Effect of humidity variations in a controlled environment chamber on tear evaporation after dry eye therapy.

PURPOSE: Many dry eye (DE) patients are sensitive to adverse environments where tear evaporation rate (TER) increases. Pilot study-A controlled environment chamber was used to determine the time of exposure required for TER to reach steady state equilibrium at 40% relative humidity (RH). Study 1-To assess the difference between normal and DE subjects in their tear physiology response. Study 2-To determine, under varying environmental conditions, the efficacy of an emulsion eye drop on tear physiology. METHODS: Pilot study-TER adaptation time was determined by exposing 3 normal and 3 DE subjects to RH of 40% at 72°F for 0, 5, 10, 15, 20, and 25 minutes. Study 1-The difference in noninvasive tear breakup time (NITBUT) and TER responses between DE and normal subjects were determined at various RH from 5% to 70% (at 72°F) for 20 subjects (10 normal subjects; 10 DE subjects). Study 2-To assess the efficacy of an emulsion eye drop, the same 20 subjects were dosed four times per day for 7 days with a drop containing emulsified castor oil and reassessed. RESULTS: Pilot study-Evaporation at 40% RH showed a peak (around 5 minutes) followed by a decline to steady state level at 10 minutes. Dry eye subjects showed greater evaporation than normal subjects at 40% and 5% RH but not at 70%, where TER declined to zero in both groups. No significant change in NITBUT was found in either group for the various exposure times of the test period (P>0.05). Study 1-TER was higher in DE compared with normal subjects at 5% or 40% RH, however reduced to almost zero in both groups at 70% RH. A significant difference in NITBUT was found between the DE and normal groups at each humidity (P<0.05). Study 2-An emulsion-based drop effectively lowered the TER, especially in DE patients. For NITBUT, a significant improvement in both normal and DE subjects was found at 5% and 40% but not at 70% RH levels. CONCLUSIONS: Pilot study-TER measurements required at least 10 minutes in the chamber to obtain a steady-state TER with no significant change to NITBUT. Study 1-TER has a reverse correlation with environmental humidity in the range of 5% to 70%, with TER reduced to zero at 70% RH. Dry eye subjects had a higher TER at all RH levels below 70%, and NITBUT is significantly different between DE and normal subjects at all humidities. Study 2-Emulsion-based drops reduced TER in DE patients by an amount equivalent to that obtained by raising environmental humidity by 30%. Noninvasive tear breakup time was improved in both normal and DE subjects at lower RH levels.

Transport of L-carnitine in human corneal and conjunctival epithelial cells.

PURPOSE: Previously we demonstrated expression and localization of carnitine/organic cation transporters, OCTN1 and OCTN2, in human corneal and conjunctival epithelia. The present study aimed to examine the characteristics of L-carnitine transporters in cultured human limbal corneal (HCLE) and conjunctival epithelial (HCjE) cells. METHODS: Time-course, Na(+)-dependence, kinetics, energy- and pH- dependence of L-carnitine transport were investigated by monitoring L-[(3)H]carnitine uptake into HCLE and HCjE cells. To determine the specificity of action, competition and inhibition studies were performed. RESULTS: The uptake of L-carnitine into HCLE and HCjE cells was saturable and time-dependent. An Eadie-Hofstee plot showed two distinct components: a high- and a low- affinity carnitine transport system in HCLE and/or HCjE cells. L-carnitine transport was significantly inhibited by the metabolic inhibitors (sodium azide, dinitrophenol, iodoacetic acid). The L-carnitine analogs (D-carnitine, acetyl-L-carnitine and γ-butyrobetaine), tetraethylammonium (TEA), 2-amino-2-norbornane carboxylic acid (BCH), strongly inhibited uptake of L-[(3)H]carnitine. Uptake of L-[(3)H]carnitine also required the presence of Na(+) in the external medium and the uptake activity was maximal at pH 5.5. The anti-OCTN2 antibody blocked L-carnitine uptake in both HCLE and HCjE cells whereas the anti-OCTN1 antibody did not significantly block L-carnitine uptake. CONCLUSIONS: L-carnitine is transported into HCLE and HCjE cells by an active carrier mediated transport system that is time-, Na(+)-, energy- and pH- dependent. The carnitine/organic cation transporter OCTN2 appears to play a dominant role in this process.

