Publications by authors named "Joseph Vehige"

24 Publications

  • Page 1 of 1

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.

Clin Ophthalmol 2020 1;14:2951-2963. Epub 2020 Oct 1.

Optometry and Vision Science, UNSW Sydney, Sydney, NSW, Australia.

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 (<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 (=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.
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http://dx.doi.org/10.2147/OPTH.S256480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534849PMC
October 2020

An artificial tear containing flaxseed oil for treating dry eye disease: A randomized controlled trial.

Ocul Surf 2020 01 14;18(1):148-157. Epub 2019 Nov 14.

Allergan Plc, Irvine, CA, USA.

Purpose: To evaluate the efficacy and safety of a nano-emulsion artificial tear (OM3) containing carboxymethylcellulose (CMC) and glycerin, flaxseed oil and castor oil, and three osmoprotectants (levocarnitine, erythritol, and trehalose) compared with an artificial tear (Refresh Optive Advanced [ROA]) containing the same ingredients with the exception of trehalose and flaxseed oil.

Methods: In this multicenter, double-masked, randomized, two-arm, parallel-group, 6-visit study (screening, baseline, and days 7, 30, 60, and 90), subjects with dry eye disease underwent an open-label, 7-day run-in with CMC 0.5% (Refresh Plus), before 1:1 randomization to OM3 or ROA for 90 days (both instilled ≥2 daily). Ocular Surface Disease Index (OSDI; primary endpoint change from baseline at day 90), tear film breakup time (TBUT), and ocular staining (combined/corneal/conjunctival) were assessed; change from baseline in these parameters was calculated at each timepoint. Treatment-related adverse events (AEs) were assessed at each visit.

Results: Overall, 242 subjects were randomized (OM3, n = 120; ROA, n = 122). At day 90, significant improvements in OSDI, ocular staining and TBUT were evident in both treatment groups. Significant (P < 0.05) between-group differences in favor of OM3 were observed for combined ocular staining (all timepoints), corneal staining (day 90), and conjunctival staining (day 30). Treatment-related AEs were higher in the ROA (9.8%) versus OM3 (6.7%) group; blurred vision was among the most commonly reported AE (OM3 0% vs ROA 4.1%).

Conclusion: These findings support the application of OM3, a novel preservative-free, nano-emulsion tear formulation with trehalose and flaxseed oil, for the treatment of dry eye disease.
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http://dx.doi.org/10.1016/j.jtos.2019.11.004DOI Listing
January 2020

Evaluation of an enhanced viscosity artificial tear for moderate to severe dry eye disease: A multicenter, double-masked, randomized 30-day study.

Cont Lens Anterior Eye 2019 08 17;42(4):443-449. Epub 2018 Dec 17.

Allergan International Medical Affairs, Marlow, Buckinghamshire, UK. Electronic address:

Purpose: In a randomized, controlled clinical trial, two lubricant artificial tear formulations with enhanced viscosity were compared: an investigational product at the time, containing carboxymethylcellulose 1.0% and glycerin 0.9% (CMC-GLY) with osmoprotectants, and a standard formula containing carboxymethylcellulose 1.0% alone (CMC).

Methods: This double-masked study recruited patients with moderate to severe dry eye at 10 US centers. After a 7-day run-in with CMC 0.5% (Refresh Tears) patients were randomized to use either CMC-GLY or CMC as needed, but at least 2 times daily for 30 days. Patients were stratified by Ocular Surface Disease Index (OSDI) score into moderate (23-32) and severe (> 32-65) subgroups. Assessments included OSDI (primary efficacy variable), corneal and conjunctival staining, tear break-up time (TBUT), symptom surveys, and safety variables. Study visits were days 1 (baseline/randomization), 7, and 30.

