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1.
Chem Pharm Bull (Tokyo) ; 67(7): 666-674, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257322

RESUMO

Dimeric sesquiterpene thioalkaloids from the rhizomes of Nuphar pumilum exhibited immunosuppressive effects using a sheep erythrocyte plaque forming cell (PFC) assay, as well as an anti-metastasis effect, and rapid apoptosis-inducing effects in tumor cell lines. In particular, dimeric sesquiterpene thioalkaloids with a hydroxy group (6-hydroxythiobinupharidine, 6,6'-dihydroxythiobinupharidine, 6-hydroxythionuphlutine B) showed substantial effects, whereas dimeric sesquiterpene thioalkaloids lacking the hydroxy group (thiobinupharidine, thionuphlutine B, 6'-hydroxythionuphlutine B, neothiobinupharidine, thionuphlutine B ß-sulfoxide, neothiobinupharidine ß-sulfoxide) and monomeric sesquiterpene alkaloids (nupharidine, 7-epideoxynupharidine, nupharolutine) showed weak activity. In this review, we summarize our studies of the biofunctional effects of these alkaloids.


Assuntos
Alcaloides/química , Nuphar/química , Sesquiterpenos/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Imunossupressores/química , Imunossupressores/isolamento & purificação , Imunossupressores/farmacologia , Nuphar/metabolismo
2.
Fitoterapia ; 137: 104190, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31163199

RESUMO

The genus Tripterygium belongs to the family Celastraceae, and contains three species, i.e. Tripterygium wilfordii Hook. F, Tripterygium hypoglaucum (Levl.) Hutch. and Tripterygium regelii Sprague et Takeda. All three species are reported to have excellent medicinal properties that help to cure rheumatoid arthritis, nephrotic syndrome, systemic lupus erythematosus and widely used as a folk medicine in China. Phytochemical studies have led to discovering more than 500 secondary metabolites in this genus, including five main types: sesquiterpenoids, diterpenes, triterpenoids, flavonoids, lignans. This work provides structurally grouping statistic of 198 secondary metabolites of Tripterygium species published from 2008 to the present, as well as pharmacological knowledges in the past five years. The information will be helpful for developing the new discoveries of medicinal value related to the genus Tripterygium.


Assuntos
Tripterygium/química , Tripterygium/classificação , Animais , Anti-Inflamatórios/química , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antivirais/química , Diterpenos/química , Flavonoides/química , Humanos , Imunossupressores/química , Lignanas/química , Estrutura Molecular , Fármacos Neuroprotetores/química , Compostos Fitoquímicos/química , Metabolismo Secundário , Sesquiterpenos/química , Triterpenos/química
3.
J Korean Med Sci ; 34(19): e145, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31099195

RESUMO

BACKGROUND: Patients with acute myocardial infarction (AMI) have worse clinical outcomes than those with stable coronary artery disease despite revascularization. Non-culprit lesions of AMI also involve more adverse cardiovascular events. This study aimed to investigate the influence of AMI on endothelial function, neointimal progression, and inflammation in target and non-target vessels. METHODS: In castrated male pigs, AMI was induced by balloon occlusion and reperfusion into the left anterior descending artery (LAD). Everolimus-eluting stents (EES) were implanted in the LAD and left circumflex (LCX) artery 2 days after AMI induction. In the control group, EES were implanted in the LAD and LCX in a similar fashion without AMI induction. Endothelial function was assessed using acetylcholine infusion before enrollment, after the AMI or sham operation, and at 1 month follow-up. A histological examination was conducted 1 month after stenting. RESULTS: A total of 10 pigs implanted with 20 EES in the LAD and LCX were included. Significant paradoxical vasoconstriction was assessed after acetylcholine challenge in the AMI group compared with the control group. In the histologic analysis, the AMI group showed a larger neointimal area and larger area of stenosis than the control group after EES implantation. Peri-strut inflammation and fibrin formation were significant in the AMI group without differences in injury score. The non-target vessel of the AMI also showed similar findings to the target vessel compared with the control group. CONCLUSION: In the pig model, AMI events induced endothelial dysfunction, inflammation, and neointimal progression in the target and non-target vessels.


