RESUMEN
Acylhydrazone (AH) derivatives represent a novel category of anti-fungal medications that exhibit potent activity against Sporothrix sp., both in vitro and in a murine model of sporotrichosis. In this study, we demonstrated the anti-fungal efficacy of the AH derivative D13 [4-bromo-N'-(3,5-dibromo-2-hydroxybenzylidene)-benzohydrazide] against both planktonic cells and biofilms formed by Sporothrix brasiliensis. In a clinical study, the effect of D13 was then tested in combination with itraconazole (ITC), with or without potassium iodide, in 10 cats with sporotrichosis refractory to the treatment of standard of care with ITC. Improvement or total clinical cure was achieved in five cases after 12 weeks of treatment. Minimal abnormal laboratory findings, e.g., elevation of alanine aminotransferase, were observed in four cats during the combination treatment and returned to normal level within a week after the treatment was ended. Although highly encouraging, a larger and randomized controlled study is required to evaluate the effectiveness and the safety of this new and exciting drug combination using ITC and D13 for the treatment of feline sporotrichosis. IMPORTANCE: This paper reports the first veterinary clinical study of an acylhydrazone anti-fungal (D13) combined with itraconazole against a dimorphic fungal infection, sporotrichosis, which is highly endemic in South America in animals and humans. Overall, the results show that the combination treatment was efficacious in ~50% of the infected animals. In addition, D13 was well tolerated during the course of the study. Thus, these results warrant the continuation of the research and development of this new class of anti-fungals.
Asunto(s)
Antifúngicos , Enfermedades de los Gatos , Quimioterapia Combinada , Itraconazol , Sporothrix , Esporotricosis , Gatos , Animales , Itraconazol/uso terapéutico , Itraconazol/administración & dosificación , Itraconazol/farmacología , Esporotricosis/tratamiento farmacológico , Esporotricosis/veterinaria , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Antifúngicos/administración & dosificación , Enfermedades de los Gatos/tratamiento farmacológico , Enfermedades de los Gatos/microbiología , Sporothrix/efectos de los fármacos , Hidrazonas/uso terapéutico , Hidrazonas/farmacología , Femenino , Masculino , Pruebas de Sensibilidad Microbiana , Biopelículas/efectos de los fármacos , Resultado del TratamientoRESUMEN
Medicinal plants have long been prescribed in Thailand for centuries. Different constituents of extracts have been used for treating of various infectious diseases. However, there is even less information available regarding the use in fungal skin infection. In order to assess traditional Thai claims about the therapeutic potential, this study is focused on exploring the anti-dermatophyte property of the plants that are currently used as traditional medicines. The potential of four different plant species were selected for investigate in vitro anti-dermatophyte activity. Ethanolic extracts of Chromolaena odorata (L.), Ageratina adenophora (Spreng.), Eclipta prostrate (Linn.), and Acorus calamus (L.). were analysed for their total phenolic content as well as total flavonoid content and were then subjected to test of their anti-dermatophyte properties using agar well diffusion method. Qualitative flavonoids and phenolics analysis of the extracts showed their biologically active constituents. Among the species examined, the result indicated that most of the extracts demonstrated anti-dermatophyte activity. In particular, A. calamus showed the highest efficacy against test organisms. The experiment confirmed the chemical constituents and efficacy of some selected plants and provides a scientific confirmation of the use of Thai plants in traditional medicine for fungal skin infections.
As plantas medicinais são prescritas há muito tempo na Tailândia, há séculos. Diferentes constituintes de extratos têm sido usados para o tratamento de várias doenças infecciosas. No entanto, existem ainda menos informações disponíveis sobre o uso em infecções fúngicas da pele. A fim de avaliar as alegações tradicionais tailandesas sobre o potencial terapêutico, este estudo está focado em explorar a propriedade antidermatófita das plantas que são usadas atualmente como medicamentos tradicionais. O potencial de quatro espécies de plantas diferentes foi selecionado para investigar a atividade antidermatófita in vitro. Extratos etanólicos de Chromolaena odorata (L.), Ageratina adenophora (Spreng.), Eclipta prostrate (Linn.) e Acorus calamus (L.) foram analisados quanto ao seu conteúdo fenólico total, bem como ao conteúdo de flavonoides totais. E então submetidos ao teste de suas propriedades antidermatófitas usando o método de difusão em ágar bem. A análise qualitativa de flavonoides e fenólicos dos extratos mostrou seus constituintes biologicamente ativos. Entre as espécies examinadas, o resultado indicou que a maioria dos extratos demonstrou atividade antidermatófita. Em particular, A. calamus mostrou a maior eficácia contra organismos de teste. O experimento confirmou os constituintes químicos e a eficácia de algumas plantas selecionadas e fornece uma confirmação científica do uso de plantas tailandesas na medicina tradicional para infecções fúngicas da pele.
