RESUMEN
This study aimed to develop microemulsions (MEs) containing α-bisabolol for the topical treatment of cutaneous leishmaniasis (CL). Initially, pseudoternary phase diagrams were developed using α-bisabolol as the oil phase, Eumulgin® CO 40 as the surfactant, Polymol® HE as the co-surfactant, and distilled water as the aqueous phase. Two transparent liquid systems (TLS) containing 5% of α-bisabolol were selected and characterized (F5E25 and F5EP25). Next, skin permeation and retention assays were performed using Franz cells. The interaction of the formulation with the stratum corneum (SC) was evaluated using the FTIR technique. The cytotoxicity was evaluated in murine peritoneal macrophages. Finally, the antileishmanial activity of microemulsions was determined in promastigotes and amastigotes of L. amazonensis (strain MHOM/BR/77/LTB 0016). As a result, the selected formulations showed isotropy, nanometric size (below 25 nm), Newtonian behavior and pH ranging from 6.5 to 6.9. The MEs achieved a 2.5-fold increase in the flux and skin-permeated amount of α-bisabolol. ATR-FTIR results showed that microemulsions promoted fluidization and extraction of lipids and proteins of the stratum corneum, increasing the diffusion coefficient and partition coefficient of the drug in the skin. Additionally, F5E25 and F5EP25 showed higher activity against promastigotes (IC50 13.27 and 18.29, respectively) compared to unencapsulated α-bisabolol (IC50 53.8). Furthermore, F5E25 and F5EP25 also showed antileishmanial activity against intracellular amastigotes of L. amazonensis, with IC50 50 times lower than free α-bisabolol and high selectivity index (up to 15). Therefore, the systems obtained are favorable to topical administration, with significant antileishmanial activity against L. amazonensis promastigotes and amastigotes, being a promising system for future in vivo trials.
Asunto(s)
Emulsiones , Macrófagos Peritoneales , Sesquiterpenos Monocíclicos , Sesquiterpenos , Piel , Animales , Sesquiterpenos Monocíclicos/farmacología , Sesquiterpenos Monocíclicos/química , Emulsiones/química , Ratones , Sesquiterpenos/farmacología , Sesquiterpenos/química , Piel/parasitología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/parasitología , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitología , Espectroscopía Infrarroja por Transformada de Fourier , Absorción Cutánea/efectos de los fármacos , Ratones Endogámicos BALB C , Femenino , Leishmania/efectos de los fármacos , Tensoactivos/farmacología , Tensoactivos/química , Antiprotozoarios/farmacología , Antiprotozoarios/químicaRESUMEN
The natural antimicrobial properties of essential oils (EOs) have contributed to the battle against multidrug-resistant microorganisms by providing new ways to develop more effective antibiotic agents. In this study, we investigated the chemical composition of Ocotea diospyrifolia essential oil (OdOE) and its antimicrobial properties combined with amikacin (AMK). Through gas chromatography-mass spectrometry (GCMS) analysis, the primary constituents of OdOE were identified as α-bisabolol (45.8 %), ß-bisabolene (9.4 %), γ-elemene (7.6 %), (Z)- ß-farnesene (5.2 %), spathulenol (3.5 %), (Z)-caryophyllene (3.3 %), and (E)-caryophyllene (3.1 %). In vitro assessments showed that the combined administration of OdOE and AMK exerted a synergistic antibacterial effect on the multidrug-resistant K. pneumoniae strain. This synergistic effect demonstrated bacteriostatic action. OdEO combined with amikacin showed protein extravasation within 2 h of treatment, leading to bacterial death, which was determined by a reduction in viable cell count. The effective concentrations showed hemocompatibility. In vivo assessments using Caenorhabditis elegans as a model showed the survival of 85 % of infected nematodes. Therefore, the combination OdEO combined with amikacin exhibited antimicrobial activity against a multidrug-resistant K. pneumoniae strain. Thus, OdOE is a promising agent that may be considered for development of antimicrobial treatment.
