To assess the efficacy and safety of lifitegrast ophthalmic solution 5.0% compared with placebo in subjects with dry eye disease.
Prospective, randomized, double-masked, placebo-controlled, parallel ...arm, multicenter clinical trial.
A total of 588 adult subjects with dry eye disease.
Eligible subjects were randomized 1:1 to receive topically administered lifitegrast (5.0%) or placebo (vehicle) twice daily for 84 days after a 14-day open-label placebo run-in period. After enrollment (day 0), subjects were evaluated at days 14, 42, and 84. Key objective (fluorescein and lissamine staining scores Ora scales) and subjective (Ocular Surface Disease Index OSDI, 7-item visual analog scale, and ocular discomfort score Ora scale) measures were assessed at all visits.
The primary objective efficacy measure (sign) was mean change from baseline inferior corneal staining score (ICSS) at day 84. The co-primary subjective efficacy measure (symptom) was the mean change from baseline in the visual-related function subscale score of the Ocular Surface Disease Index (VR-OSDI). Supportive measures included corneal fluorescein scores (superior, central, total region) and conjunctival lissamine scores (nasal, temporal, total region) and symptom scores at day 84.
The study met the primary objective efficacy ICSS end point in demonstrating superiority of lifitegrast compared with placebo (P = 0.0007). Lifitegrast significantly reduced corneal fluorescein staining (superior, P = 0.0392; total cornea, P = 0.0148) and conjunctival lissamine staining (nasal, P = 0.0039; total conjunctiva, P = 0.0086) at day 84 versus placebo. Significant (P < 0.05) improvements in nasal and total lissamine scores were observed at day 14 and maintained through day 84. The study did not meet the co-primary subjective VR-OSDI measure (P = 0.7894). However, significant improvements were observed at day 84 in ocular discomfort (P = 0.0273) and eye dryness (P = 0.0291), the most common and severe symptoms reported at baseline in both groups. There were no unanticipated or serious ocular adverse events (AEs). The most frequent reported ocular AEs were transient intermittent instillation site symptoms (irritation, discomfort) primarily on the initial lifitegrast dose at day 0.
Lifitegrast ophthalmic solution 5.0% significantly reduced corneal fluorescein and conjunctival lissamine staining and improved symptoms of ocular discomfort and eye dryness compared with placebo when administered twice daily over 84 days.
The Multi-Ethnic Study of Atherosclerosis and Air Pollution (MESA Air) was initiated in 2004 to investigate the relation between individual-level estimates of long-term air pollution exposure and the ...progression of subclinical atherosclerosis and the incidence of cardiovascular disease (CVD). MESA Air builds on a multicenter, community-based US study of CVD, supplementing that study with additional participants, outcome measurements, and state-of-the-art air pollution exposure assessments of fine particulate matter, oxides of nitrogen, and black carbon. More than 7,000 participants aged 45-84 years are being followed for over 10 years for the identification and characterization of CVD events, including acute myocardial infarction and other coronary artery disease, stroke, peripheral artery disease, and congestive heart failure; cardiac procedures; and mortality. Subcohorts undergo baseline and follow-up measurements of coronary artery calcium using computed tomography and carotid artery intima-medial wall thickness using ultrasonography. This cohort provides vast exposure heterogeneity in ranges currently experienced and permitted in most developed nations, and the air monitoring and modeling methods employed will provide individual estimates of exposure that incorporate residence-specific infiltration characteristics and participant-specific time-activity patterns. The overarching study aim is to understand and reduce uncertainty in health effect estimation regarding long-term exposure to air pollution and CVD.
To describe visual acuity (VA) and inflammation following cataract surgery in eyes with noninfectious posterior uveitis (NIPU) that were being treated with a fluocinolone acetonide (FA) intravitreal ...implant compared with those that were not.
Post hoc, subgroup analysis of data from a 3-year, dose-masked, randomized, multicenter trial evaluating the FA implant for the treatment of NIPU.
The subset of eyes that underwent cataract surgery during the 3-year trial. Eyes were either implanted with a 0.59- or a 2.1-mg FA implant, or, in the case of affected fellow eyes, received standard-of-care local treatment.
