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1.
Biomed Chromatogr ; 34(1): e4717, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634986

RESUMO

A sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was established to analyze furanodienone in rat plasma. In the process of chromatographic separation, selected reaction monitoring transitions for furanodienone and patchouli alcohol (internal standard, IS) were m/z 231.1 → 83.2 and m/z 205.1 → 95.1, respectively. Great linearity of furanodienone in plasma samples was found in the corresponding concentration range (r > 0.995). Intra- and inter-day precisions (RSD, %) were <11.3% in plasma, and the accuracy (RE, %) was within ±10.7%. This method was used to the furanodienone study on rat pharmacokinetics after a single oral dose of 10 mg/kg of furanodiene. The results indicated that the maximum observed plasma concentration was 52.4 ± 19.1 ng/ml at 1.2 ± 0.7 h with an elimination half-life of 2.2 ± 0.7 h. The obtained data indicated that furanodienone could be moderately distributed and eliminated.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Furanos/sangue , Sesquiterpenos/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Furanos/química , Furanos/farmacocinética , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/química , Sesquiterpenos/farmacocinética
2.
Int J Nanomedicine ; 14: 9217-9234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819426

RESUMO

Background: Huperzine A (HupA) is a selective acetylcholinesterase inhibitor used to treat Alzheimer's disease. The existing dosage of HupA lacks brain selectivity and can cause serious side effects in the gastrointestinal and peripheral cholinergic systems. Purpose: The aim of this study was to develop and characterize a HupA nanoemulsion (NE) and a targeted HupA-NE modified with lactoferrin (Lf) for intranasal administration. Methods: The NE was formulated using pseudo-ternary phase diagrams and optimized with response surface methodology. Particle size distribution and zeta potential were evaluated, and transmission electron microscopy was performed. We investigated the transport mechanisms of HupA-NEs into hCMEC/D3 cells, an in vitro model of the blood-brain barrier. HupA-NE, Lf-HupA-NE, and HupA solution were intranasally administered to rats to investigate the brain-targeting effects of these formulations. A drug targeting index (DTI) was calculated to determine brain-targeting efficiency. Results: Optimized HupA-NE had a particle size of 15.24±0.67 nm, polydispersity index (PDI) of 0.128±0.025, and zeta potential of -4.48±0.97 mV. The composition of the optimized HupA-NE was 3.00% isopropyl myristate (IPM), 3.81% Capryol 90, and 40% Cremophor EL + Labrasol. NEs, particularly Lf-HupA-NE, were taken up into hCMEC/D3 cells to a greater extent than pure drug alone. Western blot analysis showed that hCMEC/D3 cells contained P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance associated protein 1 (MRP1) transporters. The likely mechanisms resulting in higher NE transport to the brain were uptake by specific transporters and transcytosis. In vivo, intranasal Lf-HupA-NE significantly enhanced drug delivery to the brain compared to HupA-NE, which was confirmed by differences in pharmacokinetic parameters. The DTI of Lf-HupA-NE (3.2±0.75) demonstrated brain targeting, and the area under the curve for Lf-HupA-NE was significantly higher than that for HupA-NE. Conclusion: Lf-HupA-NE is a promising nasal drug delivery carrier for facilitating delivery of HupA to the central nervous system.


Assuntos
Emulsões/química , Lactoferrina/química , Nanopartículas/química , Administração Intranasal , Alcaloides/farmacocinética , Doença de Alzheimer/metabolismo , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Linhagem Celular , Liberação Controlada de Fármacos , Humanos , Lactoferrina/administração & dosagem , Masculino , Nanopartículas/administração & dosagem , Mucosa Nasal/metabolismo , Tamanho da Partícula , Transição de Fase , Ratos Wistar , Sesquiterpenos/farmacocinética , Solubilidade , Eletricidade Estática , Distribuição Tecidual
3.
AAPS PharmSciTech ; 20(7): 301, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31485857

