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1.
J Oncol Pharm Pract ; 26(5): 1230-1233, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31735133

RESUMO

INTRODUCTION: Immune checkpoint inhibitors and angiogenesis inhibitors are novel treatment options for renal cell carcinoma and widely used in clinical practice. They are related with adverse events that occur as a consequence of immune system activation and inhibition of angiogenesis. Herein, we report a rare case of inflammatory arthritis seen in a patient treated with an anti Programmed cell death-1 pembrolizumab and an anti-vascular endothelial growth factor pazopanib. CASE REPORT: A 60-year-old Caucasian male presented to our clinic with inflammatory arthritis with pitting edema. He had been started on pembrolizumab therapy for metastatic renal cell carcinoma after enrolling in the KEYNOTE-679 study. After six cycles of treatment with pembrolizumab, metastasis had been determined in the lung. Then, the patient's therapy was changed to pazopanib. While the patient was on pazopanib treatment, he noticed a gradual swelling of both hands. Rheumatoid factor, anti-nuclear antibody and anti-cyclic citrullinated peptide were negative. Joint ultrasonography revealed acute tenosynovitis and soft tissue swelling with pitting edema, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. Management and outcome: He was started on 10 mg prednisolone daily. His symptoms dramatically responded to corticosteroid. He continued to take pazopanib. Then, the patient was discharged with 10 mg prednisolone daily. DISCUSSION: Pembrolizumab- and/or pazopanib-induced remitting seronegative symmetrical synovitis with pitting edema can be among the rare rheumatic immune-related adverse events that clinicians may encounter as the immune check point inhibitors and anti-VEGF use increases. Corticosteroid therapy can relieve symptoms and cessation of therapy may not be necessary.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Edema/induzido quimicamente , Neoplasias Renais/tratamento farmacológico , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Sinovite/induzido quimicamente , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/diagnóstico , Quimioterapia Combinada , Edema/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Sinovite/diagnóstico
2.
J Vet Sci ; 20(6): e67, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31775194

RESUMO

The intra-articular use of hyaluronic acid (HA) for the treatment of synovitis and osteoarthritis is still controversial. As a consequence, corticosteroids remain the most frequently employed therapeutic agents, despite their potential systemic and local deleterious effects. This study examined the anti-inflammatory, antioxidant, and chondroprotective activities of low and high molecular weight hyaluronic acid (LMW-HA and HMW-HA) on lipopolysaccharide (LPS)-induced synovitis in horses compared to triamcinolone acetonide (TA). LPS was injected in the metacarpophalangeal joints, which were treated intra-articularly with either TA (as control) or LMW-HA or HMW-HA. Joint clinical evaluation and synovial fluid (SF) analysis were performed at 0, 8, 24, and 48 h. The white blood cell counts (WBC), prostaglandin E2 (PGE2), interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor-α, chondroitin sulfate (CS) and HA concentrations, oxidative burst, and HA molecular weights were measured. TA reduced the lameness, swelling, and PGE2 release but increased the SF CS concentrations enormously at 24h and 48h, and decreased the SF HA modal molecular weight. These results indicate the breakdown of articular cartilage aggrecan and SF HA. In contrast, LMW-HA and HMW-HA were less effective in reducing the inflammation symptoms, but preserved the joints because only a modest increase in CS occurred at 24 h, decreasing at 48 h, and the SF HA was maintained. The HA-treatment also had anti-inflammatory actions, and LMW-HA was the most effective in reducing the release of cytokine. In summary, the HA treatment inhibited efficiently the digestion of cartilage proteoglycans and SF HA breakdown.