VA, anterior and posterior chamber inflammation at 1 and 3 months after surgery, and rate of uveitis recurrence and serious postoperative ocular adverse events.
Of 278 patients enrolled in the main trial, 132/142 phakic implanted eyes and 39/186 phakic non-implanted eyes underwent cataract surgery. Mean improvement in VA was significantly greater in implanted than non-implanted eyes at 1 (P = 0.0047) and 3 months (P = 0.0015) postoperatively; significantly fewer anterior chamber cells were seen in implanted than non-implanted eyes at 1 (P = 0.0084) and 3 months (P = 0.0002). Severity of vitreous haze was less in implanted than non-implanted eyes at 3 months postoperatively (P = 0.0005). The postsurgical uveitis recurrence rate was lower in implanted than non-implanted eyes (26.5% vs 44.4%; P = 0.0433). Glaucoma was reported in 19.7% of implanted eyes and no non-implanted eyes (P = 0.0008) postoperatively.
In this post hoc subgroup analysis, eyes with NIPU treated with the FA intravitreal implant demonstrated better vision and less intraocular inflammation following cataract surgery than non-implanted eyes. Recurrent uveitic inflammation did not appear to be triggered by cataract surgery. Glaucoma occurred more frequently in implanted eyes.
This study objectively compares efficacy of dexamethasone Na phosphate 0.1%, fluorometholone 0.1% (FML), loteprednol etabonate 0.5% (Lotemax LE; Bausch & Lomb Pharmaceuticals, Inc., Tampa, FL), ...prednisolone acetate 1% (Pred Forte PRED F; Allergan Pharmaceuticals, Irvine, CA), and generic prednisolone acetate 1% (PRED A). These steroids were administered for 24 hours or 72 hours to New Zealand white rabbits with endotoxin-induced uveitis. Intraocular pressure (IOP), slit-lamp examination, and confocal microscopy were performed daily. Internalization of the glucocorticoid receptor (GC) was assayed in iris tissue by Western blot, and protein in aqueous humor by Bradford assay. Only LE and PRED F treatments significantly internalized GC receptor after 72 hours of treatment. Only LE and PRED A reduced protein concentration between 24 hours and 72 hours of treatment. All drugs improved clinical signs after 24 hours of treatment. None of the steroids promoted return of the inflammation-induced corneal thickness to baseline. While none returned IOP to baseline, LE was most effective. Confocal microscopy indicated that only treatment with LE reverted the abnormal endothelial-cell shape to normal. In conclusion, all steroid treatments reduced uveitis to some degree but LE was consistently effective. A longer observation period may be required to document the return of IOP and corneal thickness to baseline values.
To discourage fibrosis of the filtering bleb, 5 fluorouracil (5-FU) may be injected after trabeculectomy. 5-FU is an antimetabolite that also can damage extraocular tissues at concentrations as low ...as 0.5%. This study ascertained whether repeated injection of 5-FU has toxic effects on intraocular structures.
After unilateral trabeculectomy in anesthetized New Zealand rabbits, 5-FU (5.0 mg/0.1 mL) was injected at the trabeculectomy site every 5 days for 15 days. Evaluation included slit-lamp examination, confocal microscopy, and intraocular pressure (IOP). After sacrifice, aqueous humor (AH) was drawn and eyes excised for scanning electron microscopy (SEM) and light microscopy.
The 5-FU injection not decrease IOP beyond trabeculectomy alone. Bleb height remained constant, thickness increased, and vascularity decreased. No changes in cornea or anterior segment were observed. No inflammation was observed in the bleb or surrounding tissues by slit-lamp or histologic examination. Protein in AH increased from 0.6 +/- 0.5 microg/mL at baseline to 19.8 +/- 4.4 microg/mL after trabeculectomy but only to 0.9 +/- 0.6 microg/mL after trabeculectomy plus 5-FU. Both in vivo confocal microscopy and SEM revealed deleterious effects on corneal epithelial and endothelial cells with a minor shift toward smaller cells.
