RESUMO
α-Bisabolol (α-BIS) is a sesquiterpene alcohol present in chamomile essential oil [Chamomilla recutita (L.) Rauschert]. Despite its numerous pharmacological effects, its pharmacokinetics remain understudied. An analytical method capable of quantifying α-BIS in plasma is crucial to enable pharmacokinetic analysis. Presently, only one study has quantified it using mass spectrometry. Administering α-BIS requires a nanoemulsion for intravenous injection. This study aimed to develop and validate a bioanalytical method using high-performance liquid chromatography with an ultraviolet detector to quantify α-BIS in rat plasma. The method employed acetonitrile and ultrapure water (80:20, v/v) as the mobile phase, with a flow rate of 1 ml/min and concentrations ranging from 465 to 29.625 µg/ml. All US Food and Drug Administration-designated assays were successful, indicating the method's precision, accuracy, sensitivity and linearity in determining α-BIS in rat plasma. The developed nanoemulsion, assessed through dynamic light scattering analysis, the ensemble collection of particles and polydispersity index evaluation, proved safe and effective for intravenous administration. The pharmacokinetic parameters such as volume of distribution, clearance and half-life indicated that α-BIS tends to persist in the body. This study provides a foundation for further research to explore α-BIS's potential pharmaceutical applications in the future.
Assuntos
Emulsões , Sesquiterpenos Monocíclicos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Ratos , Emulsões/química , Reprodutibilidade dos Testes , Sesquiterpenos Monocíclicos/farmacocinética , Sesquiterpenos Monocíclicos/sangue , Sesquiterpenos Monocíclicos/química , Masculino , Projetos Piloto , Modelos Lineares , Limite de Detecção , Sesquiterpenos/farmacocinética , Sesquiterpenos/sangue , Sesquiterpenos/química , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta/métodosRESUMO
Schistosomiasis, caused by a blood fluke of the genus Schistosoma, afflicts over 230 million people worldwide. Treatment of the disease relies on just one drug, praziquantel. Cnicin (Cn) is the sesquiterpene lactone found in blessed thistle (Centaurea benedicta) that showed antiparasitic activities but has not been evaluated against Schistosoma. However, cnicin has poor water solubility, which may limit its antiparasitic activities. To overcome these restrictions, inclusion complexes with cyclodextrins may be used. In this work, we evaluated the in vitro and in vivo antischistosomal activities of cnicin and its complexes with ß-cyclodextrin (ßCD) and 2-hydroxypropyl-ß-cyclodextrin (HPßCD) against Schistosoma mansoni. Cnicin were isolated from C. benedicta by chromatographic fractionation. Complexes formed by cnicin and ßCD (Cn/ßCD), as well as by cnicin and HPßCD (Cn/HPßCD), were prepared by coprecipitation and characterized. In vitro schistosomicidal assays were used to evaluate the effects of cnicin and its complexes on adult schistosomes, while the in vivo antischistosomal assays were evaluated by oral and intraperitoneal routes. Results showed that cnicin caused mortality and tegumental alterations in adult schistosomes in vitro, also showing in vivo efficacy after intraperitoneal administration. The oral treatment with cnicin or Cn/ßCD showed no significant worm reductions in a mouse model of schistosomiasis. In contrast, Cn/HPßCD complex, when orally or intraperitoneally administered to S. mansoni-infected mice, decreased the total worm load, and markedly reduced the number of eggs, showing high in vivo antischistosomal effectiveness. Permeability studies, using Nile red, indicated that HPßCD complex may reach the tegument of adult schistosomes in vivo. These results demonstrated the antischistosomal potential of cnicin in preparations with HPßCD.
