RESUMO
PURPOSE: To characterize the ocular inflammatory side effects associated with immune checkpoint inhibitor (CPI) treatment in a Northern California population. DESIGN: Retrospective case series. PARTICIPANTS: Patients receiving CPI within an integrated healthcare delivery system. METHODS: All patients within Kaiser Permanente Northern California receiving CPI between January 1, 2012 and November 1, 2018 were identified. Medical records of those seen in the ophthalmology clinic at least once were retrospectively reviewed. MAIN OUTCOME MEASURES: Type and duration of ocular inflammation, indication for and exposure to CPI, time from exposure to diagnosis of ocular inflammation. RESULTS: 31 cases of ocular inflammation were identified in 5061 patients (0.61%) receiving CPI. Mean ± SD age was 67 ± 11.9 (range 38-89). Mean time from exposure to diagnosis was 6.8 ± 5.5 months (range 0.5-17). 87% of cases were bilateral, and 43% of cases were chronic. Average ophthalmology follow-up was 16 ± 18 months (range 0-71). 16/31 (52%) had anterior uveitis, 7/31 (23%) had serous retinal detachment or panuveitis resembling Vogt-Koyanagi-Harada syndrome, 4/31 (13%) had papillitis, and 6/31 (19%) had diplopia or ocular motility defect. There was one case each (3.2%) of melanoma associated retinopathy, corneal edema, granulomatous lacrimal gland enlargement, and choroidal neovascularization. CONCLUSIONS: Ocular inflammation is a rare immune associated side effect of CPI treatment, the most common manifestation of which is anterior uveitis.
Assuntos
Uveíte Anterior , Uveíte , Síndrome Uveomeningoencefálica , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Estudos Retrospectivos , Síndrome Uveomeningoencefálica/diagnóstico , Transtornos da Visão/tratamento farmacológico , Uveíte Anterior/tratamento farmacológico , Doença Aguda , Inflamação/tratamento farmacológico , Uveíte/tratamento farmacológicoRESUMO
PURPOSE: Oleander is a poisonous plant with extensively documented systemic side effects; however, oleander's ophthalmic side effects have not been detailed in the literature. We report a case of oleander-associated keratitis with subsequent corneal edema and anterior uveitis. METHODS: This is a case report and review of relevant literature. RESULTS: A 58-year-old woman presented with large corneal epithelial defect after being struck in the eye with an oleander leaf. Despite treatment with topical moxifloxacin, she developed severe corneal edema and anterior uveitis. A diagnosis of oleander-associated ocular inflammation with secondary corneal edema was made, given the temporal relationship, and treatment was initiated with topical prednisolone and cyclopentolate. However, the corneal edema and inflammation continued to progress until oral prednisone and topical difluprednate were initiated. Visual acuity, anterior uveitis, and corneal edema significantly improved with aggressive immunomodulation. Follow-up at 1 month confirmed complete recovery of symptoms, corneal edema and anterior uveitis. CONCLUSIONS: Severe corneal edema and anterior uveitis can be associated with oleander exposure. Aggressive treatment with oral and topical steroids may be required without persistent sequelae at the 5-month follow-up. Ophthalmologists should consider this inflammatory reaction if patients experience ocular exposure to oleander.