Assuntos
Doenças dos Cavalos/tratamento farmacológico , Ácido Hialurônico/farmacologia , Injeções Intra-Articulares/veterinária , Líquido Sinovial/efeitos dos fármacos , Sinovite/veterinária , Viscossuplementos/farmacologia , Animais , Doenças dos Cavalos/induzido quimicamente , Cavalos , Lipopolissacarídeos/administração & dosagem , Masculino , Distribuição Aleatória , Sinovite/induzido quimicamente , Sinovite/tratamento farmacológico
3.
Am J Vet Res ; 80(11): 1001-1006, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31644340

RESUMO

OBJECTIVE: To investigate the ability of a proprietary antagonist of E-type prostanoid receptor (EP) 4, grapiprant, and carprofen to attenuate lameness attributable to urate-induced synovitis in dogs. ANIMALS: 5 purpose-bred hound-cross dogs. PROCEDURES: A blinded, 3-way crossover study was performed. Dogs received each of 3 treatments (L-766, a proprietary antagonist of EP4; 4.0 mg/kg), grapiprant (an antagonist of EP4; 2.0 mg/kg), and carprofen (4.4 mg/kg); dogs received 4 doses of each treatment (14 and 2 hours before and 22 and 46 hours after urate injection). Synovitis was induced by intra-articular injection of sodium urate. Measurements (vertical ground reaction forces and clinical lameness scores) were obtained immediately before (0 hours; baseline) and 6, 12, 24, 36, and 48 hours after sodium urate injection. All data were analyzed with repeated-measures ANOVA. RESULTS: Lameness scores at 6 hours were significantly higher than baseline lameness scores for all treatments. Lameness scores for the grapiprant treatment remained significantly higher at 12 and 24 hours, compared with baseline lameness scores. Lameness scores for the carprofen treatment were significantly lower than lameness scores for the grapiprant treatment at 6, 12, and 24 hours. Analysis of peak vertical force and vertical impulse data revealed a pattern similar to that for lameness scores. Treatment with L-766 resulted in a significantly higher vertical impulse at 48 hours than did treatment with carprofen or grapiprant. CONCLUSIONS AND CLINICAL RELEVANCE: In these dogs, carprofen was the most effective treatment for attenuating lameness induced by injection of sodium urate, and grapiprant was the least effective treatment.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Carbazóis/uso terapêutico , Doenças do Cão/tratamento farmacológico , Coxeadura Animal/tratamento farmacológico , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Compostos de Sulfonilureia/uso terapêutico , Sinovite/veterinária , Animais , Carbazóis/farmacologia , Estudos Cross-Over , Cães , Marcha , Injeções Intra-Articulares/veterinária , Coxeadura Animal/induzido quimicamente , Masculino , Método Simples-Cego , Sinovite/induzido quimicamente , Sinovite/tratamento farmacológico , Ácido Úrico
4.
Sci Rep ; 9(1): 10864, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350444

RESUMO

The infrapatellar fat pad (IFP) serves as a reservoir of Mesenchymal Stem Cells (MSC), and with adjacent synovium plays key roles in joint disease including the production of Substance P (SP) affecting local inflammatory responses and transmitting nociceptive signals. Here, we interrogate human IFP-derived MSC (IFP-MSC) reaction to inflammatory and pro-fibrotic environments (cell priming by TNFα/IFNγ and TNFα/IFNγ/CTGF exposure respectively), compared with bone marrow-derived MSC (BM-MSC). Naïve IFP-MSC exhibit increased clonogenicity and chondrogenic potential compared with BM-MSC. Primed cells experienced dramatic phenotypic changes, including a sharp increase in CD10, upregulation of key immunomodulatory transcripts, and secreted growth factors/cytokines affecting key pathways (IL-10, TNF-α, MAPK, Ras and PI3K-Akt). Naïve, and more so primed MSC (both) induced SP degradation in vitro, reproduced with their supernatants and abrogated with thiorphan, a CD10 inhibitor. These findings were reproduced in vivo in a rat model of acute synovitis, where transiently engrafted human IFP-MSC induced local SP reduction. Functionally, primed IFP-MSC demonstrated sustained antagonism of activated human peripheral blood mononuclear cells (PBMC) proliferation, significantly outperforming a declining dose-dependent effect with naïve cohorts. Collectively, our in vitro and in vivo data supports cell priming as a way to enhance the immunoregulatory properties of IFP-MSC, which selectively engraft in areas of active synovitis/IFP fibrosis inducing SP degradation, resulting in a cell-based product alternative to BM-MSC to potentially treat degenerative/inflammatory joint diseases.