Assuntos
Endotélio/fisiologia , Imunossupressores/uso terapêutico , Inflamação/patologia , Infarto do Miocárdio/tratamento farmacológico , Neointima/patologia , Doença Aguda , Animais , Artérias/patologia , Contagem de Células Sanguíneas , Modelos Animais de Doenças , Stents Farmacológicos , Everolimo/química , Everolimo/uso terapêutico , Imunossupressores/química , Infarto do Miocárdio/patologia , Miocárdio/patologia , Suínos , Resultado do Tratamento
4.
Eur J Med Chem ; 176: 378-392, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31121546

RESUMO

In the past decades, triptolide has attracted considerable interests in the organic and medicinal chemistry society owing to its intriguing structure features and promising multiple pharmacological activities. However, its limited water solubility and oral bioavailability, imprecise mechanism of action and sever toxicity, scares from nature and difficulty in the synthesis have greatly hindered its clinical potential. Hence, to circumvent such problems, a lot of elegant total synthesis have been developed. With the advancement of the total synthesis, various triptolide derivatives have been synthesized and tested in the search for more drug-like derivatives for potential anticancer agents, anti-inflammatory agents, immunosuppressive agents and anti-Alzheimer's agents, etc. Meanwhile, through designing and synthesizing of various of bioactive probes, some molecular targets that are responsible for the multiple pharmacology activities as well as toxicity of triptolide have been identified. It is no doubt will help the future development of new drug-like triptolide derivatives. In order to gain a comprehensive and deep understanding of the area and provides suggestions for triptolide's further studies, i) the medicinal chemistry advancement, ii) bioactive probes-based cellular target identification and iii) clinical progress of triptolide derivatives are reviewed in this article.


Assuntos
Diterpenos/química , Diterpenos/farmacologia , Fenantrenos/química , Fenantrenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Ensaios Clínicos como Assunto , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
5.
Chem Pharm Bull (Tokyo) ; 67(5): 467-475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061372

RESUMO

The aim of this study was to establish a novel approach to in vitro dissolution evaluation using a combination of the paddle method and a dialysis membrane, both to predict the overall in vivo performance of tacrolimus microspheres and also to identify a suitable dissolution test method to describe the in vivo initial burst phenomenon. This new dissolution method for evaluating the release of tacrolimus from microspheres consisted of rotating a customized paddle inside a dialysis membrane using a conventional paddle apparatus. Findings were compared with a method in which the paddle was rotated outside the dialysis membrane, the conventional paddle method, and the flow-through cell method. We concluded that the paddle method with a dialysis membrane and internal agitation, which was designed to mimic in vivo conditions, predicted the overall pharmacokinetic (PK) profile of tacrolimus microspheres whereas the conventional paddle method described the initial burst. These findings suggest that it may not be possible to predict both the PK profile and initial burst using a single analysis method. We therefore recommend that evaluation of the initial burst be performed separately. In conclusion, we propose that combination of the paddle method with a dialysis membrane and internal agitation to evaluate the overall PK profile, together with the paddle method to describe the in vivo initial burst, represents a novel approach to in vitro dissolution evaluation for microsphere formulations.


Assuntos
Portadores de Fármacos/química , Imunossupressores/química , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Tacrolimo/química , Química Farmacêutica/instrumentação , Liberação Controlada de Fármacos , Desenho de Equipamento , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Membranas Artificiais , Microesferas , Modelos Químicos , Solubilidade , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética
6.
Eur J Pharm Sci ; 133: 104-114, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30928512