Asunto(s)
Plantas Medicinales , Fenoles/análisis , Tailandia , Extractos Vegetales/farmacología , Medicina TradicionalRESUMEN
Abstract Medicinal plants have long been prescribed in Thailand for centuries. Different constituents of extracts have been used for treating of various infectious diseases. However, there is even less information available regarding the use in fungal skin infection. In order to assess traditional Thai claims about the therapeutic potential, this study is focused on exploring the anti-dermatophyte property of the plants that are currently used as traditional medicines. The potential of four different plant species were selected for investigate in vitro anti-dermatophyte activity. Ethanolic extracts of Chromolaena odorata (L.), Ageratina adenophora (Spreng.), Eclipta prostrate (Linn.), and Acorus calamus (L.). were analysed for their total phenolic content as well as total flavonoid content and were then subjected to test of their anti-dermatophyte properties using agar well diffusion method. Qualitative flavonoids and phenolics analysis of the extracts showed their biologically active constituents. Among the species examined, the result indicated that most of the extracts demonstrated anti-dermatophyte activity. In particular, A. calamus showed the highest efficacy against test organisms. The experiment confirmed the chemical constituents and efficacy of some selected plants and provides a scientific confirmation of the use of Thai plants in traditional medicine for fungal skin infections.
Resumo As plantas medicinais são prescritas há muito tempo na Tailândia, há séculos. Diferentes constituintes de extratos têm sido usados para o tratamento de várias doenças infecciosas. No entanto, existem ainda menos informações disponíveis sobre o uso em infecções fúngicas da pele. A fim de avaliar as alegações tradicionais tailandesas sobre o potencial terapêutico, este estudo está focado em explorar a propriedade antidermatófita das plantas que são usadas atualmente como medicamentos tradicionais. O potencial de quatro espécies de plantas diferentes foi selecionado para investigar a atividade antidermatófita in vitro. Extratos etanólicos de Chromolaena odorata (L.), Ageratina adenophora (Spreng.), Eclipta prostrate (Linn.) e Acorus calamus (L.) foram analisados quanto ao seu conteúdo fenólico total, bem como ao conteúdo de flavonoides totais. E então submetidos ao teste de suas propriedades antidermatófitas usando o método de difusão em ágar bem. A análise qualitativa de flavonoides e fenólicos dos extratos mostrou seus constituintes biologicamente ativos. Entre as espécies examinadas, o resultado indicou que a maioria dos extratos demonstrou atividade antidermatófita. Em particular, A. calamus mostrou a maior eficácia contra organismos de teste. O experimento confirmou os constituintes químicos e a eficácia de algumas plantas selecionadas e fornece uma confirmação científica do uso de plantas tailandesas na medicina tradicional para infecções fúngicas da pele.
RESUMEN
Oral candidiasis (OC) is the most prevalent HIV-related oral lesion in patients on combined anti-retroviral therapy (cART) or without cART. Management is challenged in some patients by development of resistance to azole drugs, such as fluconazole. Recent scientific knowledge about OC pathogenesis, the role of OC in the immune reconstitution inflammatory syndrome (IRIS), the relationship of OC with the microbiome, and novelties in OC treatment was discussed in an international workshop format. Literature searches were conducted to address five questions: (a) Considering the pathogenesis of Candida spp. infection, are there any potential therapeutic targets that could be considered, mainly in HIV-infected individuals resistant to fluconazole? (b) Is oral candidiasis part of IRIS in HIV patients who receive cART? (c) Can management of the oral microbiome reduce occurrence of OC in patients with HIV infection? (d) What are the recent advances (since 2015) regarding plant-based and alternative medicines in management of OC? and (e) Is there a role for photodynamic therapy in management of OC in HIV-infected patients? A number of the key areas where further research is necessary were identified to allow a deeper insight into this oral condition that could help to understand its nature and recommend alternatives for care.
