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1.
Expert Opin Drug Metab Toxicol ; 15(11): 913-925, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31623470

RESUMO

Introduction: The treatment of psoriasis with conventional topical therapies and disease-modifying anti-rheumatic drugs (DMARDs) is often linked to unsatisfactory outcomes and the risk of serious adverse events. Over the last decades, research advances in understanding the role of tumor necrosis factor alpha (TNF α) and other cytokines in the pathogenesis of psoriasis have driven the introduction of biologic agents targeting specific immune mediators in everyday clinical practice. TNF α inhibitors are a consolidated treatment option for patients with moderate-to-severe disease with remarkable efficacy and a reassuring safety profile.Areas covered: The PubMed database was searched using combinations of the following keywords: psoriasis, TNF α inhibitors, biologic therapy, pharmacodynamics, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, adverse effects. The aim of this review is to describe the pharmacodynamic profile of anti-TNF α inhibitors, currently approved by the European Medicines Agency (EMA) for the treatment of psoriasis, focusing on related clinical implications, also in comparison to the new generation biological therapies targeting the interleukin 23/interleukin 17 axis.Expert opinion: Pharmacodynamics of TNF α inhibitors should be fully considered in planning patient's therapy strategies, especially in case of secondary failures, poor adherence to treatment, instable psoriasis, high risk of infection, pregnant or lactating women, metabolic comorbidities, coexistence of other immune-mediated inflammatory diseases.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Desenvolvimento de Medicamentos , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Adesão à Medicação , Psoríase/imunologia , Psoríase/patologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/metabolismo
2.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3358-3364, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602895

RESUMO

To evaluate the effect of Tripterygium Glycosides Tablets extract in the treatment of rheumatoid arthritis( RA). Clinical trials of treating rheumatoid arthritis with Tripterygium Glycosides Tablets published by Meta-analysis were retrieved from EMbase,PubMed,Clinical Trials,Web of Science,Cochrane Library,CNKI,Wanfang,VIP,CBM and Chi CTR,and comprehensively analyzed. A total of 3 studies were enrolled,the modified Sharp score( m TSS),tender join joint erosions( JE) and joint space narrowing( JSN) of Tripterygium Glycosides Tablets group were significant superior to those of control group,including positive drugs methotrexate( MTX) and salazopyridine( SSZ)( P<0. 01). Tripterygium Glycosides Tablets had an effect in treating RA. Due to the small sample size,this study shall be verified with high-quality,large-sample-size double-blinded RCTs.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Glicosídeos/farmacologia , Tripterygium/química , Humanos , Comprimidos
3.
Top Curr Chem (Cham) ; 377(5): 28, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31563994

RESUMO

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the joints, with the main clinical manifestations being chronic, symmetrical, and peripheral multi-joint inflammatory lesions. Drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), disease-modifying anti-rheumatic drugs (DMARDs), and biologics play a very important role in the treatment of RA. Of these, the most commonly used are chemical drugs, such as NSAIDs, GCs, and DMARDs. In recent years, a number of new compounds have emerged for the treatment of RA, such as SYK inhibitors, JAK inhibitors, NSAID-CAI drugs, and Syk/PDGFR-α/c-Kit inhibitors. In this review, we summarize the most recently developed anti-RA chemical drugs and discuss the synthesis and biological activities of these various new compounds.


Assuntos
Antirreumáticos/síntese química , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Animais , Antirreumáticos/química , Antirreumáticos/uso terapêutico , Humanos , Estrutura Molecular
4.
Medicine (Baltimore) ; 98(32): e16682, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393368