RESUMO

This study aimed to develop a stable and biodegradable tacrolimus loaded nanocarrier that enhanced tacrolimus corneal penetration and delivered in a sustained manner, thus to create a promising treatment to prevent immune rejection after corneal allografts. Spherical tacrolimus loaded methoxy poly (ethylene glycol)-block-poly (D,L)-lactic-co-glycolic acid (mPEG-b-PLGA) micelles with a mean diameter of 81.3 ±â€¯1.3 nm were prepared by the solvent-evaporation-induced self-assembly. The physicochemical properties of tacrolimus loaded mPEG-b-PLGA micelles were evaluated, and the in vitro release behavior, degradation, cytotoxicity and bio-safety were all assessed. The ex vivo permeation of tacrolimus using rabbit corneas was also performed, and the cumulative permeation amount of tacrolimus from mPEG-b-PLGA micelles was significantly higher than 0.05% tacrolimus eye drops (p < 0.05). These results indicated that the formulations were feasible for intraocular drug delivery. Compared with 0.05% tacrolimus eye drops, the in vivo immunofluorescence analysis indicated the tacrolimus loaded mPEG-b-PLGA micelles remarkably inhibit the immune rejection after corneal allograft, with the lower expression levels of nuclear factor of activated T cells (NFAT), cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8). In conclusion, we provided evidences that tacrolimus loaded mPEG-b-PLGA micelles would be a promising treatment for immune rejection after corneal transplantation.


Assuntos
Portadores de Fármacos/administração & dosagem , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Ceratoplastia Penetrante , Micelas , Nanopartículas/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tacrolimo/administração & dosagem , Animais , Sobrevivência Celular/efeitos dos fármacos , Córnea/metabolismo , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Imunossupressores/química , Masculino , Nanopartículas/química , Poliésteres/química , Polietilenoglicóis/química , Coelhos , Ratos Sprague-Dawley , Ratos Wistar , Tacrolimo/química
7.
Trends Pharmacol Sci ; 40(5): 327-341, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30975442

RESUMO

Triptolide, a compound isolated from a Chinese medicinal herb, possesses potent antitumor, immunosuppressive, and anti-inflammatory properties, but is clinically limited due to its poor solubility, bioavailability, and toxicity. Recently, Minnelide, a water-soluble prodrug of triptolide, was shown to have potent antitumor activity in various preclinical cancer models. Minnelide is currently in Phase II clinical trials for treatment of advanced pancreatic cancer, which has fueled increased interest in this promising agent. Here, we review the recent advances in the biological activity of triptolide and its analogs, their mechanisms of actions, and their clinical developments. A special emphasis is given to proteins and pathways within the tumor and stromal compartments that are targeted by triptolide and its analogs as well as the ongoing clinical trials.


Assuntos
Antineoplásicos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Fenantrenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Diterpenos/uso terapêutico , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Fenantrenos/química , Fenantrenos/uso terapêutico
8.
Nat Chem ; 11(4): 342-350, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30903037

RESUMO

The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure-activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term 'pharmacophore-directed retrosynthesis'. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure-activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activity.


Assuntos
Acetatos/química , Diterpenos/química , Furanos/química , Imunossupressores/química , Fármacos Neuroprotetores/química , Acetatos/síntese química , Acetatos/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Reação de Cicloadição , Diterpenos/síntese química , Diterpenos/farmacologia , Desenho de Drogas , Furanos/síntese química , Furanos/farmacologia , Humanos , Imunossupressores/síntese química , Imunossupressores/farmacologia , Membranas Mitocondriais/metabolismo , Conformação Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
9.
Int J Pharm ; 562: 1-10, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30878586

RESUMO

FK506 (tacrolimus) is an effective immunosuppressant, but its poor water solubility and low bioavailability impose barriers to ocular drug delivery. The nanomicelles (NMs) formulations comprised of amino-terminated poly(ethylene glycol-block-poly(D,L)-lactic acid) (NH2-PEG-b-PLA) and hydroxypropyl methylcellulose (HPMC) were developed to increase the penetration of hydrophobic drugs in the eye and enhance the drug bioavailability for ocular disorder therapy. Spherical FK506/NH2-PEG-b-PLA/HPMC NMs with mean diameter of 101.4 ±â€¯1.3 nm were prepared by solvent-evaporation-induced self-assembly in aqueous solution. The NMs that sufficiently solubilized FK506 were evaluated in terms of stability, drug loading, encapsulation efficiency, surface tension, cellular cytotoxicity and in vitro release, and the results revealed the NMs were suitable for intraocular drug delivery. Compared with the 0.05% FK506 suspension drops, the in vitro permeation amount of FK506 from NMs exhibited significant increase. Besides, the higher concentration and longer retention of FK506 in ocular tissue were also confirmed in vivo. Furthermore, the FK506/NH2-PEG-b-PLA/HPMC NMs obviously inhibited the allograft rejection after corneal transplantation in rats. In conclusion, FK506/NH2-PEG-b-PLA/HPMC NMs formulations as a promising ocular drug delivery system would be able to improve the bioavailability and efficacy of FK506 in anti-allograft rejection.