Assuntos
Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Neprilisina/metabolismo , Fenótipo , Proteólise/efeitos dos fármacos , Substância P/metabolismo , Sinovite/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/patologia , Adulto , Animais , Células da Medula Óssea/metabolismo , Células Cultivadas , Fator de Crescimento do Tecido Conjuntivo/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fibrose , Voluntários Saudáveis , Humanos , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon gama/farmacologia , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Sinovite/induzido quimicamente , Fator de Necrose Tumoral alfa/farmacologia
5.
BMC Vet Res ; 15(1): 225, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269952

RESUMO

BACKGROUND: Acute ruminal acidosis (ARA) is a metabolic disease of cattle characterized by an aseptic synovitis. ARA is the result of an increased intake of highly fermentable carbohydrates that frequently occurs in dairy cattle subjected to high production requirements. In human joint diseases such as rheumatoid arthritis and gout, several pro-inflammatory molecules are increased in the synovial fluid, including cytokines, prostaglandin E2 (PGE2), metalloproteinases, and neutrophil extracellular traps (NETs). The aim of this study was to identify the presence of proinflammatory mediators and neutrophils in the synovial fluid of heifers with ARA, induced by an oligofructose overload. Five heifers were challenged with an oligofructose overload (13 g/kg BW) dissolved in water. As a control, a similar vehicle volume was used in four heifers. Synovial fluid samples were collected from the tarso-crural joint and PGE2, IL-6, IL-1ß, ATP, lactate dehydrogenase (LDH), albumin, glucose, matrix metalloproteinase-9 (MMP-9), cellular free DNA, NETs, and serpin B1 were analyzed at 0, 9, and 24 h post treatment. RESULTS: At 9 h post oligofructose overload, an increase of IL-1ß, IL-6, PGE2, serpin B1 and LDH was detected in the joints when compared to the control group. At 24 h, the synovial fluid was yellowish, viscous, turbid, and contained abundant neutrophils. An increase of DNA-backbone-like traps, histone 3 (H3cit), aggregated neutrophil extracellular traps (aggNETs), and serpin B1 were observed 24 h post treatment. Furthermore, albumins, LDH, ATP, MMP-9, IL-6, and IL-1ß were increased after 24 h. CONCLUSIONS: The overall results indicate that IL-1ß, IL-6 and PGE2, were the earliest proinflammatory parameters that increased in the synovial fluid of animals with ARA. Furthermore, the most sever inflammatory response in the joint was observed after 24 h and could be associated with a massive presence of neutrophils and release of aggNETs.


Assuntos
Doenças dos Bovinos/metabolismo , Líquido Sinovial/citologia , Sinovite/veterinária , Acidose/induzido quimicamente , Acidose/patologia , Animais , Bovinos , Doenças dos Bovinos/patologia , Feminino , Neutrófilos/patologia , Oligossacarídeos/administração & dosagem , Rúmen/química , Líquido Sinovial/química , Sinovite/induzido quimicamente , Sinovite/patologia
6.
Acta Vet Scand ; 61(1): 28, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221173

RESUMO

BACKGROUND: Dexamethasone is used for the intra-articular route of administration in management of aseptic arthritis in horses. Despite its widespread use there is very little quantitative data of the disposition and response to dexamethasone. The aim of this study was to investigate and describe the synovial fluid and plasma dexamethasone concentration over time and to explore the relation between synovial fluid concentration and response using clinical endpoints as response biomarkers after IA injection of dexamethasone disodium salt solution in an equine model of synovitis. RESULTS: Inflammation was induced in the radiocarpal joint of six horses by injection of 2 ng lipopolysaccharide (LPS). Two hours later either saline or dexamethasone was injected in the same joint in a two treatment cross over design. Each horse was treated once with one of the six doses dexamethasone used (0.01, 0.03, 0.1, 0.3, 1 or 3 mg) and once with saline. Dexamethasone was quantified by means of UHPLC-MS/MS. Dexamethasone disposition was characterised by means of a non-linear mixed effects model. Lameness was evaluated both objectively with an inertial sensor based system and subjectively scored using a numerical scale (0-5). Joint circumference, skin temperature over the joint and rectal temperature were also recorded. The LPS-challenge induced lameness in all horses with high inter-individual variability. Dexamethasone significantly decreased lameness compared with saline. Other variables were not statistically significant different between treatments. Objective lameness scoring was the most sensitive method used in this study to evaluate the lameness response. A pharmacokinetic/pharmacodynamic model was successfully fitted to experimental dexamethasone and lameness data. The model allowed characterization of the dexamethasone synovial fluid concentration-time course, the systemic exposure to dexamethasone after intra-articular administration and the concentration-response relation in an experimental model of synovitis. CONCLUSIONS: The quantitative data improve the understanding of the pharmacology of dexamethasone and might serve as input for future experiments and possibly contribute to maintain integrity of equine sports.