Results: A total of 188 patients (94 CMC-GLY, 94 CMC) were enrolled. The severe subgroup had 67 CMC-GLY and 65 CMC patients. OSDI scores progressively improved and were similar at day 30 between treatment groups. At day 7, only the CMC-GLY group demonstrated significant improvements from baseline in OSDI score (all patients p < 0.001, severe p < 0.001), corneal staining (p = 0.004), and TBUT (p < 0.001). Between-group dose frequency for CMC-GLY was lower at day 7 (p = 0.031). Other efficacy results were similar between groups. The most commonly reported adverse event in both groups was blurred vision.

Conclusions: Overall, the CMC-GLY artificial tear formulation was as effective as the CMC formulation. CMC-GLY demonstrated improvements at an earlier stage (day 7). Both artificial tear formulations were safe and well tolerated, with no treatment-related serious adverse events. These results support the use of the CMC-GLY artificial tear formulation as an effective treatment to reduce the symptoms and signs of dry eye disease.
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http://dx.doi.org/10.1016/j.clae.2018.12.003DOI Listing
August 2019

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

Clin Ophthalmol 2017 12;11:1637-1642. Epub 2017 Sep 12.

Allergan plc, Irvine, CA, USA.

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).
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http://dx.doi.org/10.2147/OPTH.S135550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602465PMC
September 2017

Dual-Polymer Drops, Contact Lens Comfort, and Lid Wiper Epitheliopathy.

Optom Vis Sci 2016 08;93(8):979-86

*OD, PhD, FAAO †OD, MS, FAAO ‡OD, FAAO §PhD ∥OD School of Optometry, University of Alabama at Birmingham, Birmingham, Alabama (JJN); Southern College of Optometry, Memphis, Tennessee (CWL); Schwartz Laser Eye Center, Scottsdale, Arizona (MRB); and Allergan Clinical Research, Irvine, California (HL, PS, JV).

Purpose: This study compared a new contact lens rewetting drop containing both carboxymethylcellulose and hyaluronic acid (CMC-HA) with a standard drop containing carboxymethylcellulose only (CMC). Symptoms of discomfort typical in lens wear and lid wiper epitheliopathy (LWE) were assessed over a 3-month period in a diverse sample of contact lens wearers.

Methods: Adapted daily-wear contact lens subjects using hydrogel, silicone hydrogel, or rigid gas permeable lenses were enrolled in this prospective, randomized, double-masked, parallel-group, 90-day study conducted at 15 clinical sites. Subjects were randomized 2:1 to CMC-HA (n = 244) or CMC alone (n = 121) with dosage at least four times per day, along with their habitual lens care system. At baseline and at days 7, 30, 60, and 90, subject-completed questionnaires, bulbar conjunctival staining, LWE, contact lens distance visual acuity (CLDVA), and standard safety measures were assessed.

Results: At day 90, CMC-HA performed significantly better than CMC in ocular symptoms including dryness throughout the day (p = 0.006), and burning/stinging throughout the day (p = 0.02) and at the end of the day (p < 0.001). CMC-HA also performed numerically better for dryness at the end of day (p = 0.06). LWE staining was improved in the CMC-HA group at day 90 whereas it increased slightly in the CMC alone group, with a significant between-group difference (p = 0.009). CMC-HA also demonstrated greater reduction in conjunctival staining compared with CMC alone at day 90 (p = 0.08). No differences in CLDVA, contact lens wear time, acceptability, and product use were observed, and safety outcomes were similar between groups.

Conclusions: The addition of HA to a standard CMC rewetting drop improves clinical performance. In this comparison of rewetting drop efficacy in contact lens wearers, LWE was a useful clinical sign for differentiating clinical performance.
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http://dx.doi.org/10.1097/OPX.0000000000000878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972480PMC
August 2016

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

J Ocul Pharmacol Ther 2015 Nov 31;31(9):525-30. Epub 2015 Aug 31.

1 School of Ophthalmology and Optometry, Wenzhou Medical University , Wenzhou, Zhejiang, China .

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.
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http://dx.doi.org/10.1089/jop.2015.0042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675178PMC
November 2015

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

Clin Ophthalmol 2015 15;9:665-75. Epub 2015 Apr 15.

