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1.
Int J Mol Sci ; 20(19)2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31561511

RESUMO

The organogermanium compound 3-(trihydroxygermyl)propanoic acid (THGP) has various biological activities. We previously reported that THGP forms a complex with cis-diol structures. L-3,4-Dihydroxyphenylalanine (L-DOPA), a precursor of melanin, contains a cis-diol structure in its catechol skeleton, and excessive melanin production causes skin darkening and staining. Thus, the cosmetic field is investigating substances that suppress melanin production. In this study, we investigated whether THGP inhibits melanin synthesis via the formation of a complex with L-DOPA using mushroom tyrosinase and B16 4A5 melanoma cells. The ability of THGP to interact with L-DOPA was analyzed by 1H-NMR, and the influence of THGP and/or kojic acid on melanin synthesis was investigated. We also examined the effect of THGP on cytotoxicity, tyrosinase activity, and gene expression and found that THGP interacted with L-DOPA, a precursor of melanin with a cis-diol structure. The results also showed that THGP inhibited melanin synthesis, exerted a synergistic effect with kojic acid, and did not affect tyrosinase activity or gene expression. These results suggest that THGP is a useful substrate that functions as an inhibitor of melanogenesis and that its effect is enhanced by combination with kojic acid.


Assuntos
Agaricales/enzimologia , Levodopa/química , Levodopa/farmacologia , Melaninas/biossíntese , Monofenol Mono-Oxigenase/antagonistas & inibidores , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Animais , Vias Biossintéticas/efeitos dos fármacos , Melanoma Experimental , Camundongos
2.
AAPS PharmSciTech ; 20(8): 312, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529266

RESUMO

To enhance efficiency, convenience, and safety of Parkinson's disease (PD) treatment for geriatric patients, an advanced suspension of Levodopa/Benserazide hydrochloride (LD/BH) has been prepared by cation-exchange resin and used to synchronize sustained release of LD and BH by optimizing coating parameters and prescription. For the purpose, LD and BH were immobilized on the surface of cation-exchange resin, respectively. Based on HPLC results, the cation-exchange resin showed high loading capacity. The studies on drug loading mechanism indicated that both drugs were immobilized by electrostatic interaction rather than physical adsorption. After PEG modification, pretreated drug-resin complexes were coated by emulsion-solvent evaporation method. In order to control drug release in a sustained manner, coating parameters of drug-resin microcapsules were optimized respectively by single-factor analysis. Further, coating prescription of the microcapsules was optimized to synchronize sustained release of LD and BH in vitro by orthogonal design. Utilizing optimal LD-resin microcapsules and BH-resin microcapsules, LD/BH suspension, containing both of them, was prepared by an optimal formulation and characterized by accelerated test and pharmacokinetic study in vivo. The accelerated test confirmed high stability of LD/BH suspension. According to pharmacokinetic results in vivo, in contrast with LD/BH commercial tablets, LD/BH suspensions did not only synchronize sustained release of both drugs but also show good bioequivalence. As LD/BH sustained release suspension can synchronize sustained release of multiple active ingredients by oral administration, the suspension presents promising oral dosage forms for geriatric patients with PD. An advanced Levodopa/Benserazide hydrochloride (LD/BH) suspension, prepared by cation-exchange resin and optimized microencapsulation, synchronizes sustained releases of LD and BH in vivo to benefit Parkinson's disease treatment for geriatric patients.


Assuntos
Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/química , Benserazida/administração & dosagem , Benserazida/química , Levodopa/administração & dosagem , Levodopa/química , Administração Oral , Animais , Antiparkinsonianos/farmacocinética , Benserazida/farmacocinética , Cápsulas , Resinas de Troca de Cátion , Preparações de Ação Retardada , Combinação de Medicamentos , Composição de Medicamentos , Levodopa/farmacocinética , Lipídeos/química , Masculino , Ratos , Suspensões , Comprimidos com Revestimento Entérico
3.
Molecules ; 24(12)2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31238569