Assuntos
Dexametasona/administração & dosagem , Doenças dos Cavalos/induzido quimicamente , Doenças dos Cavalos/tratamento farmacológico , Lipopolissacarídeos , Sinovite/veterinária , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Dexametasona/farmacocinética , Cavalos , Injeções Intra-Articulares/veterinária , Sinovite/induzido quimicamente , Sinovite/tratamento farmacológico
8.
J Nutr Sci Vitaminol (Tokyo) ; 65(1): 8-18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814416

RESUMO

The present study was conducted to assess the effect of all-trans retinoic acid (ATRA) on synovial explants from rats with rheumatoid arthritis (RA) induced by lipopolysaccharides (LPS). In our study, synovial membranes were excised from the knees of healthy adult Wistar female rats under sterile conditions. We first investigated the synoviums incubated in a control medium or in a medium containing 10 µg/mL LPS, each for 24, 48, and 72 h (LPS-experiment). The changes in inflammatory response from the synoviums were observed at different culture times. Then, we assessed the synoviums exposed to different ATRA concentrations for 24 h (ATRA-experiment). The controls (blank, model group, and solvent groups) were set up. The effects of ATRA on synovitis were evaluated by measuring the production of cytokines, and nitric oxide (NO) and the expression of cartilage damage related proteases. In the LPS-experiment, LPS contributed to the release of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9) in synovial explants. Importantly, LPS did not cause a significant pathological damage. The inflammatory response observed in this model was significant for 24 h, suggesting that LPS-induced synovial explants were successfully established. In the ATRA-experiment, ATRA suppressed the expression of IL-6, TNF-α, NO, a disintegrin and metalloprotease with thrombospondin motifs-4 (ADAMTS-4), MMP-3, and MMP-9. Taken together, ATRA exhibited inhibitory effects on LPS-induced synovial immune inflammatory response stimulated by the regulation of inflammatory mediators and cartilage damage related proteases in synovial explants, demonstrating a potential protective effect on synovitis and joint destruction in the patients with RA.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Articulação do Joelho/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Lipopolissacarídeos , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Sinovite/induzido quimicamente , Sinovite/tratamento farmacológico , Sinovite/metabolismo
9.
Drug Des Devel Ther ; 12: 4095-4105, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30584274

RESUMO

Purpose: Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by aggressive and symmetric polyarthritis. Mammalian target of rapamycin (mTOR) was reported to be a new target for RA therapy and its inhibitor rapamycin can significantly reduce the invasive force of fibroblast-like synoviocytes. Here, we determined the effect of curcumin to alleviate inflammation and synovial hyperplasia for the therapy of RA. Materials and methods: Collagen-induced arthritis (CIA) was developed in Wistar rats and used as a model resembling RA in humans. Rats were treated with curcumin (200 mg/kg) and the mTOR inhibitor rapamycin (2.5 mg/kg) daily for 3 weeks. Effects of the treatment on local joint, peripheral blood, and synovial hyperplasia in the pathogenesis of CIA were analyzed. Results: Curcumin and rapamycin significantly inhibited the redness and swelling of ankles and joints in RA rats. Curcumin inhibited the CIA-induced mTOR pathway and the RA-induced infiltration of inflammatory cells into the synovium. Curcumin and rapamycin treatment inhibited the increased levels of proinflammatory cytokines including IL-1ß, TNF-α, MMP-1, and MMP-3 in CIA rats. Conclusion: Our findings show that curcumin alleviates CIA-induced inflammation, synovial hyperplasia, and the other main features involved in the pathogenesis of CIA via the mTOR pathway. These results provide evidence for the anti-arthritic properties of curcumin and corroborate its potential use for the treatment of RA.