Allergan Clinical Research, Allergan, Inc., Irvine, CA, USA.

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.
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http://dx.doi.org/10.2147/OPTH.S78184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404880PMC
May 2015

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

Clin Ophthalmol 2015 15;9:657-64. Epub 2015 Apr 15.

Ophthalmology Research and Development, Allergan, Inc., Irvine, CA, USA.

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.
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http://dx.doi.org/10.2147/OPTH.S74849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404875PMC
May 2015

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

Clin Ther 2015 Apr 4;37(4):858-68. Epub 2015 Feb 4.

Allergan Clinical Research, Allergan, Inc, Irvine, California.

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.
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http://dx.doi.org/10.1016/j.clinthera.2015.01.001DOI Listing
April 2015

Decrease in hyperosmotic stress-induced corneal epithelial cell apoptosis by L-carnitine.

Mol Vis 2013 19;19:1945-56. Epub 2013 Sep 19.

Brien Holden Vision Institute, Sydney, Australia.

Purpose: To characterize the osmoprotective properties of L-carnitine on human corneal epithelial cell volume and apoptosis during hyperosmotic stress.

Methods: Human corneal limbal epithelial (HCLE) cells were exposed to culture medium at 300 mOsm (isotonic) or 500 mOsm (hyperosmotic) with or without L-carnitine (10 mM). Induction of apoptosis was detected by quantifying the proteolytic activity of caspase-8, caspase-9, and caspase-3/7 using caspase activity assays, the expression of tumor necrosis factor (TNF)-α with enzyme-linked immunosorbent assay, and annexin V/propidium iodide staining of HCLE cells evaluated with confocal microscopy and flow cytometry. Cell volume changes in response to hyperosmotic stress were analyzed using flow cytometry.

Results: After the HCLE cells were exposed to hyperosmotic medium (500 mOsm), the percentage of shrunken cells and damaged/dead cells (stained positively for annexin V and/or propidium iodide) was six- and three-fold, respectively, higher than that under isotonic conditions (300 mOsm). This was paralleled by an increase in TNF-α concentration in media and caspase-8, -9, and -3/7 activities (six-, four-, ten-, and twelve-fold, respectively; all showing p < 0.001). Addition of L-carnitine during hyperosmotic stress partly restored cell volume and significantly reduced the concentration of TNF-α released (p = 0.005) and caspase-9 activity (p = 0.0125). Addition of L-carnitine reduced the percentage of hyperosmolarity-induced damaged/dead cells to levels observed under isotonic conditions.

Conclusions: L-carnitine can regulate human corneal epithelial cell volume under hyperosmotic stress and ameliorate hyperosmotic stress-induced apoptosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782369PMC
March 2014

Equilibrium binding interactions between lotrafilcon a soft contact lenses and the two prostaglandin antiglaucoma drugs bimatoprost and tafluprost.

Eye Contact Lens 2013 Jul;39(4):295-302

Advantar Laboratories, Inc, San Diego, CA 92121, USA.

Objectives: To determine the equilibrium binding constant (EB) values of bimatoprost and tafluprost drug product formulations in contact with lotrafilcon A soft contact lenses and to characterize the importance of drug molecule hydrophobicity in controlling the binding interactions.

Methods: Bimatoprost Ophthalmic Solution and Tafluprost Ophthalmic Solution (Saflutan) were incubated with lotrafilcon A lens material for timed intervals at 25°C and 37°C. Aliquots were withdrawn, filtered, and tested using reverse-phase ultrahigh-performance liquid chromatography with respect to [bimatoprost] or [tafluprost] remaining in the solution. A series of homologous dialkyl phthalate esters and a series of homologous p-hydroxybenzoic acid alkyl esters were also tested as reference compounds.