Assuntos
Edema da Córnea , Ceratite , Nerium , Uveíte Anterior , Edema da Córnea/etiologia , Ciclopentolato/uso terapêutico , Feminino , Humanos , Inflamação , Ceratite/diagnóstico , Ceratite/tratamento farmacológico , Ceratite/etiologia , Pessoa de Meia-Idade , Moxifloxacina/uso terapêutico , Prednisolona/uso terapêutico , Prednisona/uso terapêutico , Uveíte Anterior/diagnóstico , Uveíte Anterior/tratamento farmacológico , Uveíte Anterior/etiologiaRESUMO
PURPOSE: A significant number of children with noninfectious, chronic anterior uveitis (CAU) fail to respond to conventional therapy; however, successful alternative biologic treatments (ABT) have not been well described. This study aims to review the clinical and treatment characteristics of children with CAU who require ABT. DESIGN: Retrospective, nonrandomized clinical study. METHODS: Setting: Tertiary center. STUDY POPULATION: Children with noninfectious CAU. OBSERVATION PROCEDURES: Clinical characteristics, uveitis course, complications, and treatment were compared among patients treated with methotrexate (MTX) monotherapy, conventional TNFα inhibitors (cTNFi), and ABT for >3 months. MAIN OUTCOME MEASURE: Success of ABT (abatacept, tocilizumab, and/or golimumab) in children failing conventional treatment. RESULTS: Of the 52 children with CAU, 75% had juvenile idiopathic arthritis. CAU was controlled in 15 children receiving MTX monotherapy, 28 receiving cTNFi, and 9 receiving ABT (n = 1, abatacept; n = 3, tocilizumab; n = 5, golimumab). Patients in the ABT group had a greater number of total ocular complications per person before ABT than those in the control groups (3.4 vs 0.7 [MTX], P < .001, and 1.5 [cTNFi], P < .001, respectively). In all 9 children on ABT, treatment led to control of CAU and topical glucocorticoids tapered to ≤2 drops/d with no new ocular complications. CONCLUSIONS: In this study, alternative biologics (abatacept, golimumab, and tocilizumab) were useful for treating CAU in children who fail MTX and cTNFi therapy. Patients who were controlled on ABT had more disease activity, ocular complications, and anti-cTNFi neutralizing antibodies (before ABT) than those managed with conventional therapy. Larger studies are required to confirm these findings.
Assuntos
Antirreumáticos , Artrite Juvenil , Terapia Biológica , Uveíte Anterior , Criança , Humanos , Abatacepte/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/complicações , Metotrexato/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Uveíte Anterior/diagnóstico , Uveíte Anterior/tratamento farmacológico , Uveíte Anterior/complicações , Inibidores do Fator de Necrose Tumoral/uso terapêuticoRESUMO
Chronic anterior uveitis is the most frequent among extra-articular manifestations of juvenile idiopathic arthritis (JIA) and a relevant cause of ocular morbidity in children. Asymmetric arthritis, early onset disease, female sex, and anti-nuclear antibody (ANA) positivity are counted among risk factors for developing this complication. It usually has insidious onset and asymptomatic chronic-relapsing course, but the persistence of low-grade chronic inflammation can lead to irreversible structural ocular damage and to vision-threatening complications. For such reasons, achieving a complete absence of inflammation through early targeted and aggressive treatments is a primary therapeutic goal in these patients. This review is aimed at summarizing scientific evidence about biologic rescue therapy of JIA-related uveitis in patients who fail to achieve clinical remission, in spite of being treated with conventional disease-modifying anti-rheumatic drugs (cDMARDs) and at least one biologic tumor necrosis factor (TNF)-α inhibitor. Interleukin (IL)-6 inhibition appears a promising and safe option for refractory JIA-related uveitis. Abatacept and rituximab proved to be beneficial as well, but their efficacy together with some safety concerns needs to be more extensively evaluated.
Assuntos
Artrite Juvenil/complicações , Terapia Biológica , Uveíte Anterior/tratamento farmacológico , Abatacepte/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Rituximab/uso terapêutico , Falha de Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Uveíte Anterior/etiologiaRESUMO
BACKGROUND To relieve the signs and symptoms of anterior uveitis (AU), an ocular manifestation of Behcet's syndrome, we prescribed a synbiotic supplementation (probiotics and prebiotics) for a 49-year-old woman. CASE REPORT Seven strains of bacteria - Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus thermophilus, Bifidobacterium breve, Lactobacillus acidophilus, Bifidobacterium longum, and Lactobacillus bulgaricus, each 108 colony-forming units (CFU) - and fructo-oligosaccharide (FOS; 100 mg) were given as a capsule 2 times per day. After 7-month treatment, AU was improved and serum inflammatory markers - C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), and estimated sedimentation rate (ESR) - were suppressed. Now, if a mild AU attack occurs, the problem is resolved by treatment with 1 gtt (from the Latin "guttae", meaning drops) eye drop (prednisolone 1%) for 1 week. CONCLUSIONS Synbiotic supplementation may contribute to treating AU, which is one of the most disastrous manifestations of BS, by controlling the proinflammatory processes.
