed with pig ear skin in Franz diffusion cells. The results showed that less than 2-4% of the diselenide drug penetrated and permeated through the skin. In contrast, the percentage of PM penetration was about 25-60% without important retention in the skin. When topically applied to lesions of L. major infected BALB/c mice, the novel diselenide chitosan formulation was unable to slow lesion progression and reduce parasite burden. Considerations during the process of novel drug development and formulation discovery algorithm for CL are discussed.
authors: Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain; Pharmacy and Pharmaceutical Technology Department, University of Navarra, 31008 Pamplona, Spain.
authors: Juana
authors: J
authors: Schwartz
authors: Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain.
authors: Esther
authors: E
authors: Moreno
authors: Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain.
authors: Celia
authors: C
authors: Fernández
authors: Chemistry and Soil Sciences Department, University of Navarra, 31008 Pamplona, Spain.
authors: Iñigo
authors: I
authors: Navarro-Blasco
authors: Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain.
authors: Paul A
authors: PA
authors: Nguewa
authors: Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain; Organic and Pharmaceutical Chemistry Department, University of Navarra, 31008 Pamplona, Spain.
authors: Juan A
authors: JA
authors: Palop
authors: Pharmacy and Pharmaceutical Technology Department, University of Navarra, 31008 Pamplona, Spain.
authors: Juan M
authors: JM
authors: Irache
authors: Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain; Organic and Pharmaceutical Chemistry Department, University of Navarra, 31008 Pamplona, Spain.
authors: Carmen
authors: C
authors: Sanmartín
authors: Institute of Tropical Health, University of Navarra, 31008 Pamplona, Spain; Pharmacy and Pharmaceutical Technology Department, University of Navarra, 31008 Pamplona, Spain. Electronic address: sespuelas@unav.es.
authors: Socorro
authors: S
authors: Espuelas
mesh_terms: D000287:Administration, Topical; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage*; D048271:Chitosan / Q000008:administration & dosage / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D020100:Hydrogels / Q000008:administration & dosage* / Q000737:chemistry; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D008807:Mice, Inbred BALB C; D016566:Organoselenium Compounds / Q000008:administration & dosage* / Q000737:chemistry; D059208:Parasite Load; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013552:Swine
chemical_list: D000814:Aniline Compounds; D000981:Antiprotozoal Agents; D004337:Drug Carriers; D020100:Hydrogels; D016566:Organoselenium Compounds; C000596111:bis-4-aminophenyldiselenide; D048271:Chitosan
keywords: 4-Bis-aminophenyldiselenide; Chitosan hydrogel; Cutaneous leishmaniasis; Discovery algorithm; Topical treatment