Results: Bimatoprost and tafluprost were rapidly (within 15 min) absorbed from the solution by lotrafilcon A lenses, reaching an equilibrium within 60 min. At any lens:solution (w/v) ratio, the extent of drug binding to lens material was greater for tafluprost than for bimatoprost. The log(EB) values correlated with solute octanol:water partition coefficient (logP) values, indicating that hydrophobic interactions are important in controlling solute partitioning into the lens material.

Conclusions: This study established the quantitative relationships between tafluprost and bimatoprost binding to lotrafilcon A lenses. The fraction of bimatoprost or tafluprost that binds to lotrafilcon A increases with increasing lens:solution (w/v) ratio. For a 60 µL dose volume applied to a single contact lens, 16% of initially present bimatoprost remains in the solution, whereas only 6% of initially present tafluprost remains in the solution. These calculations clearly demonstrate that both drugs partition extensively into lotrafilcon A contact lens material. Although the clinical implications of such binding can only be surmised, it would seem prudent to caution contact lens wearers to remove the lenses before administering either prostaglandin drug.
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http://dx.doi.org/10.1097/ICL.0b013e3182973d5cDOI Listing
July 2013

Betaine stabilizes cell volume and protects against apoptosis in human corneal epithelial cells under hyperosmotic stress.

Exp Eye Res 2013 Mar 12;108:33-41. Epub 2012 Dec 12.

Brien Holden Vision Institute, Sydney, Australia.

Elevated tear osmolarity is one of the key pathological factors in dry eye leading to ocular discomfort associated with damage to the ocular surface and inflammation. The aim of this study was to determine the capacity of the organic osmolyte, betaine, to act as an osmoprotectant against hypertonic stress-induced human corneal epithelial cell shrinkage and apoptosis using in vitro cell culture models. Human corneal limbal epithelial (HCLE) cells exposed to culture medium for 16 h at 300 mOsm (isotonic) or 500 mOsm (hyperosmotic) in the presence or absence of betaine (5 or 10 mM) were evaluated for cell volume changes; cell viability; and apoptosis. Betaine (10 mM) ameliorated hyperosmotically induced reduction of cell volume (from 27% reduction to 11%) and resulted in increased mitochondrial activity (by 17%) and an increase in viable cell numbers (by 12%) compared to controls (exposure to hyperosmotic medium without betaine). Hyperosmotically shocked HCLE cells in the presence of betaine (10 mM) halved the number of damaged cells (apoptotic/necrotic) compared to cells in the absence of betaine. The presence of betaine (at 5 or 10 mM) significantly reduced the activity of caspase-8, -9 and -3/7 and release of TNF-α was also reduced by 34% or 55% after exposure of HCLE to 500 mOsm in the presence of 5 or 10 mM betaine, respectively. Using polyclonal antibody against Betaine/GABA transporter 1 (BGT-1), we detected the presence of BGT-1 in HCLE. We demonstrated that the transport of betaine was facilitated by increased osmolarity. In conclusion, betaine stabilized corneal epithelial cell volume under hyperosmotic stress and limited hyperosmotic stress-induced HCLE apoptosis.
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http://dx.doi.org/10.1016/j.exer.2012.12.001DOI Listing
March 2013

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

Mol Vis 2010 Sep 4;16:1823-31. Epub 2010 Sep 4.

Brien Holden Vision Institute, The University of New South Wales, Sydney, NSW, Australia.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956661PMC
September 2010

Role of carnitine in disease.

Nutr Metab (Lond) 2010 Apr 16;7:30. Epub 2010 Apr 16.

Institute for Eye Research, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1186/1743-7075-7-30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861661PMC
April 2010

Effect of castor oil emulsion eyedrops on tear film composition and stability.

Cont Lens Anterior Eye 2010 Apr 6;33(2):76-82. Epub 2009 Dec 6.

OTG Research & Consultancy, London, UK.