Assuntos
Anti-Inflamatórios/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/prevenção & controle , Curcumina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Membrana Sinovial/efeitos dos fármacos , Sinovite/prevenção & controle , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/enzimologia , Artrite Experimental/patologia , Colágeno Tipo II , Hiperplasia , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Membrana Sinovial/enzimologia , Membrana Sinovial/patologia , Sinovite/induzido quimicamente , Sinovite/enzimologia , Sinovite/patologia , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
10.
BMC Musculoskelet Disord ; 19(1): 291, 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115046

RESUMO

BACKGROUND: The major complaint of knee osteoarthritis (OA) is persistent pain. Unlike acute inflammatory pain, persistent pain is usually difficult to manage since its pathology is not fully understood. To elucidate the underlying mechanisms of persistent pain, we established 2 different inflammation-induced arthritis models by injecting monoiodo-acetic acid (MIA) into the joint cavity and performed integrated analyses of the structural changes in the synovial tissue and articular cartilage, sensory neuron rearrangement, and pain avoidance behavior in a rat arthritis model. METHODS: Male Wistar rats received intra-articular injections of MIA (0.2 mg/30 µL, low-dose group; 1 mg/30 µL, high-dose group) in the right knee and phosphate buffered saline (PBS; 30 µL, control group) in the left knee. Fluorogold (FG), a retrograde neural tracer, was used to label the nerve fibers for the identification of sensory neurons that dominate the joints in the dorsal root ganglion (DRG). Both knees were subjected to the intra-articular injection of 2% FG in PBS (5 µL) under anesthesia 5-7 days prior to sacrifice. We performed pain avoidance behavior tests (incapacitance and von Frey tests) at 0, 1, 3, 5, 7, 14, 21, and 28 days. At 5, 14, and 28 days, the rats were sacrificed and the knee joint and DRG were excised for histological assessment. The knee joints were stained with hematoxylin and eosin, safranin O, and calcitonin gene-related peptide (CGRP). The DRG were immunostained with CGRP. RESULTS: A transient inflammatory response followed by mild articular cartilage degeneration was observed in the low-dose MIA model versus persistent inflammation with structural changes in the synovial tissue (fibrosis) in the high-dose model. In the high-dose model, full-thickness cartilage degeneration was observed within 2 weeks post-MIA injection. The pain avoidance behavior tests indicated that persistent synovial inflammation and structural changes of the infrapatellar fat pad may play important roles in persistent knee joint pain before the articular cartilage degeneration reaches the subchondral bone. CONCLUSIONS: Transient inflammation without structural changes of the synovial tissues did not induce persistent pain in the rat knee joint before degradation of the articular cartilage reached the subchondral bone plate.


Assuntos
Artralgia/patologia , Cartilagem Articular/patologia , Osteoartrite/patologia , Membrana Sinovial/patologia , Sinovite/patologia , Animais , Artralgia/induzido quimicamente , Artralgia/metabolismo , Artralgia/psicologia , Aprendizagem da Esquiva , Comportamento Animal , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Cartilagem Articular/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Ácido Iodoacético , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/metabolismo , Osteoartrite/psicologia , Percepção da Dor , Ratos Wistar , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Membrana Sinovial/metabolismo , Sinovite/induzido quimicamente , Sinovite/metabolismo , Sinovite/psicologia , Fatores de Tempo
11.
Osteoarthritis Cartilage ; 26(10): 1369-1378, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30031926

