CLINICAL SCIENCE

Efficacy of Hypotonic 0.18% Sodium Hyaluronate Eye Drops in Patients With Dry Eye Disease Hyo Seok Lee, MD, Yong Sok Ji, MD, PhD, and Kyung Chul Yoon, MD, PhD

Purpose: The aim of this study was to evaluate the efficacy of hypotonic 0.18% sodium hyaluronate (SH) eye drops under the clinical settings of the dry eye workshop treatment guideline for mild dry eye disease (DED).

Methods: This analysis included 60 patients with DED. Patients with level 1 DED were treated with either isotonic 0.1% SH (group 1) or with hypotonic 0.18% SH eye drops (group 2). Patients with level 2 DED were treated with 0.1% fluorometholone, 0.05% cyclosporine A, and either isotonic 0.1% SH (group 3) or hypotonic 0.18% SH (group 4) eye drops. Tear film breakup time (TBUT), Schirmer test, corneal staining with fluorescein, and ocular surface disease index score were recorded at baseline, 1 month, and 3 months after treatment. Results: In group 2, TBUT at 3 months (P = 0.03) and corneal

staining scores at 1 and 3 months (P # 0.03) were significantly improved after the treatment compared with baseline scores, whereas these parameters were not changed during the follow-up period in group 1. In groups 3 and 4, TBUT and corneal staining scores at 1 and 3 months, and ocular surface disease index score and Schirmer test results at 3 months after the treatment showed significant improvements compared with the baseline score (P , 0.05). Group 4 patients showed an extended TBUT and an improved corneal staining score (P # 0.01) at 3 months after treatment, compared with the values of group 3.

Conclusions: Hypotonic 0.18% SH eye drops seemed to be effective in improving tear film stability and ocular surface integrity compared with isotonic 0.1% SH eye drops in patients with mild DED. Key Words: dry eye disease, hypotonicity, sodium hyaluronate (Cornea 2014;33:946–951)

Received for publication March 25, 2014; revision received April 22, 2014; accepted April 22, 2014. Published online ahead of print June 9, 2014. From the Department of Ophthalmology, Chonnam National University Medical School and Hospital, Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, South Korea. The authors have no conflicts of interest to disclose. Supported by the CNUH Biomedical Research Institute (CRI 13906-22) and Forest Science and Technology Projects (Project No. S121313L50100) provided by Korea Forest Service. Reprints: Kyung Chul Yoon, MD, PhD, Department of Ophthalmology, Chonnam National University Hospital, 42 Jebong-ro, Dong-Gu, Gwang-Ju 501-757, South Korea (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins

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D

ry eye disease (DED) is one of the most common ocular diseases frequently seen in ophthalmic practice, with an estimated prevalence of 14% to 33% of the population worldwide at various ages.1–3 It is a multifactorial disease caused by tear film instability, ocular surface inflammation, and tear hyperosmolarity resulting in decreased visual performance and quality of life because of chronic irritation, pain, and blurred and fluctuating vision.4,5 Among various risk factors and causative factors of DED, there is increasing evidence that hyperosmolarity in the tear film plays a pivotal role in the pathogenesis of dry eye.4 In previous in vivo and in vitro studies, elevated tear osmolarity resulted in the overexpression of matrix metalloproteinase, proinflammatory cytokines, and chemokines, such as tumor necrosis factor-alpha, interleukin (IL)-1, and IL-8.6–10 In addition, tear hyperosmolarity can increase the expression of human leukocyte antigen-DR in human conjunctiva, which is associated with helper T cells at the initial stage of the immune response.11 Tear hyperosmolarity may also cause pathologic changes in the corneal epithelium, such as increased desquamation, disruptions in cell membranes, and cellular swelling with decreased cytoplasmic density.12,13 Those changes eventually lead to decreased corneal epithelial glycogen and conjunctival goblet cells, and corneal and lacrimal epithelial cell apoptosis, which further exacerbate tear film instability and ocular surface damage and form a vicious cycle of aggravation.13–15 The goals for DED treatment are to improve patient ocular comfort and to maintain ocular surface and tear film homeostasis.16 In 2007, the Dry Eye Workshop (DEWS) recommended a therapeutic approach based on disease severity. The dry eye severity-grading scheme in the DEWS report contains 4 levels of disease severity based on the signs and symptoms of patients with DED. In this scheme, the treatment recommendation for level 1 DED is the use of artificial tear substitutes and life style modifications. For level 2 DED– affected patients, adjuvant antiinflammatories in addition to artificial tears are suggested.4 Among those, application of artificial tears has been considered as the mainstay for the treatment of DED.4,17 Currently available artificial tears containing various viscosity agents, such as sodium hyaluronate (SH) and carboxymethylcellulose (CMC), can supply water content for aqueous inadequacy, protect the ocular surface, and alleviate dry eye symptoms and objective signs.18–20 However, these conventional artificial tears can only provide temporary symptom relief, and cannot resolve tear film hyperosmolarity and associated ocular surface disorders.4 Given the role of tear hyperosmolarity in the pathogenesis of DED, it has been postulated that hypotonic tear Cornea  Volume 33, Number 9, September 2014