RESUMO

Some patients have poor response to adult-onset Still disease (AOSD) traditional treatment, which easily recurs during the reduction of prednisone. We observed the efficacy and safety of tocilizumab combined with methotrexate (MTX) in the treatment of refractory AOSD, and to explore the possibility of reducing the dosage of tocilizumab after disease control.A total of 28 refractory AOSD cases who had an inadequate response to corticosteroids combined with at least 1 traditional immunosuppressive agent, and even large-dose prednisone could not relieve their conditions after recurrence, were selected in this study. They were treated with tocilizumab (intravenous 8 mg/kg) combined with MTX (oral 12.5 mg once a week). In detail, tocilizumab was firstly given every 4 weeks and after 6-month remission, it was then given every 8 weeks. Some items including body temperature, skin rash, joint swelling and pain, hepatosplenomegaly, blood routine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum ferritin, and dosage of prednisone were observed before treatment as well as 2, 4, 8, 12, 24, 36, and 48 weeks after treatment. The adverse reactions occurring during the treatment were recorded.The body temperature was normal, the skin rash as well as joint swelling and pain disappeared, and laboratory indexes including CRP, ESR, white blood cell, neutrophilic granulocyte, platelet, hemoglobin, and ferritin were significantly improved after 8-week treatment (all P < .05). The clinical symptoms and laboratory indexes above mentioned were continuously improved 12, 24, 36, and 48 weeks after treatment. The mean dosage of prednisone was reduced from 71.4 ±â€Š20.7 mg/day to 55.0 ±â€Š11.1 mg/day after 2-week treatment, and to 3.3 ±â€Š2.1 mg/day after 48-week treatment (all P < .05). Prednisone was discontinued in 5 cases after 36-week treatment and in 7 cases after 48-week treatment. No serious adverse reactions occurred during the treatment.Tocilizumab can rapidly and markedly improve the clinical symptoms and laboratory indexes and contribute to reduction and discontinuation of prednisone in refractory AOSD. The patients' conditions are stable after reduction or discontinuation of prednisone and the tocilizumab possesses good safety.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Metotrexato/administração & dosagem , Doença de Still de Início Tardio/tratamento farmacológico , Administração Intravenosa , Administração Oral , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Antirreumáticos/farmacologia , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Masculino , Metotrexato/farmacologia , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Resultado do Tratamento
5.
Chem Pharm Bull (Tokyo) ; 67(8): 786-794, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366828

RESUMO

Teriflunomide (TEF, A771726) is the active metabolite of leflunomide (LEF), a disease-modifying anti-rheumatic drug. The main purpose of this study was to develop and evaluate water-in-oil (W/O) microemulsion formulation of TEF. The W/O microemulsion was optimized formula is the physical and chemical stability of lecithin, ethanol, isopropyl myristate (IPM) and water (20.65/20.78/41.52/17.05 w/w) by using the pseudo-ternary phase diagram and the average droplet size is about 40 nm. The permeability of TEF microemulsion is about 6 times higher than control group in vitro penetration test. The results of anti-inflammatory effect showed that compared with the control group, the external TEF microemulsion group could significantly inhibit swelling of paw in rats, and no significant difference compared with oral LEF group. The results of hepatotoxicity test show that there were normal content of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and no obvious inflammatory infiltration of TEF microemulsion group compared with LEF group. The plasma concentration curve showed that compared with LEF group, the peak concentration of TEF microemulsion group was decreased, the half-life (t1/2) was prolonged, and the relative bioavailability of TEF microemulsion was 75.35%. These results suggest that TEF W/O microemulsion can be used as a promising preparation to play an anti-inflammatory role while significantly reducing hepatotoxicity.


Assuntos
Antirreumáticos/farmacologia , Crotonatos/farmacologia , Sistemas de Liberação de Medicamentos , Edema/tratamento farmacológico , Toluidinas/farmacologia , Animais , Antirreumáticos/química , Crotonatos/química , Composição de Medicamentos , Edema/patologia , Emulsões/síntese química , Emulsões/química , Estrutura Molecular , Óleos/química , Medição da Dor , Ratos , Ratos Sprague-Dawley , Toluidinas/química , Água/química
6.
Life Sci ; 233: 116703, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31356903