RESUMO

l-3,4-dihydroxyphenylalanine (l-DOPA) is a medically relevant compound in Parkinson's disease therapy. Several extraction methods of l-DOPA from beans, including velvet and faba beans, have been described in the literature. However, these methods require the use of strong acids, long extraction times, or complex downstream processing, which makes the extraction of l-DOPA expensive and energy-demanding, limiting its industrial application. In addition, the stability of l-DOPA during the extraction process is critical, further complicating the extraction of adequate amounts of this amino acid. This work is the first report on a simple, rapid, greener, and robust extraction method of l-DOPA. The developed method consists of a quick homogenization step followed by a double extraction with 0.2% v/v acetic acid for 20 min and was applied to faba bean at a ratio of 1:25 with respect to the extracting solvent. This study also investigated the stability of l-DOPA during extraction and thermal treatment. The proposed method demonstrated to be robust and extraordinarily efficient for numerous cultivars of faba bean, velvet bean, and food products containing faba beans.


Assuntos
Fracionamento Químico , Levodopa/isolamento & purificação , Fracionamento Químico/métodos , Árvores de Decisões , Concentração de Íons de Hidrogênio , Levodopa/química , Estrutura Molecular , Reprodutibilidade dos Testes , Solventes , Fluxo de Trabalho
4.
Biosens Bioelectron ; 141: 111357, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31170501

RESUMO

The development of versatile platforms to construct novel and sensitive immunosensors is nowadays an intense research field. Nanomaterials and polymers are often combined to fabricate new platforms to immobilize capture antibodies. Here we evaluate for the first time the co-electropolymerization of dopamine (DA) and L-3,4-dihydroxyphenylalanine (L-DOPA) on carbon nano-onion (CNO) modified electrodes as versatile platform to develop electrochemical immunosensors. Mixtures of DA and L-DOPA at different molar rations were co-electropolymerized on CNO-modified glassy carbon electrodes to form a poly(L-DOPA/DA) film. Immobilization of aminoferrocene was used to estimate the number of accessible carboxylic acid groups on the surface (11.3 nmol/cm2), a value comparable to three-dimensional matrices. This platform was applied to the electrochemical detection of IgA antibodies using both a HRP-based sandwich type assay and label-free detection based on [Fe(CN)6]3-/4- signal blocking. The sandwich and the label-free assays showed a wide linear response with LOD of 19 and 48 ng/mL, respectively, allowing the detection of serum IgA deficiency. Most remarkably, the incorporation of CNO layer led to a significant improvement (three-orders of magnitude) of the analytical performance of these immunosensors due to a combination of high surface area and increased electron transfer rates provided by the CNO layer.


Assuntos
Técnicas Biossensoriais/métodos , Carbono/química , Dopamina/química , Imunoglobulina A/sangue , Levodopa/química , Anticorpos Imobilizados/química , Eletrodos , Humanos , Imunoensaio/métodos , Limite de Detecção , Modelos Moleculares , Nanoestruturas/química , Polimerização , Polímeros/química
5.
Biomolecules ; 9(6)2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216771

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons at level of substantia nigra pars compacta. To date, there is no cure for this pathology, except for some drugs able to alleviate the symptoms of PD. In this paper we report the synthesis and biological evaluation of novel sulfur- and selenyl-l-Dopa (LD) derivatives (SP1-6) obtained through the amide junction between the amino group of LD and carboxylic moiety of sulfur- and selenyl-organic compounds, which are commercially available. Biological activity was evaluated on human undifferentiated and retinoic acid/phorbol myristyl acetate (RA/PMA)-differentiated SY-SH5Y neuroblastoma cell line using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Antioxidant activity against oxidative stress was measured using nitroblue tetrazolium (NBT) and 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) assays. Finally, physico-chemical characterization and plasma stability studies of SP1-6 were also performed. Biological data revealed that SP6 has a significant protective action against the neurotoxic action of 6-hydroxydopamine (6-OHDA) and H2O2 in a RA/PMA-differentiated SY-SH5Y neuroblastoma cell line that proved to be an effective antioxidant and protective compound. SP6, endowed with a lipophilic nature, low molecular weight, and plasma stability, can easily cross biological membranes via passive diffusion such as through the blood-brain barrier. SP6 has great potential for developing novel pharmacological approach for neurodegenerative diseases, such as PD. Further studies will help define its exact antioxidant mechanism and determine whether the neuroprotective action is mediated or modulated by glutathione peroxidase (GPx).