Assuntos
Síndrome de Behçet/complicações , Suplementos Nutricionais , Probióticos/administração & dosagem , Simbióticos/administração & dosagem , Uveíte Anterior/tratamento farmacológico , Uveíte Anterior/etiologia , Síndrome de Behçet/diagnóstico , Feminino , Humanos , Lactobacillus acidophilus , Lacticaseibacillus casei , Lacticaseibacillus rhamnosus , Pessoa de Meia-Idade , Prognóstico , Recidiva , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Uveíte Anterior/fisiopatologiaRESUMO
PURPOSE: To summarize the available published data regarding the treatment of JIA-associated chronic uveitis. METHODS: Available peer-reviewed publications regarding the treatments of JIA-associated uveitis were read by multiple authors (RMA, EM, JET, and DH) and the data from these reports were synthesized for this review. RESULTS: Juvenile idiopathic arthritis (JIA)-associated chronic uveitis is a significant cause of ocular morbidity and visual impairment in children, often resulting in more frequent complications and worse visual outcomes than other types of pediatric uveitis. Since not all patients respond to the first medication introduced, it is useful to have a wide range of available treatment modalities to address recalcitrant disease. Treatment options for JIA-associated uveitis have increased substantially over the past decade, particularly with the availability of newer biological agents in addition to established medication classes such as anti-inflammatories (including topical and systemic corticosteroids) and antimetabolites. CONCLUSIONS: Although data are increasing regarding biologic agents, definitive randomized prospective clinical trials would be helpful to determine their optimal dose, frequency, treatment duration, and long-term safety in children.
Assuntos
Artrite Juvenil/tratamento farmacológico , Uveíte Anterior/tratamento farmacológico , Artrite Juvenil/patologia , Terapia Biológica , Doença Crônica , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Estudos Prospectivos , Uveíte Anterior/patologiaRESUMO
PURPOSE OF REVIEW: Ophthalmic disorders are highly prevalent in the United States, with approximately 3.5 million individuals aged at least 40 either blind or having impaired vision. This article reviews the current leading agents and pipeline therapies for the treatment of anterior ocular inflammatory disease (AOID). RECENT FINDINGS: There has been great progress in the understanding of ocular pathophysiology in recent years. Although current treatments for AOID are effective and well tolerated in many patients, a continued demand persists for more efficacious alternatives to the limited modalities available to clinicians. SUMMARY: Several promising modalities for AOID, particularly for allergic conjunctivitis, immune treatments for uveitis and dry eye syndrome are in late-stage development that could offer optimal treatment paradigm once available in the clinic.
Assuntos
Anti-Infecciosos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Conjuntivite Alérgica/tratamento farmacológico , Ciclosporina/uso terapêutico , Síndromes do Olho Seco/terapia , Imunoterapia/tendências , Uveíte Anterior/tratamento farmacológico , Quimiocina CCL11/imunologia , Ensaios Clínicos como Assunto , Dibenzoxepinas/uso terapêutico , Fluoroquinolonas/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Levofloxacino/uso terapêutico , Moxifloxacina , Cloridrato de OlopatadinaRESUMO
Spondyloarthrites (SPA) represent a group of heterogenous rheumatic diseases (ankylosing spondylitis/SA, psoriatic arthritis/PsA, reactive arthritis/ReA, spondyloarthritis in bowel inflammatory diseases/BID, undifferentiated spondyloarthritis/undif SpA) with distinct clinical features and common genetic predisposition (HLA-B27). SpA may also affect other organs, ocular involvement, represented by uveitis and conjunctivitis, being one of the most important extraskeletal manifestations. Pathogenic mechanisms of ocular involment in SpA are not entirely known; nevertheless, the inflammatory process which characterizes the main rheumatic diseases seems to be responsible for this extraskeletal manifestation. SpA treatment targeted at clinical remission has a favourable effect not only on articular but also on ocular involvement. The discovery of new pathogenic mechanisms of both rheumatic and eye disease in SpA have contributed to identification of new pathogenic therapies. The interdisciplinary team work of rheumatologists and ophtalmologists have prove essential for the management of SpA patients with ocular manifestations.