Purpose: An emulsion eyedrop containing castor oil has been shown to modify the tear film lipid layer and increase tear film stability. The primary objectives of this investigation were to measure the prevalence of castor oil in the tear fluid over time and quantify the effects on the lipid layer. A secondary objective was to quantify the initial effects on ocular symptomatology.

Methods: The investigation was an open label pilot study on 5 normal and 10 dry eye subjects. A single eyedrop (Castor oil emulsion, Allergan) was instilled in each eye; the tear film appearance and composition were monitored for 4h via in vivo visualisation using the Tearscope and post in vivo tear samples analysis by HPLC.

Results: Combined results for both normal and dry eye subjects showed that castor oil was detected up to 4h after a single eyedrop instillation and associated with an increase in the level of tear film lipid. The relative amount of various lipid families was also changed. An increase in tear lipid layer thickness was significant up to one hour post-instillation for the symptomatic sub-population. The changes in tear film characteristics were associated with significantly lower symptoms up to four hours post-instillation for the symptomatic sub-population.

Conclusion: This pilot investigation showed that castor oil eyedrops achieved a residence time of at least four hours post-instillation, producing a more stable tear film and an associated significant decrease in ocular symptoms over the entire follow-up period for the symptomatic subjects.
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http://dx.doi.org/10.1016/j.clae.2009.10.005DOI Listing
April 2010

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

Invest Ophthalmol Vis Sci 2008 Nov 18;49(11):4844-9. Epub 2008 Jul 18.

Institute for Eye Research, The University of New South Wales, NSW, Australia.

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.
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http://dx.doi.org/10.1167/iovs.07-1528DOI Listing
November 2008

Carboxymethyl cellulose stimulates rabbit corneal epithelial wound healing.

Curr Eye Res 2008 Jul;33(7):567-73

Institute for Eye Research, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1080/02713680802140213DOI Listing
July 2008

Dynamic distribution of artificial tears on the ocular surface.

Arch Ophthalmol 2008 May;126(5):619-25

Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, 1638 NW 10th Ave, McKnight Bldg, Room 506, Miami, FL 33136, USA.

Objective: To study the effects of artificial tear viscosity on tear film thickness, upper and lower tear menisci, and tear volume using optical coherence tomography.

Methods: The central tear film and tear menisci before and immediately after the instillation of different artificial tears were imaged in 40 eyes of 20 healthy individuals. Carboxymethylcellulose sodium, 1.0% (viscosity, 70 cP), propylene glycol, 0.3%, and polyethylene glycol, 0.4% (10 cP), carboxymethylcellulose, 0.5% (3 cP), and isotonic sodium chloride solution (1 cP) were tested on 2 consecutive days. All measurements, including tear film thickness, the height, radius, and area of the tear meniscus, and the estimated tear volume, were obtained at 0, 5, 20, 40, and 60 minutes after instillation.

Results: At instillation, all artificial tears and isotonic sodium chloride solution caused an increase in all tear variables (P < .001). Tear film thickness remained significantly elevated for all drops at 5 minutes (P < .001) and returned to baseline at 20 minutes. Other variables returned to baseline at 5 minutes. Comparing the different drops, tear film thickness and lower meniscus variables at instillation were increased with the more viscous drops (P < .05).

Conclusion: Optical coherence tomography demonstrated that all tear preparations, including isotonic sodium chloride solution, increased tear film thickness for at least 5 minutes and other variables immediately after instillation.
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http://dx.doi.org/10.1001/archopht.126.5.619DOI Listing
May 2008

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

Cornea 2007 Apr;26(3):294-302

Eye Care Research and Development, Allergan LLC, Irvine, CA 92612 , USA.

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.
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http://dx.doi.org/10.1097/ICO.0b013e31802e1e04DOI Listing
April 2007

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

Invest Ophthalmol Vis Sci 2007 Apr;48(4):1559-67

Institute for Eye Research, University of New South Wales, Sydney, NSW 2052, Australia.