Assuntos
Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Sesquiterpenos/farmacologia , 2-Hidroxipropil-beta-Ciclodextrina , Administração Oral , Animais , Centaurea/química , Modelos Animais de Doenças , Composição de Medicamentos , Fezes/parasitologia , Feminino , Injeções Intraperitoneais , Masculino , Camundongos , Contagem de Ovos de Parasitas , Carga Parasitária , Permeabilidade , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Esquistossomose mansoni/parasitologia , Esquistossomicidas/administração & dosagem , Esquistossomicidas/química , Esquistossomicidas/farmacocinética , Sesquiterpenos/administração & dosagem , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Solubilidade , beta-CiclodextrinasRESUMO
BACKGROUND: The ß-caryophyllene (BCP), a phytocannabinoid present in various essential oils, demonstrated selective action on the CB2 endocannabinoid receptor and attracted considerable attention because of its several pharmacological activities. Despite this recognized potential, this hydrophobic compound is a volatile and acid-sensitive sesquiterpene that readily oxidizes when exposed to air, and has low bioavailability in oral formulations. Thus, the development of formulations that guarantee its stability and increase its bioavailability is a challenge for its use in the pharmaceutical field. METHODS: The present review brings for the first time a comprehensive overview of the controlled and vectorized release formulations tested for BCP administration. Among these, we have addressed nanoemulsions, inclusion complexes with cyclodextrins, liposomes, wound dressings, nanocomposites and nanoparticles. A literature search was performed on Pubmed, Web of Science and Science direct, and patents documents were also searched on European Patent Office, World Intellectual Property Organization and Brazilian National Institute of Industrial Property. RESULTS: The systems presented here may represent an interesting approach to overcome the limitations already mentioned for this terpene. These systems proved to be promising for improving solubility, stability and controlled release of this pharmacological relevant sesquiterpene. In the industrial field, some companies have filed patent applications for the commercial use of the BCP, however, the use of pharmaceutical formulations still appeared moderate. CONCLUSION: This prospective study evidenced the new perspectives related to BCP vectorization systems in the pharmaceutical and industrial marketing field and may serve as a basis for further research and pharmaceutical use of this powerful cannabinoid.
Assuntos
Sistemas de Liberação de Medicamentos , Sesquiterpenos/farmacocinética , Administração Oral , Estabilidade de Medicamentos , Humanos , Sesquiterpenos Policíclicos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/química , SolubilidadeRESUMO
Lychnopholide, a lipophilic sesquiterpene lactone, is efficacious in mice at the acute and chronic phases of Chagas disease. Conventional poly-ε-caprolactone (PCL) and long-circulating poly(D,L-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules containing lychnopholide were developed and characterized. Lychnopholide presented high association efficiency (>90%) with the nanocapsules. A new, fast and simple HPLC-UV-based bioanalytical method was developed, validated in mouse plasma and applied to lychnopholide quantification in in vitro release kinetics and pharmacokinetics. The nanocapsules had mean hydrodynamic diameters in the range of 100-250 nm, negative zeta potentials (-30 mV to -57 mV), with good physical stability under storage. Atomic force microscopy morphological analysis revealed spherical monodispersed particles and the absence of lychnopholide crystallization or aggregation. Association of lychnopholide to PLA-PEG nanocapsules resulted in a 16-fold increase in body exposure, a 26-fold increase in plasma half-life and a dramatic reduction of the lychnopholide plasma clearance (17-fold) in comparison with free lychnopholide. The improved pharmacokinetic profile of lychnopholide in long-circulating nanocapsules is in agreement with the previously reported improved efficacy observed in Trypanosoma cruzi-infected mice. The present lychnopholide intravenous dosage form showed great potential for further pre-clinical and clinical studies in Chagas disease and cancer therapies.
Assuntos
Lactonas/administração & dosagem , Lactonas/farmacocinética , Nanoestruturas/química , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacocinética , Administração Intravenosa , Animais , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Feminino , Lactonas/análise , Camundongos , Microscopia de Força Atômica , Nanoestruturas/administração & dosagem , Poliésteres/química , Polietilenoglicóis/química , Reprodutibilidade dos Testes , Sesquiterpenos/análise , Tripanossomicidas/análiseRESUMO
OBJECTIVES: Analysis of the biopharmaceutical properties of eremantholide C, sesquiterpene lactone with proven pharmacological activity and low toxicity, is required to evaluate its potential to become a drug. METHODS: Preliminary analysis of the physicochemical characteristics of eremantholide C was performed in silico. Equilibrium solubility was evaluated using the shake-flask method, at 37.0 °C, 100 rpm during 72 h in biorelevant media. The permeability was analysed using parallel artificial membrane permeability assay, at 37.0 °C, 50 rpm for 5 h. The donor compartment was composed of an eremantholide C solution in intestinal fluid simulated without enzymes, while the acceptor compartment consisted of phosphate buffer. KEY FINDINGS: Physicochemical characteristics predicted in silico indicated that eremantholide C has a low solubility and high permeability. In-vitro data of eremantholide C showed low solubility, with values for the dose/solubility ratio (ml): 9448.82, 10 389.61 e 15 000.00 for buffers acetate (pH 4.5), intestinal fluid simulated without enzymes (pH 6.8) and phosphate (pH 7.4), respectively. Also, it showed high permeability, with effective permeability of 30.4 × 10-6 cm/s, a higher result compared with propranolol hydrochloride (9.23 × 10-6 cm/s). CONCLUSIONS: The high permeability combined with its solubility, pharmacological activity and low toxicity demonstrate the importance of eremantholide C as a potential drug candidate.