RESUMO

Huperzine A (hup A), extracted from the Chinese medicinal plant Huperzia serrata, is a reversible and highly selective second-generation acetylcholine esterase (AchE) inhibitor for treating Alzheimer's disease (AD), but it suffers from low bioavailability in the brain. This study aimed to develop a nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of hup A (hup A-M-TPISG). The optimal formulation was obtained by central composite design and response surface methodology. The optimized mucoadhesive formulation, hup A-M-TPISG, was composed of pluronic F127 (20.80%), pluronic F68 (2.8%), and chitosan (0.88%) as the gel matrix, which could gelatinize under physiological conditions (29-34°C, pH 6.5) because of its temperature and pH responsiveness. The optimized hup A-M-TPISG formulation was further evaluated by in vitro release and in vivo pharmacokinetic studies via microdialysis. The in vitro release study showed continuous and steady drug release from hup A-M-TPISG, which was in accordance with the first-order model. Moreover, the pharmacokinetic results revealed that the optimized formulation for nasal administration, with convenient administration and improved patient compliance, could achieve similar brain-targeting properties as intravenous administration. In conclusion, the hup A-M-TPISG for intranasal administration, as an effective and safe vehicle, could enhance the absorption of hup A in vivo and would be a promising noninvasive alternative for partially improving brain-targeting therapy.


Assuntos
Alcaloides/administração & dosagem , Inibidores da Colinesterase/administração & dosagem , Sistemas de Liberação de Medicamentos , Sesquiterpenos/administração & dosagem , Administração Intranasal , Alcaloides/química , Alcaloides/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Composição de Medicamentos , Emulsões , Géis , Concentração de Íons de Hidrogênio , Masculino , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Temperatura
4.
Pharm Res ; 36(8): 121, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31214786

RESUMO

PURPOSE: ß-elemene and cisplatin combined chemotherapy currently is one of the most important settings available for lung cancer therapy in China. However, the clinical outcome is limited by their pharmacokinetic drawbacks. On the other hand, most of nanomedicines have failed in clinical development due to the huge differences between heterogeneous clinical tumor tissues and homogenous cell-derived xenografts. In this work, we fabricated a ß-elemene and cisplatin co-loaded liposomal system to effectively treat lung cancer. METHOD: In vitro cytotoxicity of co-loaded liposomes was studied by MTT, trypan and Hoechst/PI staining, and western blot in A549, A549/DDP, and LCC cells. In vivo antitumor efficacy was evaluated in cell-derived and clinically relevant patient-derived xenografts. RESULTS: Co-loaded liposomes were more cytotoxic to cancer cells, especially than the combination of single-loaded liposomes, benefiting from their simultaneous drug internalization and release. As a result, they exhibited desirable therapeutic outcome in both cell-derived and patient-derived xenografts. CONCLUSION: ß-elemene and cisplatin co-loaded liposomes are a clinically promising candidate for effective lung cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/farmacocinética , Lipossomos/química , Neoplasias Pulmonares/tratamento farmacológico , Sesquiterpenos/farmacocinética , Células A549 , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Colesterol/química , Cisplatino/administração & dosagem , Composição de Medicamentos , Liberação Controlada de Fármacos , Xenoenxertos , Humanos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Sesquiterpenos/administração & dosagem , Distribuição Tecidual
5.
PLoS One ; 14(6): e0218628, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31226154

RESUMO

Ptaquiloside is a natural toxin present in bracken ferns (Pteridium sp.). Cattle ingesting bracken may develop bladder tumours and excrete genotoxins in meat and milk. However, the fate of ptaquiloside in cattle and the link between ptaquiloside and cattle carcinogenesis is unresolved. Here, we present the toxicokinetic profile of ptaquiloside in plasma and urine after intravenous administration of ptaquiloside and after oral administration of bracken. Administered intravenously ptaquiloside, revealed a volume of distribution of 1.3 L kg-1 with a mean residence-time of 4 hours. A large fraction of ptaquiloside was converted to non-toxic pterosin B in the blood stream. Both ptaquiloside and pterosin B were excreted in urine (up to 41% of the dose). Oral administration of ptaquiloside via bracken extract or dried ferns did not result in observations of ptaquiloside in body fluids, indicating deglycosolidation in the rumen. Pterosin B was detected in both plasma and urine after oral administration. Hence, transport of carcinogenic ptaquiloside metabolites over the rumen membrane is indicated. Pterosin B recovered from urine counted for 7% of the dose given intravenously. Heifers exposed to bracken for 7 days (2 mg ptaquiloside kg-1) developed preneoplastic lesions in the urinary bladder most likely caused by genotoxic ptaquiloside metabolites.