Asunto(s)
Antifúngicos , Candidiasis Bucal , Infecciones por VIH , Antifúngicos/uso terapéutico , Candidiasis Bucal/tratamiento farmacológico , Candidiasis Bucal/prevención & control , Fluconazol/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , HumanosRESUMEN
Leishmaniasis is an infectious disease caused by protozoan parasites of the genus Leishmania. The treatment of all forms of leishmaniasis relies on first-line drug, pentavalent antimonial, and in cases of drug failure, the second-line drug amphotericin B has been used. Besides the high toxicity of drugs, parasites can be resistant to antimonial in some areas of the World, making it necessary to perform further studies for the characterization of new antileishmanial agents. Thus, the aim of the present work was to evaluate the leishmanicidal activity of tolnaftate, a selective reversible and non-competitive inhibitor of the fungal enzyme squalene epoxidase, which is involved in the biosynthesis of ergosterol, essential to maintain membrane physiology in fungi as well as trypanosomatids. Tolnaftate eliminated promastigote forms of L. (L.) amazonensis, L. (V.) braziliensis and L. (L.) infantum (EC50 ~ 10 µg/mL and SI ~ 20 for all leishmanial species), and intracellular amastigote forms of all studied species (EC50 ~ 23 µg/mL in infections caused by dermatotropic species; and 11.7 µg/mL in infection caused by viscerotropic species) with high selectivity toward parasites [SI ~ 8 in infections caused by dermatotropic species and 17.4 for viscerotropic specie]. Promastigote forms of L. (L.) amazonensis treated with the EC50 of tolnaftate displayed morphological and physiological changes in the mitochondria and cell membrane. Additionally, promastigote forms treated with tolnaftate EC50 reduced the level of ergosterol by 5.6 times in comparison to the control parasites. Altogether, these results suggest that tolnaftate has leishmanicidal activity towards Leishmania sp., is selective, affects the cell membrane and mitochondria of parasites and, moreover, inhibits ergosterol production in L. (L.) amazonensis.
Asunto(s)
Antifúngicos/uso terapéutico , Antiprotozoarios/uso terapéutico , Ergosterol/antagonistas & inhibidores , Leishmania/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Tolnaftato/uso terapéutico , Animales , Antifúngicos/farmacología , Antiprotozoarios/farmacología , Supervivencia Celular , Humanos , Ratones , Tolnaftato/farmacologíaRESUMEN
Sporothrix brasiliensis is the causative agent of zoonotic sporotrichosis in Brazil and is currently referred to as the most virulent species among those of clinical importance within the genus. Sporotrichosis is an emergent disease that has come to the forefront over two decades with a recent hot spot of sporotrichosis infection emerging in the state of Rio de Janeiro. The source of these infections is now at epidemic proportions with more than 4000 cases reported in Rio de Janeiro, Brazil, alone since 1998. We developed a focused library of a rare pentathiepin ring system and identified a potent substitution pattern that yielded compounds 21 and 22. These compounds were more potent than itraconazole which is the current standard of care for sporotrichosis.
RESUMEN
Among different Candida species triggering vaginal candidiasis, Candida albicans is the most predominant yeast. It is commonly treated using azole drugs such as Tioconazole (TIO) and Econazole (ECO). However, their low water solubility may affect their therapeutic efficiency. Therefore, the aim of this research was to produce a novel chitosan nanocapsule based delivery system comprising of TIO or ECO and to study their suitability in vaginal application. These systems were characterized by their physicochemical properties, encapsulation efficiency, in vitro release, storage stability, cytotoxicity, and in vitro biological activity. Both nanocapsules loaded with TIO (average hydrodynamic size of 146.8 ± 0.8 nm, zeta potential of +24.7 ± 1.1 mV) or ECO (average hydrodynamic size of 127.1 ± 1.5 nm, zeta potential of +33.0 ± 1.0 mV) showed excellent association efficiency (99% for TIO and 87% for ECO). The analysis of size, polydispersity index, and zeta potential of the systems at 4, 25, and 37 °C (over a period of two months) showed the stability of the systems. Finally, the developed nanosystems presented fungicidal activity against C. albicans at non-toxic concentrations (studied on model human skin cells). The results obtained from this study are the first step in the development of a pharmaceutical dosage form suitable for the treatment of vaginal candidiasis.