RESUMO

AIMS: The initiation of pressure ulcers is accompanied by inflammation. Sinomenine emerges as a potential anti-inflammation agent. The aim of this study was to corroborate its anti-inflammatory property in skin keratinocyte HaCaT cells. Long non-coding RNA colon cancer associated transcript-1 (CCAT1)-associated mechanisms were also investigated. MAIN METHODS: HaCaT cells were stimulated with lipopolysaccharide (LPS) for 6 h after sinomenine pre-administration. Transfection was carried out to induce CCAT1 overexpression or silence it in HaCaT cells. Viability and apoptosis of HaCaT cells were determined by MMT and observed using flow cytometry, respectively. Protein expression was quantified using Western blot or ELISA. CCAT1 was measured by qRT-PCR. KEY FINDINGS: LPS notably decreased cell viability and exaggerated apoptosis with the cleavage of caspase-3/-9. The secretion of inflammatory factors was promoted. Sinomenine pre-administration maintained cell viability, blocked apoptosis and relieved inflammation with the decrease in cleaved caspase-3/-9 and inflammatory factors. LPS-induced phosphorylation of p65, IκBα and p38MAPK and overexpression of CCAT1 were precluded by sinomenine. CCAT1 overexpression, which per se induced inflammatory lesions, negated the positive effects of sinomenine with the restored phosphorylation of p65, IκBα, and p38MAPK. SIGNIFICANCE: Sinomenine played a protective role against LPS-induced inflammation. The anti-inflammatory activity of sinomenine might be mediated by CCAT1 down-regulation.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Queratinócitos/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Morfinanos/farmacologia , RNA Longo não Codificante/genética , Pele/efeitos dos fármacos , Antirreumáticos/farmacologia , Células Cultivadas , Regulação para Baixo , Regulação da Expressão Gênica , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Queratinócitos/citologia , Queratinócitos/metabolismo , Pele/citologia , Pele/metabolismo
7.
Expert Opin Investig Drugs ; 28(7): 573-581, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31208237

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease, which affects joints and extra-articular structures. Nowadays, the armamentarium of therapeutic options is progressively expanding and embraces several mechanisms of action: TNF inhibition, B-cell depletion, T-cell co-stimulation inhibition, IL-6 blockade, and JAK-inhibition. Granulocyte-Monocyte-Colony-Stimulating-Factor (GM-CSF) is a mediator acting as a cytokine with a proven pathogenetic role in RA, providing a potential alternative target for the management of the disease. Mavrilimumab is a monoclonal antibody against GM-CSF receptor, which has been successfully tested in RA patients. Areas covered: Beginning with a description of the preclinical evidence and the rationale for GM-CSF blockade in RA, this review will provide a wide overview of mavrilimumab efficacy and safety profile by analyzing phase I/II RCTs conducted in patients with moderate to severe RA. Expert opinion: According to the promising results from phase I-II RCTs, mavrilimumab could be considered as an additional therapeutic option for RA patients multi-resistant to the available targeted drugs. However, the optimal dose and the profile of this new drug should be confirmed in phase III RCTs before the marketing.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Artrite Reumatoide/fisiopatologia , Resistência a Medicamentos , Humanos , Terapia de Alvo Molecular , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Índice de Gravidade de Doença
8.
Drugs ; 79(8): 887-891, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31093950

RESUMO

Peficitinib [Smyraf® (Astellas Pharma)] is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor recently approved in Japan for the treatment of rheumatoid arthritis. Inhibition of JAK suppresses the activation of cytokine signalling pathways involved in inflammation and joint destruction in rheumatoid arthritis. Peficitinib has been shown to significantly improve ACR20 and other measures of disease severity and to reduce the mean modified total Sharp score change from baseline in clinical trials. This article summarizes the milestones in the development of peficitinib leading to this first approval as a treatment for rheumatoid arthritis in patients who have an inadequate response to conventional therapies.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Antirreumáticos/farmacologia , Aprovação de Drogas , Humanos , Janus Quinases/antagonistas & inibidores , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores
9.
Expert Rev Clin Pharmacol ; 12(6): 547-554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059310

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacologia , Adamantano/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/enzimologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico
10.
Expert Opin Drug Saf ; 18(5): 415-425, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31066297