Assuntos
Carcinógenos/farmacocinética , Bovinos/metabolismo , Indanos/farmacocinética , Sesquiterpenos/farmacocinética , Animais , Inativação Metabólica , Indanos/sangue , Indanos/urina , Pteridium/química , Rúmen/metabolismo , Sesquiterpenos/sangue , Sesquiterpenos/urina
6.
Molecules ; 24(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052317

RESUMO

Paclitaxel is highly effective at killing many malignant tumors; however, the development of drug resistance is common in clinical applications. The issue of overcoming paclitaxel resistance is a difficult challenge at present. In this study, we developed nano drugs to treat paclitaxel-resistant lung adenocarcinoma. We selected cabazitaxel and ß-elemene, which have fewer issues with drug resistance, and successfully prepared cabazitaxel liposome, ß-elemene liposome and cabazitaxel-ß-elemene complex liposome with good flexibility. The encapsulation efficiencies of cabazitaxel and ß-elemene in these liposomes were detected by precipitation microfiltration and microfiltration centrifugation methods, respectively. Their encapsulation efficiencies were all above 95%. The release rates were detected by a dialysis method. The release profiles of cabazitaxel and ß-elemene in these liposomes conformed to the Weibull equation. The release of cabazitaxel and ß-elemene in the complex liposome were almost synchronous. The pharmacodynamics study showed that cabazitaxel flexible liposome and ß-elemene flexible liposome were relatively good at overcoming paclitaxel resistance on paclitaxel-resistant lung adenocarcinoma. As the flexible complex liposome, the dosage of cabazitaxel could be reduced to 25% that of the cabazitaxel injection while retaining a similar therapeutic effect. It showed that ß-elemene can replace some of the cabazitaxel, allowing the dosage of cabazitaxel to be reduced, thereby reducing the drug toxicity.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Lipossomos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Taxoides/administração & dosagem , Taxoides/farmacocinética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Lipossomos/química , Camundongos , Estrutura Molecular , Paclitaxel/farmacologia , Tamanho da Partícula , Sesquiterpenos/química , Taxoides/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Drug Des Devel Ther ; 13: 1087-1098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118562

RESUMO

Purpose: Co-delivery of drugs to achieve the synergistic anticancer effect is a promising strategy for lung cancer therapy. The purpose of this research is to develop a doxorubicin (DOX) and ß-elemene (ELE) co-loaded, pH-sensitive nanostructured lipid carriers (DOX/ELE Hyd NLCs). Methods: In this study, DOX/ELE Hyd NLCs were produced by a hot homogenization and ultrasonication method and used for lung cancer treatment. In vitro and in vivo efficiency as well as toxicity of the system was evaluated on lung cancer cell lines and lung tumor-bearing mice. Results: DOX/ELE Hyd NLCs had a particle size of 190 nm, with a PDI lower than 0.2. DOX/ELE Hyd NLCs exhibited a significantly enhanced cytotoxicity (drug concentration causing 50% inhibition was 7.86 µg/mL), synergy antitumor effect (combination index lower than 1), and profound tumor inhibition ability (tumor inhibition ratio of 82.9%) compared with the non pH-responsive NLCs and single-drug-loaded NLCs. Conclusion: Since the synergistic effect of the drugs was found in this system, it would have great potential to inhibit lung tumor cells and tumor growth.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanoestruturas/química , Sesquiterpenos/uso terapêutico , Células A549 , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Quimioterapia Combinada , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Distribuição Tecidual
8.
Mar Drugs ; 17(3)2019 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-30884884