Asunto(s)
Amicacina , Antibacterianos , Farmacorresistencia Bacteriana Múltiple , Sinergismo Farmacológico , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Aceites Volátiles , Amicacina/farmacología , Aceites Volátiles/farmacología , Aceites Volátiles/química , Animales , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Antibacterianos/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Caenorhabditis elegans/efectos de los fármacos , Infecciones por Klebsiella/tratamiento farmacológico , Infecciones por Klebsiella/microbiología , Sesquiterpenos Monocíclicos/farmacología , Sesquiterpenos Policíclicos/farmacología , Sesquiterpenos Policíclicos/química , Sesquiterpenos/farmacologíaRESUMEN
INTRODUCTION: Amphotericin B (AmB), used for systemic fungal infections, has a limited clinical application because of its high nephrotoxicity. Natural antioxidant and anti-inflammatory substances have been widely studied for protection against drug-induced nephrotoxicity. α-Bisabolol (BIS) has demonstrated a nephroprotective effect on both in vitro and in vivo models. AIMS: The aim of this work was to evaluate the effect of BIS against AmB-induced nephrotoxicity in vitro. MATERIAL AND METHODS: LLC-MK2 cells were pre- and post-treated with non-toxic BIS concentrations and/or AmB IC50 (13.97 µM). Cell viability was assessed by MTT [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)] assay. Flow cytometry analyses were used to assess cell death mechanism, production of reactive oxidative stress (ROS) and mitochondrial transmembrane potential. Kidney Injury Molecule-1 (KIM-1) levels were measured via ELISA. KEY FINDINGS: The present work showed that BIS pretreatment (125; 62.5 and 31.25 µM) increased cell viability when compared to the group treated only with AmB IC50. AmB treatment induced both necrosis (7-AAD-labeled cells) and late apoptosis (AnxV-labeled). BIS was able to prevent the occurrence of these events. These effects were associated with a decrease of ROS accumulation, improving transmembrane mitochondrial potential and protecting against tubular cell damage, highlighted by the inhibition of KIM-1 release after BIS treatment. SIGNIFICANCE: BIS presented a potential effect on model of renal cytotoxicity induced by AmB, bringing perspectives for the research of new nephroprotective agents.
Asunto(s)
Supervivencia Celular/efectos de los fármacos , Túbulos Renales Proximales/efectos de los fármacos , Sesquiterpenos Monocíclicos/farmacología , Anfotericina B/farmacología , Anfotericina B/toxicidad , Animales , Antifúngicos/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Riñón/metabolismo , Túbulos Renales Proximales/metabolismo , Macaca mulatta , Sesquiterpenos Monocíclicos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacologíaRESUMEN
The aim of this study was to examine if the peripheral antinociception of α-bisabolol involves the participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous injection into the dorsal surface of the paw of vehicles or increasing doses of α-bisabolol (100-300 µg/paw). To determine whether the peripheral antinociception induced by α-bisabolol was mediated by either the opioid receptors or the NO-cGMP-K+ channels pathway, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicles, naloxone, naltrexone, NG-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]-oxadiazolo[4,2-a]quinoxalin-1-one (ODQ), glibenclamide, glipizide, apamin, charybdotoxin, tetraethylammonium, or 4-aminopyridine on the antinociceptive effects induced by local peripheral α-bisabolol (300 µg/paw) were assessed. α-Bisabolol produced antinociception during both phases of the formalin test. α-Bisabolol antinociception was blocked by L-NAME, ODQ, and all the K+ channels blockers. The peripheral antinociceptive effect produced by α-bisabolol was not blocked by the opioid receptor inhibitors. α-Bisabolol was able to active the NO-cGMP-K+ channels pathway to produce its antinoceptive effect. The participation of opioid receptors in the peripheral local antinociception induced by α-bisabolol is excluded.