Safety and Efficacy of a Preservative-Free Artificial Tear Containing Carboxymethylcellulose and Hyaluronic Acid for Dry Eye Disease: A Randomized, Controlled, Multicenter 3-Month Study.

PURPOSE: To compare the efficacy and safety of an artificial tear combining the polymers carboxymethylcellulose (CMC) and hyaluronic acid (HA), to a formulation of CMC alone in subjects with dry eye. METHODS: A preservative-free artificial tear (CMC-HA) was compared with an existing artificial tear (CMC). Subjects with mild-to-severe signs and symptoms of dry eye were enrolled in this double-masked, randomized, multicenter trial, and dosed at least twice daily for 90 days, with follow-up visits at Days 7, 30, 60, and 90. Ocular Surface Disease Index (OSDI) was the primary outcome measure. Secondary outcome measures were tear break-up time (TBUT), ocular surface staining, Schirmer test with anesthesia, and visual analog scale (VAS) scores of dry eye symptom severity and formulation acceptability. Safety measures included adverse events, biomicroscopy, and visual acuity. RESULTS: A total of 460 subjects were enrolled across 45 sites (38 in Europe; 7 in Australia), of whom 454 were randomized to receive treatment. The per-protocol (PP) population consisted of 394 subjects, 364 (92.4%) of whom completed the study. In the PP population, the mean ± SD change from baseline in OSDI score at the primary timepoint, Day 90, was -16.9±17.5 for CMC-HA and -16.0±16.1 for CMC. CMC-HA was non-inferior to CMC based upon a confidence interval method. Both treatments significantly improved (P<0.001) OSDI, symptom VAS scores, TBUT, and ocular surface staining from baseline at all follow-up visits, with minimal differences between groups. Greater reduction of overall ocular pain/discomfort was reported in subjects using CMC-HA versus CMC (P=0.048). Approximately 10% of subjects in each group reported treatment-related adverse events of generally mild to moderate severity. CONCLUSION: The new CMC-HA formulation was effective and well tolerated, and demonstrates a greater potential for symptom relief compared with CMC. These data support implementation of this formula for the management of dry eye patients.

Physicochemical Properties of Hyaluronic Acid-Based Lubricant Eye Drops.

PURPOSE: To assess the physicochemical properties of hyaluronic acid (HA)-based artificial tears. METHODS: The average molecular weight (MW) and polydispersion index (PDI) of HA in 18 commercially available artificial tears were determined by light scattering/high-performance liquid chromatography. Osmolality, pH, viscosity, and sodium concentration were determined using an osmometer, pH meter, rheometer, and inductively coupled plasma mass spectrometer, respectively. RESULTS: The MW of HA varied considerably between formulations. The PDI was >2.0 in two formulations (2.28 and 4.94), suggesting the presence of a copolymer and/or HA size variability. Three formulations exhibited viscosity exceeding the blur threshold at different shear rates. Viscosity at low shear rates was generally highest in formulations containing high-MW HA. Correlations were found between observed viscosity and a predictive/calculated value, except for four copolymer-containing formulations, and osmolality (range, 154-335 mOsm/kg) and sodium concentration (range, 22-183 mM), with two exceptions. Compared with organic osmolytes, adding sodium decreased viscosity, particularly at lower shear rates. CONCLUSIONS: In the context of the literature, our findings suggest that for most patients with dry eye disease, the ideal HA-based artificial tear should include high-MW HA with a low PDI and exhibit enhanced viscosity at low shear rate (without exceeding the blur threshold). The inclusion of synergistic copolymers and a low sodium concentration may increase viscosity, but whether any of these physicochemical properties or correlations can predict clinical efficacy will require further investigation. TRANSLATIONAL RELEVANCE: Understanding the properties of HA-based artificial tears will support the development of unique formulations that target specific ocular surface conditions.

Management of post-LASIK dry eye: a multicenter randomized comparison of a new multi-ingredient artificial tear to carboxymethylcellulose.

