Cendo Eye Fresh Eye Drop 443233

CENDO EYE FRESH EYE DROP Spesifikasi Produk Komposisi HPMC 3,00 mg , Dextran(70) 1,00 mg. Indikasi Mengurangi iritasi pada mata yang kering karena kekurangan sekresi air mata, melindungi mata terhadap iritasi lebih lanjut, mengurangi rasa tidak nyaman karena iritasi mata ringan, terkana angin dan sinar matahari Kelompok Obat mata Bentuk drop Cara Pakai tetes Peringatan Khusus hanya untuk pemakaian luar, tidak dianjurkan untuk anak, jika mata terasa sakit dan prubahan pengelihatan selama 72ja, hentikanpemakaian dan konsultasikan ke dokter SEDIAAN OBAT MATA Ophthalmic Preparations Obat mata tersedia dalam berbagai bentuk sediaan, beberapa diantaranya memerlukan perhatian khusus. Larutan Larutan obat mata adalah larutan steril, bebas partikel asing, merupakan sediaan yang dibuat dan dikemas sedemikian rupa hingga sesuai digunakan pada mata. Pembuatan larutan obat mata membutuhkan perhatian khusus dalam hal toksisitas bahan obat, nilai isotonisitas, kebutuhan akan dasar, kebutuhan akan pengawet (dan jika perlu pemilihan pengawet) sterilisasi dan kemasan yang tepat. Perhatian yang sama juga dilakukan untuk sediaan hidung dan telinga. Nilai isotonisitas Cairan mata isotonik dengan darah dan mempunyai nilai isotonisitas sesuai dengan larutan natrium klorida P 0,9%. Secara ideal larutan obat mata harus mempunyai nilai isotonis tersebut, tetapi mata tahap terhadap nilai isotonis rendah yang setara dengan larutan natrium klorida P 0,6% dan tertinggi setara gangguan nyata. Beberapa larutan obat mata perlu hipertonik untuk meningkatkan daya serap dan menyediakan kadar

bahan aktif yang cukup tinggi untuk menghasilan efek obat yang cepat dan efektif. Apabila larutan obat seperti ini digunakan dalam jumlah kecil, pengenceran dengan air mata cepat terjadi sehingga rasa perih akibat hipertonisitas hanya sementara. Tetapi penyesuaian isotonisitas oleh pengenceran dengan air mata tidak berarti, jika digunakan larutan hipertonik dalam jumlah besar sebagai koliria untuk membasahi mata. Jadi yang penting adalah larutan obat mata untuk keperluan ini harus mendekati isotonik. Pendaparan Banyak Obat, khususnya garam alkaloid, paling efektif pada pH optimal bagi pembentkan basa bebas tidak terdisosiasi. Tetapi pada pH ini obat mungkin menjadi tidak stabil, sehingga pH harus diatur dan dipertahankan dengan penambahan dapar. Salah satu maksud pendaparan larutan obat mata adalah untuk mencegah kenaikan pH yang disebabkan pelepasan lambat ion hidroksil dari wadah kaca. Kenaikan pH dapat mengganggu kelarutan dan stabilitas obat. Penambahan dapar dalam pembuatan obat mata harus didasarkan pada beberapa pertimbangan tertentu. Air mata normal memiliki pH lebih kurang 7,4 dan mempunyai kapasitas dapar tertentu. Penggunaan obat mata merangsang pengeluaran air mata dan penetralan cepat setiap kelebihan ion hidrogen atau ion hidroksil dalam kapasitas pendaparan air mata. Berbagai obat mata seperti garam alkaloid bersifat asam lemah dan hanya mempunyai kapasitas dapar yang lemah. Jika hanya satu atau dua tetes larutan yang mengandung obat tersebut diteteskan pada mata, pendaparan oleh air mata biasanya cukup untuk menaikan pH sehingga tidak terlalu merangsang mata. Dalam beberapa hal, pH dapat berkisar antara 3,5 dan 8,5. Beberapa obat, seperti pilokarpin hidroklorida dan epinefrin bitartrat, lebih asam sehingga melebihi kapasitas dapar air mata. Secara ideal larutan obat mata mempunyai pH dan isotonisitas yang sama dengan air mata. Hal ini tidak selalu dapat dilakukan karena pada pH 7,4 banyak obat yang tidak cukup larut dalam air. Sebagian besar garam alkaloid mengendap sebagai alkaloid bebas pada pH ini. Selain itu banyak obat tidak stabil secara kimia pada pH mendekati 7,4. Ketidakstabilan ini lebih nyata pada suhu tinggi yang