Asunto(s)
Antifúngicos/administración & dosificación , Quitosano/química , Portadores de Fármacos/química , Nanopartículas/química , Antifúngicos/química , Candida albicans/efectos de los fármacos , Fenómenos Químicos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Estabilidad de Medicamentos , Econazol/administración & dosificación , Econazol/química , Imidazoles/administración & dosificación , Imidazoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nanocápsulas/química , Nanopartículas/ultraestructuraRESUMEN
Leishmaniasis is an infectious disease caused by protozoal parasites belonging to Leishmania genus. Different clinical outcomes can be observed depending on the parasite species and health condition of patients. It can range from single cutaneous lesion until deadly visceral form. The treatment of all forms of leishmaniasis is based on pentavalent antimonials, and in some cases, the second-line drug, amphotericin B is used. Beside the toxicity of both drugs, parasites can be resistant to antimonial in some areas of the world. This makes fundamental the characterization of new drugs with leishmanicidal effect. Thus, the aim of the present work was to study the leishmanicidal activity of drugs able to interfere with ergosterol pathway (fenticonazole, tioconazole, nystatin, rosuvastatin and voriconazole) against promastigote and amastigote forms of L.(L.) amazonensis, L.(V.) braziliensis and L.(L.) infantum, and its impact on morphological and physiological changes in L.(L.) amazonensis or in host macrophages. We observed that fenticonazole, tioconazole and nystatin drugs eliminated promastigote and intracellular amastigotes, being fenticonazole and nystatin the most selective towards amastigote forms. Rosuvastatin and voriconazole did not present activity against amastigote forms of Leishmania sp. In addition, the drugs with leishmanicidal activity interfered with parasite mitochondrion. Although drugs did not stimulate NO and H2O2, specially fenticonazole was able to alkalize infected host macrophages. These results suggest well established and non-toxic antifungal drugs can be repurposed and used in leishmaniasis.
Asunto(s)
Antiprotozoarios/farmacología , Imidazoles/farmacología , Leishmania/efectos de los fármacos , Nistatina/farmacología , Antiprotozoarios/química , Imidazoles/química , Nistatina/química , Pruebas de Sensibilidad Parasitaria , Especificidad de la EspecieRESUMEN
Candida albicans biofilms exhibit unique characteristics and are highly resistant to antifungal agents. Antimicrobial photodynamic therapy (aPDT) is an alternative treatment limited to treating superficial infections due to the poor light penetration. In this manuscript, the antifungal properties of sonodynamic therapy (SDT) were assessed. SDT uses ultrasound instead of light, enabling the treatment of deeper infections. Planktonic cells and biofilms of C. albicans were treated with aPDT or SDT, in addition to combined aPDT/SDT, with cell survival determined using colony forming units. The total biomass and structural integrity of the biofilms were also investigated. The results demonstrated that while individual aPDT or SDT eradicated suspensions, they had little impact on biofilms. However, combined aPDT/SDT significantly reduced the viability and total biomass of biofilms. Microscopic images revealed that biofilms treated with aPDT/SDT were thinner and comprised mainly of dead cells. These results highlight the potential of combined aPDT/SDT for the inactivation of C. albicans biofilms.