RESUMO

INTRODUCTION: Two classes of biologics, anti-tumor necrosis factor (TNF) and non-anti-TNF targeted, are currently available for the treatment of rheumatic diseases. AREAS COVERED: Discussion on the need for LTBI diagnosis in rheumatic patients treated csDMARDs and non-anti-TNFs through a review of the literature. The literature, updated to 15 April 2019, on tuberculosis (TB) reactivation risk in patients exposed to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and non-anti-TNF biologics was reviewed. EXPERT OPINION: An increased risk of TB reactivation in patients receiving csDMARDs (except sulphasalazine) resulted, while a review of clinical trials, and Periodic Safety Update Reports from pharmaceutical Companies evidenced a very low or absent risk for non-anti-TNF biologics. Hence, a contradiction emerges considering that latent TB infection (LTBI) screening is recommended for non-anti-TNF candidates but not for csDMARDs. Concerning the low TB incidence countries, several actions could be undertaken, including to screen all patients independently on the treatment, to omit the procedure in non-anti-TNF candidates, or to perform the LTBI investigations only in high-risk patients. According to WHO guidelines, LTBI screening in low TB risk countries seems unnecessary, except in high TB risk subjects.


Assuntos
Antirreumáticos/efeitos adversos , Produtos Biológicos/efeitos adversos , Tuberculose/etiologia , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Produtos Biológicos/uso terapêutico , Humanos , Tuberculose Latente/diagnóstico , Tuberculose Latente/etiologia , Programas de Rastreamento/métodos , Guias de Prática Clínica como Assunto , Doenças Reumáticas/tratamento farmacológico , Fatores de Risco , Tuberculose/diagnóstico
11.
Phytomedicine ; 59: 152755, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005814

RESUMO

BACKGROUND: Kaempferia parviflora Wall. ex Baker (KP) has long been used in traditional medicine to treat various diseases because active compounds in rhizome extracts are important anti-inflammatory agents. PURPOSE: This study aims to investigate the effects of an ethanolic extract of KP on the molecular mechanisms associated with rheumatoid arthritis (RA), which was induced by a combination of proinflammatory cytokines (IL-1ß or TNF-α with IL-17A) in a human synovial sarcoma cell line (SW982) culture model. METHODS: SW982 cells pretreated with cytokines were incubated with KP extract at 3-30 µg/ml, or three major compounds of KP (5,7-dimethoxyflavone, 5,7,4'-trimethoxyflavone, and 3,5,7,3',4'-pentamethoxyflavone) for up to 72 h. Dexamethasone was used as positive control. RA-associated genes and inflammatory products were measured in parallel with cell death genes. Apoptosis by flow cytometry and migration assay were also analyzed. Western blotting was used to examine the effects on intracellular signaling mechanisms. RESULTS: KP extract markedly reduced the expression of genes and levels of proinflammatory cytokines, inflammatory mediators, and matrix-degraded enzymes, but neither induced apoptosis nor altered the cell cycle. Its major constituents differently exerted suppressive effects on inflammatory genes. The KP extract downregulated the expression of genes associated with autophagosome and necroptosome formations. The extract also inhibited cell migration, reduced the mRNA expression of cadherin-11, and selectively reduced the phosphorylation of p38 MAPK, STAT1, and STAT3 signaling molecules, but did not interfere with the NF-κB pathway. CONCLUSION: These results suggest that the anti-arthritic potential of KP extract results from anti-inflammation and anti-migration via the suppression of the cytokines-induced p38/STAT1 and STAT3 pathways.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/metabolismo , Flavonas/farmacologia , Extratos Vegetais/farmacologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Zingiberaceae/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Apoptose/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Citocinas/metabolismo , Flavonas/uso terapêutico , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Extratos Vegetais/uso terapêutico , Rizoma , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Pharmazie ; 74(4): 212-220, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940304

