George W. Ousler

Alternative reference values for tear film break up time in normal and dry eye populations.

In several tissues and cell lines, including epithelial cells of the prostate, breast and seminal vesicles, and in acinar cells of the meibomian and other sebaceous glands, androgens have a major stimulatory effect on the production, accumulation and/or secretion of lipids.1–11 In most of these tissues and cell lines, the composition of these lipids is complex. Accumulating lipids include cholesterol esters, diacylglycerides, triglycerides and wax esters. Depending on the tissue type, these lipids may have different physiological functions and dysregulation of their production is related to pathological conditions as diverse as acne, dry eye syndromes and cancer. In acne and dry eye syndromes local modulation of androgen action may provide an effective therapy.7,12

Methodologies for the Study of Ocular Surface Disease

The ability to obtain reliable results from clinical trials of therapies for ocular allergic disease and dry eye disease is often limited because of inadequate control of variables, such as environment, patient life style, compliance, and individual fluctuations that occur from one assessment visit to another. The controlled allergen challenge (CAC) model of allergic conjunctivitis allows signs and symptoms of the disease to be elicited in a physiologically accurate and reproducible manner. The rigid criteria for subject selection, the controlled allergic reaction, and the standardized and quantified grading systems allow for a reproducible baseline from which statistically and clinically significant differences between formulations can be assessed. Similarly, the controlled adverse environment (CAE) model for dry eye mimics the environmental stimuli that lead to ocular surface drying. Preselected subjects have a reproducible, homogeneous baseline reaction from which the effects of various treatments can be significantly evaluated and compared. CAC and CAE provide accurate means to study highly variable and individual ocular surface disease.

An evaluation of the ocular drying effects of 2 systemic antihistamines: loratadine and cetirizine hydrochloride

BACKGROUND Systemic antihistamines, such as loratadine and cetrizine hydrochloride, have proven efficacious in the control of many allergic conditions; however, patients complain about their drying effects. OBJECTIVE To investigate the ocular drying effects of loratadine and cetirizine hydrochloride in individuals with normal ocular health exposed to a controlled adverse environment (CAE). METHODS Eighteen individuals completed a randomized, double-masked study. Participants were evaluated in a CAE (a chamber that regulates humidity, temperature, airflow, and visual tasking) at baseline and after taking 10 mg of either loratadine or cetirizine hydrochloride daily for 4 days. Keratitis, conjunctival staining, and tear film break-up time (TFBUT) were examined before and after a 45-minute CAE exposure. Participant-reported ocular discomfort was recorded every 5 minutes during CAE challenge. RESULTS After 4 days, use of loratadine yielded a mean increase of 0.75 points (107%) in keratitis (P < .001), a mean increase of 1.35 points (133%) in conjunctival staining (P < .001), a mean decrease of 1.38 seconds (33.7%) in TFBUT (P < .001), and a mean increase of 0.32 points (24.8%) in ocular discomfort (P = .05) vs baseline. After 4 days, use of cetirizine hydrochloride yielded a mean increase of 0.57 points (60%) in keratitis (P < .001), a mean increase of 0.7 points (49.7%) in conjunctival staining (P = .005), and a mean decrease of 0.76 seconds (19.6%) in TFBUT (P = .05) vs baseline. Loratadine was shown to induce 93% greater conjunctival staining after 4 days of use and CAE exposure vs cetirizine hydrochloride (P = .04). CONCLUSIONS Loratadine and cetirizine hydrochloride induced signs and symptoms associated with ocular dryness, including increased corneal and conjunctival staining, decreased TFBUT, and increased ocular discomfort in healthy individuals. Loratadine induced significantly more conjunctival staining than cetirizine hydrochloride.

Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial

Purpose: To assess safety and efficacy of EGP-437 (dexamethasone phosphate 40 mg/mL [DP]) in dry eye patients. Methods: The study employed a prospective, single-center, double-masked design utilizing a Controlled Adverse Environment (CAE). Patients (n = 103) with confirmed signs and symptoms of dry eye syndrome were randomized into 1 of 3 iontophoresis treatment groups: 7.5 mA-min at 2.5 mA (DP 7.5, n = 41); 10.5 mA-min at 3.5 mA (DP 10.5, n = 37); or 10.5 mA-min at 3.5 mA (placebo, n = 25). Three CAE visits and 4 follow-up visits occurred over 3 weeks. Patients meeting enrollment criteria received iontophoresis in both eyes after the second CAE exposure (visit 3) and before the third CAE exposure (visit 5). Primary efficacy endpoints were corneal staining and ocular discomfort. Secondary endpoints included tear film break-up time, ocular protection index (OPI), and symptomatology. Results: The DP 7.5 and DP 10.5 treatment groups showed statistically significant improvements in signs and symptoms of dry eye at various time points; however, the primary endpoints were not achieved. The DP 7.5 treatment group exhibited statistically significant improvements in corneal staining (when comparing the differences between study entry and exit, 3 weeks, P = 0.039), OPI (immediately following the second treatment, P = 0.048) and ocular discomfort at follow-up visits (a week after the first treatment, P = 0.032; 24 hours after the second treatment, P = 0.0032). Treatment-emergent adverse events (AEs) were experienced by 87% of patients and were consistent across all treatment groups. Most AEs were mild and no severe AEs were observed. Conclusion: Ocular iontophoresis of EGP-437 demonstrated statistically and clinically significant improvements in signs and symptoms of dry eye syndrome within a CAE model.