RESUMO

An ilimquinone (IQ) mixture isolated from Hippiospongia metachromia, consisting of IQ and epi-ilimaquinone (epi-IQ), exerts anti-HIV, anti-microbial, anti-inflammatory, and anti-cancer effects. An HPLC-MS/MS method was developed for simultaneous determination of the two epimers in rat plasma, separating them using a biphenyl column. Ascorbic acid is added during the sample preparation to ensure the stability of both isomers. The plasma concentrations of the isomers were monitored following intravenous and oral administration of the IQ mixture in rats as well as the individual epimers that were separately orally administered. Compare to IQ, epi-IQ was much more stable in rat plasma, likely due to its configurations of decalin. Both substances decayed in more than bi-exponential pattern, with an elimination rate constant of 1.2 h-1 for IQ and 1.7 h-1 for epi-IQ. The epi-IQ was distributed more widely than IQ by about two-fold. Consequently, the clearance of epi-IQ was greater than that of IQ by about three-fold. The oral absolute bioavailability for IQ was 38%, and, that for epi-IQ, was 13%. Although the systemic exposure of IQ was greater than that of epi-IQ by ~8.7-fold, the clearance of each isomer was similar when administered either orally or intravenously, when normalized for bioavailability. The stereo-specific behavior of the isomers appears to originate from differences in both their tissue distribution and gastrointestinal permeability.


Assuntos
Poríferos/química , Quinonas/química , Quinonas/farmacocinética , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão/métodos , Isomerismo , Masculino , Quinonas/administração & dosagem , Quinonas/sangue , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/administração & dosagem , Sesquiterpenos/sangue , Espectrometria de Massas em Tandem/métodos
9.
Nutrients ; 11(1)2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30641865

RESUMO

Resveratrol is one of the most widely studied polyphenols and it has been assigned a plethora of metabolic effects with potential health benefits. Given its low bioavailability and extensive metabolism, clinical studies using resveratrol have not always replicated in vitro observations. In this review, we discuss human metabolism and biotransformation of resveratrol, and reported molecular mechanisms of action, within the context of metabolic health and obesity. Resveratrol has been described as mimicking caloric restriction, leading to improved exercise performance and insulin sensitivity (increasing energy expenditure), as well as having a body fat-lowering effect by inhibiting adipogenesis, and increasing lipid mobilization in adipose tissue. These multi-organ effects place resveratrol as an anti-obesity bioactive of potential therapeutic use.


Assuntos
Obesidade/tratamento farmacológico , Resveratrol/metabolismo , Resveratrol/farmacocinética , Adiposidade/efeitos dos fármacos , Animais , Metabolismo Energético , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Resistência à Insulina , Modelos Animais , Polifenóis/sangue , Polifenóis/metabolismo , Polifenóis/farmacocinética , Resveratrol/sangue , Sesquiterpenos/sangue , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacocinética
10.
J Pharm Biomed Anal ; 166: 291-294, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30684930

RESUMO

Ilimaquinone, a metabolite isolated from the marine sponge Hippiospongia metachromia, has antimicrobial, cytotoxic, anti-HIV, anti-inflammatory, and anti-cancer activities. A new quantitative analytical method for determination of ilimaquinone in rat plasma using HPLC-MS/MS was developed and validated. Ascorbic acid was added to ensure the stability of ilimaquinone in plasma. After protein precipitation using acetonitrile plus diclofenac as an internal standard, the analytes were chromatographed on a biphenyl column with a mobile phase of methanol and water (8:2, v/v, including 0.1% formic acid). This method was successfully applied in a pharmacokinetic study of ilimaquinone after oral administration in rats.