PURPOSE: To compare the efficacy and safety of a preservative-free, multi-ingredient formulation of carboxymethylcellulose 0.5%, hyaluronic acid 0.1%, and organic osmolytes (CMC-HA), to preservative-free carboxymethylcellulose 0.5% (CMC) in the management of postoperative signs and symptoms of dry eye following laser-assisted in situ keratomileusis (LASIK). METHODS: This was a double-masked, randomized, parallel-group study conducted in 14 clinical centers in Canada and Australia. Subjects with no more than mild dry eye instilled CMC-HA or CMC for 90 days post-LASIK. Ocular Surface Disease Index© (OSDI; primary efficacy measure), corneal staining, tear break-up time (TBUT), Schirmer's test, acceptability/tolerability surveys, and visual acuity were assessed at screening and days 2, 10, 30, 60, and 90 post-surgery. Safety analyses included all enrolled. RESULTS: A total of 148 subjects (CMC-HA, n=75; CMC, n=73) were enrolled and assigned to receive treatment, and 126 subjects completed the study without any protocol violations. Post-LASIK, dry eye signs/symptoms peaked at 10 days. OSDI scores for both groups returned to normal with no differences between treatment groups at day 90 (P=0.775). Corneal staining, Schirmer's test, TBUT, and survey results were comparable. Higher mean improvements in uncorrected visual acuity were observed in the CMC-HA group at all study visits, reaching statistical significance at day 30 (P=0.013). Both treatments were well tolerated. CONCLUSION: CMC-HA-containing artificial tears relieved post-LASIK ocular dryness as well as CMC alone, and demonstrated incremental benefit in uncorrected vision, with a favorable safety profile. Results support use of CMC-HA eye drops to reduce signs and symptoms of ocular dryness post-LASIK.

Carboxymethylcellulose binds to human corneal epithelial cells and is a modulator of corneal epithelial wound healing.

PURPOSE: In this study, the ability of carboxymethylcellulose (CMC), used in artificial tear formulations, to interact with corneal-epithelial-cells (HCECs) and facilitate corneal epithelial wound healing was investigated. METHODS: HCECs were incubated with fluorescein-labeled CMC (F-CMC). CMC-epithelial binding was measured by spectrophotometry. The effect on F-CMC binding by hyaluronic acid (HA) or glucose was measured after preincubation in HA, mAb to CD44, or glucose, or mAb to GluT-1. F-CMC binding to fibronectin or collagen was measured by incubating proteins with F-CMC. The wound widths were measured 18 hours after confluent HCECs were scratch wounded. The ability of CMC to induce cell chemotaxis, proliferation, or migration was measured by quantitative assay. The efficacy of CMC in promoting epithelial wound healing was also tested in a rabbit epithelial scrape-wound model. RESULTS: CMC remained bound to the HCECs for 2 hours. Preincubation of HCECs with glucose or mAb to GluT-1, but not with HA or mAb to CD44, reduced the binding of CMC to HCECs from 43.7% to 67.2% or 10.9% to 25.3%, respectively. CMC bound significantly to fibronectin (3.1-fold) or collagen (9.3-fold) compared with the control (BSA), and such binding enhanced cell adhesion. CMC stimulated re-epithelialization of HCECs scratched in vitro and in vivo rabbit cornea epithelial scrape wounds. CMC stimulated cell migration but not proliferation. CONCLUSIONS: CMC probably binds to HCECs through interaction of its glucopyranose subunits with glucose transporters. CMC binding to the matrix proteins stimulated HCEC attachment, migration, and re-epithelialization of corneal wounds.

Clinical performance of a mid-viscosity artificial tear for dry eye treatment.

PURPOSE: We report the results of 3 studies conducted to evaluate the performance of a 1.0% carboxymethylcellulose (CMC) mid-viscosity artificial tear compared to currently marketed low-viscosity tears. METHODS: First, a single-center, double-masked, randomized, crossover study was performed to compare the effect on the Ocular Protection Index (OPI) of the mid-viscosity tear compared to low-viscosity tears in 39 subjects with mild to moderate dry eye. Second, a 1-month, 2-arm, parallel, randomized double-masked clinical study assessed objective signs and subjective symptoms of dry eye in 103 subjects with mild to moderate dry eye. Third, in a 1-month home-use test, 465 artificial tear users compared the mid-viscosity tear or a current low-viscosity tear to their current artificial tear. RESULTS: The OPI study showed prolonged tear breakup time and improved OPI for at least 20 minutes after instillation of the mid-viscosity tear. The low-viscosity tears showed improvements for 5 to 10 minutes. The 1-month clinical study showed a significant reduction in staining and dry eye symptoms after 1 week of treatment, with a further reduction in staining after 1 month in the mid-viscosity group. Subjects provided more reports of blur with the mid-viscosity tear than with a low-viscosity tear, but equivalent overall acceptability. The home use test showed general acceptability of the mid-viscosity tear, including more subjects indicating that it was needed less frequently than their prior low-viscosity tear. CONCLUSIONS: This 1% CMC mid-viscosity tear showed protection of the ocular surface after instillation and significant reduction in signs and symptoms of dry eye. Improvements were greater than with low-viscosity tears. The mid-viscosity artificial tear was rated well in comfort, duration of benefit, and general acceptability.