Diurnal variation of visual function and the signs and symptoms of dry eye.

Purpose: Subjects with dry eye often complain of disturbances in visual function and worsening of symptoms in the evening. To clinically substantiate these reports of diurnal variations, the present study tested subjects with dry eye on a series of visual function and ocular physiology measures. Methods: Twenty-one subjects with dry eye were enrolled and underwent ophthalmic examinations, including best spectacle-corrected visual acuity, visual function decay as measured by the interblink interval visual acuity decay test without ocular anesthetic, reading rate test, slit-lamp biomicroscopy, and tear film breakup time. Keratitis, conjunctival redness, and corneal sensitivity were also assessed. Examinations occurred once during the morning and for a second time in the evening. Subjects also completed a modified version of the Ocular Surface Disease Index at both study visits. Results: Subjects with dry eye showed impaired visual function in the evening, as compared to that in the morning; they maintained their best spectacle-corrected visual acuity for a shorter time between blinks (P < 0.01) and had longer readings times (P < 0.05) in the evening as compared with that in the morning. These findings were qualified by Ocular Surface Disease Index results showing greater subjective visual impairment in the evening. Subjects also demonstrated a significant increase in keratitis and conjunctival redness from morning to evening testing. Less ocular discomfort was reported in the evening than in the morning; this effect significantly correlated with corneal sensitivity in the evening. Conclusions: Subjects with dry eye experience significant diurnal variations of visual function and ocular surface physiology. These daily rhythms should be considered when designing clinical trials and when quantifying disease severity.

An evaluation of tear film breakup time extension and ocular protection index scores among three marketed lubricant eye drops.

Purpose: To report the performance of an artificial tear containing propylene glycol and polyethylene glycol as active demulcents with hydroxypropyl-guar as a gelling agent (Systane Lubricant Eye Drops; Alcon, Fort Worth, TX) and compare it with that of 2 artificial tears containing carboxymethylcellulose (Refresh Tears and Refresh Endura Lubricant Eye Drops; Allergan, Irvine, CA). Methods: This was a single-center, 3-visit, randomized, double-masked crossover study that evaluated the effect of Systane versus Refresh Tears and Refresh Endura using tear film breakup time (TFBUT) and ocular protection index (OPI) in subjects with dry eye (n = 50). TFBUT values (5, 10, 15, 20, 30, 45, and 60 minutes after instillation) divided by interblink interval (IBI) yielded OPI scores. Results: Systane significantly improved TFBUT at 5, 10, 15, 20, and 60 minutes versus Refresh Tears and at 5, 10, 15, 20, and 30 minutes versus Refresh Endura. Systane OPI scores were significantly higher than Refresh Tears at 15 and 30 minutes and than Refresh Endura at 5 minutes. Conclusions: This study suggests that Systane Lubricant Eye Drops was more effective than Refresh Tears at prolonging TFBUT up to 20 minutes after instillation and more effective than Refresh Endura at prolonging TFBUT up to 30 minutes after instillation. These data show that Systane is an effective first-line dry eye therapy and a superior ocular surface protector compared with Refresh Endura and Refresh Tears in the sample test population.

Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye.