Asunto(s)
Analgésicos/farmacología , GMP Cíclico/metabolismo , Sesquiterpenos Monocíclicos/farmacología , Óxido Nítrico/metabolismo , Nocicepción/efectos de los fármacos , Canales de Potasio/metabolismo , Receptores Opioides/metabolismo , Animales , Masculino , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/química , Canales de Potasio/genética , Ratas , Ratas Wistar , Receptores Opioides/química , Receptores Opioides/genéticaRESUMEN
This study aimed to investigate the acaricidal activity of (E)-cinnamaldehyde and α-bisabolol on populations of Rhipicephalus microplus with different resistance profiles. The adult immersion test (AIT) was used to characterize the susceptibility of tick populations (50 field populations) to synthetic acaricides: deltamethrin, amitraz, and chlorfenvinphos. The larval packet test (LPT) was used to determine the LC50 values for (E)-cinnamaldehyde (populations 1-25) and α-bisabolol (populations 26-50) at the concentrations of 0.31, 0.62, 1.25, 2.0, 2.5, 5.0 and 10.0â¯mg/mL. The susceptible strain Porto Alegre (POA) was used as a reference for calculating the resistance ratio (RR). In the AIT, deltamethrin did not show efficacy >95 % for any of the populations, whereas amitraz and chlorfenvinphos have presented efficacy >95 % for three (6 %) and 15 (30 %) populations, respectively. In the LPT, the LC50 values of (E)-cinnamaldehyde and α-bisabolol varied from 0.23 to 2.36â¯mg/mL and 1.57-3.01â¯mg/mL, respectively. The RR50 for (E)-cinnamaldehyde showed 20 (80 %) populations with values <1.0 and no population with values>1.5. As for α-bisabolol, only two (8%) populations have presented RR50 <1.0, whereas three (12 %) populations showed incipient resistance to this sesquiterpene (RR50 between 1.5 and 2.0). The results indicate that all studied tick populations showed low susceptibility to at least one of the commercial acaricides tested. In addition, comparison between the LC50 values of (E)-cinnamaldehyde and α-bisabolol for the field populations and the susceptible strain POA suggests that there is no cross-resistance of (E)-cinnamaldehyde and α-bisabolol for the tick populations evaluated, and that the differences in the LC50 values are due to population variations.
Asunto(s)
Acaricidas/farmacología , Acroleína/análogos & derivados , Resistencia a Medicamentos , Sesquiterpenos Monocíclicos/farmacología , Rhipicephalus/efectos de los fármacos , Acroleína/farmacología , Animales , Brasil , FemeninoRESUMEN
(-)-α-Bisabolol (BISA) is an unsaturated monocyclic sesquiterpenes compound, mainly found in the essential oil of chamomile (Matricaria chamomilla). It has been reported that this compound has several biological activities, but there are few studies evaluating the activity of this compound in the systemic inflammatory response in infectious processes. The aim of this study was to evaluate the effect of BISA on the inflammatory response and survival rate in a systemic infection model, and in vitro neutrophils phagocytic activity. BISA at concentration of 3, 10, 30, and 90 µg/ml did not presented in vitro cytotoxicity in MTT assay, and at concentrations of 1 and 3 µg/ml the BISA treatment increased in vitro phagocytic neutrophil activity. For the inflammatory response study, we verified the BISA treatment effect in a cecal ligation and puncture (CLP)-induced systemic infection model in mice; in this model, we demonstrate that BISA at dose of 100 mg/kg reduced the leukocyte recruitment in peritoneal cavity; at dose of 200 mg/kg, the NO concentration was increased in the peritoneal cavity. The bacteria CFU number was reduced in mice blood in the BISA treatment, at doses of 100 and 200 mg/kg. The BISA treatment at doses of 50 and 100 mg/kg increased the myeloperoxidase activity and reduction NO production in lung tissue of mice in CLP model. At dose of 100 mg/kg, the BISA treatment was able to reduce the mortality rate of mice submitted to CLP-induced sepsis and observed for 7 days. The results suggest an effect of BISA on inflammatory response, with activity on leukocyte chemotactic and NO production, in addition to increasing the survival rate of animals submitted to CLP model.
Asunto(s)
Antiinflamatorios/farmacología , Inflamación/prevención & control , Sesquiterpenos Monocíclicos/farmacología , Neutrófilos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Sepsis/tratamiento farmacológico , Animales , Carga Bacteriana , Células Cultivadas , Quimiotaxis de Leucocito/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Patógeno , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/microbiología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/microbiología , Óxido Nítrico/metabolismo , Peritoneo/efectos de los fármacos , Peritoneo/inmunología , Peritoneo/metabolismo , Peritoneo/microbiología , Sepsis/inmunología , Sepsis/metabolismo , Sepsis/microbiologíaRESUMEN
Acute Kidney Injury (AKI) is associated with high morbidity and mortality. Ischemia and reperfusion (I/R) are events that lead to AKI through hypoxia, reactive oxygen species (ROS) production, oxidative stress and apoptosis. We aimed to evaluate the mechanism of nephroprotection mediated by Bisabolol in human tubular kidney cells after injury by I/R in vitro. HK2 cells were exposed to I/R and treated with Bisabolol. Cell viability was accessed by MTT assay. Cells were submitted to flow cytometry to evaluate necrotic/apoptotic cells, reactive oxygen species production and mitochondrial transmembrane depolarization. TBARS and GSH were used as parameters of redox balance. Also, KIM-1 supernatant levels were measured. In order to identify an interaction between bisabolol and NOX4, molecular docking and enzymatic assays were performed. Expression of isoform NOX4 on treated cells was examined by western-blot. Finally, cells were visualized by scanning electron microscopy. Bisabolol improved cell viability and prevented cell death by apoptosis, indicated also by the decreased levels of KIM-1. It was observed a decrease on reactive oxygen species production and mitochondrial depolarization, with antioxidant regulation by increased GSH and decreased lipid peroxidation. It was also demonstrated that bisabolol treatment can inhibit NOX4. Finally, SEM images showed that bisabolol reduced I/R-induced cell damage. Bisabolol treatment protects HK2 cells against oxidative damage occasioned by I/R. This effect is related to inhibition of apoptosis, decrease on KIM-1 release, reactive oxygen species accumulation and mitochondrial dysfunction. Bisabolol inhibited NOX4 activity in the tubular cells, impairing reactive oxygen species synthesis.