digunakan pada sterilitasi dengan pemanasan. Oleh karena itu sistem dapar harus dipilih sedekat mungkin dengan pH fisiologis yaitu 7,4 dan tidak menyebabkan pengendapan obat atau mempercepat kerusakan obat. Pembuatan obat mata dengan sistem dapar mendekati pH fisiologis dapat dilakukan dengan mencampurkan secara aseptik larutan obat steril dengan larutan dapar steril. Walaupun demikian, perlu diperhatikan mengenai kemungkinan berkurangnya kestabilan obat pada pH yang lebih tinggi, pencapaian dan pemeliharaan sterilitas selama proses pembuatan. Berbagai obat, bila didapar pada pH yang dapat digunakan secara terapetik, tidak akan stabil dalam larutan untuk jangka waktu yang lama. Sediaan ini dibeku-keringkan dan direkonstitusikan segera sebelum digunakan (misalnya Asetikolin Klorida untuk Larutan Obat Mata). Sterilisasi Pada larutan yang digunakan untuk mata yang luka, sterilitas adalah yang paling penting. Sediaan steril dalam wadah khusus untuk penggunaan perorangan pada pasien harus tersedia pada setiap rumah sakit atau instalasi lain yang melakukan perawatan mata karena kecelakaan atau pembedahan mata. Metode untuk mencapai sterilitas terutama ditentukan oleh sifat sediaan tersebut (seperti yang tertera pada Sterilisasi dan Jaminan Sterilitas Bahan Kompendia <1371>). Jika memungkinkan, penyaringan dengan penyaring membran steril secara aseptik merupakan metode yang lebih baik. Jika dapat ditunjukkan bahwa pemanasan tidak mempengaruhi stabilitas sediaan, sterilisasi obat dalam wadah akhir dengan otoklaf juga merupakan metode yang baik. Pendaparan obat tertentu disekitar pH fisiologis, dapat menyebabkan obat tidak stabil pada suhu tinggi. Penyaringan menggunakan penyaringan bakteri adalah suatu cara yang baik untuk menghindari pemanasan, namun perlu perhatian khusus dalam pemilihan, perakitan dan penggunaan alat-alat. Sedapat mungkin gunakan penyaring steril sekali pakai. Pengawet Larutan obat mata dapat dikemas dalam wadah takaran ganda bila digunakan secara perorangan pada pasien dan bila tidak terdapat kerusakan pada

permukaan mata. Wadah larutan obat mata harus tertutup rapat dan disegel untuk menjamin sterilitas pada pemakaian pertama. Larutan harus mengandung zat atau campuan zat sesuai untuk mencegah pertumbuhan atau memusnahkan bakteri yang mungkin masuk pada waktu wadah dibuka saat digunakan. Sedangkan untuk penggunaan pada pembedahan, disamping steril, larutan obat mata tidak boleh mengandung bahan antibakteri karena dapat menimbulkan iritasi pada jaringan mata. Bahan pengental Metilselulosa khusus untuk sediaan farmasi (misal 1% bila kekentalan 25 sentipois atau 0,25% bila kekentalan 4000 sentipois) atau bahan pengental lain yang sesuai seperti hidroksipropil metilselulose atau kadang-kadang polivinil alkohol dapat ditambahkan untuk meningkatkan kekentalan sehingga obat lebih lama kontak dengan jaringan. Larutan obat mata yang dikentalkan harus bebas dari partikel yang dapat terlihat.