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substitutes could lower tear osmolarity, restore osmotic balance, and thereby improve the environmental condition of the ocular surface.15,21,22 As a consequence, several hypotonic SH artificial tears have been developed and studied worldwide and have proven to be effective in terms of alleviating subjective symptoms and stabilizing precorneal tear film, and ocular surface damage markers, compared with isotonic artificial tear substitutes with the same or different substance concentration.22–27 However, those studies did not reflect the DEWS recommendation for DED treatment, which emphasizes a stepwise approach according to the severity level. Therefore, we tried to evaluate the efficacy of commercially available hypotonic 0.18% SH artificial tears compared with that of conventional isotonic 0.1% SH eye drops under the therapeutic strategies of the DEWS treatment guideline for DED levels 1 and 2.

PATIENTS AND METHODS To conduct comparative analysis of the effect of topical hypotonic 0.18% SH versus isotonic 0.1% SH in DED, 60 patients who were initially diagnosed with DED were enrolled in this study. Dry eye was diagnosed based on patients’ report of ocular discomfort (soreness, scratchiness, grittiness, dryness, and/or burning sensation), tear film breakup time (TBUT), Schirmer test, and corneal staining with fluorescein and on other general ophthalmic examinations. These tests were used to qualify patients for inclusion in the study and for grading dry eye severity.28 Patients with external ocular diseases, glaucoma or other concomitant ocular pathologies, a history of ocular surgery (within the recent 6 months), use of any ophthalmic eye drops or contact lenses (within 1 month), eyelid or eyelash abnormalities, nasolacrimal apparatus abnormalities, diabetes, or other systemic diseases or those using systemic medication potentially interfering with tear production or evaporation (eg, sleeping tablets, dopaminergics, and benzodiazepines) were excluded. Institutional review board/ethics committee approval was obtained from the Chonnam National University Hospital Institutional Review Board, and the study protocol followed the guidelines of the Declaration of Helsinki.

Clinical Assessments Clinical assessments included best-corrected visual acuity, subjective dry eye symptom grading, slit-lamp examination, TBUT measurements, Schirmer test, and corneal staining with fluorescein. The ocular surface disease index (OSDI) questionnaire was used for the grading of the symptom score.29 Ocular surface examinations were performed on both eyes by the same physician (K.C.Y.). TBUT and Schirmer test were performed as previously described.30,31 Corneal staining with fluorescein was evaluated using the National Eye Institute method, a standardized scale (0–3) for each of the 5 regions of the cornea: central, inferior, nasal, superior, and temporal.32 Patients’ signs and symptoms were graded according to the DEWS classification table, modified by Asbell et al.28,33 Individual test results of each patient were rated on the numeric dry eye severity scale. Ó 2014 Lippincott Williams & Wilkins

Efficacy of Hypotonic 0.18% Sodium Hyaluronate

Severity scale grade 1 consists of an OSDI score between 12 and 15, TBUT between 10 and 15 seconds, Schirmer test results between 10 and 15 mm, and a corneal staining score between 0 and 3. Severity scale grade 2 consists of an OSDI score between 16 and 30, TBUT between 5 and 9 seconds, Schirmer test results between 6 and 9 mm, and a corneal staining score between 4 and 8. Based on the mode and arithmetic mean of the individual severity grade, overall DED severity levels of 1 or 2 out of 4 were determined.28 Patients with an overall DED severity level of $3 were excluded from this study.