Assuntos
Conjuntivite/etiologia , Espondilartrite/complicações , Uveíte Anterior/etiologia , Antirreumáticos/uso terapêutico , Biomarcadores/metabolismo , Conjuntivite/diagnóstico , Conjuntivite/tratamento farmacológico , Conjuntivite/imunologia , Antígeno HLA-B27/imunologia , Humanos , Equipe de Assistência ao Paciente , Proibitinas , Espondilartrite/diagnóstico , Espondilartrite/tratamento farmacológico , Espondilartrite/etiologia , Espondilartrite/imunologia , Resultado do Tratamento , Uveíte Anterior/diagnóstico , Uveíte Anterior/tratamento farmacológico , Uveíte Anterior/imunologiaRESUMO
IMPORTANCE: Measurement of retinal nerve fiber layer (RNFL) thickness using optical coherence tomography can aid in the diagnosis and management of glaucoma. We observed a previously unreported phenomenon in eyes with uveitis-associated glaucoma in which paradoxical changes in RNFL thickness were noted. OBSERVATIONS: Four eyes of 3 patients with uveitis-associated glaucoma had a relatively normal RNFL measurement on presentation during periods of active uveitis and raised intraocular pressure. Subsequent control of uveitis and intraocular pressure was associated with a paradoxical thinning of the RNFL and increased cupping. CONCLUSIONS AND RELEVANCE: Normal-appearing measurements of RNFL thickness in patients with uveitis should be interpreted cautiously in those with a raised intraocular pressure. Physicians should recognize that continued thinning of the RNFL and increased cupping, despite good intraocular pressure control in such eyes, may be due to resolution of edema of the RNFL.
Assuntos
Glaucoma de Ângulo Aberto/diagnóstico , Fibras Nervosas/patologia , Disco Óptico/patologia , Células Ganglionares da Retina/patologia , Uveíte Anterior/diagnóstico , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Feminino , Glaucoma de Ângulo Aberto/tratamento farmacológico , Glucocorticoides/uso terapêutico , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Tomografia de Coerência Óptica , Tonometria Ocular , Uveíte Anterior/tratamento farmacológico , Campos VisuaisRESUMO
PURPOSE: To evaluate the effect of a traditional Chinese medicine, Rheum Polysaccharide (RP), on the in vitro production of tumor necrosis factor alpha (TNF- α ) and interleukin-10 (IL-10) by lipopolysaccharide- (LPS-)stimulated human monocytes from HLA-B27 associated acute anterior uveitis patients of convalescence stage. METHOD: PBMC samples were isolated from 10 HLA-B27 associated acute anterior uveitis, incubated, respectively, and divided into 4 groups as follows: (1) controls, PBS was added in final concentration of 1 mg·L⻹, (2) stimulated by LPS, LPS was added in final concentration of 1 mg·L⻹, (3) stimulated by LPS + HTA125, 30 minutes before the adding of LPS in final concentration of 1 mg·L⻹, the final concentration of 5 mg·L⻹ of the HTA125 was added, and (4) stimulated by LPS + RP, 30 minutes before the adding of LPS in final concentration 1 mg·L⻹, the final concentration 100 mg·L⻹ of the RP was added. Supernatants were used to quantify the amounts of TNF- α and IL-10 released in time course using enzyme-linked immunosorbent assay (ELISA). RESULT: After stimulated by lps, the concentrations of TNF- α and IL-10 in culture supernatants of patients are significantly higher than control group at all time points (P < 0.01). Blockage of TLR-4 by HTA125 can decrease the production of TNF- α and IL-10 compared with lps group (P < 0.01, except at 4 h group of IL-10). Concentration of TNF- α and IL-10 also decreases in the LPS + RP group (P < 0.01) but not so significantly as in the LPS + HTA125 group. CONCLUSION: As anti-TLR4 monoclonal antibodies, rheum Polysaccharide can also inhibit the secretion of cytokines produced by monocytes from HLA-B27 positive AAU patients of convalescence stage.
Assuntos
Polissacarídeos/farmacologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/sangue , Uveíte Anterior/sangue , Convalescença , Antígeno HLA-B27/metabolismo , Humanos , Interleucina-10/sangue , Medicina Tradicional Chinesa , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Polissacarídeos/química , Rheum/química , Receptor 4 Toll-Like/antagonistas & inibidores , Uveíte Anterior/tratamento farmacológico , Uveíte Anterior/patologiaAssuntos
Iris/efeitos da radiação , Fototerapia/efeitos adversos , Regeneração da Pele por Plasma/efeitos adversos , Lesões por Radiação/etiologia , Uveíte Anterior/etiologia , Adulto , Pálpebras , Feminino , Glucocorticoides/administração & dosagem , Humanos , Midriáticos/administração & dosagem , Fotofobia/tratamento farmacológico , Fotofobia/etiologia , Fotofobia/fisiopatologia , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/fisiopatologia , Rejuvenescimento , Uveíte Anterior/tratamento farmacológico , Uveíte Anterior/fisiopatologia , Acuidade Visual/fisiologiaRESUMO
OBJECTIVE: To report a case of toxic anterior uveitis probably secondary to the use of topical podophyllum. DESIGN: Case report, interventional. METHODS: The authors present a 78-year-old male with acute anterior uveitis that developed within a couple of hours of application of topical podophyllum. In vivo confocal microscopy showed unique findings that disappeared following treatment with topical steroids alone. The patient reapplied podophyllum 2 months later and a recurrence of uveitis was noted. RESULTS: A score of 7 was obtained using the adverse drug reaction probability scale, suggesting that the anterior uveitis is a probable adverse reaction to topical podophyllum. CONCLUSIONS: Anterior uveitis may occur after topical application of podophyllum.
