Efficiency and safety of subconjunctival injection of anti-VEGF agent - bevacizumab - in treating dry eye.

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Efficiency and safety of subconjunctival injection of anti-VEGF agent - bevacizumab - in treating dry eye.

Author(s): Xiaodan Jiang, Huibin Lv, Weiqiang Qiu, Ziyuan Liu, Xuemin Li, Wei-wei Wang

Publication date: 2015

Journal: Drug Design, Development and Therapy

Keywords: anti-VEGF, bevacizumab, dry eye, ocular surface inflammation, subconjunctival

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Abstract

Dry eye is a chronic inflammatory ocular surface disease with high prevalence. The current therapies for dry eye remain to be unspecific and notcomprehensive. This study aims to explore safety and efficacy of a novel treatment - subconjunctival injection of bevacizumab - in dry eye patients.

Most cited references 26

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Analysis of inflammatory cytokines in the tears of dry eye patients.

Xiaohong Li, Penny Asbell, Dongmei Chen … (2009)

To determine the levels of 8 important cytokines and 1 chemokine in tears of patients with dry eye disease. Tear samples were collected from 7 patients with dry eye disease and 7 healthy volunteers, and impression cytology samples were collected from 3 of the dry eye patients and 3 of the normal controls. Tears were analyzed for the presence of 8 cytokines [interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-1beta] and 1 chemokine (IL-8). The cytokines and chemokine in each tear sample were measured using Invitrogen's Multiplex Bead Immunoassays. The impression cytology samples were analyzed for IL-1beta, IL-6, IL-8, and TNF-alpha mRNA expression using real-time reverse transcriptase polymerase chain reaction anlaysis. All cytokines and the chemokine measured were significantly increased in the tears of dry eye patients as compared to normal controls. mRNA of all four markers was increased, and the fold increase correlated well with the fold increase of the cytokine concentration found in the tear samples. Tears from dry eye patients contain significantly increased concentrations of cytokines that show correlation to severity of the disease. The upregulation of their respective genes in the conjunctiva suggests that the concentration increase is not the result of evaporative effects, but of overproduction. These findings suggest that cytokines may play an important role in dry eye disease and topical cytokine modulators may be explored as a therapeutic approach to dry eye disease.

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Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease

Amalia Enríquez-de-Salamanca, Evangelina Castellanos, Michael E. Stern … (2010)

Purpose Inflammatory molecules have been demonstrated in the tear film of patients with severe dry eye disease (DED). However, little attention has been paid to the most frequent moderate forms of DED. This study analyzes tear cytokine levels and their clinical correlations in patients with moderate evaporative-type DED due to meibomian gland disease (MGD). Methods Twenty three evaporative-type DED patients (46 eyes) of mild-to-moderate intensity and nine healthy subjects (18 eyes) were recruited. Two symptom questionnaires were self-answered and multiple DED-related clinical tests were performed. Unstimulated tears from each eye were isolated and were not pooled. Levels of 15 cytokines and chemokines were measured by multiplex bead analysis, compared with control levels, and correlated with clinical tests. Results Fourteen out of the 15 molecules were reliably detected in 1 μl of unstimulated tears from DED patients. Epidermal growth factor (EGF), fractalkine/CX3CL1, interleukin (IL) 1-receptor antagonist (Ra), IL-8/CXCL8, interferon inducible protein (IP)-10/CXCL10, and vascular endothelial growth factor (VEGF) were found in 94%–100% of samples; IL-6 in 65% (significantly more detected in older patients); IL-1β, interferon gamma (IFN-γ), and IL-10 in 30%–48%; IL-17 in 13%; granulocyte macrophage colony stimulating factor (GM-CSF), IL-13, and tumor necrosis factor alpha (TNF-α) in 2%–9%; and IL-5 was never detected. EGF, fractalkine/CX3CL1, IL-1Ra, IP-10/CXCL10, and VEGF levels were significantly increased compared to normal controls. Pain was correlated with IL-6 and IL-8/CXCL8. Tear break-up time correlated inversely with IL1-Ra. Schirmer test and tear lysozyme levels negatively correlated with IL-1Ra, IL-8/CXCL8, fracktalkine/CX3CL1, IL-6, IP-10/CXCL10, and VEGF had the same tendency. Conjunctival staining correlated negatively with EGF and positively with IL-6. Conclusions In this sample of moderate evaporative-type DED patients, five inflammatory molecules were elevated. Fracktalkine was demonstrated to be present and elevated in tears in human DED. IL-1Ra, IL-6, IL-8/CXCL8, and EGF levels correlated with pain and with clinical parameters measuring tear stability, tear production or ocular surface integrity. These results suggest that inflammation plays a role not only in severe DED but also in moderate evaporative DED.

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Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells.

X Song, Stephen Pflugfelder, Yu Luo … (2004)

To investigate whether exposure of human corneal epithelial cells to hyperosmotic stress activates the c-Jun NH(2)-terminal kinase (JNK) stress-activated protein kinase (SAPK) pathway, and stimulates production of the matrix metalloproteinases (MMPs): gelatinase (MMP-9), collagenases (MMP-1 and -13), and stromelysin (MMP-3). Primary human corneal epithelial cells cultured in normal osmolar medium (312 mOsM) were exposed to media with higher osmolarity (350-500 mOsM) achieved by adding NaCl, with or without SB202190, an inhibitor of the JNK pathway; dexamethasone; or doxycycline for different lengths of time. The conditioned media were collected after 24 hours of exposure for zymography and ELISA. Total RNA was extracted from cultures treated for 6 hours and subjected to semiquantitative RT-PCR. Cells treated for 5 to 60 minutes were lysed in RIPA buffer and subjected to Western blot with phospho (p)-specific antibodies against p-JNK and p-c-Jun. JNK1 activation was also detected with an immunoassay system. The concentrations of MMP-9, -1, and -3 proteins in 24-hour conditioned media of corneal epithelial cells progressively increased as the media's osmolarity was increased from 312 to 500 mOsM by the addition of NaCl. The concentration of MMP-13 progressively increased to a peak at 450 mOsM. Active p-JNK-1, p-JNK-2, and p-c-Jun were detected by Western blot as early as 5 minutes and peaked at 60 minutes in cells exposed to hyperosmolar media. The levels of p-JNK-1, p-JNK-2, and p-c-Jun correlated positively with the osmolarity of the culture media. The p-JNK inhibitor SB202190 and doxycycline markedly inhibited the stimulation of p-JNK-1, p-JNK-2, and p-c-Jun, as well as MMP-9, -1, -13, and -3 at both the mRNA and protein levels in the cells exposed to hyperosmolar media. Expression and production of MMP-9, -1, -13, and -3 by human corneal epithelial cells correlated positively with increasing media osmolarity. This increase was mediated at least in part through activation of the JNK SAPK pathway. Doxycycline, an agent used to treat MMP-mediated ocular surface disease, inhibited the hyperosmolarity-induced MMP production and JNK activation. The relevance of these findings to stimulated production of MMPs by the elevated tear osmolarity in dry eye remains to be determined.