RESUMO

OBJECTIVE: Knee osteoarthritis (OA) is associated with ongoing pain and joint damage that can be punctuated by acute flares of pain and inflammation. Synovitis in normal knees might resolve without long-term detriment to joint function. We hypothesised that osteoarthritis is associated with impaired resilience to inflammatory flares. DESIGN: We induced synovitis by injecting carrageenan into rat knees with or without meniscal transection (MNX)-induced OA, and measured synovitis, weightbearing asymmetry (pain behaviour), and joint damage up to 35 days after OA induction (23 days after carrageenan-injection). RESULTS: Carrageenan injection induced weightbearing asymmetry for 1 week, transient increase in knee diameter for 2 days, and a sustained increase in synovial macrophages, endothelial cell proliferation and vascular density compared with naive vehicle-injected controls. MNX surgery induced weightbearing asymmetry and histological evidence of OA. Carrageenan-injection in MNX-operated knees was followed for 2 days by increased weightbearing asymmetry compared either to MNX+vehicle or to sham+carrageenan groups. OA structural damage and synovitis at day 35 were greater in MNX+carrageenan compared to MNX+vehicle and sham+carrageenan groups. Carrageenan injection did not induce OA in Sham-operated knees. CONCLUSION: Intra-articular injection of the pro-inflammatory compound carrageenan in OA and sham-operated control knees induced a short term increase in joint pain. Even though pain flares resolved in both groups and damage was not induced in sham-operated knees, carrageen injection exacerbated long-term joint damage in OA knees. OA knees display less resilience to inflammatory episodes. Preventing inflammatory flares may be particularly important in preventing symptoms and long term joint damage in OA.


Assuntos
Artralgia/diagnóstico , Artrite Experimental , Cartilagem Articular/patologia , Articulação do Joelho/patologia , Osteoartrite do Joelho/diagnóstico , Sinovite/patologia , Animais , Artralgia/etiologia , Carragenina/toxicidade , Masculino , Osteoartrite do Joelho/complicações , Ratos , Ratos Endogâmicos Lew , Sinovite/induzido quimicamente , Sinovite/complicações
12.
Drug Deliv Transl Res ; 8(5): 1421-1435, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29947020

RESUMO

Polyelectrolyte nanoparticle constructs (NPs) comprising salmon calcitonin (sCT), chitosan (CS), and hyaluronic acid (HA) were previously established as having anti-inflammatory potential when injected via the intra-articular (i.a.) route to a mouse model. We attempted to translate the formulation to a large animal model, the lipopolysaccharide (LPS)-stimulated equine model of joint inflammation. The aim was to manufacture under aseptic conditions to produce sterile pyrogen-free NPs, to confirm physicochemical characteristics, and to test toxicity and efficacy in a pilot study. NP dispersions were successfully formulated using pharmaceutical-grade source materials and were aseptically manufactured under GMP-simulated conditions in a grade A modular aseptic processing workstation. The NP formulation had no detectable pathogen or endotoxin contamination. NPs were then tested versus a lactated Ringer's solution control following single i.a. injections to the radiocarpal joints of two groups of four horses pre-treated with LPS, followed by arthrocentesis at set intervals over 1 week. There was no evidence of treatment-related toxicity over the period. While there were no differences between clinical read-outs of the NP and the control, two synovial fluid-derived biomarkers associated with cartilage turnover revealed a beneficial effect of NPs. In conclusion, NPs comprising well-known materials were manufactured for an equine i.a.-injectable pilot study and yielded no NP-attributable toxicity. Evidence of NP-associated benefit at the level of secondary endpoints was detected as a result of decreases in synovial fluid inflammatory biomarkers.


Assuntos
Calcitonina/administração & dosagem , Quitosana/administração & dosagem , Ácido Hialurônico/administração & dosagem , Nanoconjugados/química , Sinovite/tratamento farmacológico , Animais , Artrocentese , Biomarcadores/metabolismo , Calcitonina/farmacologia , Quitosana/farmacologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Cavalos , Ácido Hialurônico/farmacologia , Injeções Intra-Articulares , Lipopolissacarídeos/efeitos adversos , Nanoconjugados/toxicidade , Projetos Piloto , Líquido Sinovial/metabolismo , Sinovite/induzido quimicamente , Sinovite/metabolismo
13.
BMC Res Notes ; 11(1): 255, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29695269

RESUMO

OBJECTIVE: To identify if synovial fluid prostaglandin E2 increases in response to a single intra-articular dose of bupivacaine in the normal canine stifle. RESULTS: There were no significant differences in synovial fluid prostaglandin E2 (PGE2) concentrations between treatment groups or over time within bupivacaine or saline groups. Samples requiring ≥ 3 arthrocentesis attempts had significantly higher PGE2 concentrations compared to samples requiring 1 or 2 attempts. Following correction for number of arthrocentesis attempts, PGE2 concentrations were significantly higher than baseline at 24 and 48 h in the bupivacaine group; however there were no significant differences between the bupivacaine and saline groups. In normal dogs, a single bupivacaine injection did not cause significant synovial inflammation, as measured by PGE2 concentrations, compared to saline controls. Future research should minimize aspiration attempts and include evaluation of the synovial response to bupivacaine in clinical cases with joint disease.