Effect of an oil-in-water emulsion on the tear physiology of patients with mild to moderate dry eye.

PURPOSE: To determine the effect of an oil-in-water emulsion eye drop compared with a conventional dry eye supplement (hypromellose) on tear physiology in dry eye. METHODS: A randomized parallel, longitudinal, and investigator-masked study of the efficacy of 1.25% castor oil emulsion and 0.32% hypromellose solution was carried out. A total of 53 patients with mild to moderate dry eye (27 in emulsion group and 26 in hypromellose group) were recruited for the study. Patients were enrolled if they reported at least 2 symptoms on a McMonnies Dry Eye Questionnaire together with 1 of the following screening tests: noninvasive tear breakup time (5-10 seconds) and Schirmer test without anesthesia (2-5 mm in 5 minutes). Patients were instructed to use the test solutions 3 times a day for 30 days. Tear production, evaporation, lipid layer structure, and osmolality were measured before and 30 days after use of the drops. RESULTS: A statistically significant decrease was seen after 1 month in tear evaporation rates with both emulsion (7.25 +/- 5.43 g/m2/h) and hypromellose (2.02 +/- 4.75 g/m2/h). However, the decrease with emulsion was significantly greater than with hypromellose (P < 0.001). Lipid layer structure improved from day 1 to day 30 of the study with the emulsion but not with the hypermellose. No significant changes were seen in tear production and osmolality with either of the drops. CONCLUSIONS: The oil-water emulsion was more effective in reducing tear evaporation than hypromellose after repeated application over a 1-month period. This finding signifies the potential of the emulsion in the management of evaporative dry eye.

Investigating the potential benefits of a new artificial tear formulation combining two polymers.

PURPOSE: Artificial tear formulations typically contain a water-soluble polymer to enhance residence time, moisture retention, and binding to the mucin coat of the ocular surface, which facilitate corneal healing. This study investigated the potential advantages of combining carboxymethylcellulose (CMC) and hyaluronic acid (HA) polymers in a single formulation. MATERIALS AND METHODS: Individual CMC and HA solutions were prepared and tested for bulk viscosity in comparison to a solution that combined CMC and HA. Rheometry determined the differences between solutions at increasing shear rates, simulating eye movement and blinking. RESULTS: The bulk viscosity of the individual 0.5% CMC and 0.1% HA solutions was 2.5 and 5.7 cP, respectively. The viscosity of the combined solution (13.1 cP) was 60% higher than predicted by additive effects. Rheometry revealed shear rates between 10/second (open eye) and 10,000/second (blinking eye). At these rates, viscosity ranged from 2.7 to 3.5 cP for 0.5% CMC, 2.8 to 6.8 cP for 0.1% HA, and 5.2 to 15.3 cP for the 0.5% CMC-0.1% HA combination. Low-shear viscosity of the CMC-HA combination increased 48% over the sum of the individual solutions, but high-shear viscosity remained virtually unchanged. Data from CMC and HA solutions at higher concentrations were consistent with these results. CONCLUSION: Combining CMC and HA polymers produced a synergistic increase in low-shear viscosity (which cannot be fully explained by simple molecular entanglement), while the high-shear viscoelasticity of the combined solution remained unaffected. These data suggest that CMC-HA combinations have properties that may be used to formulate artificial tears that optimize ocular retention (through higher low-shear viscosity), while minimizing blur and stickiness during blinking (through lower high-shear viscosity).

Comparison of novel lipid-based eye drops with aqueous eye drops for dry eye: a multicenter, randomized controlled trial.