RESUMO

Rheumatoid arthritis is an autoimmune pathology that manifests as chronic inflammatory arthropathy and synovitis. Treatment of rheumatoid arthritis is based on the administration of different types of drugs, including leflunomide, an antirheumatic drug. However, the long-term systemic use of leflunomide may be associated with adverse effects. Local therapy could be an efficient strategy to treat synovitis triggered by rheumatoid arthritis without inducing adverse effects. In this study, leflunomide-loaded poly(ε-caprolactone) implants (leflunomide PCL implants) were evaluated as local drug delivery systems capable of attenuating inflammation and angiogenesis, which represent events of synovitis. Leflunomide PCL implants were designed by hot molding technique; and they were characterized by FTIR and DSC. These analytical techniques demonstrated the chemical integrity and dispersion of drug into the polymeric chains. Then, a spectrophometric method was developed and validated to quantify the leflunomide incorporated into the PCL implants and released from them. Linearity was obtained by ordinary least squares regression method to estimate the linear regression equation. Residues were evaluated considering normality, independence and homoscedasticity. Precision was lower than 5 %, and accuracy ranged from 98 to 104.5 %. Quantitation limit was 2.0 µg mL-1. PCL implants provided controlled and sustained release of leflunomide for 30 consecutive days after inserting these systems in the subcutaneous tissue of mice. The main mechanisms of drug delivery were solubilization and diffusion from polymer. Then, a non-biocompatible sponge was inserted into the subcutaneous tissue of mice to function as a frame to develop the inflammatory and angiogenic processes. Leflunomide PCL implants were inserted in direct contact with the sponge. At 4, 7 and 10 days after-sponge implantation, the key components of inflammatory angiogenesis were measured to verify the regression of these events induced by drug. Leflunomide controlled released from polymeric implants downregulated the neutrophil and monocyte/macrophage infiltration due to the reduced expression of myeloperoxidase (MPO) and N-acetyl-ß-d-glucosaminidase (NAG), respectively. As the influx of these pro-inflammatory cells was modulated by leflunomide, the production of nitric oxide (NO), a pro-inflammatory substance, reached low concentrations in the sponge. As a consequence of the modulation of inflammation at the pathological site, the angiogenic process was downregulated, since the hemoglobin levels in the sponge were drastically reduced. The accumulation of leflunomide in the pathological site did not induce nephrotoxicity or hepatototoxicity, as confirmed by histological analyses. Finally, intra-articular leflunomide PCL implants represent a potential therapeutic alternative to treat locally the synovitis triggered by rheumatoid arthritis without inducing systemic adverse effects.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Leflunomida/administração & dosagem , Sinovite/tratamento farmacológico , Animais , Antirreumáticos/farmacologia , Antirreumáticos/toxicidade , Varredura Diferencial de Calorimetria , Modelos Animais de Doenças , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Implantes de Medicamento , Feminino , Inflamação/tratamento farmacológico , Inflamação/patologia , Leflunomida/farmacologia , Modelos Lineares , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Óxido Nítrico/metabolismo , Poliésteres/química , Espectrofotometria/métodos , Espectroscopia de Infravermelho com Transformada de Fourier , Sinovite/patologia
14.
Biomed Pharmacother ; 113: 108759, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30856539

RESUMO

OBJECTIVE: The objective of the present study is to investigate the inhibitory effects of sinomenine (SIN) on angiogenesis in a collagen-induced arthritis (CIA) mouse model. METHODS: Arthritis assessments for all mice were recorded. The histopathological assessments were performed following haematoxylin and eosin (HE) staining. Immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) analyses were used to detect the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and angiopoietin 1 (ANG-1) in the serum and in the membrane. Immunohistochemistry was employed to detect the synovium microvessel density (MVD). RESULTS: Compared with the CIA model group, SIN significantly ameliorated swelling and erythema extension, decreased the arthritis index, reduced inflammation, cartilage damage and bone erosion, and lessened the number of CD31 positive cells on the synovium. Moreover, the levels of HIF-1α, VEGF and ANG-1 in the synovium and in the peripheral serum were increased in the untreated CIA model group but were significantly reduced in the 30 mg/kg, 100 mg/kg and 300 mg/kg SIN treatment groups. CONCLUSION: SIN could mitigate CIA by inhibiting angiogenesis, and the mechanism may associate with the HIF-1α-VEGF-ANG-1 axis. Additionally, our study provides a referable experimental basis for the use of SIN for the treatment of rheumatoid arthritis.