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.
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http://dx.doi.org/10.1167/iovs.06-0848DOI Listing
April 2007

A pre-application drop containing carboxymethylcellulose can reduce multipurpose solution-induced corneal staining.

Optom Vis Sci 2007 Jan;84(1):65-71

Southern California College of Optometry, Fullerton, Fullerton, California 92831, USA.

Purpose: Use of polyhexanide based multipurpose solutions (MPSs) for contact lens disinfection has been linked to low-grade corneal staining. In vitro data suggest that carboxymethylcellulose (CMC) may neutralize polyhexanides. The purpose of this investigation was to determine whether a pre-application drop of CMC reduces polyhexanide staining in vivo.

Methods: Thirty adapted soft contact lens (SCL) wearers participated in this investigator-masked, randomized, two-way cross-over study. Subjects wore a new Group II lens (alphafilcon A, 66% water) daily for 4 weeks and disinfected lenses using a MPS containing 0.0001% polyaminopropyl biguanide. A lens lubricant containing either CMC or povidone as the primary viscolyzer was applied to the lens each day before lens wear. Biomicroscopic signs and symptomatology were assessed. The difference in scores, 0 to 4 weeks and the difference between lubricants were analyzed.

Results: The cumulative fluorescein staining scores for combined eyes demonstrated a significant increase over time (e.g., cumulative staining score; p=0.004 and p<0.001 for CMC and povidone, respectively, matched pairs t-test, two-tailed), suggesting that for both lubricants the staining worsened with wear. This effect was expected and likely driven by the MPS. However, the mean cumulative staining scores for CMC and povidone were 2.8 and 2.6 out of 20 possible at baseline, increasing to 4.9 and 7.1 at 4 weeks, respectively. The increases were significantly different (p=0.003, matched pairs t-test, two-tailed) suggesting a greater increase in corneal staining for the povidone lubricant. The symptom scores were not significantly different, 0 to 4 weeks by regimen or between preinstillation drops.

Conclusions: These results suggest that a CMC-containing preapplication drop can reduce corneal staining resulting from disinfection with a polyhexanide MPS. This result is consistent with a proposed mechanism for CMC to neutralize cationic disinfectants and may offer clinicians another means to reduce this type of corneal staining.
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http://dx.doi.org/10.1097/01.opx.0000254044.94356.23DOI Listing
January 2007

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

Clin Exp Optom 2004 Nov;87(6):367-71

Brennan Consultants Pty Ltd, 110 Auburn Road, Auburn Village, Melbourne, VIC, 3122, Australia.

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.
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http://dx.doi.org/10.1111/j.1444-0938.2004.tb03096.xDOI Listing
November 2004

Cytoprotective properties of carboxymethyl cellulose (CMC) when used prior to wearing contact lenses treated with cationic disinfecting agents.

Eye Contact Lens 2003 Jul;29(3):177-80

Consumer Eye Care Research and Development, Allergan, Inc., Irvine, CA, USA.

Purpose: Disinfecting agents found in current multipurpose solutions (MPS) may produce low-grade ocular surface insults. This study investigates the potential for carboxymethylcellulose (CMC) to chemically complex residual disinfectants in situ.

Methods: The chemical availability of the MPS disinfectant polyhexamethylene biguanide (PHMB) was examined using a spectrophotometric assay. PHMB bioactivity was assessed by survival of bacteria in the presence of MPS with varying amounts of added CMC.

Results: Chemical availability of PHMB in water or MPS was reduced within 10 minutes of adding CMC. With the addition of CMC to MPS, survival rates for bacteria improved substantially, depending on the bacterial species, concentration, and exposure time.

Conclusions: Carboxymethylcellulose rapidly binds PHMB and reduces its chemical availability and bioactivity. These results suggest a potential cytoprotective effect of CMC on the ocular surface when used before lens insertion.
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http://dx.doi.org/10.1097/01.ICL.0000074106.82322.17DOI Listing
July 2003
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