BACKGROUND: Dry eye may be caused or exacerbated by deficient lipid secretion. Recently, lipid-containing artificial tears have been developed to alleviate this deficiency. Our study compared the efficacy, safety, and acceptability of lipid-containing eye drops with that of aqueous eye drops. METHODS: A non-inferiority, randomized, parallel-group, investigator-masked multicenter trial was conducted. Subjects with signs and symptoms of dry eye were randomized to use one of two lipid-containing artificial tears, or one of two aqueous artificial tears. Subjects instilled assigned drops in each eye at least twice daily for 30 days. The primary efficacy analysis tested non-inferiority of a preservative-free lipid tear formulation (LT UD) to a preservative-free aqueous tear formulation (AqT UD) for change in Ocular Surface Disease Index (OSDI) score from baseline at day 30. Secondary measures included OSDI at day 7, tear break-up time (TBUT), corneal and conjunctival staining, Schirmer's test, acceptability and usage questionnaires, and safety assessments. RESULTS: A total of 315 subjects were randomized and included in the analyses. Subjects reported instilling a median of three doses of study eye drops per day in all groups. At days 7 and 30, all groups showed statistically significant improvements from baseline in OSDI (P<0.001) and TBUT (P≤0.005). LT UD was non-inferior to AqT UD for mean change from baseline in OSDI score at day 30. No consistent or clinically relevant differences for the other efficacy variables were observed. Acceptability was generally similar across the groups and there was a low incidence of adverse events. CONCLUSION: In this heterogeneous population of dry eye subjects, there were no clinically significant differences in safety, effectiveness, and acceptability between lipid-containing artificial tears and aqueous eye drops. The results suggest that lipid-containing artificial tears can be used to counteract lipid deficiency that is common in dry eye, without compromising overall acceptability.

Efficacy and safety of two new formulations of artificial tears in subjects with dry eye disease: a 3-month, multicenter, active-controlled, randomized trial.

PURPOSE: To evaluate and compare the efficacy and safety of two investigational artificial tear formulations (CHO-1 and CHO-2) containing carmellose sodium, hyaluronic acid at different concentrations, and osmoprotectants, with a standard carmellose sodium-containing formulation (Refresh Tears [RT]) in the treatment of dry eye disease. SUBJECTS AND METHODS: In this 3-month, double-masked, multicenter study, subjects (n=305) were randomized 1:1:1 to receive CHO-1, CHO-2, or RT, used as needed but at least twice daily. The primary endpoint was change in ocular surface disease index (OSDI) score from baseline to day 90. Other key outcomes included symptoms evaluated on a visual analog scale, corneal and conjunctival staining, and adverse events. RESULTS: OSDI scores and dry eye symptoms showed a rapid and sustained reduction from baseline in each group. Both CHO-1 and CHO-2 met the primary efficacy endpoint of noninferiority to RT in day 90 OSDI score change from baseline. OSDI ocular symptoms subscale improved more with CHO-1 than CHO-2 (P=0.048). In subjects with clinically relevant baseline ocular surface staining (>14 total score of a maximum of 55), day 90 improvements were greater with CHO-1 and CHO-2 than RT (P≤0.044). Day 90 improvements in OSDI ocular symptoms subscale scores were also greater with CHO-1 than RT (P<0.007) in subjects with clinically relevant ocular staining. All treatments were well tolerated. CONCLUSION: Both combination artificial tear formulations were efficacious and well tolerated in subjects with dry eye. CHO-1 demonstrated the best performance in improving ocular symptoms and reducing ocular staining in this heterogeneous study population.

Efficacy, safety, and acceptability of a lipid-based artificial tear formulation: a randomized, controlled, multicenter clinical trial.

