title: Combinations of ascaridole, carvacrol, and caryophyllene oxide against Leishmania.
abstract: To date there are no vaccines against Leishmania and chemotherapy remains the mainstay for the control of leishmaniasis. The drugs currently used for leishmaniasis therapy are significantly toxic, expensive, and result in a growing frequency of refractory infections. In this study, we evaluated the effect of combinations of the main components of essential oil from Chenopodium ambrosioides (ascaridole, carvacrol, and caryophyllene oxide) against Leishmaniaamazonensis. Anti-leishmanial effects of combinations of pure compounds were evaluated in vitro and the fractional inhibitory concentration (FIC) indices were calculated. BALB/c mice infected with L. amazonensis were treated with different concentrations of ascaridole-carvacrol combinations by intralesional doses every 4 days. Disease progression and parasite burden in infected tissues were determined. In vitro experiments showed a synergistic effect of the combination of ascaridole-carvacrol against promastigotes of Leishmania with a FIC index of 0.171, while indifferent activities were observed for ascaridole-caryophyllene oxide (FIC index=3.613) and carvacrol-caryophyllene oxide (FIC index=2.356) combinations. The fixed ratio method showed that a 1:4 ascaridole-carvacrol ratio produced a better anti-protozoal activity on promastigotes, lower cytotoxicity, and synergistic activity on intracellular amastigotes (FIC index=0.416). Significant differences (p<0.05) in lesion size and parasite burden were demonstrated in BALB/c mice experimentally infected and treated with the ascaridole-carvacrol combinations compared with control animals. Carvacrol showed significant higher anti-radical activity in the DPPH assay compared with caryophyllene oxide. Electron spin resonance spectroscopy in combination with spin trapping suggested the presence of carbon-centered radicals after activation of ascaridole by Fe(2+). The intensity of the signals is preferably decreased upon addition of carvacrol. The ascaridole-carvacrol combination could represent a future alternative to monotherapeutic anti-leishmanial agents.
authors.affiliation: Parasitology Department, Institute of Tropical Medicine "Pedro Kouri", Havana, Cuba.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Pastor
authors.affiliation: Parasitology Department, Institute of Tropical Medicine "Pedro Kouri", Havana, Cuba.
authors.forename: Marley
authors.initials: M
authors.lastname: García
authors.affiliation: Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Steinbauer
authors.affiliation: University of Alabama in Huntsville, Huntsville, USA.
authors.forename: William N
authors.initials: WN
authors.lastname: Setzer
authors.affiliation: Department of Chemistry, Institute of Pharmacy and Food, Havana University, Cuba.
authors.forename: Ramón
authors.initials: R
authors.lastname: Scull
authors.affiliation: Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Lars
authors.initials: L
authors.lastname: Gille
authors.affiliation: Parasitology Department, Institute of Tropical Medicine "Pedro Kouri", Havana, Cuba. Electronic address: monzote@ipk.sld.cu.
authors.forename: Lianet
authors.initials: L
authors.lastname: Monzote
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D027464:Chenopodium ambrosioides / Q000737:chemistry; D000081005:Cyclohexane Monoterpenes; D000081007:Cymenes; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D007891:Leishmania / Q000187:drug effects*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D039821:Monoterpenes / Q000008:administration & dosage*; D009822:Oils, Volatile / Q000494:pharmacology; D010545:Peroxides / Q000008:administration & dosage*; D008517:Phytotherapy; D010938:Plant Oils / Q000008:administration & dosage / Q000494:pharmacology; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000008:administration & dosage*
chemical_list: D000981:Antiprotozoal Agents; D000081005:Cyclohexane Monoterpenes; D000081007:Cymenes; D004338:Drug Combinations; D039821:Monoterpenes; D009822:Oils, Volatile; D010545:Peroxides; D010938:Plant Oils; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; C043372:ascaridole; C073316:carvacrol; C515179:caryophyllene oxide
keywords: Ascaridole; BALB; Carvacrol; Caryophyllene oxide; Drug combination; Leishmania amazonensis; c mice