Study Population and Material The study sample consisted of 60 patients: 30 patients with level 1 DED and 30 patients with level 2 DED. As mentioned above, patients with level 1 DED were instructed to use artificial tear substitutes, and patients with level 2 DED were instructed to use antiinflammatory agents along with artificial tear substitutes, according to the DEWS treatment guideline. In this study, 15 patients (group 1) received preservative-free isotonic (300 mOsm/L) 0.1% SH eye drops (Kynex; Alcon, Seoul, Korea), and the other 15 patients (group 2) received preservative-free hypotonic (150 mOsm/L) SH eye drops (Kynex 2; Alcon) in level 1 DED–affected patients. Artificial tears were applied 4 times per day for 3 consecutive months. In level 2 DED, 15 patients (group 3) received isotonic 0.1% SH eye drops (Kynex; Alcon) 4 times per day along with topical 0.1% fluorometholone (Ocumetholone; Samil, Seoul, Korea) and 0.05% cyclosporine A (Restasis; Allergan Inc, Irvine, CA) twice a day. In another 15 patients (group 4), hypotonic 0.18% SH eye drops (Kynex 2; Alcon), topical fluorometholone (Ocumetholone; Samil), and cyclosporine A (Restasis; Allergan Inc) were applied in the same manner. Evaluation for subjective symptoms and objective signs of DED was repeated at each follow-up visit, and data obtained 1 month and 3 months after the initial visit were collected for analysis. New treatments, including any eye drops or punctual plug insertion, were not added during the follow-up period.

Statistical Analysis Statistical Package for Social Sciences (SPSS, version 17.0, Chicago, IL) was used for statistical analysis. Only data from the right eye were used for analysis, and results are presented as mean 6 SD. Patients’ demographic data were first analyzed using descriptive statistics. To ensure group similarity at the baseline between groups 1 and 2/groups 3 and 4, the Mann–Whitney U test was performed. Sphericity assumption was tested with a Mauchly test. In the case of violation, data were adjusted with an Epsilon Greenhouse–Geisser statistic. Changes in the outcome measures over the follow-up period were assessed with a repeated measure analysis of variance followed by the Bonferroni post hoc test. The probability level of P , 0.05 was considered to be statistically significant.

RESULTS Table 1 summarizes demographics and characteristics for all 4 groups. The mean ages of groups 1–4 were www.corneajrnl.com |

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TABLE 1. Demographics and Characteristics of Patients Group 1 Age, yrs Sex (M/F) OSDI score (0–100) TBUT, s Schirmer test, mm/5 min Corneal staining score (0–15)

56.87 6 7/8 13.87 6 9.60 6 8.47 6 2.07 6

8.61 5.49 1.86 1.22 0.56

Group 2 54.13 6 6/9 14.34 6 9.53 6 8.53 6 1.93 6

9.90 4.73 1.83 1.17 0.56

Group 3

Group 4

51.47 6 14.20 7/8 28.01 6 5.09 7.33 6 0.98 6.80 6 0.88 4.07 6 0.56

52.07 6 16.82 7/8 27.95 6 7.28 7.33 6 1.15 6.93 6 0.90 3.93 6 0.56

Data are expressed as the mean 6 SD.