Assuntos
Levodopa/síntese química , Levodopa/farmacologia , Doença de Parkinson/tratamento farmacológico , Enxofre/química , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Linhagem Celular Tumoral , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Humanos , Interações Hidrofóbicas e Hidrofílicas , Levodopa/química , Levodopa/uso terapêutico , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos
6.
Pharmacol Res Perspect ; 7(2): e00473, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30977301

RESUMO

A new levodopa-carbidopa intestinal gel (LCIG) system featuring a higher levodopa/carbidopa (LD/CD) concentration and viscosity, LCIG-HV, is being developed to reduce the intrajejunal volume of LD/CD that is administered as compared to the current commercial formulation, LCIG-LV. This study characterizes the LCIG-HV formulation and compares it to the LCIG-LV formulation via dissolution testing and a clinical pharmacokinetic bioequivalence study. In vitro release profiles of LD/CD were determined using a USP Dissolution Apparatus 2 with 500 mL of phosphate buffer (pH 4.5) operating at 25 RPM. A single dose, open-label study was conducted according to a two-period, randomized, crossover design in 28 healthy subjects. The point estimate (PE) of the levodopa Cmax geometric mean for the LCIG-HV formulation was 4% higher than that of the LCIG-LV formulation. PEs of levodopa AUCt and AUCinf geometric means were comparable for both formulations. PEs of carbidopa Cmax , AUCt and AUCinf geometric means for the LCIG-HV formulation were 3%-5% higher than those of the LCIG-LV formulation. For both formulations, the median Tmax for levodopa was 1.0 and 3.0 hours for carbidopa. The levodopa half-life harmonic mean was 1.6 hour for both formulations. The carbidopa half-life harmonic mean was 1.9 and 2.0 hour, respectively, for the LCIG-HV and LCIG-LV formulations. Cmax , AUCt and AUCinf of LD/CD carbidopa were comparable for both formulations. The current study demonstrates that the LCIG-LV and LCIG-HV formulations are clinically bioequivalent for LD/CD according to FDA guidance. However, the dissolution method was over discriminatory of formulation differences.


Assuntos
Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Carbidopa/química , Carbidopa/farmacocinética , Levodopa/química , Levodopa/farmacocinética , Adulto , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/sangue , Carbidopa/efeitos adversos , Carbidopa/sangue , Estudos Cross-Over , Combinação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Géis , Humanos , Levodopa/efeitos adversos , Levodopa/sangue , Masculino , Pessoa de Meia-Idade , Equivalência Terapêutica
7.
FEBS Open Bio ; 9(4): 791-800, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30984552

RESUMO

Melanin-producing Cryptococcus and Aspergillus are highly invasive and can suppress or escape the immune system of the host. Since non-melanin-producing strains do not affect the immune system, melanin may play a role in immune system suppression. Artificial melanin synthesized using conventional methods is insoluble, making structural and functional analysis of this chemical difficult. In this study, we describe a melanin solubilization method based on polymerization of homogentisic acid (solubilizing component) and an equivalent amount of L-DOPA in the presence of laccase. In addition, we investigated the effect of melanin on the immune system. Homogentisic acid and L-DOPA mixed melanin (HALD), the synthetic solubilized melanin, did not exert a cytotoxic effect on mouse macrophages. HALD suppressed cytokine and reactive oxygen species production by macrophages when they were stimulated by fungal components. HALD also suppressed the phagocytosis of fungal components by macrophages. These results suggest that HALD can suppress the function of macrophages without causing cytotoxicity.