PURPOSE: Dry eye disease is highly prevalent worldwide, causing discomfort and visual disturbances that can limit basic activities such as reading and driving. Although artificial tears represent first-line therapy, there is a paucity of published controlled clinical trials. The present study compared the efficacy, clinical safety, and acceptability of 2 multicomponent, lipid-based tear formulations (ADV1 and ADV2) to those of an existing lipid-based tear formulation (DET) in patients with signs and symptoms of dry eye disease. METHODS: This 3-month, multicenter, double-masked study was conducted in patients with dry eye symptoms, reduced tear break-up time (TBUT), and ocular surface damage. Patients were randomized to receive 1 of 2 lipid-based tear formulations containing carboxymethylcellulose, glycerin, polysorbate 80, and emulsified lipid (ADV1 or ADV2) or DET, and instilled 1 to 2 drops per eye at least twice daily. The primary end point was the mean change from baseline in Subjective Evaluation of Symptom of Dryness score at day 90 to determine noninferiority of the 2 ADV formulations versus DET. Secondary end points included Ocular Surface Disease Index (OSDI) score, TBUT, ocular surface staining, and tolerability. FINDINGS: Of 288 randomized patients, 256 completed the study. All 3 groups showed improvement in symptoms, and the 2 lipid-based formulations were noninferior to DET in reducing the severity of symptoms of dryness at 90 days. Of the 3 treatment groups, the ADV2 group had the greatest improvements in TBUT and OSDI. Significant improvements in mean tolerability scores for comfort, soothing, burning/stinging, and discomfort were observed in the ADV2 group versus the DET group at 90 days. Treatment-related adverse events were reported in 13 patients (13.4%) receiving ADV1, 8 (8.4%) receiving ADV2, and 21 (21.9%) receiving DET. Four patients (4.1%) in the ADV1 group and 2 (2.1%) in the ADV2 group discontinued owing to an adverse event compared with 14 (14.6%) receiving DET. IMPLICATIONS: In these patients with dry eye symptoms, ADV2 was an effective and relatively well-tolerated artificial tear for first-line therapy and should be considered as a treatment option for dry eye, especially in those patients who would benefit from a lipid-based formulation in addition to lubrication. https://clinicaltrials.gov/ct2/show/NCT01010282.

Evaluation of a Novel Artificial Tear in the Prevention and Treatment of Dry Eye in an Animal Model.

PURPOSE: To evaluate effects of a novel multi-ingredient artificial tear formulation containing carboxymethylcellulose (CMC) and hyaluronic acid (HA) in a murine dry eye model. METHODS: Dry eye was induced in mice (C57BL/6) using an intelligently controlled environmental system (ICES). CMC+HA (Optive Fusion™), CMC-only (Refresh Tears(®)), and HA-only (Hycosan(®)) artificial tears and control phosphate-buffered saline (PBS) were administered 4 times daily and compared with no treatment (n = 64 eyes per group). During regimen 1 (prevention regimen), mice were administered artificial tears or PBS for 14 days (starting day 0) while they were exposed to ICES, and assessed on days 0 and 14. During regimen 2 (treatment regimen), mice exposed to ICES for 14 days with no intervention were administered artificial tears or PBS for 14 days (starting day 14) while continuing exposure to ICES, and assessed on days 0, 14, and 28. Corneal fluorescein staining and conjunctival goblet cell density were measured. RESULTS: Artificial tear-treated mice had significantly better outcomes than control groups on corneal staining and goblet cell density (P < 0.01). Mice administered CMC+HA also showed significantly lower corneal fluorescein staining and higher goblet cell density, compared with CMC (P < 0.01) and HA (P < 0.05) in both regimens 1 and 2. CONCLUSIONS: The artificial tear formulation containing CMC and HA was effective in preventing and treating environmentally induced dry eye. Improvements observed for corneal fluorescein staining and conjunctival goblet cell retention suggest that this combination may be a viable treatment option for dry eye disease.

The influence of lens conditioning on signs and symptoms with new hydrogel contact lenses.

BACKGROUND: Daily disposable contact lenses are considered to be the pinnacle of safe contact lens wear, yet it has been suggested that it takes some period of wear for the lens surface to reach optimal compatibility with the ocular surface. This study assesses the influence of brief treatment with a conditioning drop on the ocular response to new contact lenses over a single day of wear. METHODS: The study was a single-masked, paired (contralateral) comparison of the signs and symptoms with wear of new Acuvue 2 contact lenses pretreated with a conditioning agent containing carboxymethylcellulose (carmellose, CMC) against new lenses inserted directly from the blister pack. Sixty-one subjects participated in the study, of whom 59 were considered eligible for data analysis. Subjects were also divided into symptomatic and asymptomatic lens wearers based on their overall comfort level in lens wear. Symptoms and signs were recorded at lens delivery and following eight hours of wear. RESULTS: A set of slitlamp signs, comprising corneal staining (p <0.05), limbal redness (p <0.05), bulbar conjunctival hyperaemia (p <0.05), bulbar conjunctival staining (p <0.01) and palpebral conjunctival redness (p <0.05) showed small but statistically significant (p <0.05) end-of-day mean values in favour of the lens that was conditioned with the rewetting agent. These data were supported by the proportion of subjects showing lower gradings with conditioned lenses versus unconditioned lenses, as follows: corneal staining (35 per cent versus 12 per cent, p <0.05), limbal redness (43 per cent versus 22 per cent, p <0.05), bulbar conjunctival hyperaemia (50 per cent versus 15 per cent, p <0.05), bulbar conjunctival staining (46 per cent versus 30 per cent, p <0.1) and palpebral conjunctival hyperaemia (28 per cent versus 17 per cent, NS). For those subjects reporting symptoms with lens wear (n=12), there was a statistically significant (p <0.05) preference in terms of comfort as a result of preconditioning. CONCLUSIONS: The results of the investigation suggest that use of a conditioning agent can provide a more physiologically suitable environment for a new lens, thereby reducing the clinical signs associated with lens discomfort. The protocol used here, which is based on a statistical paradigm using standard pictorial grading scales, allows high sensitivity in detecting small changes in ocular parameters.