Assuntos
Inibidores da Angiogênese/farmacologia , Artrite Experimental/tratamento farmacológico , Morfinanos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Angiopoietina-1/metabolismo , Animais , Antirreumáticos/farmacologia , Artrite Experimental/fisiopatologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Colágeno/toxicidade , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/patologia , Membrana Sinovial/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Biomed Pharmacother ; 113: 108730, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30861411

RESUMO

Arthritis is a common chronic joint disorder, with general symptoms including stiffness and joint pain. ß-methylphenylalanine is a well-known non-proteogenic unnatural amino acid. This study analyzes the anti-arthritic activity of ß-methylphenylalanine in experimental rats. The experimental groups were as follows: group I, sham; group II, control; group III, 100 mg/kg of ß-methylphenylalanine; and group IV, 200 mg/kg of ß-methylphenylalanine. Lipid peroxidation, glutathione peroxidase (Gpx), reduced glutathione (GSH), superoxide dismutase (SOD), catalase, prostaglandin E2 (PGE2), matrix metalloproteinase-3 (MMP-3), ceruloplasmin, zinc, copper, mRNA, and protein expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were determined. Supplementation with ß-methylphenylalanine significantly reduced lipid peroxidation, copper, PGE2 and MMP-3 levels, whereas GSH, Gpx, catalase, SOD and zinc levels were increased. Supplementation with ß-methylphenylalanine significantly reduced NF-κB mRNA expression by 26% and 47.8% in groups III and IV, respectively (P < 0.045), while iNOS mRNA expression was reduced by 14.3 and 47.6% in groups III and IV, respectively. NF-κB and iNOS protein expression increased by 160% and 120% respectively, in the control rats compared to the sham rats. However, supplementation with ß-methylphenylalanine significantly reduced NF-κB protein expression by 27% and 50% in groups III and IV, respectively, while iNOS protein expression was reduced by 22.7% and 45.4% in groups III and IV, respectively. Taken together, our data show that supplementation of ß-methylphenylalanine was effective against arthritis in a rat model.


Assuntos
Aminobutiratos/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Aminobutiratos/administração & dosagem , Animais , Antirreumáticos/administração & dosagem , Artrite Experimental/patologia , Catalase/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/metabolismo , Ratos , Superóxido Dismutase/metabolismo , Zinco/metabolismo
16.
Drugs ; 79(6): 655-663, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30895473

RESUMO

Tofacitinib (Xeljanz®) is the first Janus kinase (JAK) inhibitor approved at a dosage of 5 mg twice daily (BID) in the EU and the USA for the treatment of active psoriatic arthritis (PsA), where it is indicated in combination with methotrexate for patients who have had an inadequate response or who have been intolerant to a prior therapy with a disease-modifying antirheumatic drug (DMARD). Two well-designed phase III trials (OPAL Broaden and OPAL Beyond) in patients with PsA with or without prior tumour necrosis factor inhibitor (TNFi) therapy showed that tofacitinib 5 mg BID (co-administered with methotrexate or another approved conventional synthetic DMARD) significantly improved the key clinical signs/symptoms and disability associated with PsA after 3 months of treatment, while also improving skin psoriasis, enthesitis, dactylitis, physical function and fatigue. According to interim data, the improvements in clinical signs/symptoms were maintained for up to 30 months in the ongoing long-term extension study OPAL Balance, with minimal radiographic progression seen after 12 months' therapy in the OPAL Broaden study. Tofacitinib 5 mg BID had an acceptable tolerability profile, with low incidences of serious infections, malignancies, cardiovascular events and gastrointestinal perforations over 36 months. Changes in laboratory parameters generally remained stable over 36 months of treatment. Although further studies are required to more definitively establish its efficacy and safety, currently available evidence indicates that tofacitinib expands the treatment options available for the treatment of PsA in patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Metotrexato/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/farmacologia , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/farmacologia , Resultado do Tratamento , Adulto Jovem
17.
Phytomedicine ; 58: 152876, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851579