Assuntos
Anestésicos Locais/efeitos adversos , Bupivacaína/efeitos adversos , Dinoprostona/metabolismo , Joelho de Quadrúpedes/efeitos dos fármacos , Líquido Sinovial/efeitos dos fármacos , Sinovite/induzido quimicamente , Anestésicos Locais/administração & dosagem , Animais , Artrocentese , Bupivacaína/administração & dosagem , Cães , Injeções Intra-Articulares , Masculino , Sinovite/metabolismo
15.
J Med Case Rep ; 12(1): 48, 2018 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-29478412

RESUMO

BACKGROUND: Novel immune checkpoint inhibitors have been often utilized for different types of malignancies as salvage therapy with varying success. One obstacle to immune checkpoint inhibitor use is the higher incidence of immune-mediated side effects that can prompt discontinuation of therapy. Remitting seronegative symmetrical synovitis with pitting edema has been described with immune checkpoint inhibitors only once previously. We report a case of a patient who developed remitting seronegative symmetrical synovitis with pitting edema related to immune checkpoint inhibitor therapy and stress that these symptoms can be managed without cessation of immune checkpoint inhibitor therapy. CASE PRESENTATION: We present a 70-year-old white man who presented with 4 months of progressive inflammatory arthritis with pitting edema. He had been started on nivolumab therapy for his metastatic melanoma with excellent response prior to symptom onset. The symptoms started in his knees and subsequently involved both hands and feet. On evaluation, he was wheelchair bound and completely dependent for all activities of daily living. Evaluation revealed negative serological testing and plain film imaging. Ultrasound demonstrated diffuse flexor tenosynovitis and soft tissue swelling, and a diagnosis of remitting seronegative symmetrical synovitis with pitting edema was made. He was treated with orally administered corticosteroids (0.5 mg/kg per day) which improved his symptoms significantly and allowed him to regain prior independent functioning. His corticosteroids were tapered (0.15 mg/kg per day) but not discontinued and his nivolumab treatment was not interrupted. In follow up he continued to have stable control of his melanoma as well as his remitting seronegative symmetrical synovitis with pitting edema. CONCLUSIONS: In conclusion we present the first case of nivolumab-induced remitting seronegative symmetrical synovitis with pitting edema that is controlled by maintenance low-dose orally administered corticosteroids allowing for continuation of nivolumab therapy. Clinicians who encounter mild-to-moderate immune checkpoint inhibitor immune-mediated adverse effects can consider maintaining immune checkpoint inhibitor therapy with concomitant low-dose corticosteroids rather than abrupt cessation of the immune checkpoint inhibitor.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Edema/induzido quimicamente , Melanoma/tratamento farmacológico , Sinovite/induzido quimicamente , Administração Oral , Idoso , Edema/tratamento farmacológico , Glucocorticoides/administração & dosagem , Mãos/diagnóstico por imagem , Humanos , Imunoterapia/efeitos adversos , Masculino , Nivolumabe , Prednisona/administração & dosagem , Radiografia , Sinovite/diagnóstico por imagem , Sinovite/tratamento farmacológico
16.
J Oncol Pharm Pract ; 24(5): 389-392, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28355971

RESUMO

Pembrolizumab, a selective anti-PD-1 humanized monoclonal antibody, reactivates T cells to fight cancer. Immune-related adverse events such as autoimmune colitis, pneumonitis, hepatitis, nephritis, hypophysitis, and thyroiditis may occur during, or weeks to months after therapy. Pemprolizumab-induced synovitis is rarely reported. With the wide use of immunotherapy to treat cancers, physicians need to be aware of this rare immune-related adverse event and provide immediate treatment to avoid permanent joint damage.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Sinovite/induzido quimicamente , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/uso terapêutico , Feminino , Humanos , Imunoterapia , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade
17.
Semin Arthritis Rheum ; 47(6): 907-910, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29191375