Assuntos
Portadores de Fármacos/administração & dosagem , Derivados da Hipromelose/administração & dosagem , Imunossupressores/administração & dosagem , Lactatos/administração & dosagem , Micelas , Nanopartículas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Tacrolimo/administração & dosagem , Administração Oftálmica , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Olho/metabolismo , Feminino , Derivados da Hipromelose/química , Derivados da Hipromelose/farmacocinética , Imunossupressores/química , Imunossupressores/farmacocinética , Lactatos/química , Lactatos/farmacocinética , Masculino , Nanopartículas/química , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Ratos Sprague-Dawley , Ratos Wistar , Tacrolimo/química , Tacrolimo/farmacocinética
10.
Int J Pharm ; 562: 96-104, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902706

RESUMO

The present work reports the development, optimization and characterization of novel lipid based nanoformulations viz., Liquid crystalline nanoparticles (LCNP), solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and liposomes loaded with Tacrolimus (Tac) for topical delivery. Different nanoformulations were developed after screening lipids and suitable surfactants depending upon emulsification ability. The various nanoformulations were then optimized (to achieve higher entrapment efficacy, lower particle size, PDI and zeta potential), characterized and loaded into gel. The gels loaded with nanoformulations were also characterized depending upon rheology and viscosity. The gels were analyzed for in vitro drug release, HaCaT cell lines studies and skin permeation studies. The in vivo efficacy studies were carried out using mouse tail model and skin irritation studies using Draize patch test and measurement of TEWL. The developed nanoformulations showed optimum particle size (<200 nm), polydispersity index (PDI < 0.3), zeta potential (≥-10 mV) and higher entrapment efficiency (>85%). The nanoformulations showed higher penetration of Tac into skin. Tac-LCNP, Tac-SLN, Tac-NLC and Tac-liposomes loaded gels showed 14, 11.5, 12.5 and 3.7 folds increment in dermal bioavailability respectively, in comparison to free Tac loaded gel and 2.5, 2 and ∼2 folds augmentation in dermal bioavailability respectively as compared to Tacroz™ Forte. In case of Tac-liposomes, the dermal bioavailability was lower as compared with the marketed formulation, Tacroz™ Forte. Despite, the increased bioavailability into the skin, the developed nanoformulations showed no significant skin irritation. The above mentioned nanoformulations were able to achieve greater penetration of Tac into the skin as compared to marketed ointment of Tac, Tacroz™ Forte.


Assuntos
Portadores de Fármacos/administração & dosagem , Imunossupressores/administração & dosagem , Lipídeos/administração & dosagem , Cristais Líquidos , Nanopartículas/administração & dosagem , Tacrolimo/administração & dosagem , Administração Cutânea , Animais , Linhagem Celular , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Imunossupressores/química , Lipídeos/química , Cristais Líquidos/química , Camundongos Endogâmicos BALB C , Nanopartículas/química , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Pele/metabolismo , Testes de Irritação da Pele , Suínos , Tacrolimo/química , Resultado do Tratamento
11.
Adv Mater ; 31(17): e1806957, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30856290

RESUMO

Patients with advanced melanoma that is of low tumor-associated antigen (TAA) expression often respond poorly to PD-1/PD-L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents (HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti-PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH-sensitive calcium carbonate nanoparticles (CaCO3 NPs), which are then encapsulated in the ROS-responsive hydrogel together with Zeb (Zeb-aPD1-NPs-Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10-melanoma-bearing mice.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/síntese química , Citidina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Imunossupressores/química , Melanoma/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Carbonato de Cálcio/química , Linhagem Celular Tumoral , Citidina/farmacologia , Liberação Controlada de Fármacos , Quimioterapia Combinada/métodos , Humanos , Concentração de Íons de Hidrogênio , Imunossupressores/farmacologia , Imunoterapia/métodos , Nanopartículas/química , Receptor de Morte Celular Programada 1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos
13.
Colloids Surf B Biointerfaces ; 177: 169-177, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30731393