In this study 5-FU did not provoke an intraocular inflammatory response and had minimal effect on extraocular structures. Changes in corneal epithelium and endothelium detectable by confocal microscopy suggest a small toxic effect. These in vivo measurements by confocal microscopy were confirmed by SEM. Repeated administration did not cause additional cumulative toxic effects in the anterior segment. Therefore, multiple injections of 5- FU into the filtering bleb pose minimal risk to intraocular structures.
The integrin alpha v beta 6 is only expressed in epithelial cells. In healthy adult epithelia, this receptor is barely detectable, but expression is rapidly induced following epithelial injury. Mice ...homozygous for a null mutation in the gene encoding the beta 6 subunit had juvenile baldness associated with infiltration of macrophages into the skin, and accumulated activated lymphocytes around conducting airways in the lungs. beta 6 super(-/-) mice also demonstrated airway hyperresponsiveness to acetylcholine, a hallmark feature of asthma. These results suggest that the epithelial integrin alpha v beta 6 participates in the modulation of epithelial inflammation. Genetic or acquired alterations in this integrin could thus contribute to the development of inflammatory diseases of epithelial organs, such as the lungs and skin.
Conjunctival and corneal manifestations of atopic keratoconjunctivitis (AKC) are chronic, disabling and may be blinding. In common with other allergic diseases, such as asthma and atopic dermatitis, ...AKC is characterised by an allergen-induced immune response mediated through expression of IgE. The humanised monoclonal IgE antibody Xolair (omalizumab) complexes with free circulating IgE, thereby preventing binding of IgE to FcepsilonRI receptors on immune cells. Omalizumab effectively alleviates the signs and symptoms of asthma. Given the pivotal role of IgE in the allergic cascade, it is hypothesised that omalizumab has potential as an entirely new therapeutic approach to AKC.
A model for predicting the response of a conductimetric urea biosensor was developed and validated experimentally. The biosensor under consideration is formed by immobilizing the enzyme urease onto ...the surface of a planar interdigitated electrode array. The enzymatic hydrolysis of urea produces ionic products, such as ammonium and bicarbonate ions, which increase the electrical conductivity of the solution proximal to the electrode array. The model combines an analysis of the diffusive transport and enzymatic hydrolysis of urea in the vicinity of the biosensor surface with an electric fields model for calculating interelectrode impedance. To validate the model, urea biosensors were constructed by immobilizing urease to the interdigit space of microfabricated interdigitated electrodes. The responses of these sensors were investigated in urea solutions prepared in deionized water, at concentrations ranging from 10 μM to 5 mM. Using reasonable estimates for the parameters, the predictions of the model were in good agreement with the experimental data over the entire range of concentrations.
Long-term evaluation of dihematoporphyrin ether (DHE) safety and efficacy as photodynamic therapy (PDT) for patients with corneal neovascularization (KNV).
Prospective multi-center interventional ...case series.
Seven patients were enrolled after Institutional Review Board approval and a detailed informed consent were obtained. Eligible patients presented with clinically stable KNV without active vessel progression or inflammation. All patients with severe hypertension, history of renal or hepatic disease, or sensitivity to porphyrins, and those with active keratitis or uncontrolled ocular surface disease were excluded. DHE was administered as an intravenous bolus (2 mg/kg). Seventy-two hours later, PDT was carried out using argon green laser (514 nm). The main outcome measure, extent of vascular thrombosis, was estimated during postoperative follow-up examinations performed at day 1, 1 week, 6 months, and up to 12 years postoperative.
All patients obtained an immediate reduction in measurable corneal vascularization. With at least 6 months of follow-up, six of seven patients maintained a significant reduction (52.5% ± 19.6%,
P < .01) in KNV. The mean length of followup was 5.4 years (Range = 6 months to 12 years) during which time there were no other ocular changes attributable to laser treatment. Three patients suffered significant systemic short-term phototoxicity reactions.
Intravenous DHE followed by photodynamic treatment in humans is effective for the reduction of inactive, established KNV. However, the significant short-term adverse effects related to systemic administration of this drug are of particular concern and warrant further investigation.
Abstract Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic ...fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as “a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF”. The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR-RDs.
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