RESUMO

OBJECTIVE: Immune checkpoint inhibitors are effective cancer therapies that have been associated with immune-related adverse events (irAEs). Recent reports of irAEs describe symptoms resembling classic rheumatologic syndromes, most notably associated with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor blockade. Though cases have been described, there are fewer reports of rheumatologic disease associated with programmed cell death protein-1 (PD-1) inhibitors. Here, we describe a series of four patients presenting to the Brigham and Women's Hospital (BWH) Arthritis Center with de novo polymyalgia rheumatica (PMR)-type conditions and/or peripheral synovitis after treatment with PD-1/PD-Ligand 1 (PD-L1) pathway inhibitors. METHODS: Patients with metastatic renal cell carcinoma (RCC) who were treated with PD-1/PD-L1 pathway inhibitors and subsequently developed complaints of new joint pain were referred to the BWH Arthritis Center as part of routine care and identified retrospectively. The electronic medical record was reviewed for cancer history and treatment, rheumatologic symptoms, physical exam, laboratory testing, and clinical course. RESULTS: All four patients developed irAEs consistent with a PMR-type syndrome and/or peripheral synovitis. Symptoms persisted despite discontinuation of the PD-1/PD-L1 pathway inhibitors; however, three of the patients responded well to oral glucocorticoids alone while one patient required the addition of oral methotrexate. All patients had an eventual decline in inflammatory markers. CONCLUSION: These cases highlight the need for both oncologists and rheumatologists to recognize the development of rheumatologic disease during treatment with immune checkpoint blockade. Further investigation is needed to optimize the management of irAEs, particularly considering the increasing use of checkpoint inhibitors to treat malignancies.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Polimialgia Reumática/induzido quimicamente , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sinovite/induzido quimicamente , Idoso , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Pessoa de Meia-Idade , Nivolumabe , Estudos Retrospectivos
19.
Vet J ; 229: 54-59, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29183574

RESUMO

Joint disease and osteoarthritis are common problems in the horse and numerous experimental studies have been developed to determine the safety and efficacy of new therapies. Synovitis, a critical component of joint disease, has been experimentally induced using recombinant interleukin-1 beta (reIL-1ß) to investigate new joint therapies in a controlled environment, although the use of reIL-1ß has not been reported in the equine tarsocrural joint. A common consequence of performing controlled experiments is that articular tissue collection typically requires general anesthesia or euthanasia. This report describes a minimally invasive surgical biopsy technique to harvest joint tissues from the tarsocrural joint in standing horses. The aims of the study were to assess subjective and objective pain parameters following reIL-1ß induced synovitis in the tarsocrural joint and to describe the surgical technique including the location and quantity of tissues obtained with this method. Experimental synovitis was induced using reIL-1ß in one equine tarsocrural joint of each horse using a randomised controlled design. The minimally invasive surgical technique provided sufficient amounts of articular cartilage from the medial malleolus of the tibia and synovium to perform viability, biochemical and histological assessments without necessitating general anesthesia. The minimally invasive technique also allowed for lameness assessment that could have been influenced by more invasive methods of tissue collection. No incisional or lameness complications were detected after use. The synovitis model and surgical technique provided ample tissue for laboratory evaluation and avoided general anesthesia or sacrifice of the horse.


Assuntos
Artroscopia/veterinária , Doenças dos Cavalos/patologia , Interleucina-1beta/administração & dosagem , Líquido Sinovial/efeitos dos fármacos , Sinovite/veterinária , Tarso Animal , Animais , Cartilagem Articular/patologia , Feminino , Cavalos , Injeções Intra-Articulares/veterinária , Interleucina-1beta/farmacologia , Coxeadura Animal , Masculino , Dor Pós-Operatória/veterinária , Postura , Sinovite/induzido quimicamente , Sinovite/patologia , Resultado do Tratamento
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