RESUMO

Benznidazole (BNZ) is the drug of choice for the treatment of Chagas disease in many countries. However, its low water solubility produces low and/or variable oral bioavailability. Thus, the aim of this work was to formulate micro- and nanoparticles based on Eudragit® RS PO and Eudragit® RL PO as a convenient approach to increase the dissolution rate of BNZ. The microparticles were obtained by means of spray-drying process while the nanoparticles were prepared through the nanoprecipitation technique and further freeze-drying. The results indicated that nanoparticles were obtained in 86% yield while microparticles were obtained in 68% yield. In both cases, the encapsulation efficiency of particles was greater than 78% while drug loading capacity was nearly 24% w/w and 18% w/w, after spray-drying and freeze-drying procedures, respectively. Images of scanning electron microscopy showed that the particles obtained by spray-drying and freeze-drying were in the micrometer and nanometer scale, respectively. FT-IR spectra of BNZ-loaded particles obtained by both methods showed characteristic bands of BNZ confirming that part of drug remained on their surface. Thermal analysis revealed that the drug crystallinity after both methods decreased. Physical stability evaluation of the nanoparticles confirmed that Pluronic® F68 was suitable to keep the particles size in a range of 300 nm after 70 days storage at 4 ± 2 °C. In-vitro release studies showed increased dissolution rate of drug from the particles obtained by both methods respect to untreated BNZ. The kinetics of drug release in acid media followed the Higuchi kinetics indicating drug diffusion mechanism from particles.


Assuntos
Doença de Chagas/tratamento farmacológico , Imunossupressores/química , Imunossupressores/uso terapêutico , Nanopartículas/química , Nitroimidazóis/química , Nitroimidazóis/uso terapêutico , Criança , Liberação Controlada de Fármacos , Humanos , Hidrodinâmica , Imunossupressores/síntese química , Cinética , Nitroimidazóis/síntese química , Tamanho da Partícula , Propriedades de Superfície
14.
Cell Mol Life Sci ; 76(10): 2003-2013, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30747251

RESUMO

To successfully feed, ticks inject pharmacoactive molecules into the vertebrate host including cystatin cysteine protease inhibitors. However, the molecular and cellular events modulated by tick saliva remain largely unknown. Here, we describe and characterize a novel immunomodulatory cystatin, Iristatin, which is upregulated in the salivary glands of feeding Ixodes ricinus ticks. We present the crystal structure of Iristatin at 1.76 Å resolution. Purified recombinant Iristatin inhibited the proteolytic activity of cathepsins L and C and diminished IL-2, IL-4, IL-9, and IFN-γ production by different T-cell populations, IL-6 and IL-9 production by mast cells, and nitric oxide production by macrophages. Furthermore, Iristatin inhibited OVA antigen-induced CD4+ T-cell proliferation and leukocyte recruitment in vivo and in vitro. Our results indicate that Iristatin affects wide range of anti-tick immune responses in the vertebrate host and may be exploitable as an immunotherapeutic.


Assuntos
Proteínas de Artrópodes/farmacologia , Cistatinas/farmacologia , Imunossupressores/farmacologia , Cistatinas Salivares/farmacologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Cristalografia por Raios X , Cistatinas/classificação , Cistatinas/genética , Citocinas/metabolismo , Compostos de Epóxi/metabolismo , Feminino , Imunossupressores/química , Imunossupressores/metabolismo , Ixodes/química , Ixodes/genética , Ixodes/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Filogenia , Proteólise/efeitos dos fármacos , Cistatinas Salivares/química , Cistatinas Salivares/genética , Homologia de Sequência de Aminoácidos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo
15.
Biomed Res Int ; 2019: 9461960, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30723745

RESUMO

In this study, we evaluated the immunity-enhancing effects of Orostachys japonicus A. Berger (OJ). To examine the immune protective effect in vitro, primary mouse splenocytes were treated with water or ethanol extracts of OJ in the absence or presence of cyclophosphamide (CY), which is a cytotoxic, immunosuppressive agent. The extracts increased the propagation of splenocytes and inhibited CY-induced cytotoxicity. Further, to examine the immunostimulatory effects in vivo, adult Wistar rats were orally administered OJ extracts with or without CY treatment. With the administration of OJ extracts, CY-treated immunosuppressed rats showed improved physical endurance, as assessed by the forced swim test. In addition, extract administration increased not only the number of immunity-related cells but also the levels of plasma cytokines. OJ extracts also recovered splenic histology in CY-treated rats. These findings suggest that an OJ regimen can enhance immunity by increasing immune cell propagation and specific plasma cytokine levels.