Assuntos
Fitoterapia/efeitos adversos , Preparações de Plantas/administração & dosagem , Preparações de Plantas/efeitos adversos , Podophyllum/efeitos adversos , Uveíte Anterior/etiologia , Administração Tópica , Idoso , Face , Humanos , Masculino , Microscopia Confocal , Midriáticos/administração & dosagem , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia , Esteroides/administração & dosagem , Uveíte Anterior/tratamento farmacológico , Uveíte Anterior/patologia , Verrugas/tratamento farmacológico , Verrugas/patologiaRESUMO
PURPOSE: To promote awareness and prevention of ocular damage that can occur during Intense Pulsed Light (IPL) treatments of the periocular areas. METHODS: A retrospective chart review was conducted of 2 cases involving ocular damage following IPL procedures that were treated at Bascom Palmer Eye Institute for ocular complications. Routine data were collected during ophthalmic examinations. RESULTS: Case 1: A 36-year-old female presented with eye pain, marked pupillary constriction, and anterior uveitis an hour after receiving IPL treatment to the face. Within 1 month, the damage had progressed to posterior synechiae and iris transillumination defects. She continues to have pain and severe photophobia due to permanent iris atrophy and transillumination that have persisted for years. Case 2: A 27-year-old female presented with severe eye pain, vision disturbances, pupillary defects, and anterior uveitis 3 days after IPL of an eyelid freckle. At 2 months follow up, the iris and pupillary defects remain permanent. The patient continues to suffer from photophobia and pain. CONCLUSIONS: The pigmented iris absorbs light in the same wavelength range of IPL, thus remaining vulnerable to IPL exposure, especially when applied to the periocular area. The fact that IPL is not a laser may give people a false sense of security regarding damage to the eye. The cases presented give evidence that periorbital IPL treatment may permanently affect pigmented intraocular structures. It is imperative for treating physicians to be aware of these hazards and to use appropriate eye protection to prevent ocular damage.
Assuntos
Dor Ocular/etiologia , Fototerapia/efeitos adversos , Distúrbios Pupilares/etiologia , Lesões por Radiação/etiologia , Uveíte Anterior/etiologia , Adulto , Dor Ocular/tratamento farmacológico , Doenças Palpebrais/terapia , Dermatoses Faciais/terapia , Feminino , Glucocorticoides/administração & dosagem , Humanos , Melanose/terapia , Pomadas , Soluções Oftálmicas/administração & dosagem , Distúrbios Pupilares/tratamento farmacológico , Lesões por Radiação/tratamento farmacológico , Estudos Retrospectivos , Uveíte Anterior/tratamento farmacológicoRESUMO
Ocular inflammatory diseases impose a significant medical and economic burden on society. Corticosteroids are potent anti-inflammatory agents that have been used successfully to treat ocular inflammation. Topical corticosteroids provide maximal drug delivery, and are used to reduce the signs and symptoms of intraocular and ocular surface inflammation. However, side effects associated with topical corticosteroids-including increased intraocular pressure, risk of cataract formation after long-term use, and decreased resistance to infection-are concerns. Loteprednol etabonate (LE) is an ester corticosteroid with a high therapeutic index that contains an ester, rather than a ketone, at carbon-20 of the prednisolone core structure. LE blocks the release and action of inflammatory mediators and is clinically effective in the treatment of steroid-responsive inflammatory conditions including giant papillary conjunctivitis, seasonal (intermittent) allergic conjunctivitis and uveitis. LE relieves ocular surface and lacrimal gland inflammation associated with dry eye and is used in combination with ciclosporin A as a treatment of dry eye. LE is also effective in the treatment of postoperative ocular inflammation. Because of its rapid de-esterification to inactive metabolites, LE appears to have an improved safety profile compared with ketone corticosteroids, and may be more suitable than ketone corticosteroids for the treatment for ocular inflammatory conditions in which long-term therapy is necessary. However, further comparative safety studies are needed.