Assuntos
Bioquímica/métodos , Ácido Homogentísico/química , Levodopa/química , Macrófagos/imunologia , Melaninas/imunologia , Animais , Lacase/química , Masculino , Melaninas/química , Camundongos , Camundongos Endogâmicos C57BL , Polimerização , Solubilidade
8.
Mater Sci Eng C Mater Biol Appl ; 101: 472-486, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029342

RESUMO

In this study, an efficient drug delivery system composed of Fe3O4, CaAl layered double hydroxide (LDH) and l-Dopa has been synthesized through hydrogen bonds between l-Dopa and CaAl-LDH encapsulated Fe3O4 nanoparticles (Fe3O4@CaAl-LDH@l-Dopa). The structural features of Fe3O4@CaAl-LDH@l-Dopa were characterized using XRD, SEM, TEM, EDX, FT-IR, VSM, TGA, XPS, zeta potential analysis and BET. All of the characterization techniques show the uniform high surface area core-shell structure with about 120 nm in average size. Also, the obtained results clearly indicate that this drug delivery system possess high potent for adsorption of l-Dopa (52 wt%) and high drug encapsulation efficiency (71%). The amount of l-Dopa release in low pHs (53.8%) which simulates the environment of cancer cells is greater than higher pHs. The in vitro cytotoxic and anticancer activities of Fe3O4@CaAl-LDH@l-Dopa were investigated against Mel-Rm Cells Melanoma (NCIt: C3224) using LDH colorimetric assay and differential staining cell death assay. The results showed Fe3O4@CaAl-LDH@l-Dopa with a lower concentration of l-Dopa, illustrate a higher cytotoxicity and anticancer activity.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Hidróxidos/farmacologia , Levodopa/farmacologia , Melanoma/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/química , Humanos , Concentração de Íons de Hidrogênio , Hidróxidos/química , Levodopa/química
9.
Mikrochim Acta ; 186(3): 174, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771008

RESUMO

A carbon paste electrode (CPE) was modified with graphite oxide (GrO) and ß-cyclodextrin (CD) to obtain a sensor for simultaneous voltammetric determination of levodopa (LD), piroxicam (PRX), ofloxacin (OFX) and methocarbamol (MCB). The morphology, structure and electrochemical properties of the functionalized GrO were characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy, contact angle measurements and cyclic voltammetry. Under the optimal experimental conditions, the sensor is capable of detecting LD, PRX, OFX and MCB by square wave voltammetry (SWV) at working potentials of +0.40, +0.60, +1.03 and + 1.27 V (versus Ag/AgCl), respectively. Response is linear from 1.0 to 20 µM for LD, from 1.0 to 15 µM for PRX, from 1.0 to 20 µM for OFX, and from 1.0 to 50 µM for MCB. The respective limits of detection are 65, 105, 89 and 400 nM. The method was successfully applied to the simultaneous determination of LD, PRX, OFX and MCB in (spiked) real river water and synthetic urine samples, and the results were in agreement with those obtained using a spectrophotometric method, with recoveries close to 100%. Graphical abstract Schematic presentation of a novel electroanalytical method employing a carbon paste electrode modified with graphite oxide and ß-cyclodextrin for the simultaneous determination of levodopa, piroxicam, ofloxacin and methocarbamol in urine and river water samples by square wave voltammetry.


Assuntos
Grafite/química , Levodopa/urina , Metocarbamol/urina , Ofloxacino/urina , Piroxicam/urina , beta-Ciclodextrinas/química , Técnicas Eletroquímicas/métodos , Eletrodos , Levodopa/química , Limite de Detecção , Metocarbamol/química , Ofloxacino/química , Óxidos/química , Piroxicam/química , Reprodutibilidade dos Testes , Rios/química
10.
Biomater Sci ; 7(4): 1623-1631, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30702723

RESUMO

Polymers that spontaneously self-assemble in water can form spherical micelles. These micelles are typically used in drug delivery and gene therapeutics. Importantly, the generated emulsion during the process of polymers self-assembly could be crystallized under suitable conditions. The formed crystal structure can enhance the mechanisms of nanoparticle formation. In this study, levodopa-loaded crystallization nanoparticles (LD crystalsomes) were prepared by a mini-emulsion crystallization method. The LD crystalsomes exhibited a positive zeta potential, nanoscale range and longer releasing time for levodopa (LD). Moreover, the therapeutic effects of LD crystalsomes on an MPTP-induced Parkinson's diseases (PD) mouse model were examined. The results showed that pre-administration twice with LD crystalsomes significantly enhanced locomotor activities and climbing times in the PD mouse model. For pathological changes, the numbers of the tyrosine hydroxylases positive neurons (TH+ neuron) of nigral and tyrosine hydroxylases (TH) protein expression of striatum were significantly increased than that in a PD mouse model. Besides, in comparison with bulk LD treatment, the LD crystalsomes administration exhibited better effects on improving behavioral deficits and TH expression. These results suggest that the unique crystalsomes represents a new type of nanoparticle and could be excellent potential drug carriers for drug control and release.