Assuntos
Quinonas/farmacocinética , Sesquiterpenos/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Poríferos/química , Quinonas/administração & dosagem , Quinonas/sangue , Quinonas/isolamento & purificação , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/administração & dosagem , Sesquiterpenos/sangue , Sesquiterpenos/isolamento & purificação , Espectrometria de Massas em Tandem
11.
Biomed Chromatogr ; 33(3): e4433, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30414211

RESUMO

A sensitive and accurate LC-MS/MS method was established for quantifying bisabolangelone in rat plasma and tissues. Bisabolangelone was isolated and purified from Angelicae Pubescentis Radix. The pharmacokinetic and tissue distribution of bisabolangelone after administration to rat was performed by LC-MS/MS. Separation was carried out on a C8 (4.6 × 100 mm, 1.8 µm) column. The MS/MS transitions of bisabolangelone and tussilagone (internal standard) were set at m/z 249.1 → 109.1 and m/z 391.4 → 217.4, respectively. The lower limit of quantification in plasma and other tissues ranged from 1 to 4 ng/mL. The biosamples were prepared using protein precipitation method with acetonitrile. The recovery was >92%. The results showed that values of maximum concentrations and area under the curve depended linearly on the studied doses (2.5, 5 and 7.5 mg/kg body weight). The other ingredients in Angelicae Pubescentis Radix extract possibly reduce the absorption of bisabolangelone in rat. Tissue distribution revealed that bisabolangelone was widely distributed in vivo. The highest and lowest concentrations of bisabolangelone were found in the stomach and in the brain, respectively. It was concluded that the newly established HPLC-MS/MS method was suitable to describe the pharmacokinetic characteristics of bisabolangelone in rat after administration.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Sesquiterpenos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Feminino , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/sangue , Sesquiterpenos/química , Distribuição Tecidual
12.
Xenobiotica ; 49(10): 1158-1163, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30484368

RESUMO

Parthenolide (PTL) and micheliolide (MCL) are sesquiterpene lactones with similar structures, and both of them have been reported to exhibit multiple biochemical and pharmacological activities. This study aims to investigate the inhibition of these two compounds on the activity of UDP-glucuronosyltransferases (UGTs). In vitro incubation mixture for recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was utilized to investigate the inhibition potential. Inhibition kinetics (including inhibition type and parameters) were determined, and in silico docking was employed to elucidate the inhibition difference between PTL and MCL on UGT1A1. MCL showed no inhibition toward all the UGT isoforms, and PTL showed strong inhibition toward UGT1A1. The half-maximal inhibitory concentration (IC50) of PTL on the activity of UGT1A1 was determined to be 64.4 µM. Inhibition kinetics determination showed that PTL exerted noncompetitive inhibition toward UGT1A1, and the inhibition kinetic constant (Ki) was determined to be 12.1 µM. In silico docking method has been employed to show that hydrogen bonds between PTL and the activity cavity of UGT1A1 contributed to the stronger inhibition of PTL on the activity of UGT1A1 than MCL. In conclusion, PTL can more easily induce drug-drug interaction (DDI) with clinical drugs mainly undergoing UGT1A1-catalyzed glucuronidation.


Assuntos
Inibidores Enzimáticos , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/química , Sesquiterpenos de Guaiano , Sesquiterpenos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Sesquiterpenos/farmacologia , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacocinética , Sesquiterpenos de Guaiano/farmacologia
13.
J Chromatogr Sci ; 57(2): 163-176, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496359

RESUMO

Atractylodes macrocephala Koidz (AMK) is a traditional Chinese medicine widely used in the treatment of various diseases, especially spleen deficiency. As the principle active constituents of AMK, however, the metabolites of Atractylenolide-III (A-lactone-III) have not been identified in rats yet. In this study, a three-step high throughput method based on UHPLC-Q-TOF-MS-MS was developed to profile and characterize the metabolites of A-lactone-III in rat feces, urine and plasma. The initial step was a full-scan that utilized a multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS). PeakView®1.2 and Metabolitepilot™1.5 software was then used to obtain data and seek possible metabolites. Finally, MS-MS spectra of the parent drug and possible metabolites were compared by the fragment ion peaks and retention times, which enabled metabolites to be identified. As a result, 53 metabolites were characterized in rats in vivo. The metabolic pathways of A-lactone-III were identified as including methylation, oxidation, hydroxylation, dihydroxylation, hydrogenation, glycosylation, sulfonation, and glucuronide, cysteine and N-acetylcysteine conjugation.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Lactonas/análise , Lactonas/metabolismo , Sesquiterpenos/análise , Sesquiterpenos/metabolismo , Espectrometria de Massas em Tandem/métodos , Animais , Fezes/química , Lactonas/química , Lactonas/farmacocinética , Masculino , Redes e Vias Metabólicas , Ratos , Ratos Sprague-Dawley , Sesquiterpenos/química , Sesquiterpenos/farmacocinética
14.
Biomed Chromatogr ; 33(2): e4388, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30238481