56.87 6 8.61, 54.13 6 9.90, 51.47 6 14.20, and 52.07 6 16.82 years, respectively. Groups 1, 3, and 4 consisted of 7 men and 8 women. Group 2 comprises 6 men and 9 women. There were no statistically significant differences in age, sex, OSDI score, TBUT, Schirmer test, and corneal staining score between groups 1 and 2, and between groups 3 and 4 at the initial visit (P . 0.05). In level 1 DED, the OSDI scores were 12.67 6 4.28 at 1 month (P = 0.23) and 12.57 6 4.63 (P = 0.09) at 3 months after the treatment in group 1 and 13.61 6 4.15 at 1 month (P = 0.12) and 13.20 6 3.66 (P = 0.12) at 3 months in group 2, compared with the baseline. TBUTs were 9.73 6 2.08 at 1 month (P = 0.41) and 9.80 6 2.16 seconds (P = 0.26) at 3 months after treatment in group 1 and 10.07 6 0.97 at 1 month (P = 0.15) and 10.20 6 1.33 seconds (P = 0.03) at 3 months in group 2. Schirmer test results in group 1 were 8.60 6 1.31 (P = 0.16) and 8.67 6 1.31 mm (P = 0.08) at 1 and 3 months, respectively, and the corresponding Schirmer test results in group 2 were 8.80 6 0.95 (P = 0.16) and 8.87 6 0.93 (P = 0.27) at 1 and 3 months. Corneal staining scores at 1 and 3 months in group 2 were 1.87 6 0.60 (P = 0.32) and 1.80 6 0.52 (P = 0.25) at 1 and 3 months in group 1 and 1.60 6 0.59 (P = 0.03) and 1.40 6 0.59 (P = 0.01), respectively (Fig. 1). In level 2 DED, OSDI scores were 26.32 6 5.79 at 1 month (P = 0.06) and 25.40 6 4.91 (P = 0.01) at 3 months after treatment in group 3 and 26.20 6 7.34 at 1 month (P = 0.08) and 25.00 6 5.97 (P = 0.02) at 3 months in group 4, compared with baseline. TBUTs were 8.00 6 0.61 at 1 month (P = 0.02) and 8.33 6 0.58 seconds (P = 0.01) at 3 months after treatment in group 3 and 8.47 6 0.48 at 1 month (P , 0.01) and 9.27 6 0.90 seconds (P , 0.01) at 3 months in group 4. Schirmer test results in group 3 were 7.07 6 0.66 (P = 0.16) and 7.33 6 0.98 mm (P = 0.01) at 1 and 3 months, respectively, and the corresponding Schirmer test results in group 4 were 7.13 6 0.78 (P = 0.18) and 7.47 6 0.78 (P = 0.03) at 1 and 3 months. The corneal staining scores at 1 and 3 months in group 4 were 2.73 6 0.75 (P , 0.01) and 2.53 6 0.60 (P , 0.01) at 1 and 3 months in group 3 and 2.47 6 0.48 (P , 0.01) and 1.93 6 0.43 (P , 0.01), respectively (Fig. 2). In level 1 DED, there were no significant differences between groups 1 and 2 in all parameters (P . 0.05). In level 2 DED, TBUT was higher (P , 0.01), and the corneal staining score was lower (P = 0.01) with statistical significance in group 4, compared with that in group 3 at 3 months after the treatment. There was no significant intergroup difference in terms of the OSDI score and Schirmer test results (P . 0.05).

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No serious adverse events or complications were observed during this study.