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune diseased state, characterized by hyperplasia of the synovial membrane, degradation of cartilage, and bone erosion of diarthrodial joints. Kadsura heteroclita (Roxb) Craib (Schizandraceae), a traditional Tujia ethnomedicine called Xue Tong in China, has been long used for the prevention and treatment of rheumatic and arthritic diseases, especially in the southern China. This study aimed to evaluate anti-arthritic effects of the ethanol extract of Kadsura heteroclita stems (KHS) on complete Freund's adjuvant (CFA)-induced arthritis (AIA) in rats, as well as to explore the underlying mechanisms of anti-arthritis. METHODS: AIA was established in male Sprague-Dawley (SD) rats as described previously, and animals were daily treated by gavage with KHS ethanol extract (200, 400, or 800 mg/kg) or vehicle (0.3% CMCNa) throughout the 30-day experiment. The incidence and severity of arthritis were evaluated using clinical parameters. At the end of experiments, tissue swelling and bone destruction of the hind paws were assessed by computed tomography (CT) and histopathological analyses. Serum levels of tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), IL-6, and IL-17A and IL-17F were measured by ELISA, and protein expression of matrix metalloproteinases-1 (MMP-1), MMP-3 and tissue inhibitor of MMP-1 (TIMP-1) were detected by Western blot. RESULTS: Treatment with KHS dose-dependently inhibited paw swelling and reduced arthritis scores of AIA rats. CT images displayed that KHS remarkably protected AIA rats from tissue swelling and bone erosion of joints. Histopathological analyses revealed that KHS markedly reduced inflammatory cell infiltration, synovial proliferation, and the formation of pannus in the ankle joints of AIA rats. KHS was found to significantly suppress the production of TNF-α, IL-1 ß, IL-6, IL-17A and IL-17F, inhibited the protein expression of MMP-1 and MMP-3, and elevated the protein expressions of TIMP-1. CONCLUSION: KHS demonstrates potential anti-arthritic effects via inhibiting pivotal mediators of inflammation and cartilage destruction. This study strongly supports identification and isolation of active fractions of KHS which would be a potential candidate for further investigation as a new anti-arthritic botanical drug.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Kadsura/química , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/química , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Edema/tratamento farmacológico , Adjuvante de Freund/toxicidade , Interleucinas/sangue , Masculino , Caules de Planta/química , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Necrose Tumoral alfa/sangue
18.
Inflamm Res ; 68(4): 261-274, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30739130

RESUMO

OBJECTIVE/DESIGN: In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant. PATIENTS/TREATMENT: Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52). METHODS: Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics. RESULTS: Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected. CONCLUSIONS: While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Benzimidazóis/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Receptores Histamínicos H4/antagonistas & inibidores , Adolescente , Adulto , Idoso , Antirreumáticos/farmacologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Benzimidazóis/farmacologia , Método Duplo-Cego , Feminino , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Interleucina-17/imunologia , Masculino , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Piperidinas/farmacologia , Pirimidinas/farmacologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Resultado do Tratamento , Adulto Jovem
19.
Res Vet Sci ; 124: 32-37, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30807910