Purpose To evaluate the safety and efficacy of ophthalmic MIM-D3, a tyrosine kinase TrkA receptor agonist, in patients with dry eye. Design A prospective, two-center, randomized, double-masked, placebo-controlled Phase 2 study. Methods A total of 150 dry eye patients were randomized 1:1:1 to study medication (1% MIM-D3, 5% MIM-D3, or placebo) and dosed twice daily (BID) for 28 days. Key eligibility criteria included exacerbation in corneal staining and ocular discomfort in the Controlled Adverse Environment (CAESM) on two visits, separated by 1 week of BID dosing with artificial tears. Safety and efficacy were evaluated at baseline, throughout treatment, and for 2 weeks post-treatment. The pre-specified primary outcome measures were fluorescein corneal staining post-CAE at day 28 and diary worst symptom scores over 28 days. Secondary outcomes included the pre-, post-, and the change from pre- to post-CAE fluorescein and lissamine green staining in both corneal and conjunctival regions, as well as individual diary symptoms. Results The prespecified primary endpoints were not met. Compared with placebo, fluorescein corneal staining at day 28 was significantly improved (P < 0.05) in the 1% MIM-D3 group for the assessment of change from pre-CAE to post-CAE. In addition, following CAE exposure, patients in the 1% MIM-D3 group showed significant improvements versus placebo (P < 0.05) in inferior fluorescein and lissamine green staining after 14 and 28 days. Compared with placebo, patients in the 5% MIM-D3 group reported significantly lower daily diary scores for ocular dryness (P < 0.05). In a subgroup defined by higher symptom scores during the run-in period, significant treatment effects (P < 0.05) were observed for diary symptoms for both MIM-D3 doses. Ocular adverse events were mild and not considered to be treatment-related. Conclusion Treatment with topical ophthalmic MIM-D3 demonstrated protection against the effects of a CAE challenge on dry eye signs, reduced patient-reported diary symptoms, with a favorable safety profile.

Automated grading system for evaluation of ocular redness associated with dry eye

Background We have observed that dry eye redness is characterized by a prominence of fine horizontal conjunctival vessels in the exposed ocular surface of the interpalpebral fissure, and have incorporated this feature into the grading of redness in clinical studies of dry eye. Aim To develop an automated method of grading dry eye-associated ocular redness in order to expand on the clinical grading system currently used. Methods Ninety nine images from 26 dry eye subjects were evaluated by five graders using a 0–4 (in 0.5 increments) dry eye redness (Ora Calibra™ Dry Eye Redness Scale [OCDER]) scale. For the automated method, the Opencv computer vision library was used to develop software for calculating redness and horizontal conjunctival vessels (noted as “horizontality”). From original photograph, the region of interest (ROI) was selected manually using the open source ImageJ software. Total average redness intensity (Com-Red) was calculated as a single channel 8-bit image as R – 0.83G – 0.17B, where R, G and B were the respective intensities of the red, green and blue channels. The location of vessels was detected by normalizing the blue channel and selecting pixels with an intensity of less than 97% of the mean. The horizontal component (Com-Hor) was calculated by the first order Sobel derivative in the vertical direction and the score was calculated as the average blue channel image intensity of this vertical derivative. Pearson correlation coefficients, accuracy and concordance correlation coefficients (CCC) were calculated after regression and standardized regression of the dataset. Results The agreement (both Pearson’s and CCC) among investigators using the OCDER scale was 0.67, while the agreement of investigator to computer was 0.76. A multiple regression using both redness and horizontality improved the agreement CCC from 0.66 and 0.69 to 0.76, demonstrating the contribution of vessel geometry to the overall grade. Computer analysis of a given image has 100% repeatability and zero variability from session to session. Conclusion This objective means of grading ocular redness in a unified fashion has potential significance as a new clinical endpoint. In comparisons between computer and investigator, computer grading proved to be more reliable than another investigator using the OCDER scale. The best fitting model based on the present sample, and usable for future studies, was C4=−12.24+2.12C2HOR+0.88C2RED:C4 is the predicted investigator grade, and C2HOR and C2RED are logarithmic transformations of the computer calculated parameters COM-Hor and COM-Red. Considering the superior repeatability, computer automated grading might be preferable to investigator grading in multicentered dry eye studies in which the subtle differences in redness incurred by treatment have been historically difficult to define.

Dry eye in 2008.

Purpose of review Although researchers continue to investigate the multifarious etiologic, anatomical, physiological, and pathological factors of dry eye, successful treatment remains a challenge. Recent findings Dry eye prevalence is substantial across populations and the term ‘dry eye’ is used to describe numerous causes and varied pathophysiologies. Advanced study of the physiological aspects of the ocular anatomy (e.g. cornea and conjunctiva, tear film, eyelids) allows improved understanding of the mechanisms involved in dry eye and the impact of different causes on these entities. Sophisticated diagnostics are being developed to efficiently identify dry eye. Management options include a variety of novel agents in the pipeline. Summary The development of improved etiological understanding and diagnostics for dry eye, as well as emerging therapeutics, will likely allow targeted therapy in the future.

Evaluation of the Time to “Natural Compensation” in Normal and Dry Eye Subject Populations During Exposure to a Controlled Adverse Environment

Approximately 1 of every 5 Americans suffers from dry eye symptomatology. 1 Since the American population constantly encounters adverse environments, visual tasking, and systemic antihistamines, of which all can cause ocular drying, the high incidence of symptoms is hardly surprising. Furthermore, as the prevalence of these factors increase, the incidence of dry eye symptoms can be expected to escalate, and tolerance to symptoms of dry eye may decrease.