RESUMEN
AIM: The purpose of this study was to evaluate the antifungal activity and toxicological parameters of 8-hydroxyquinoline derivatives PH151 and PH153 using alternative animal models, to understand their behaviour when subjected to in vivo experiments. METHODS AND RESULTS: We used Toll-deficient Drosophila melanogaster to test the protective effect of compounds against Candida albicans infection. Toxicological parameters were investigated in chicken and zebrafish embryos. PH151 and PH153 showed low toxicity and the treated flies with these compounds had a significantly higher survival rate than untreated flies after 7 days of infection. The compounds did not cause interruption of chicken embryogenesis. Zebrafish embryos exposed to compounds showed dose-dependent toxicity. CONCLUSIONS: The data supported the potential of PH151 and PH153 for the treatment of systemic candidiasis and demonstrated to be appropriate drug candidates for further studies using mammalian models. SIGNIFICANCE AND IMPACT OF THE STUDY: The increased incidence of Candida infections resistant to antifungals currently available requires acceleration of the discovery of new agents with properties of inhibiting this fungal pathogen. In this study, we have described the antifungal potential and toxicity of two 8-hydroxyquinoline derivatives using in vivo alternative models, and the results confirm their potential to be developed as new drug candidates.
Asunto(s)
Antifúngicos/uso terapéutico , Candidiasis/tratamiento farmacológico , Modelos Animales de Enfermedad , Oxiquinolina/uso terapéutico , Sulfonamidas/uso terapéutico , Animales , Antifúngicos/química , Candida albicans/efectos de los fármacos , Candidiasis/microbiología , Embrión de Pollo , Drosophila melanogaster , Oxiquinolina/química , Sulfonamidas/química , Pez CebraRESUMEN
The current treatment of leishmaniasis has been hampered due to the high toxicity of the available drugs and long duration protocols, which often lead to its abandonment. In the present study, a poloxamer 407-based delivery system was developed, and a molecule, 8-hydroxyquinoline (8-HQN), was incorporated with it, leading to an 8-HQN/micelle (8-HQN/M) composition. Assays were performed to evaluate the in vitro antileishmanial activity of 8-HQN/M against Leishmania amazonensis stationary promastigotes. The cytotoxicity in murine macrophages and in human red cells, as well as the efficacy of the treatment in macrophages infected by parasites, was also assessed. This product was also evaluated for the treatment of murine tegumentary leishmaniasis, using L. amazonensis-infected BALB/c mice. To evaluate the in vivo efficacy of the treatment, the average lesion diameter (area) in the infected tissue, as well as the parasite load at the site of infection (skin), spleen, liver and draining lymph nodes were examined. Non-incorporated micelle (B-8-HQN/M) and the free molecule (8-HQN) were used as controls, besides animals that received only saline. The parasite burden was evaluated by limiting dilution and quantitative real-time PCR (qPCR) techniques, and immunological parameters associated with the treatments were also investigated. In the results, the 8-HQN/M group, when compared to the others, presented more significant reductions in the average lesion diameter and in the parasite burden in the skin and all evaluated organs. These animals also showed significantly higher levels of parasite-specific IFN-γ, IL-12, and GM-CSF, associated with low levels of IL-4 and IL-10, when compared to the saline, 8-HQN/M, and B-8-HQN groups. A predominant IL-12-driven IFN-γ production, against parasite proteins, mainly produced by CD4+ T cells, was observed in the treated animals, post-infection. In conclusion, 8-HQN/M was highly effective in treating L. amazonensis-infected BALB/c mice and can be considered alone, or combined with other drugs, as an alternative treatment for tegumentary leishmaniasis. Graphical Abstract Therapeutic scheme and immunological and parasitological parameters developed in the present study.
Asunto(s)
Leishmania mexicana/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Oxiquinolina/uso terapéutico , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eritrocitos/parasitología , Femenino , Humanos , Leishmaniasis Cutánea/parasitología , Hígado/parasitología , Macrófagos/parasitología , Ratones , Ratones Endogámicos BALB C , Micelas , Oxiquinolina/administración & dosificación , Carga de Parásitos , Polímeros , Bazo/parasitología , Linfocitos T/inmunologíaRESUMEN
The development of new therapeutic strategies to treat leishmaniasis has become a priority. In the present study, the antileishmanial activity of 8-hydroxyquinoline (8-HQN) was investigated against in vitro promastigotes and in vivo intra-macrophage amastigotes of three Leishmania species: Leishmania amazonensis, Leishmania infantum and Leishmania braziliensis. Studies were performed to establish the 50% Leishmania inhibitory concentration (IC50) of 8-HQN, as well as its 50% cytotoxic concentration (CC50) on murine macrophages and in human red blood cells. The inhibition of macrophages infection was also evaluated using parasites that were pre-treated with 8-HQN. The effects of this compound on nitric oxide (NO) production and in the mitochondrial membrane potential were also evaluated. Finally, the therapeutic efficacy of 8-HQN was assessed in a known murine model, L. amazonensis-chronically infected BALB/c mice. Our results showed that 8-HQN was effective against promastigote and amastigote stages of all tested Leishmania species, presenting a selectivity index of 328.0, 62.0 and 47.0 for L. amazonensis, L. infantum and L. braziliensis, respectively. It was effective in treating infected macrophages, as well as in preventing the infection of these cells using pre-treated parasites. In addition, 8-HQN caused an alteration in the mitochondrial membrane potential of the parasites. When administered at 10mg/kg body weight/day by subcutaneous route, this product was effective in reducing the lesion diameter, as well as the parasite load in evaluated tissues and organs of infected animals. The results showed the in vitro and in vivo efficacy of 8-HQN against three different Leishmania species causing tegumentary and/or visceral leishmaniasis, and it could well be used for future therapeutic optimization studies to treat leishmaniasis.
Asunto(s)
Leishmania infantum/efectos de los fármacos , Leishmania/efectos de los fármacos , Oxiquinolina/farmacología , Animales , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Antiprotozoarios/toxicidad , Eritrocitos/efectos de los fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Leishmania braziliensis/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Visceral/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Oxiquinolina/uso terapéutico , Oxiquinolina/toxicidad , Carga de Parásitos , Resultado del TratamientoRESUMEN
A 72-year-old man consulted in November 2012 for abdominal pain in the right upper quadrant. The patient had a history of suspected hepatic amebiasis treated in Senegal in 1985 and has not traveled to endemic areas since 1990. Abdominal CT scan revealed a liver abscess. At first, no parasitological tests were performed and the patient was treated with broad-spectrum antibiotics. Only after failure of this therapy, serology and PCR performed after liver abscess puncture established the diagnosis of hepatic amebiasis. The patient was treated with metronidazole and tiliquinol-tilbroquinol. Amebic liver abscess is the most frequent extra-intestinal manifestation. Hepatic amebiasis 22 years after the last visit to an endemic area is exceptional and raises questions on the mechanisms of latency and recurrence of these intestinal protozoan parasites.