Effectiveness of dry eye therapy under conditions of environmental stress.

PURPOSE: Dry eye is often characterized by increased tear evaporation due to poor tear film quality, especially of the lipid component of the tear film. Using an environmental chamber to induce environmental stress, this study compared the effect of three lubricant eye drops on various aspects of tear physiology in a crossover design (evaporation was the principal outcome measure). METHODS: Three eye drop formulas were tested: 0.5% carmellose sodium (Drop C), 0.5% carmellose sodium with added lipid (Drop C-L) and 1.0% glycerine with added lipid (Drop G-L). Nineteen control and 18 dry eye subjects used each product for 2 weeks, three times per day, in a random order, with a minimum 1-week washout between treatment periods. Tear evaporation, break up time, osmolarity, tear structure (by interferometry) and patient symptoms were assessed with the subjects adapted for 10 min in an environmental chamber controlled at 20% relative humidity and 22 °C. The treatment effects were analyzed using general linear model repeated measures analyses of variance. RESULTS: In dry eye subjects, evaporation, break up time, osmolarity and symptoms improved for all formulas (p < 0.05). Normal subjects showed some improvements: evaporation with C-L, osmolarity with C and symptoms with C-L and G-L. Change in evaporation was greater for both C-L and G-L versus C (p < 0.05), and there was a trend for C-L to reduce evaporation more than G-L (p < 0.11). There were no significant treatment effects on tear film structure. CONCLUSION: Overall, the eye drop formula containing both carmellose sodium and lipid (C-L) produced a greater treatment effect on tear evaporation than the other formulations containing only one of these ingredients. This study also demonstrates the utility of a controlled environmental chamber in showing the difference in performance between dry eye treatments.

Role of carnitine in disease.

Carnitine is a conditionally essential nutrient that plays a vital role in energy production and fatty acid metabolism. Vegetarians possess a greater bioavailability than meat eaters. Distinct deficiencies arise either from genetic mutation of carnitine transporters or in association with other disorders such as liver or kidney disease. Carnitine deficiency occurs in aberrations of carnitine regulation in disorders such as diabetes, sepsis, cardiomyopathy, malnutrition, cirrhosis, endocrine disorders and with aging. Nutritional supplementation of L-carnitine, the biologically active form of carnitine, is ameliorative for uremic patients, and can improve nerve conduction, neuropathic pain and immune function in diabetes patients while it is life-saving for patients suffering primary carnitine deficiency. Clinical application of carnitine holds much promise in a range of neural disorders such as Alzheimer's disease, hepatic encephalopathy and other painful neuropathies. Topical application in dry eye offers osmoprotection and modulates immune and inflammatory responses. Carnitine has been recognized as a nutritional supplement in cardiovascular disease and there is increasing evidence that carnitine supplementation may be beneficial in treating obesity, improving glucose intolerance and total energy expenditure.

Expression and localization of carnitine/organic cation transporter OCTN1 and OCTN2 in ocular epithelium.