DISCUSSION According to the 2007 Report of the International DEWS,4 tear hyperosmolarity was indicated as the primary causative mechanism leading to eye discomfort, ocular surface damage, and inflammation. Based on this theory, several hypotonic SH artificial tears have been developed in the expectation of correcting hyperosmolarity of the tear film and normalizing osmotic balance in the ocular surface environment, and proved to be effective in ameliorating the typical symptoms of dry eye, increasing the vitality of the corneal epithelial cells, and improving conjunctival conditions.23,26,34 In this study, the level 1 DED group using hypotonic 0.18% SH eye drops showed an increased TBUT at 3 months and a decreased corneal staining score at 1 month and 3 months from the treatment, compared with the baseline value. Moreover, in the level 2 DED–affected patients, the group using hypotonic SH eye drops showed an improved corneal staining score and a higher TBUT compared with the values of the group using isotonic SH eye drops at 3 months after the treatment. This finding is consistent with that of our previous study about the effect of hypotonic 0.18% SH eye drops in a murine dry eye model.35 In that study using a mouse model of desiccating stress-induced experimental dry eye, the corneal irregularity score and surface staining score were improved compared with the 0.5% CMC and 0.1% isotonic SH-treated groups. In addition, inflammatory parameters, such as tumor necrosis factor-alpha, IL-1b, monokine induced by g-interferon, interferon g–induced protein-10 in conjunctival tissues of the hypotonic 0.18% SH-treated group, were significantly lower compared with the 0.5% CMC and 0.1% isotonic SH-treated groups. In addition, our findings are in agreement with those of previous studies, demonstrating the efficacy of hypotonic SH eye drops. Aragona et al23 and Troiano et al26 proved that applications of topical hypotonic 0.4% SH eye drops have better effects on the improvement of ocular symptoms, TBUT, corneal and conjunctival staining score in DED-affected patients compared with that of isotonic 0.4% SH eye drops. Our study demonstrated that the effectiveness of hypotonic artificial tears on the corneal surface and tear film stability over isotonic artificial tears is maintained when used in the clinical Ó 2014 Lippincott Williams & Wilkins

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FIGURE 1. Changes of the ocular surface disease index score (A), TBUT (B), Schirmer test (C), and corneal staining score (D) in groups 1 and 2 before and after the treatment. *P , 0.05 compared with the baseline value. †P , 0.05 compared between groups 1 and 2.

setting, along with topical antiinflammatory agents such as topical steroid and cyclosporine A in level 2 DED. As mentioned above, the 2 treatment options containing SH differ not only in the osmolarity of this viscosity agent but also in the SH concentration. The isotonic agent contained 0.1% SH, and the hypotonic agent contained 0.18% SH. SH is

a viscosity agent that helps to stabilize tear films, lubricate the ocular surface, and to enhance the residence time during and between blinking.36,37 Previous reports proved that the effect of SH on corneal epithelial healing is concentration dependent in vivo.38,39 In addition, previous reports have demonstrated that more concentrated 0.3% SH eye drops seemed to have

FIGURE 2. Changes of ocular surface disease index score (A), TBUT (B), Schirmer test (C), and corneal staining score (D) in groups 3 and 4 before and after the treatment. *P , 0.05 compared with the baseline value. †P , 0.05 compared between groups 3 and 4. Ó 2014 Lippincott Williams & Wilkins

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better effects on dry eye symptoms and TBUT than those of 0.1% SH eye drop.19,40 Improvement of corneal surface parameters and tear film stability by hypotonic 0.18% SH in our study can be partially explained by the intrinsic and dosedependent properties of SH. A further controlled study under clinical circumstances is warranted for the exact measurement of the effect of hypotonicity on the treatment of DED. In this study, the mean values of the OSDI score and corneal staining score tended to decrease, and TBUT and Schirmer test results tended to increase in group 1 over the treatment period. Contrary to the previous reports,23,41,42 0.1% isotonic SH eye drops failed to demonstrate significant changes in tear film and ocular surface parameters in level 1 DED–affected patients when compared with the baseline value. This discrepancy between our results and previous reports on the efficacy of 0.1% SH eye drops might reflect differences in the range of inclusion criteria. Previous reports included DED-affected patients regardless of severity, and analyzed data of DED-affected patients as a whole. However, our study allocated DED-affected patients into level 1 and level 2 based on the DED severity scale. We assumed that the mild decrease of tear film stability and ocular surface parameters of level 1 DED–affected patients failed to produce a statistically significant improvement by treatment with only 0.1% SH eye drops. In addition, the relatively small sample size and less frequent eye drop application compared with those in previous reports might have contributed to the statistical insignificance in level 1 DED–affected patients using isotonic 0.1% SH eye drops. Our study has several limitations. Because we used commercially available SH artificial tear substitutes from the some company, the concentration of SH was not identical in both products. In addition, tear osmolarity was not measured in our study. Measurement of tear osmolarity before and after treatment might have contributed to identifying the role of hypotonicity in the treatment of DED. To confirm the role of hypotonicity in artificial tears, comparison of isotonic and hypotonic artificial tears with the same SH concentration will be needed under the clinical setting of the DEWS guideline. Because the follow-up duration was relatively short, the longterm effect of topical hypotonic 0.18% SH might have been missed. In our research, the study population was not randomized, and selection bias should be considered in the interpretation of the results. Further prospective, casecontrolled studies with a longer follow-up period are warranted. In conclusion, topical hypotonic 0.18% SH eye drops were found to be effective in improving tear film stability and ocular surface integrity of patients with mild DED. In clinical settings, hypotonic 0.18% SH eye drops seemed to have a better therapeutic effect over conventional isotonic 0.1% SH eye drops when managed according to the DEWS treatment guideline. REFERENCES 1. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17:584–589. 2. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:93–107.