Assuntos
Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Nanopartículas/química , Doença de Parkinson/tratamento farmacológico , Temperatura , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/química , Cristalização , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Emulsões/síntese química , Emulsões/química , Emulsões/uso terapêutico , Feminino , Levodopa/síntese química , Levodopa/química , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Relação Estrutura-Atividade
11.
Carbohydr Polym ; 207: 391-397, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30600021

RESUMO

A carboxylate chitooligomer (C-COS) containing carboxyl groups attached to chitooligomer (COS) molecules has been prepared by laccase/2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) system, which is a green-chemistry method. Several experiments were designed to evaluate inhibition effects on melanin and mechanisms of C-COS. The results indicated that C-COS exhibited more distinct anti-melanogenic effects compared to COS. C-COS inhibits melanin production with tyrosine (Tyr) and DOPA as the substrate of melanin formation, and the inhibition rates are, respectively, 89.07% and 84.45%, which reach 1.4-2 times those of COS. UV-vis spectroscopy was used to elucidate the interaction mechanism between C-COS and tyrosinase (TYR). It is C-COS chelating with metal Cu ions in tyrosinase (TYR) that decreases the enzyme activity. Half-maximal inhibitory concentrations (IC50) of C-COS were calculated as 13.49 and 4.07 mg/mL for monophenolase (cresolase) and diphenolase (catecholase), respectively.


Assuntos
Quitina/análogos & derivados , Melaninas/antagonistas & inibidores , Preparações Clareadoras de Pele/química , Agaricales/enzimologia , Quelantes/síntese química , Quelantes/química , Quitina/síntese química , Quitina/química , Cobre/química , Óxidos N-Cíclicos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Química Verde/métodos , Lacase/química , Levodopa/química , Melaninas/química , Modelos Biológicos , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/química , Oxirredução , Preparações Clareadoras de Pele/síntese química , Tirosina/química
12.
ACS Appl Mater Interfaces ; 11(5): 5561-5569, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30644715

RESUMO

In this paper, we propose a novel concept of a biointerface, a polymeric nanofilter, for the potentiometric detection of small biomolecules using an extended-Au-gate field-effect transistor (EG-Au-FET). A Au electrode has the potential capability to detect various small biomolecules with ultrasensitivity at nM levels on the basis of a surface redox reaction, but it exhibits no selective response to such biomolecules. Therefore, a suitable polymeric nanofilter is designed and modified on the Au electrode, so that a small target biomolecule reaches the Au surface, resulting in an electrical signal, whereas low-molecular-weight interferences not approaching the Au surface are captured in the polymeric nanofilter. The polymeric nanofilter is composed of two layers. The first layer is electrografted as an anchor layer by a cyclic voltammetry method. Then, a filtering layer is precisely polymerized as the second layer by a photo-mediated surface-initiated atom transfer radical polymerization method. The thickness and density of the polymeric nanofilter are controlled to specifically detect a small target biomolecule with high sensitivity. As a model case, l-cysteine as the small target biomolecule at nM levels is specifically detected by filtering l-DOPA as a low-molecular-weight interference using the polymeric nanofilter-grafted EG-Au-FET on the basis of the following mechanism. The phenylboronic acid (PBA) that copolymerizes with the polymeric nanofilter captures l-DOPA through diol binding, whereas l-cysteine reaches the Au surface through the filter layer. The polymeric nanofilter can also effectively prevent the interaction between biomacromolecules such as albumin and the Au electrode. A platform based on a polymeric nanofilter-grafted EG-Au-FET biosensor is suitable for the ultrasensitive and specific detection of a small biomolecule in biological samples such as tears and sweat, which include small amounts of low-molecular-weight interferences, which generate nonspecific electrical signals.