PURPOSE: The existence of an organic cation transport process in rabbit cornea and conjunctiva that mediates absorption of carnitine has previously been suggested. This study was conducted to determine the expression and localization of the carnitine/organic cation transporter (OCTN1 and OCTN2) in corneal or conjunctival epithelium. METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for OCTN1 and OCTN2 mRNA expression in cultured human corneal-limbal epithelial (HCLE) or human conjunctival epithelial (HCjE) cells. Immunofluorescence staining with polyclonal antibody against human OCTN1 or OCTN2 was performed to investigate transporter expression in ocular epithelial cells or rabbit corneal and conjunctival epithelium. Polarity of the transporter expression was determined using Western blot analysis of the apical or basal membrane proteins extracted from the cultured cells. Apical or basal uptake of [H(3)]-L-carnitine was determined using the polarized epithelial cells grown onto collagen-coated porous filter support. RESULTS: OCTN1 and OCTN2 mRNA expression was detected in HCLE and HCjE cells of rabbits and humans. OCTN1 and OCTN2 were predominately localized in the apical membranes of the cells. HCLE and HCjE cells were able to take up L-carnitine; most carnitine uptake occurred through the apical surfaces. CONCLUSIONS: This report is the first to document OCTN1 and OCTN2 expression in human corneal and conjunctival epithelial cells. These findings suggest potential involvement of OCTN1 and OCTN2 in the transport of carnitine in ocular tissues.

Effect of artificial tears on tear stress test.

PURPOSE: To determine the effect of two artificial tears of different viscosities in the relief of environmental dry eye induced with a novel tear stress test (TST). METHODS: A novel TST was developed and validated. The following four test conditions were evaluated in 12 healthy normal subjects in a cross-over and subject masked study; unprotected (no test solution used), relief (test solution instilled just after application of TST), immediate protection (test solution instilled just before application of TST), and chronic protection (1 week prophylactic use of the solution). The test solutions were Cellumed, with high viscosity, and Refresh Contacts, with low viscosity. Low contrast visual acuity, symptoms with analogue scales (symptom scoring), non-invasive tear break-up time, and tear evaporation were measured before (prestress) and 2 min after (poststress) application of TST. Two weeks of washout period was allowed after first test solution. RESULTS: In unprotected test condition, there was no significant difference between pre- and poststress visual acuity (p = 0.102), tear evaporation (p = 0.530), and non-invasive tear break-up time (p = 0.878), however, poststress total symptom score was significantly higher than prestress (p = 0.002). No significant differences were seen between pre- and post-total symptom score at relief (p = 0.241 for Cellumed and 0.114 for Refresh Contacts) and immediate protection (p = 0.890 for Cellumed and 0.136 for Refresh Contacts) for both test solutions, whereas postsymptoms total score was significantly higher than prestress at chronic protection (p = 0.003 for both). No significant differences were seen in the effect of the two solutions in all test conditions. CONCLUSIONS: There is an increase in dry eye symptomatology after ocular stress. The use of artificial tears just before or after ocular stress is helpful in relieving resultant symptoms in normals.

Carboxymethyl cellulose stimulates rabbit corneal epithelial wound healing.

PURPOSE: Previously, we reported carboxymethyl cellulose (CMC) binding to human corneal epithelial cells and promoting corneal epithelial wound closure in vitro. Using an animal model, the efficacy of CMC in promoting corneal wound healing was examined. MATERIALS AND METHODS: Following corneal epithelial wounding of NZ white rabbits, CMC (0.2% or 1.0%) or control vehicle (PBS) was administered topically (4 times daily for 3 days) to wounded and unwounded eyes with or without contact lens wear. Wound healing in response to the treatments was measured as percentage reduction of fluorescein-stained wound area 0 to 72 hr post-wounding. Corneas were examined histologically and expression of zonula occludens-1 (ZO-1) tight-junction was detected by immunohistochemistry. RESULTS: Percentage wound reduction in CMC-treated groups was significantly greater than controls (p < 0.05) at 24 and 32 hr. Complete wound closure was observed by 48 hr in 100% of CMC-treated eyes compared to 45% of vehicle-treated eyes. CMC also promoted wound closure dose-dependently. Epithelial cells formed an intact layer following CMC-treatment whereas vehicle-treated cells were less ordered. Strong ZO-1 expression in corneal epithelia of CMC-treated eyes was observed at 72 hr. Contact lens wear appeared to delay wound closure compared to without lens wear during CMC-treatment (p = 0.001). CONCLUSIONS: CMC promoted dose-dependent corneal epithelial wound healing. CMC stimulated ZO-1 expression, indicating accelerated corneal epithelial resistance barrier regeneration.