Assuntos
Androstadienos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Conjuntivite/tratamento farmacológico , Uveíte Anterior/tratamento farmacológico , Conjuntivite Alérgica/tratamento farmacológico , Síndromes do Olho Seco/tratamento farmacológico , Endoftalmite/prevenção & controle , Humanos , Etabonato de Loteprednol , Complicações Pós-Operatórias/prevenção & controleRESUMO
PURPOSE: To describe a case of Euphorbia lactea sap keratouveitis and to review all reported cases of ocular toxicity caused by Euphorbia species. METHODS: Case report and review of literature. RESULTS: A 79-year-old woman presented 34 hours after she felt some sap of an E. lactea plant spray into her right eye. Visual acuity was counting fingers at 1 m. Examination revealed ciliary injection, 90% corneal epithelial defect, marked stromal edema with Descemet folds, and anterior-chamber flare with a 1-mm hypopyon. There was no vitreitis, and funduscopy was unremarkable. No foreign body was seen on B scan ultrasound or computed tomography scan of the orbits. Corneal scraping excluded bacterial and herpetic keratitis. Intensive topical antibiotic therapy was started with cephalothin 5% and gentamicin 0.9%, and the pupil was dilated with atropine. Topical steroids were started once the epithelial defect had healed. Examination 11 weeks after the injury revealed minimal subepithelial corneal haze and marked improvement in visual acuity. CONCLUSIONS: To the best of our knowledge, this is only the third reported case of E. lactea sap keratouveitis. The clinical course of E. lactea sap keratouveitis is compared with that reported for other Euphorbia species.
Assuntos
Córnea/efeitos dos fármacos , Euphorbia/química , Ceratite/induzido quimicamente , Extratos Vegetais/efeitos adversos , Uveíte Anterior/induzido quimicamente , Idoso , Anti-Infecciosos/administração & dosagem , Edema da Córnea/induzido quimicamente , Edema da Córnea/tratamento farmacológico , Quimioterapia Combinada , Feminino , Humanos , Ceratite/tratamento farmacológico , Uveíte Anterior/tratamento farmacológico , Acuidade Visual/efeitos dos fármacosRESUMO
Heat shock protein (Hsp) 90 inhibitors, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), constitute promising novel therapeutic agents. We investigated the anti-inflammatory activity of 17-AAG in endotoxin-induced uveitis (EIU) in rats. After the induction of EIU with a footpad injection of lipopolysaccharide (LPS), female Lewis rats received a single intraperitoneal. (i.p.) injection of 17-AAG or vehicle. Twenty-four hours later, the retinas were extracted and assayed for leukocyte adhesion; blood-retinal barrier breakdown; VEGF, TNF-alpha, IL-1beta, and CD14 protein levels; NF-kappaB and HIF-1alpha activity; hsp90 and 70 levels and expression and phosphorylation of the tight junction proteins ZO-1 and occludin. 17-AAG treatment significantly suppressed the LPS-induced increase in retinal leukocyte adhesion; vascular leakage; NF-kappaB, HIF-1alpha, p38, and PI-3K activity; and VEGF, TNF-alpha, and IL-1beta levels. 17-AAG also suppressed phosphorylation of ZO-1 and occludin by inhibiting their association with p38 and PI-3K. Although 17-AAG treatment did not reduce the LPS-induced increase in total CD14 levels in leukocytes, it significantly decreased membrane CD14 levels. These data suggest that Hsp90 inhibition suppresses several cardinal manifestations of endotoxin-induced uveitis in the rat. 17-AAG has demonstrated a favorable safety profile in clinical trials in cancer patients and represents a promising therapeutic agent for the treatment of inflammatory eye diseases.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Benzoquinonas/uso terapêutico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/uso terapêutico , Uveíte Anterior/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Toxinas Bacterianas/toxicidade , Barreira Hematorretiniana/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Membrana Celular/química , Avaliação Pré-Clínica de Medicamentos , Endotoxinas/toxicidade , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-1beta/biossíntese , Interleucina-1beta/sangue , Leucócitos/química , Leucostasia/etiologia , Leucostasia/prevenção & controle , Receptores de Lipopolissacarídeos/sangue , Masculino , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Ocludina , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Ratos Long-Evans , Vasculite Retiniana/induzido quimicamente , Vasculite Retiniana/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/biossíntese , Regulação para Cima/efeitos dos fármacos , Uveíte Anterior/induzido quimicamente , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/sangue , Proteína da Zônula de Oclusão-1 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