Assuntos
Técnicas Biossensoriais/instrumentação , Nanoestruturas/química , Nanotecnologia/instrumentação , Potenciometria/instrumentação , Ácidos Borônicos/química , Eletrodos , Desenho de Equipamento , Ouro/química , Levodopa/química , Levodopa/isolamento & purificação , Polimerização , Transistores Eletrônicos
13.
Colloids Surf B Biointerfaces ; 173: 454-469, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30326362

RESUMO

The time-dependent bioadhesive performance of various polymers was evaluated using a texture analyzer apparatus and freshly excised rat small intestinal tissue. A series of novel bioadhesive polymers were prepared by conjugating L-phenylalanine, L-tyrosine, and L-DOPA to either a low molecular weight poly (butadiene-maleic anhydride) or a high molecular weight poly (ethylene-maleic anhydride). Bioadhesive force was characterized as a function of time relative to polycarbophil, a slightly cross-linked poly (acrylic acid)-derivative, revealing different fracture strengths and tensile work for each of the six backbone-side chain conjugations that were studied. While polycarbophil showed a rapid and significant loss of bioadhesion over the testing period, the newly developed synthetic polymers were able to maintain their bioadhesive performance over the course of 91 min with the overall magnitude of bioadhesion corresponding to the hydrogen bonding potential of the associated side chains. These results highlight the potential of these polymers for use in the development of more effective bioadhesive oral drug delivery systems.


Assuntos
Adesivos/síntese química , Mucosa Intestinal/química , Intestino Delgado/química , Levodopa/química , Fenilalanina/química , Tirosina/química , Resinas Acrílicas/química , Adesividade , Adesivos/metabolismo , Animais , Butadienos/química , Ligação de Hidrogênio , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Levodopa/metabolismo , Anidridos Maleicos/química , Fenilalanina/metabolismo , Polimerização , Ratos , Fatores de Tempo , Técnicas de Cultura de Tecidos , Tirosina/metabolismo
14.
Langmuir ; 35(5): 1119-1125, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30137995

RESUMO

This work reports a study of electropolymerization kinetics, film thickness, stability, and antifouling properties of polydopamine (PDA) and its three analogues: poly(3-(3,4-dihydroxyphenyl)-l-alanine) (PL-DOPA), poly(5-hydroxytryptophan) (PL-5-HTP), and poly(Adrenalin) (PAdrenalin). It was observed that the number of the hydroxyl groups on the benzene ring and the type (primary vs secondary) of amine group significantly affect the electropolymerization kinetics and thus the thickness of the obtained polymer films. Monomers with two hydroxyl groups (except Adrenalin) resulted in films that were thicker (∼10-15 nm) than the one with only one hydroxyl group (PL-5-HTP) (∼5-8 nm) under similar conditions. Adrenalin containing a secondary amino group could not be deposited onto the ITO substrate, while the other three compounds containing a primary amino group completely covered the ITO. The PDA films had better electrochemical stability than the other films. No film showed stable antifouling surfaces against protein.


Assuntos
Di-Hidroxifenilalanina/análogos & derivados , Indóis/química , Polímeros/química , 5-Hidroxitriptofano/química , Adsorção , Di-Hidroxifenilalanina/síntese química , Di-Hidroxifenilalanina/química , Dopamina/química , Técnicas Eletroquímicas , Epinefrina/química , Fibrinogênio/química , Indóis/síntese química , Levodopa/química , Estrutura Molecular , Polimerização , Polímeros/síntese química , Técnicas de Microbalança de Cristal de Quartzo
15.
Nanomedicine ; 15(1): 1-11, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30189294