RESUMO

In this study, we developed a method for the determination of Penicillium griseofulvum-oriented pyripyropene A (PPPA), a selective inhibitor of acyl-coenzyme A:cholesterol acyltransferase 2, in mouse and human plasma and validated it using liquid chromatography-tandem mass spectrometry. Pyripyropene A (PPPA) and an internal standard, carbamazepine, were separated using a Xterra MS C18 column with a mixture of acetonitrile and 0.1% formic acid as the mobile phase. The ion transitions monitored in positive-ion mode [M + H]+ of multiple-reaction monitoring (MRM) were m/z 148.0 from m/z 584.0 for PPPA and m/z 194.0 from m/z 237.0 for the internal standard. The detector response was specific and linear for PPPA at concentrations within the range from 1 to 5,000 ng/mL. The intra-/inter-day precision and accuracy of the method was acceptable by the criteria for assay validation. The matrix effects of PPPA ranged from 97.6 to 104.2% and from 93.3 to 105.3% in post-preparative mouse and human plasma samples, respectively. PPPA was also stable under various processing and/or handling conditions. Finally, PPPA concentrations in the mouse plasma samples could be measured after intravenous, intraperitoneal, or oral administration of PPPA, suggesting that the assay is useful for pharmacokinetic studies on mice and applicable to human studies.


Assuntos
Cromatografia Líquida/métodos , Penicillium/química , Piridinas/sangue , Piridinas/farmacocinética , Sesquiterpenos/sangue , Sesquiterpenos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Camundongos , Camundongos Endogâmicos ICR , Piridinas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/química , Esterol O-Aciltransferase/antagonistas & inibidores
15.
Eur J Drug Metab Pharmacokinet ; 44(2): 295-303, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30209793

RESUMO

BACKGROUND: Isoalantolactone and alantolactone are the main sesquiterpene lactones in Radix Inulae (dried root of Inula helenium L. or I. racemosa Hook. F.), which is a frequently utilized herbal medicine. They also occur in several plants and have various pharmacologic effects. However, they have been found to have poor oral bioavailability in rats. OBJECTIVES: To understand the intestinal absorptive characteristics of isoalantolactone and alantolactone as well specific influx and efflux transporters in their absorption. METHODS: Bidirectional permeabilities of isoalantolactone and alantolactone were investigated across Caco-2 cell monolayers. Transport assays were performed using different concentrations of two lactones and specific inhibitors of ATP-binding cassette transporters and influx transporters. RESULTS: The absorption permeability of isoalantolactone and alantolactone was high at the tested concentrations (5, 20 and 80 µmol/l), and the major permeation mechanism of both lactones was found to be passive diffusion with active efflux mediated by multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). CONCLUSION: Our results demonstrated that the absorption permeability of isoalantolactone and alantolactone was good in the Caco-2 cell model. The isoalantolactone and alantolactone absorption elucidated in this study provides useful information for further pharmacokinetics studies. Since low intestinal absorption can now be ruled out as a cause, further studies are needed to explain the low oral bioavailability of the two sesquiterpene lactones.