PURPOSE: The aims of this study were to examine the in vivo effects of berberine, an alkaloid isolated from some medicinal herbs, on monocyte chemotactic protein-1 (MCP-1) and cytokine-induced neutrophil chemoattractant-1 (CINC-1) expression in rat lipopolysaccharide (LPS)-induced uveitis. METHODS: LPS was injected intraperitoneally. Berberine was orally administered. MCP-1 mRNA and CINC-1 mRNA were measured by semiquantitative reverse-transcription polymerase chain reaction and real-time polymerase chain reaction. MCP-1 and CINC-1 protein concentration in the aqueous humor were measured by enzyme-linked immunosorbent assay. Histopathologic study was performed in the anterior ocular segments. RESULTS: Berberine dose-dependently inhibited LPS-induced MCP-1 mRNA and CINC-1 mRNA expression of the iris-ciliary body. The alkaloid inhibited chemokines, protein and cell levels in the aqueous humor in rats stimulated with LPS. On histopathologic study, the inflammatory cell infiltration was diminished by the berberine treatment. CONCLUSIONS: These findings indicate that berberine dose-dependently inhibited the expression of MCP-1 and CINC-1 induced by LPS and diminished the anterior uveitis.
Assuntos
Berberina/uso terapêutico , Quimiocina CCL2/genética , Quimiocinas CXC/genética , Expressão Gênica/efeitos dos fármacos , RNA Mensageiro/metabolismo , Uveíte Anterior/tratamento farmacológico , Animais , Quimiocina CXCL1 , Corpo Ciliar/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Iris/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Reação em Cadeia da Polimerase , Ratos , Ratos Wistar , Uveíte Anterior/induzido quimicamente , Uveíte Anterior/metabolismoRESUMO
PURPOSE: Aronia crude extract (ACE) with high levels of polyphenol compounds has been reported to have antioxidative effects in vitro and in vivo. In this study, attention was focused on the antioxidant effect of ACE. The purpose of the present study was to investigate the effect of ACE on endotoxin-induced uveitis (EIU) in rats. In addition, the endotoxin-induced expression of the inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 proteins was investigated in a mouse macrophage cell line (RAW 264.7) treated with ACE in vitro, to clarify the anti-inflammatory effect. METHODS: EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). Immediately after the LPS inoculation, 1, 10, or 100 mg ACE or 10 mg prednisolone was injected intravenously. After 24 hours, the aqueous humor was collected from both eyes, and the number of infiltrating cells, protein concentration, nitric oxide (NO), prostaglandin (PG)-E2, and TNF-alpha levels in the aqueous humor were determined. RAW 264.7 cells treated with various concentrations of ACE were incubated with 10 mug/mL LPS for 24 hours. Levels of NO, PGE2, and TNF-alpha were determined by an enzyme-linked immunosorbent assay. The expression of iNOS and COX-2 proteins was analyzed by Western blot analysis. RESULTS: The number of inflammatory cells, the protein concentrations, and the levels of NO, PGE2, and TNF-alpha in the aqueous humor in the groups treated with ACE were significantly decreased in a dose-dependent manner. In addition, the anti-inflammatory effect of 100 mg ACE was as strong as that of 10 mg prednisolone. The anti-inflammatory action of ACE was stronger than that of either quercetin or anthocyanin administered alone. ACE also suppressed LPS-induced iNOS and COX-2 protein expressions in RAW 264.7 cells in vitro in a dose-dependent manner. CONCLUSIONS: The results suggest that ACE has a dose-dependent anti-ocular inflammatory effect that is due to the direct blocking of the expression of the iNOS and COX-2 enzymes and leads to the suppression of the production of NO, PGE2, and TNF-alpha.