RESUMO

OBJECTIVE: To determine antioxidant effects of prophylactic treatment with gold nanoparticles (AuNPs) in the early stage of collagen-induced arthritis (CIA). METHODS: The preventive treatment with 13 nm or 50 nm AuNPs injected intraarticularly (i.a.) was started at the induction day (0) of CIA and finished in the early stage of arthritis at the day 10. At the end of experiment blood indices (erythrocyte sedimentation rate, leukocyte and erythrocyte counts), pro-/antioxidant status of blood serum (the amount of malondialdehyde, catalase and total antioxidant activity), and internal organs' weight as well as the changes in the joint tissues and their microscopic structure were evaluated. RESULTS: Both 13 nm and 50 nm AuNPs showed antioxidant effect by increasing the level of catalase activity in the early stage of experimental arthritis. Preventive treatment with 50 nm more than with 13 nm AuNPs suppressed joint swelling. Histopathological asssesment revealed statistically significant reduction of synovial angiogenesis and erosion formation in the cartilage. Pilot transmission electron microscopy (TEM) analysis showed predominant accumulation of 13 nm in the synovial fibroblast lineage cells. CONCLUSIONS: Intraarticular injections of 13 nm or 50 nm AuNPs showed an antioxidant action significantly raising catalase activity without causing negative effects on hematological indices. Prophylactic treatment with 50 nm more than with 13 nm AuNPs suppressed joint swelling, synovial angiogenesis and cartilage erosion in the initial stage of arthritis.


Assuntos
Antioxidantes/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Colágeno/efeitos adversos , Ouro/farmacologia , Nanopartículas Metálicas , Animais , Artrite Experimental/induzido quimicamente , Masculino , Tamanho da Partícula , Distribuição Aleatória , Ratos , Ratos Wistar
20.
J Ethnopharmacol ; 235: 248-254, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30769038

RESUMO

ETHNOPHARMMACOLOGICAL RELEVANCE: Aleurites moluccana is used in folk medicine to treat pain, fever, asthma, hepatitis, gastric ulcer and inflammatory process in general, and the nut oil had been topically applied to treat arthritis and other joint pain, however the seeds are classified as toxic for oral use. AIM: Faced with the need for new alternative to treat the symptoms and modify rheumatoid arthritis (RA) the aim of this work was to evaluate the effects of A. moluccanus' leaves dried extract in rats and mice submitted to complete Freund adjuvant (CFA)-induced RA. MATERIAL AND METHODS: Wistar Rats and Swiss mice were submitted to CFA-induced RA in the right hindpaw. They received A. moluccanus extract (orally; p.o.), dexamethasone (subcutaneously), 2″-O-rhamnosylswertisin (p.o.) or vehicle (p.o.), from the 14th day after the CFA injection for up to 8 days. The mechanical hypersensitivity was evaluated using the von Frey filaments and the paw-oedema was measured using a plethysmometer. The rats' injected hindpaw was used to perform the histological analysis. RESULTS: A. moluccanus was able to significantly reduce the mechanical hypersensitivity in both ipsi- and contralateral hindpaws of mice injected with CFA, in a dose dependent manner. Furthermore, the paw-oedema was progressively reduced by A. moluccanus. Similar results were obtained for the positive-control drug dexamethasone and the isolated compound 2″-O-rhamnosylswertisin. Besides the effects mentioned above, the extract was also effective to repair the joint damage in CFA-induced RA rats, including reduction of fibrosis, cartilage degradation and bone erosion scores. CONCLUSION: These results together with the literature data reinforce the anti-hypersensitivity and anti-inflammatory activity of A. moluccanus extract. Part of the observed effects is due to the presence of the compound 2″-O-rhamnosylswertisin. The fact that the extract acted as a disease modifier point this herbal product as a promisor and safe tool to treat RA and other associated chronic diseases.


Assuntos
Aleurites/química , Artrite Experimental/tratamento farmacológico , Flavonas/farmacologia , Extratos Vegetais/farmacologia , Ramnose/análogos & derivados , Animais , Antirreumáticos/isolamento & purificação , Antirreumáticos/farmacologia , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Edema/tratamento farmacológico , Edema/patologia , Flavonas/isolamento & purificação , Adjuvante de Freund/administração & dosagem , Masculino , Medicina Tradicional/métodos , Camundongos , Extratos Vegetais/isolamento & purificação , Folhas de Planta , Ratos , Ratos Wistar , Ramnose/isolamento & purificação , Ramnose/farmacologia
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