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3. Lin PY, Tsai SY, Cheng CY, et al. Prevalence of dry eye among an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology. 2003;110:1096–1101. 4. Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:179–193. 5. Baudouin C. A new approach for better comprehension of diseases of the ocular surface [in French]. J Fr Ophthalmol. 2007;30:239–246. 6. Li DQ, Luo L, Chen Z, et al. JNK and ERK MAP kinases mediate induction of IL-1beta, TNF-alpha and IL-8 following hyperosmolar stress in human limbal epithelial cells. Exp Eye Res. 2006;82:588–596. 7. Li DQ, Chen Z, Song XJ, et al. Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2004;45:4302–4311. 8. Solomon A, Dursun D, Liu Z, et al. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001;42:2283–2292. 9. Choi W, Li Z, Oh HJ, et al. Expression of CCR5 and its ligands CCL3, -4, and -5 in the tear film and ocular surface of patients with dry eye disease. Curr Eye Res. 2012;37:12–17. 10. Yoon KC, Park CS, You IC, et al. Expression of CXCL9, -10, -11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome. Invest Ophthalmol Vis Sci. 2010;51:643–650. 11. Versura P, Profazio V, Schiavi C, et al. Hyperosmolar stress upregulates HLA-DR expression in human conjunctival epithelium in dry eye patients and in vitro models. Invest Ophthalmol Vis Sci. 2011;52: 5488–5496. 12. Corrales RM, Stern ME, De Paiva CS, et al. Desiccating stress stimulates expression of matrix metalloproteinases by the corneal epithelium. Invest Ophthalmol Vis Sci. 2006;47:3293–3302. 13. Gilbard JP, Rossi SR, Gray KL, et al. Tear film osmolarity and ocular surface disease in two rabbit models for keratoconjunctivitis sicca. Invest Ophthalmol Vis Sci. 1988;29:374–378. 14. Luo L, Li DQ, Pflugfelder SC. Hyperosmolarity-induced apoptosis in human corneal epithelial cells is mediated by cytochrome c and MAPK pathways. Cornea. 2007;26:452–460. 15. Gilbard JP, Farris RL. Tear osmolarity and ocular surface disease in keratoconjunctivitis sicca. Arch Ophthalmol. 1979;97:1642–1646. 16. Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop. Ocul Surf. 2007;5:163–178. 17. Jackson WB. Management of dysfunctional tear syndrome: a Canadian consensus. Can J Ophthalmol. 2009;44:385–394. 18. Grene RB, Lankston P, Mordaunt J, et al. Unpreserved carboxymethylcellulose artificial tears evaluated in patients with keratoconjunctivitis sicca. Cornea. 1992;11:294–301. 19. Johnson ME, Murphy PJ, Boulton M. Effectiveness of sodium hyaluronate eyedrops in the treatment of dry eye. Graefes Arch Clin Exp Ophthalmol. 2006;244:109–112. 20. Bruix A, Adán A, Casaroli-Marano RP. Efficacy of sodium carboxymethylcellulose in the treatment of dry eye syndrome [in Spanish]. Arch Soc Esp Oftalmol. 2006;81:85–92. 21. Baudouin C, Aragona P, Messmer EM, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf. 2013;11:246–258. 22. Iester M, Orsoni GJ, Gamba G, et al. Improvement of the ocular surface using hypotonic 0.4% hyaluronic acid drops in keratoconjunctivitis sicca. Eye (Lond). 2000;14:892–898. 23. Aragona P, Di Stefano G, Ferreri F, et al. Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren’s syndrome patients. Br J Ophthalmol. 2002;86:879–884. 24. Papa V, Aragona P, Russo S, et al. Comparison of hypotonic and isotonic solutions containing sodium hyaluronate on the symptomatic treatment of dry eye patients. Ophthalmologica. 2001;215:124–127. 25. Evangelista M, Koverech A, Messano M, et al. Comparison of three lubricant eye drop solutions in dry eye patients. Optom Vis Sci. 2011; 88:1439–1444. 26. Troiano P, Monaco G. Effect of hypotonic 0.4% hyaluronic acid drops in dry eye patients: a cross-over study. Cornea. 2008;27:1126–1130. 27. Baeyens V, Bron A, Baudouin C, et al. Efficacy of 0.18% hypotonic sodium hyaluronate ophthalmic solution in the treatment of signs and symptoms of dry eye disease. J Fr Ophthalmol. 2012; 35:412–419.