RESUMO

The blood-brain barrier (BBB) is a protective endothelial barrier lining the brain microvasculature which prevents brain delivery of therapies against brain diseases. Hence, there is an urgent need to develop vehicles which efficiently penetrate the BBB to deliver therapies into the brain. The drug L-DOPA efficiently and specifically crosses the BBB via the large neutral amino acid transporter (LAT)-1 protein to enter the brain. Thus, we synthesized L-DOPA-functionalized multi-branched nanoflower-like gold nanoparticles (L-DOPA-AuNFs) using a seed-mediated method involving catechols as a direct reducing-cum-capping agent, and examined their ability to cross the BBB to act as brain-penetrating nanovehicles. We show that L-DOPA-AuNFs efficiently penetrate the BBB compared to similarly sized and shaped AuNFs functionalized with a non-targeting ligand. Furthermore, we show that L-DOPA-AuNFs are efficiently internalized by brain macrophages without inducing inflammation. These results demonstrate the application of L-DOPA-AuNFs as a non-inflammatory BBB-penetrating nanovehicle to efficiently deliver therapies into the brain.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Endotélio Vascular/metabolismo , Ouro/química , Levodopa/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Animais , Células Cultivadas , Dopaminérgicos/administração & dosagem , Dopaminérgicos/química , Sistemas de Liberação de Medicamentos , Endotélio Vascular/citologia , Humanos , Levodopa/química , Masculino , Nanopartículas Metálicas/química , Ratos , Ratos Wistar
16.
Biomed Chromatogr ; 33(1): e4382, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30203852

RESUMO

A simple, accurate, and reproducible HPLC-UV method has been developed and validated for the quantification of levodopa (l-Dopa) in human plasma. The method involves a simple protein precipitation procedure to extract both l-Dopa and methyldopa, the internal standard. The chromatographic analysis was achieved on a Shimadzu LC 20A HPLC system equipped with a Zorbax Eclipse XDB C18 column and an isocratic mobile phase consisting of 20 mm KH2 PO4 (pH 2.5) and methanol (95:5, v/v) run at a flow rate of 1 mL/min. The UV detection wavelength was set at 230 nm. The method exhibited good linearity (R2 > 0.999) over the assayed concentration range (0.1-10 µg/mL) and demonstrated good intra- and inter-day precision and accuracy (relative standard deviations and the deviation from predicted values were <15%). This method was also successfully applied for studying the potential effect of ketogenic diet on the pharmacokinetics of l-Dopa in Parkinson's participants. Our data analysis indicates that ketogenic diet does not significantly affect the pharmacokinetics of l-Dopa.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dieta Cetogênica , Levodopa/sangue , Levodopa/farmacocinética , Doença de Parkinson/metabolismo , Animais , Humanos , Levodopa/química , Limite de Detecção , Modelos Lineares , Doença de Parkinson/tratamento farmacológico , Ratos , Reprodutibilidade dos Testes
17.
J Biol Chem ; 293(52): 20157-20168, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30385508

RESUMO

Natural brown-black eumelanin pigments confer structural coloration in animals and potently block ionizing radiation and antifungal drugs. These functions also make them attractive for bioinspired materials design, including coating materials for drug-delivery vehicles, strengthening agents for adhesive hydrogel materials, and free-radical scavengers for soil remediation. Nonetheless, the molecular determinants of the melanin "developmental road traveled" and the resulting architectural features have remained uncertain because of the insoluble, heterogeneous, and amorphous characteristics of these complex polymeric assemblies. Here, we used 2D solid-state NMR, EPR, and dynamic nuclear polarization spectroscopic techniques, assisted in some instances by the use of isotopically enriched precursors, to address several open questions regarding the molecular structures and associated functions of eumelanin. Our findings uncovered: 1) that the identity of the available catecholamine precursor alters the structure of melanin pigments produced either in Cryptococcus neoformans fungal cells or under cell-free conditions; 2) that the identity of the available precursor alters the scaffold organization and membrane lipid content of melanized fungal cells; 3) that the fungal cells are melanized preferentially by an l-DOPA precursor; and 4) that the macromolecular carbon- and nitrogen-based architecture of cell-free and fungal eumelanins includes indole, pyrrole, indolequinone, and open-chain building blocks that develop depending on reaction time. In conclusion, the availability of catecholamine precursors plays an important role in eumelanin development by affecting the efficacy of pigment formation, the melanin molecular structure, and its underlying scaffold in fungal systems.