Asunto(s)
Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Sesquiterpenos Monocíclicos/farmacología , NADPH Oxidasas/metabolismo , Oxígeno/metabolismo , Daño por Reperfusión/prevención & control , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citoprotección/efectos de los fármacos , Glutatión/metabolismo , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Humanos , Túbulos Renales/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
New therapeutic approaches are necessary to control strongyloidiasis due to the side effects of, and resistance to, currently available drugs thiabendazole, albendazole, and ivermectin. This study examined the anthelmintic properties of extracts and isolated compounds from Siparuna guianensis against Strongyloides venezuelensis eggs and larvae, using the egg hatching test (EHT) and larval motility test (LMT). Albendazole (0.025 mg/ml) and ivermectin (0.316 mg/ml) were used as the positive controls for the EHT and LMT assays, respectively. Strongyloides venezuelensis eggs or larvae (±50 specimens) were treated with ethanol extract (0.05-1.0 mg/ml), ethyl acetate and aqueous fractions (0.05-0.8 mg/ml), essential oil (0.2-1.0 mg/ml) and α-bisabolol (0.2-1.0 mg/ml) from S. guianensis, and analysed by optical microscopy after 48 h (EHT), or after 24, 48 and 72 h (LMT). All the tested compounds exhibited ovicidal activity equivalent to the positive control and changed the morphology of the eggs. The S. guianensis ethanol extract and aqueous fraction were as effective as the positive control. Phytochemical analysis of the ethanol extract and fractions revealed the presence of phenolic compounds, tannins and flavonoids. Therefore, S. guianensis is effective against S. venezuelensis eggs and larvae in vitro, and can be considered as a potential alternative treatment for strongyloidiasis.
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Antihelmínticos/farmacología , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Strongyloides/efectos de los fármacos , Tracheophyta/química , Animales , Antihelmínticos/química , Larva/efectos de los fármacos , Sesquiterpenos Monocíclicos/química , Sesquiterpenos Monocíclicos/farmacología , Aceites Volátiles/química , Óvulo/efectos de los fármacos , Extractos Vegetales/químicaRESUMEN
Vigna unguiculata, one of the most important legumes, mainly in underdeveloped countries, is susceptible to post-harvest losses in storage by Callosobruchus maculatus (Fabricius, 1775) (Coleoptera: Chrysomelidae). The work evaluated the toxicity, inhibition of oviposition, instantaneous rate of population growth (ri) and the development of fumigated C. maculatus with the essential oil of Vanillosmopsis arborea and its major constituent, α-bisabolol. The experimental units consisted of 0.8 L flasks treated with concentrations of 1.2-11.2 µL L-1of air of the essential oil of V. arborea or its major constituent applied to disks of filter paper. α-Bisabolol was quantified as 409.33 mL L-1 of the essential oil. The development rate of C. maculatus was evaluated by daily adult counts. Oviposition was evaluated at lethal concentrations (LC50, LC25, LC10 and LC1). The LC50 and LC95 of the essential oil of V. arborea and α-bisabolol were 5.23 and 12.97 µL L-1 of air and 2.47 and 8.82 µL L-1 of air, respectively. At some concentrations, the α-bisabolol was more toxic to males than to females of the insect. Increased concentrations of the essential oil reduced the ri, rate of development, oviposition, and number of eggs of C. maculatus and therefore have potential for pest control.