Asunto(s)
Biopelículas , Candida albicans/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Antifúngicos/farmacología , Candida albicans/fisiología , FotoquimioterapiaRESUMEN
The ability of the versatile dioctadecyldimethylammonium bromide (DODAB), a bilayer-forming synthetic lipid previously shown to solubilize Amphotericin B (AMB), inspired this evaluation of in vivo activity of the DODAB/AMB formulation (DOD/AMB) against systemic candidiasis in a mouse model from survival and tissue burden experiments. AMB was simply added to a DODAB powder dispersion in water previously obtained by sonication with tip at concentrations 0.1 and 10 mg/mL, respectively, organic solvents completely absent. AMB aggregation state was evaluated from UV-visible light absorption and dynamic light scattering for aggregate sizing. AMB was stabilized by the DODAB bilayer fragments in its monomeric form, causing disappearance of large water insoluble drug aggregates. From survival and tissue burden experiments, DOD/AMB efficacy was equivalent to the one exhibited by Fungizone (DOC/AMB) - 100 and 70% survival respectively, at 0.4 mg/kg/day given i.p. for 10 days (P>0.05) -, regarding elimination of Candida colonization in spleen and kidneys. In summary, DOD/AMB, was effective for treating systemic candidiasis in a mouse model.
A habilidade do brometo de dioctadecildimetilamônio (DOBAB), em formar bicamada de lipídio sintético e a demonstração prévia do forte poder solubilizante de anfotericina B (ANB) , incentivou-nos a realizar a avaliação da atividade de DODAB/AMB in vivo contra candidíase sistêmica em modelo de camundongos para verificar a sua sobrevida bem como a recuperação das leveduras de C. albicans dos órgãos colonizados (baço e rins). O AMB foi simplesmente adicionado à DODAB em pó previamente disperso em água e sonicado com auxílio de ponteiras, nas concentrações de 0,1e 10 mg/mL, respectivamente, assegurando-se a completa ausência de solventes orgânicos nesta formulação. O estado de agregação do AMB foi avaliado por meio do espectro de absorção da luz UV-visível e a distribuição de tamanhos das formulações estudadas, determinadas por meio de analisador ZetaPlus Brookhaven Instruments Corporation, Holtsville, NY) equipado com um laser de 570 nm e dynamic light scattering (90ºC) para a medição dos tamanhos (Grabowski & Morrison, 1983). AMB foi estabilizada na bicamada de DODAB em forma monomérica, eliminando-se os grandes agregados de AMB insolúveis em água. Tanto a sobrevida dos animais como os experimentos com recuperação das leveduras dos órgãos colonizados (baço e rins) mostraram eficácia equivalente à demonstrada por Fungizona (DOC/AMB) - a sobrevida foi de 100 e 70% respectivamente nas concentrações de 0.4 mg/kg/dia via i.p. por 10 dias (P>0.05), em relação a eliminação da colonização de C. albicans dos rins e baço. Em resumo, DOD/AMB foi efetivo no tratamento de candidíase sistêmica em modelo animal.
RESUMEN
The ability of the versatile dioctadecyldimethylammonium bromide (DODAB), a bilayer-forming synthetic lipid previously shown to solubilize Amphotericin B (AMB), inspired this evaluation of in vivo activity of the DODAB/AMB formulation (DOD/AMB) against systemic candidiasis in a mouse model from survival and tissue burden experiments. AMB was simply added to a DODAB powder dispersion in water previously obtained by sonication with tip at concentrations 0.1 and 10 mg/mL, respectively, organic solvents completely absent. AMB aggregation state was evaluated from UV-visible light absorption and dynamic light scattering for aggregate sizing. AMB was stabilized by the DODAB bilayer fragments in its monomeric form, causing disappearance of large water insoluble drug aggregates. From survival and tissue burden experiments, DOD/AMB efficacy was equivalent to the one exhibited by Fungizone (DOC/AMB) - 100 and 70% survival respectively, at 0.4 mg/kg/day given i.p. for 10 days (P>0.05) -, regarding elimination of Candida colonization in spleen and kidneys. In summary, DOD/AMB, was effective for treating systemic candidiasis in a mouse model.