Assuntos
Crassulaceae/química , Imunidade Inata/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Baço/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Ciclofosfamida/administração & dosagem , Citocinas/imunologia , Hospedeiro Imunocomprometido/efeitos dos fármacos , Hospedeiro Imunocomprometido/imunologia , Imunossupressores/administração & dosagem , Imunossupressores/química , Extratos Vegetais/química , Ratos , Baço/citologia , Baço/imunologia
16.
Eur J Med Chem ; 161: 239-251, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30359820

RESUMO

A set of CB2R ligands, based on the thiophene scaffold, was synthesized and evaluated in in vitro assays. Compounds 8c-i, k, l, bearing the 3-carboxylate and 2-(adamantan-1-yl)carboxamido groups together with apolar alkyl/aryl substituents at 5-position or at 4- and 5-positions of the thiophene ring possess high CB2R affinity at low nanomolar concentration, good receptor selectivity, and agonistic functional activity. The full agonist 8g, showing the best balance between receptor affinity and selectivity, was tested in vitro in an experimental model of allergic contact dermatitis and proved to be able to block the release of MCP-2 in HaCaT cells at 10 µM concentration.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Imunossupressores/farmacologia , Inflamação/tratamento farmacológico , Receptor CB2 de Canabinoide/agonistas , Dermatopatias/tratamento farmacológico , Tiofenos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Imunossupressores/síntese química , Imunossupressores/química , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Estrutura Molecular , Dermatopatias/patologia , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
17.
J Antibiot (Tokyo) ; 72(3): 174-177, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30542160

RESUMO

Two new isochromanone derivatives, (3S,4S)-3,8-dihydroxy-6-methoxy-3,4,5-trimethylisochroman-1-one (1) and methyl (S)-8-hydroxy-6-methoxy-5-methyl-4a-(3-oxobutan-2-yl)benzoate (2), together with six known compounds (3‒8) were isolated from the cultures of an endophytic fungus Phoma sp. PF2 obtained from Artemisia princeps. The chemical structures of the isolated compounds were elucidated by interpretation of spectroscopic data (1D, 2D NMR, HRESIMS, and CD) and calculation of ECD. All the isolated compounds (1‒8) showed moderate inhibitory activities on nitric oxide levels in lipopolysaccharide-induced RAW264.7 machrophage cells.


Assuntos
Artemisia/microbiologia , Ascomicetos/metabolismo , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Endófitos/metabolismo , Imunossupressores/isolamento & purificação , Imunossupressores/farmacologia , Animais , Ascomicetos/crescimento & desenvolvimento , Ascomicetos/isolamento & purificação , Produtos Biológicos/química , Dicroísmo Circular , Meios de Cultura/química , Endófitos/crescimento & desenvolvimento , Endófitos/isolamento & purificação , Imunossupressores/química , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Células RAW 264.7 , Espectrometria de Massas por Ionização por Electrospray
18.
Pak J Pharm Sci ; 31(6 (Supplementary): 2623-2628, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30587470

RESUMO

Among immunosuppressive agents cyclosporine A is drug of unique importance. This drug has a low therapeutic index, and it has many toxic effects. After oral administration its absolute bioavailability is variable due to poor absorption. Niosomes are new and versatile carriers to deliver drug. The bioavailability of immunosuppressant drug cyclosporine A can be increased by niosomal drug delivery system. So our basic theme was to prepare niosomes of immunosuppressant drug using cholesterol, span 60 and tween 60 etc. Niosomes were characterized for zeta potential, size, poly dispersivity index(PDI), entrapment efficiency and In vitrorelease profiles. Six niosomal formulations (F1-F6) were successfully developed using thin film hydration technique. Among various formulations F2 showed the highest entrapment efficiency 77.29 %. The DSC thermograms of physical mixtures and niosomal formulations indicated the presence of drug in crystalline form. In vitro drug release study demonstrated higher drug release values as compared to drug aqueous dispersion. Niosomal formulations were capable of releasing drug in sustained manner. The overall results demonstrated that developed niosomal carriers are competitive candidates for improving dissolution profile of cyclosporine A leading to increased bioavailability at the site of action.