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28. Suzuki M, Massingale ML, Ye F, et al. Tear osmolarity as a biomarker for dry eye disease severity. Invest Ophthalmol Vis Sci. 2010;51:4557–4561. 29. Schiffman RM, Christianson MD, Jacobsen G, et al. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000; 118:615–621. 30. Yoon KC, Im SK, Kim HG, et al. Usefulness of double vital staining with 1% fluorescein and 1% lissamine green in patients with dry eye syndrome. Cornea. 2011;30:972–976. 31. Jeong IY, Park YW, Lee SS, et al. Long term follow-up results of topical 0.05% cyclosporine a in patient with dry eye. Chonnam Med J. 2008;44:151. 32. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J. 1995;21:221–232. 33. Asbell PA, Lemp MA. Dry Eye Disease: the Clinician’s Guide to Diagnosis and Treatment. New York: Thieme; 2006. 34. Gilbard JP, Kenyon KR. Tear diluents in the treatment of keratoconjunctivitis sicca. Ophthalmology. 1985;92:646–650. 35. Oh HJ, Li Z, Park SH, et al. Effect of hypotonic 0.18% sodium hyaluronate eyedrops on inflammation of the ocular surface in experimental dry eye. J Ocul Pharmacol Ther. 2014 [Epub ahead of print] doi:10.1089/ jop.2013.0050.

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36. Tiffany JM. Viscoelastic properties of human tears and polymer solutions. Adv Exp Med Biol. 1994;350:267–270. 37. Nakamura M, Hikida M, Nakano T, et al. Characterization of water retentive properties of hyaluronan. Cornea. 1993;12:433–436. 38. Camillieri G, Bucolo C, Rossi S, et al. Hyaluronan-induced stimulation of corneal wound healing is a pure pharmacological effect. J Ocul Pharmacol Ther. 2004;20:548–553. 39. Nakamura M, Hikida M, Nakano T. Concentration and molecular weight dependency of rabbit corneal epithelial wound healing on hyaluronan. Curr Eye Res. 1992;11:981–986. 40. Hamano T, Horimoto K, Lee M, et al. Sodium hyaluronate eyedrops enhance tear film stability. Jpn J Ophthalmol. 1996;40:62–65. 41. Lee JH, Ahn HS, Kim EK, et al. Efficacy of sodium hyaluronate and carboxymethylcellulose in treating mild to moderate dry eye disease. Cornea. 2011;30:175–179. 42. McDonald CC, Kaye SB, Figueiredo FC, et al. A randomised, crossover, multicentre study to compare the performance of 0.1% (w/v) sodium hyaluronate with 1.4% (w/v) polyvinyl alcohol in the alleviation of symptoms associated with dry eye syndrome. Eye (Lond). 2002; 16:601–607.

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Efficacy of hypotonic 0.18% sodium hyaluronate eye drops in patients with dry eye disease.

The aim of this study was to evaluate the efficacy of hypotonic 0.18% sodium hyaluronate (SH) eye drops under the clinical settings of the dry eye wor...
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