A habilidade do brometo de dioctadecildimetilamônio (DOBAB), em formar bicamada de lipídio sintético e a demonstração prévia do forte poder solubilizante de anfotericina B (ANB) , incentivou-nos a realizar a avaliação da atividade de DODAB/AMB in vivo contra candidíase sistêmica em modelo de camundongos para verificar a sua sobrevida bem como a recuperação das leveduras de C. albicans dos órgãos colonizados (baço e rins). O AMB foi simplesmente adicionado à DODAB em pó previamente disperso em água e sonicado com auxílio de ponteiras, nas concentrações de 0,1e 10 mg/mL, respectivamente, assegurando-se a completa ausência de solventes orgânicos nesta formulação. O estado de agregação do AMB foi avaliado por meio do espectro de absorção da luz UV-visível e a distribuição de tamanhos das formulações estudadas, determinadas por meio de analisador ZetaPlus Brookhaven Instruments Corporation, Holtsville, NY) equipado com um laser de 570 nm e dynamic light scattering (90ºC) para a medição dos tamanhos (Grabowski & Morrison, 1983). AMB foi estabilizada na bicamada de DODAB em forma monomérica, eliminando-se os grandes agregados de AMB insolúveis em água. Tanto a sobrevida dos animais como os experimentos com recuperação das leveduras dos órgãos colonizados (baço e rins) mostraram eficácia equivalente à demonstrada por Fungizona (DOC/AMB) - a sobrevida foi de 100 e 70% respectivamente nas concentrações de 0.4 mg/kg/dia via i.p. por 10 dias (P>0.05), em relação a eliminação da colonização de C. albicans dos rins e baço. Em resumo, DOD/AMB foi efetivo no tratamento de candidíase sistêmica em modelo animal.
RESUMEN
The ability of the versatile dioctadecyldimethylammonium bromide (DODAB), a bilayer-forming synthetic lipid previously shown to solubilize Amphotericin B (AMB), inspired this evaluation of in vivo activity of the DODAB/AMB formulation (DOD/AMB) against systemic candidiasis in a mouse model from survival and tissue burden experiments. AMB was simply added to a DODAB powder dispersion in water previously obtained by sonication with tip at concentrations 0.1 and 10 mg/mL, respectively, organic solvents completely absent. AMB aggregation state was evaluated from UV-visible light absorption and dynamic light scattering for aggregate sizing. AMB was stabilized by the DODAB bilayer fragments in its monomeric form, causing disappearance of large water insoluble drug aggregates. From survival and tissue burden experiments, DOD/AMB efficacy was equivalent to the one exhibited by Fungizone (DOC/AMB) - 100 and 70% survival respectively, at 0.4 mg/kg/day given i.p. for 10 days (P>0.05) -, regarding elimination of Candida colonization in spleen and kidneys. In summary, DOD/AMB, was effective for treating systemic candidiasis in a mouse model.
A habilidade do brometo de dioctadecildimetilamônio (DOBAB), em formar bicamada de lipídio sintético e a demonstração prévia do forte poder solubilizante de anfotericina B (ANB) , incentivou-nos a realizar a avaliação da atividade de DODAB/AMB in vivo contra candidíase sistêmica em modelo de camundongos para verificar a sua sobrevida bem como a recuperação das leveduras de C. albicans dos órgãos colonizados (baço e rins). O AMB foi simplesmente adicionado à DODAB em pó previamente disperso em água e sonicado com auxílio de ponteiras, nas concentrações de 0,1e 10 mg/mL, respectivamente, assegurando-se a completa ausência de solventes orgânicos nesta formulação. O estado de agregação do AMB foi avaliado por meio do espectro de absorção da luz UV-visível e a distribuição de tamanhos das formulações estudadas, determinadas por meio de analisador ZetaPlus Brookhaven Instruments Corporation, Holtsville, NY) equipado com um laser de 570 nm e dynamic light scattering (90ºC) para a medição dos tamanhos (Grabowski & Morrison, 1983). AMB foi estabilizada na bicamada de DODAB em forma monomérica, eliminando-se os grandes agregados de AMB insolúveis em água. Tanto a sobrevida dos animais como os experimentos com recuperação das leveduras dos órgãos colonizados (baço e rins) mostraram eficácia equivalente à demonstrada por Fungizona (DOC/AMB) - a sobrevida foi de 100 e 70% respectivamente nas concentrações de 0.4 mg/kg/dia via i.p. por 10 dias (P>0.05), em relação a eliminação da colonização de C. albicans dos rins e baço. Em resumo, DOD/AMB foi efetivo no tratamento de candidíase sistêmica em modelo animal.