Assuntos
Absorção Intestinal , Inula/química , Lactonas/farmacocinética , Sesquiterpenos de Eudesmano/farmacocinética , Sesquiterpenos/farmacocinética , Administração Oral , Disponibilidade Biológica , Células CACO-2 , Relação Dose-Resposta a Droga , Humanos , Lactonas/administração & dosagem , Lactonas/isolamento & purificação , Permeabilidade , Raízes de Plantas , Sesquiterpenos/administração & dosagem , Sesquiterpenos/isolamento & purificação , Sesquiterpenos de Eudesmano/administração & dosagem , Sesquiterpenos de Eudesmano/isolamento & purificação
16.
Molecules ; 23(12)2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30544552

RESUMO

Atractylodis Rhizoma is the dried rhizome of Atractylodes lancea (Thunb.) DC. or Atractylodes chinensis (DC.) Koidz and is often processed by stir-frying with wheat bran to reduce its dryness and increase its spleen tonifying activity. However, the mechanism by which the processing has this effect remains unknown. To explain the mechanism based on the pharmacokinetics of the active compounds, a rapid, sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was developed to analyze atractylenolides I, II, and III, and atractyloside A simultaneously in rat plasma after oral administration of raw and processed Atractylodis Rhizoma. Acetaminophen was used as the internal standard and the plasma samples were pretreated with methanol. Positive ionization mode coupled with multiple reaction monitoring mode was used to analyze the four compounds. The method validation revealed that all the calibration curves displayed good linear regression over the concentration ranges of 3.2⁻350, 4⁻500, 4⁻500, and 3.44⁻430 ng/mL for atractylenolides I, II, and III, and atractyloside A, respectively. The relative standard deviations of the intra- and inter-day precisions of the four compounds were less than 6% with accuracies (relative error) below 2.38%, and the extraction recoveries were more than 71.90 ± 4.97%. The main pharmacokinetic parameters of the four compounds were estimated with Drug and Statistics 3.0 and the integral pharmacokinetics were determined based on an area under the curve weighting method. The results showed that the integral maximum plasma concentration and area under the curve increased after oral administration of processed Atractylodis Rhizoma.


Assuntos
Atractylodes/química , Atractilosídeo/sangue , Fibras na Dieta , Lactonas/sangue , Rizoma/química , Sesquiterpenos/sangue , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Área Sob a Curva , Atractilosídeo/farmacocinética , Cromatografia Líquida de Alta Pressão , Lactonas/farmacocinética , Limite de Detecção , Modelos Lineares , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sesquiterpenos/farmacocinética
17.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1102-1103: 152-158, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391729

RESUMO

Nardostachyos Radix et Rhizoma (NR) is a valuable medicinal herb widely used in Korea, India, and China for the treatment of many diseases. Desoxo-narchinol A (DA) and nardosinonediol (ND) are the two main bioactive compounds belonging to the sesquiterpene group. Desoxo-narchinol A possesses anti-inflammatory activity while ND exhibits anti-depressant and cardioprotective activities. A pharmacokinetic study is important to decide whether the isolated compounds or the NR extract have better pharmacological activity. Hence, we developed an analytical method for studying the pharmacokinetics of DA and ND after oral administration of the pure compounds and herbal extract. An optimized liquid chromatography-mass spectrometry method (LC-MS/MS) with solid-phase extraction (SPE) for sample preparation was developed. A ZORBAX Extend C18 column (2.1 × 50 mm, 3.5 µm) was used under gradient elution with acetonitrile and 0.1% formic acid in water as the mobile phase. Validation experiments assessing accuracy, precision, and stability were satisfactory; the lower limit of quantification was 5 ng/mL. For the pharmacokinetic study, three groups of rats were administrated pure DA, pure ND, or NR extract orally. Concentrations of DA and ND in their plasma were determined by the developed method. Pharmacokinetic parameters, including the time to achieve maximum plasma concentration (Tmax) and the area under the plasma concentration curve from time zero to infinity (AUC0-∞), were compared for the herbal extract and pure compounds. The Tmax of the pure compound and the NR extract for DA was 7.50 and 8.33 min, respectively, compared to 5.00 and 5.83 min for the pure compound and the NR extract for ND, respectively. The AUC0-∞ of the pure compound and the NR extract for DA was 156.34 and 133.90 µg min/mL, respectively, and that for the NR extract for ND was 6.42 and 4.15 µg min/mL, respectively. LC-MS/MS was used to determine DA and ND in rat plasma. The pharmacokinetic profile of each pure compound and those in the extract were characterized and compared.