Assuntos
Simulação por Computador , Absorção Gastrointestinal , Modelos Biológicos , Sesquiterpenos/administração & dosagem , Humanos , Concentração de Íons de Hidrogênio , Membranas Artificiais , Permeabilidade , Propranolol/farmacocinética , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , SolubilidadeRESUMO
Lychnopholide is a sesquiterpene lactone usually obtained from Lychnophora and Eremanthus species and has pharmacological activities that include anti-inflammatory and anti-tumor. Lychnopholide isolated from Eremanthus matogrossenssis was analyzed in this study. The aims of this study were to develop and validate an analytical methodology by LC-MS/MS and to quantify lychnopholide in rat plasma. Chromatographic separation was achieved on a C18 column using isocratic elution with the mobile phase consisting of methanol and water (containing 0.1% formic acid) at a flow rate of 0.4 mL/min. The detection was performed in multiple-reaction monitoring mode using electrospray ionization in positive mode. The method validation was performed in accordance with regulatory guidelines and the results met the acceptance criteria. The linear range of detection was 10-200 ng/mL (r > 0.9961). The intra- and inter-day assay variability were <6.2 and <11.7%, respectively. The extraction recovery was approximately 63% using liquid-liquid extraction with chloroform. Lychnopholide was detected in plasma up to 60 min after intravenous administration in rats. This rapid and sensitive method for the analysis of the sesquiterpene lactone lychnopholide in rat plasma can be applied to pharmacokinetic studies of this compound. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Cromatografia Líquida/métodos , Lactonas/sangue , Sesquiterpenos/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Lactonas/farmacocinética , Limite de Detecção , Ratos , Reprodutibilidade dos Testes , Sesquiterpenos/farmacocinéticaRESUMO
The pharmacokinetic properties of a new molecular entity are important aspects in evaluating the viability of the compound as a pharmacological agent. The sesquiterpene lactone lychnopholide exhibits important biological activities. The objective of this study was to characterize the pharmacokinetics of lychnopholide after intravenous administration of 1.65 mg/kg (n = 5) and oral administration of 3.3 mg/kg (n = 3) lychnopholide in rats (0.2 ± 0.02 kg in weight) through nonlinear mixed effects modeling and non-compartmental pharmacokinetic analysis. A highly sensitive analytical method was used to quantify the plasma lychnopholide concentrations in rats. Plasma protein binding of this compound was over 99â% as determined by a filtration method. A two-compartment body model plus three transit compartments to characterize the absorption process best described the disposition of lychnopholide after both routes of administration. The oral bioavailability was approximately 68â%. The clearance was 0.131 l/min and intercompartmental clearance was 0.171 l/min; steady-state volume of distribution was 4.83 l. The mean transit time for the absorption process was 9.15 minutes. No flip-flop phenomenon was observed after oral administration. The pharmacokinetic properties are favorable for further development of lychnopholide as a potential oral pharmacological agent.
Assuntos
Lactonas/farmacocinética , Modelos Biológicos , Sesquiterpenos/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Lactonas/química , Masculino , Estrutura Molecular , Ligação Proteica , Ratos , Ratos Wistar , Sesquiterpenos/químicaRESUMO
Copaiba oil is largely used in the Amazonian region for the treatment of inflammation, and recent studies demonstrated that one of the major components of the oil, ß-caryophyllene (CAR), is a potent anti-inflammatory. The nanoemulsification of this oleoresin, which has unctuous character, converts it in a more acceptable hydrophilic formulation and may improve CAR penetration through the skin due to the small droplet size and the high contact surface afforded by the nanoemulsions. This paper describes the validation of a novel, sensitive, practical and solvent free method that uses gas chromatography in headspace mode coupled with mass spectrometry to evaluate the skin permeation/retention of CAR from the crude copaiba oil and its nanoemulsion. Our results show that the bioanalytic method was fully validated, demonstrating linearity (r(2)>0.99), specificity (no peaks co-eluting with CAR retention time), precision (RSD<15%) and accuracy (recovery>90%) within the accepted parameters and that the copaiba oil nanoemulsion presented a better skin penetration compared to the crude oil, with CAR achieving the most profound layer of the skin, the dermis.