Assuntos
Anti-Inflamatórios/uso terapêutico , Photinia/química , Fitoterapia , Extratos Vegetais/uso terapêutico , Uveíte Anterior/tratamento farmacológico , Animais , Humor Aquoso/citologia , Humor Aquoso/metabolismo , Western Blotting , Linhagem Celular , Ciclo-Oxigenase 2 , Dinoprostona/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Frutas , Injeções Intravenosas , Isoenzimas/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Prednisolona/uso terapêutico , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Ratos Endogâmicos Lew , Salmonella typhimurium , Fator de Necrose Tumoral alfa/metabolismo , Uveíte Anterior/induzido quimicamente , Uveíte Anterior/enzimologia , Uveíte Anterior/patologiaRESUMO
The purpose of this study was to evaluate the effects of extracts of Coptidis rhizoma, Phellodendri cortex and Gardeniae fructus, which are medicinal herbs in Orengedoku-to (Huanglin-Jie-Du-Tang in Chinese), and crocetin (a major component of Gardeniae fructus) on experimental elevation of aqueous flare in pigmented rabbits. To produce aqueous flare elevation, 0.5 microg/kg lipopolysaccharide (LPS) was injected into the ear vein, or prostaglandin E2 (PGE2) 25 microg/ml, was applied to the cornea by means of a glass cylinder. Animals were pretreated by oral administration of 150 g/day of food containing 0.15% (w/w) extract powder of Coptidis rhizoma, 0.10% (w/w) extract powder of Phellodendri cortex or 0.15% (w/w) extract powder of Gardeniae fructus for 4 days, or by intravenous injection of crocetin, 0.3, 3, 30 or 300 microg/kg, 30 minutes before aqueous flare elevation. Aqueous flare was measured with a laser flare-cell meter. Aqueous flare intensity was expressed as the area under the curve (AUC) in arbitrary units. The AUC of LPS- and PGE2-induced aqueous flare elevation was 4685 and 1386 arbitrary units, respectively. Pretreatment by oral administration of 0.15% (w/w) extract of Coptidis rhizoma or 0.10% (w/w) extract of Phellodendri cortex did not inhibit LPS-induced aqueous flare elevation. Pretreatment by oral administration of 0.15% extract of Gardeniae fructus suppressed LPS-induced aqueous flare elevation (AUC: 1411 arbitrary units). Pretreatment by intravenous injection of 3, 30 or 300 microg/kg of crocetin-inhibited LPS-induced aqueous flare elevation in a dose-dependent manner. Pretreatment with 3 or 30 microg/kg of crocetin did not inhibit PGE2-induced aqueous flare elevation, but 300 microg/kg of crocetin inhibited PGE2-induced aqueous flare elevation (AUC: 918 arbitrary units).
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacologia , Humor Aquoso/efeitos dos fármacos , Carotenoides/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Administração Oral , Animais , Área Sob a Curva , Dinoprostona , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intravenosas , Lipopolissacarídeos , Masculino , Coelhos , Fatores de Tempo , Uveíte Anterior/induzido quimicamente , Uveíte Anterior/tratamento farmacológico , Vitamina A/análogos & derivadosRESUMO
OBJECTIVE: To explore the effect of Tripterygium wilfordii polyglycoside (TWP) on level of serum interleukin 2 (IL-2), and tumor necrosis factor alpha (TNF-alpha) in patients of acute anterior uveitis (AAU). METHODS: Patients of AAU were randomly divided into two groups. The treated group (n = 50) was mainly treated with TWP and the control group (n = 50) treated with bimolani. The level of IL-2 and TNF-alpha before and after treatment were determined and compared between the two groups and also compared between the treated group and normal group consisted of 50 healthy subjects. RESULTS: Levels of IL-2 and TNF-alpha in the treated group before treatment were 1.31 +/- 0.27 micrograms/L and 1.20 +/- 0.65 micrograms/L, and after treatment 1.19 +/- 0.27 micrograms/L and 0.96 +/- 0.54 microgram/L, those in the control group were 1.31 +/- 0.26 micrograms/L and 1.22 +/- 0.66 micrograms/L before treatment and 1.20 +/- 0.27 micrograms/L and 0.98 +/- 0.51 microgram/L after treatment respectively. Comparisons of the two parameters before and after treatment in both groups showed significant difference (P < 0.05 in TWP group and P < 0.01 in bimolani group). The two parameters in both treated groups were all higher than those in the normal group before treatment (P < 0.05), but showed insignificant difference after treatment (P > 0.05). CONCLUSION: Abnormal changes of IL-2 and TNF-alpha exist in AAU patients, TWP could suppress both parameters markedly therefore has a reliable effect in treatment of AAU.