Assuntos
Ciclosporina/farmacocinética , Portadores de Fármacos/farmacocinética , Composição de Medicamentos/métodos , Desenvolvimento de Medicamentos/métodos , Imunossupressores/farmacocinética , Ciclosporina/química , Portadores de Fármacos/química , Imunossupressores/química , Lipossomos
19.
Int J Nanomedicine ; 13: 8281-8296, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30584300

RESUMO

Introduction: Cyclosporine-A (CsA) is generally used as an immunosuppressant and is also prescribed for some ophthalmic applications such as vernal keratoconjunctivitis and dry eye. However, it is limited clinically due to its low aqueous solubility and ocular bioavailability. Methods: In this work, lyophilized methoxy poly(ethylene glycol)-poly(lactide) (mPEG-PLA) polymer micelles were prepared for ophthalmic formulations as a promising nanocarrier for hydrophobic drugs like CsA. A mPEG-PLA diblock polymer was synthesized by ring opening polymerization and CsA was loaded into mPEG-PLA micelles by a simple film dispersion method. A uniform design of experiments was utilized to optimize the final formulation. The obtained formulation was characterized for diameter (57.0±3.2 nm), entrapment efficiency % (98.51±1.4), and in vitro release. Moreover, incorporating the stabilizer mPEG2000 could increase the in vitro stability of the lyophilized CsA-loaded mPEG-PLA micelles. Results: Results showed a sustained release of CsA from the micelles. Drug concentration and time-dependent cytotoxicity of human corneal epithelial-2 cells was observed. Additionally, the transcorneal mechanism of mPEG-PLA micelles was studied and the results showed that the mPEG-PLA micelles mainly absorbed by a paracellular pathway via corneal epithelial cells. Conclusion: Taken together, the results proved that this mPEG-PLA diblock polymer can be potentially used as a nanoscopic carrier to deliver hydrophobic drugs in a controlled manner to the ocular region and, thus, deserves further attention.


Assuntos
Córnea/efeitos dos fármacos , Ciclosporina/efeitos adversos , Ciclosporina/farmacologia , Liofilização , Micelas , Soluções Oftálmicas/farmacologia , Polímeros/química , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Ciclosporina/química , Portadores de Fármacos , Liberação Controlada de Fármacos , Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Imunossupressores/efeitos adversos , Imunossupressores/química , Imunossupressores/farmacologia , Irritantes , Tamanho da Partícula , Poliésteres/síntese química , Poliésteres/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polimerização , Polímeros/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Coelhos , Solubilidade , Temperatura Ambiente
20.
Chem Commun (Camb) ; 54(85): 12002-12005, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30221278

RESUMO

The direct, catalytic vicinal difluorination of terminal alkenes via an I(i)/I(iii) manifold was exploited to install a chiral, hybrid bioisostere of the CF3 and Et groups (BITE) in Gilenya®; the first orally available drug for the clinical management of Multiple Sclerosis (MS). This subtle fluorination pattern allows lipophilicity (log D) to be tempered compared to the corresponding CF3 and Et derivatives (CH2CH3 > CH2CF3 > CHFCH2F).


Assuntos
Cloridrato de Fingolimode/análogos & derivados , Cloridrato de Fingolimode/química , Imunossupressores/química , Animais , Estabilidade de Medicamentos , Cloridrato de Fingolimode/síntese química , Halogenação , Hepatócitos/efeitos dos fármacos , Humanos , Imunossupressores/síntese química , Microssomos Hepáticos/metabolismo , Esclerose Múltipla/tratamento farmacológico , Ratos
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