Assuntos
Anti-Inflamatórios/análise , Óleos de Plantas/química , Sesquiterpenos/análise , Pele/química , Animais , Anti-Inflamatórios/farmacocinética , Fabaceae/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Limite de Detecção , Permeabilidade , Sesquiterpenos Policíclicos , Sensibilidade e Especificidade , Sesquiterpenos/farmacocinética , SuínosRESUMO
The drugs available for Chagas disease treatment are toxic and ineffective. We studied the in vivo activity of a new drug, lychnopholide (LYC). LYC was loaded in nanocapsules (NC), and its effects were compared to free LYC and benznidazole against Trypanosoma cruzi. Infected mice were treated in the acute phase at 2.0 mg/kg/day with free LYC, LYC-poly-ε-caprolactone NC (LYC-PCL), and LYC-poly(lactic acid)-co-polyethylene glycol NC (LYC-PLA-PEG) or at 50 mg/kg/day with benznidazole solution by the intravenous route. Animals infected with the CL strain, treated 24 h after infection for 10 days, evaluated by hemoculture, PCR, and enzyme-linked immunosorbent assay exhibited a 50% parasitological cure when treated with LYC-PCL NC and 100% cure when treated with benznidazole, but 100% of the animals treated during the prepatent period for 20 days with these formulations or LYC-PLA-PEG NC were cured. In animals with the Y strain treated 24 h after infection for 10 days, only mice treated by LYC-PCL NC were cured, but animals treated in the prepatent period for 20 days exhibited 100, 75, and 62.5% cure when treated with LYC-PLA-PEG NC, benznidazole, and LYC-PCL NC, respectively. Free LYC reduced the parasitemia and improved mice survival, but no mice were cured. LYC-loaded NC showed higher cure rates, reduced parasitemia, and increased survival when used in doses 2five times lower than those used for benznidazole. This study confirms that LYC is a potential new treatment for Chagas disease. Furthermore, the long-circulating property of PLA-PEG NC and its ability to improve LYC efficacy showed that this formulation is more effective in reaching the parasite in vivo.
Assuntos
Doença de Chagas/tratamento farmacológico , Lactonas/uso terapêutico , Nanocápsulas/química , Nitroimidazóis/uso terapêutico , Sesquiterpenos/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Lactonas/química , Lactonas/farmacocinética , Lactonas/farmacologia , Camundongos , Nitroimidazóis/química , Nitroimidazóis/farmacocinética , Nitroimidazóis/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Sesquiterpenos/farmacologia , Trypanosoma cruzi/efeitos dos fármacosRESUMO
In a previous study, we uncovered the anticonvulsant properties of turmeric oil and its sesquiterpenoids (ar-turmerone, α-, ß-turmerone and α-atlantone) in both zebrafish and mouse models of chemically-induced seizures using pentylenetetrazole (PTZ). In this follow-up study, we aimed at evaluating the anticonvulsant activity of ar-turmerone further. A more in-depth anticonvulsant evaluation of ar-turmerone was therefore carried out in the i.v. PTZ and 6-Hz mouse models. The potential toxic effects of ar-turmerone were evaluated using the beam walking test to assess mouse motor function and balance. In addition, determination of the concentration-time profile of ar-turmerone was carried out for a more extended evaluation of its bioavailability in the mouse brain. Ar-turmerone displayed anticonvulsant properties in both acute seizure models in mice and modulated the expression patterns of two seizure-related genes (c-fos and brain-derived neurotrophic factor [bdnf]) in zebrafish. Importantly, no effects on motor function and balance were observed in mice after treatment with ar-turmerone even after administering a dose 500-fold higher than the effective dose in the 6-Hz model. In addition, quantification of its concentration in mouse brains revealed rapid absorption after i.p. administration, capacity to cross the BBB and long-term brain residence. Hence, our results provide additional information on the anticonvulsant properties of ar-turmerone and support further evaluation towards elucidating its mechanism of action, bioavailability, toxicity and potential clinical application.