Assuntos
Cryptococcus neoformans/metabolismo , Levodopa/metabolismo , Melaninas/biossíntese , Sistema Livre de Células/química , Sistema Livre de Células/metabolismo , Cryptococcus neoformans/química , Levodopa/química , Melaninas/química
18.
J Chromatogr A ; 1578: 91-98, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30327181

RESUMO

Levodopa (L-DOPA) is promising as chiral stationary phase for open tubular capillary electrochromatography (OT-CEC) enantioseparation owing to its self-polymerization adhesive property and chiral recognition potential. In this work, CuSO4/H2O2 was used as a trigger agent to accelerate the polymerization process of L-DOPA and the poly-levodopa (poly-(L-DOPA)) coated column was successfully prepared for the first time by depositing it on the inner wall of fused silica capillary via the rapid and in-situ approach at room temperature. The performance of the poly-(L-DOPA) coated capillary was validated by the separation of different chiral analytes, including chiral amine drugs, neurotransmitters and amino acids, and the good enantioseparation efficiencies were achieved. For five consecutive runs, the relative standard deviations (RSDs) for the migration time of the analytes for intra-day, inter-day and column-to-column were in the range of 0.19-1.33%, 0.96-4.47%, and 2.21-7.79%, respectively. Additionally, the poly-(L-DOPA) coated capillary column could be successively used over 250 runs without observable change in the separation efficiency.


Assuntos
Eletrocromatografia Capilar/instrumentação , Técnicas de Química Analítica/instrumentação , Técnicas de Química Analítica/métodos , Levodopa/química , Sulfato de Cobre/química , Peróxido de Hidrogênio/química , Dióxido de Silício/química , Estereoisomerismo
19.
Anal Biochem ; 560: 7-11, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30176231

RESUMO

Tyrosine phenol-lyase (TPL) naturally catalyzes the reversible ß-elimination of l-tyrosine to phenol, pyruvate and ammonium. With its reverse reaction (synthetic activity), l-tyrosine and its derivatives could be synthesized with high atom economy, which are widely used in pharmaceutical industries. In this study, a high-throughput screening method for synthetic activity of TPL was developed. One of the substrate, sodium pyruvate was found to react with salicylaldehyde under alkali condition, forming a yellow color compound. The concentration of sodium pyruvate can be quantified according to the absorbance of the colorimetric compound at wavelength of 465 nm and the activity of TPL could be screened according to the decrease of the absorbance. After optimization of the colorimetric reaction conditions, the established high-throughput screening method was successfully used for screening of TPL with enhanced activity for l-DOPA synthesis. The confirmed sensitivity and accuracy demonstrated the feasibility and application potential of this screening method.


Assuntos
Colorimetria/métodos , Fusobacterium nucleatum/enzimologia , Ensaios de Triagem em Larga Escala/métodos , Tirosina Fenol-Liase , Cinética , Levodopa/química , Mutação , Especificidade por Substrato , Tirosina/análogos & derivados , Tirosina/biossíntese , Tirosina Fenol-Liase/química , Tirosina Fenol-Liase/genética
20.
Eur J Pharm Sci ; 123: 475-483, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30076956

RESUMO

The aim of this work was to carry out preliminary experiments for preparation of levodopa (LEVO)-containing intranasal powder. The experiments were designed according to the Quality by Design (QbD) concept. Based on prior risk assessment, LEVO and chitosan (CH) or sodium hyaluronate (HA) as mucoadhesive matrix formers were co-milled using planetary ball mill to prepare microparticles as drug delivery systems. The rotation speed, the milling time and the drug-additive ratio were evaluated to be the most relevant milling factors - as a result of the initial risk assessment; which were set according to a factorial design. The effects of critical process parameters and excipients were investigated on the particle size and surface characteristics of products, and on the crystallinity, in vitro dissolution and permeability of LEVO. Milling in the presence of higher amount of HA resulted in smaller average particle size of powders (D50 = 13.068 µm) and higher initial dissolution and permeation of LEVO compared to CH-containing formulations (D50 = 21.667 µm).


Assuntos
Antiparkinsonianos/química , Química Farmacêutica/métodos , Levodopa/química , Tecnologia Farmacêutica/métodos , Adesividade , Administração Intranasal , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/normas , Química Farmacêutica/normas , Quitosana/química , Cristalização , Preparações de Ação Retardada , Portadores de Fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Ácido Hialurônico/química , Cinética , Levodopa/administração & dosagem , Levodopa/normas , Tamanho da Partícula , Permeabilidade , Pós , Dados Preliminares , Controle de Qualidade , Solubilidade , Tecnologia Farmacêutica/normas
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