Assuntos
Naftóis/farmacocinética , Nardostachys , Extratos Vegetais/farmacocinética , Sesquiterpenos/farmacocinética , Administração Oral , Animais , Cromatografia Líquida/métodos , Estabilidade de Medicamentos , Modelos Lineares , Naftóis/sangue , Naftóis/química , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Sesquiterpenos/sangue , Sesquiterpenos/química , Espectrometria de Massas em Tandem/métodos
18.
Artif Cells Nanomed Biotechnol ; 46(sup3): S931-S942, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30307334

RESUMO

BACKGROUND: Combinations of natural products with low toxicities using tumor-targeting carriers may improve cancer treatment. The combined parthenolide and ginsenoside compound K (CK) within tLyp-1 liposomes, with the aim of improving the efficacy of lung cancer treatment. RESULTS: In vitro studies in A549 human pulmonary adenocarcinoma cells demonstrated that parthenolide/CK tLyp-1 liposomes increased reactive oxygen species levels and induced mitochondrial apoptosis. It enters into cells via receptor-mediated uptake and micropinocytosis, followed by endosomal/lysosomal escape. In vivo studies illustrated that it produced a greater antitumor effect than combined administration of these compounds, with minimal toxicity. CONCLUSION: The findings of this study indicated that combined application of natural products in nanocarriers could offer attractive therapeutic options.


Assuntos
Apoptose/efeitos dos fármacos , Ginsenosídeos , Neoplasias Pulmonares , Mitocôndrias/metabolismo , Sesquiterpenos , Células A549 , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Ginsenosídeos/química , Ginsenosídeos/farmacocinética , Ginsenosídeos/farmacologia , Humanos , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/química , Sesquiterpenos/farmacocinética , Sesquiterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Int J Nanomedicine ; 13: 6279-6296, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349250

RESUMO

ß-elemene is a noncytotoxic Class II antitumor drug extracted from the traditional Chinese medicine Curcuma wenyujin Y. H. Chen et C. Ling. ß-elemene exerts its effects by inhibiting cell proliferation, arresting the cell cycle, inducing cell apoptosis, exerting antiangiogenesis and antimetastasis effects, reversing multiple-drug resistance (MDR), and enhancing the immune system. Elemene injection and oral emulsion have been used to treat various tumors, including cancer of the lung, liver, brain, breast, ovary, gastric, prostate, and other tissues, for >20 years. The safety of both elemene injection and oral emulsion in the clinic has been discussed. Recently, the secondary development of ß-elemene has attracted the attention of researchers and made great progress. On the one hand, studies have been carried out on liposome-based systems (including solid lipid nanoparticles [SLNs], nanostructured lipid carriers [NLCs], long-circulating liposomes, active targeting liposomes, and multidrug-loaded liposomes) and emulsion systems (including microemulsions, self-emulsion drug delivery systems [SEDDSs], and active targeting microemulsion) to solve the issues of poor solubility in water, low bioavailability, and severe phlebitis, as well as to improve antitumor efficacy. The pharmacokinetics of different drug delivery systems of ß-elemene are also summarized. On the other hand, a number of highly active anticancer ß-elemene derivatives have been obtained through modification of the structure of ß-elemene. This review focuses on the two drug delivery systems and derivatives of ß-elemene for cancer therapy.


Assuntos
Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Sesquiterpenos/uso terapêutico , Animais , Humanos , Lipossomos/farmacologia , Nanopartículas/química , Sesquiterpenos/química , Sesquiterpenos/farmacocinética
20.
Curr Pharm Des ; 24(29): 3440-3453, 2018 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-30207226

RESUMO

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 , Solubilidade
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