Pada pasien dry eye syndrome terjadi penurunan jumlah air mata, sensitifitas permukaan, fungsi ketajaman penglihatan, dapat terjadi pula reaksi infeksi dan inflamasi sehingga sangat berbahaya karena mengakibatkan penurunan penglihatan (Catania et al., 2010; Alkhozi et al., 2013). Penurunan volume lapisan air mata serta munculnya gejala-gejala tersebut perlu segera ditangani untuk mencegah kondisi klinis pasien yang semakin memburuk. Tujuan dari terapi adalah pengurangan gejala, peningkatan diameter lapisan air mata dan perbaikan kondisi klinis pada permukaan mata (Asbell et al., 2010). Rekomendasi terapi berdasarkan dengan gejalanya yang disusun dalam International Dry Eye Workshop pada tahun 2007 mengkategorikan tingkatan terapi menjadi empat. Tingkat 1 adalah manajemen lingkungan, mengeliminasi pengobatan sistemik, dan penggunaan artificial tears. Apabila terapi tersebut tidak dapat mengatasi keluhan maka naik ke tingkat 2 dan seterusnya (Pflugfelder et al., 2007). Penanganan yang paling penting dan paling sering diberikan adalah artificial tears (Asyari Fatma, 2007). Artificial tears atau air mata buatan bertujuan untuk mengurangi osmolaritas, homeostasis normal dari permukaan mata, ihkan kotoran pengiritasi dan toksik pada lapisan air mata dan melindungi permukaan mata (Pflugfelder et al., 2007; Asyari Fatma, 2007). Adapun tujuan dalam penelitian ini adalah untuk mengkaji penggunaan artificial tears dalam mengatasi keluhan akibat dry eye syndrome terhadap pasien yang dirawat di Klinik Mata Surabaya. Penelitian dilakukan secara observasional prospektif terhadap data tes schirmer dan kuesioner pasien selama periode 1 Maret – 6 Juni 2016. Jumlah total pasien yang mendapatkan terapi artificial tears adalah sebanyak 27 pasien. Namun hanya 10 pasien yang melakukan kontrol sehingga data outcome terapi diambil dari 10 pasien tersebut. Dalam penelitian ini artificial tears yang digunakan terdiri dari berbagai macam bahan yaitu sodium hyaluronat, hidroksi propil metil selulosa (HPMC), Dextran 70, Gliserin, Polyvinyl pirolidon, vitamin A, CMC sodium, carbomer, fexofenadin, metil selulosa (MC), natrium klorida, dan kalium klorida. Bahan yang paling banyak digunakan sebagai terapi adalah sodium hyaluronat yaitu sebanyak 85,2% pasien. Sodium hyaluronat mempunyai duration of action yang panjang serta dapat mencegah

kerusakan mata dengan cara menyimpan molekul H2O sehingga mencegah penguapan, menghilangkan rasa terbakar, iritasi dan ketidaknyamanan yang disebabkan karena kekeringan pada mata sehingga dapat mempercepat perbaikan permukaan mata yang rusak (Chris et al., 2013; Asyari Fatma, 2007; Essa Laika, 2014). Viskositasnya yang sesuai dapat menstabilkan lapisan air mata, mengurangi gejala berpasir dan terbakar (Essa Laika, 2014). Dari hasil penelitian yang dilakukan diketahui bahwa artificial tears dapat mengatasi keluhan akibat dry eye syndrome yang dibuktikan dengan hasil perhitungan statistik metode paired sample t test data volume air mata pasien sebelum dan sesudah terapi menggunakan parameter schirmer’s test yang didapatkan sig 0,000 < 0,05. Hal ini menunjukkan adanya perbedaan volume lapisan air mata sebelum dan setelah terapi artificial tears. Serta dibuktikan dengan wawancara yang dilakukan kepada pasien melalui kuesioner McMonnies yang menunjukkan adanya pengurangan gejala hingga hilangnya semua gejala. Berdasarkan penelitian yang dilakukan tidak ditemukan adanya efek samping pemberian artificial tears pada pasien dry eye syndrome serta tidak ditemukan pula adanya interaksi dengan pemberian obat-obatan lain yang digunakan. Hal ini menunjukkan bahwa terapi artificial tears aman digunakan dalam penyembuhan dry eye syndrome. Namun penelitian selanjutnya perlu dilakukan dengan waktu yang lebih lama untuk melihat efektivitas dari terapi artificial tears terhadap pasien dry eye syndrome.

Artificial tears adalah larutan yang terkandung dalam obat tetes mata, dan memiliki kemiripan dengan air mata asli manusia, sehingga disebut air mata buatan. Bahan-bahan artificial tears biasanya berupa garam yang dapat menjaga tekanan osmotik pada mata, misalnya sodium chloride (NaCl) dan potassium choride (KCl). Artificial tears baik untuk mengatasi mata kering.

Masoud Safarzadeh,a,⁎ Parvin Azizzadeh,b and Pedram Akbarshahic Author information ► Article notes ► Copyright and License information ► Disclaimer Go to:ﾧ Introduction Dry eye syndrome (DES) is a multifactorial disease of the ocular surface. Rapid evaporation of tear film, inadequate production of tears, and inflammation of the ocular surface are among the causes of this syndrome. This condition can result in the ocular symptoms of foreign body sensation, redness, and discomfort, as well as the signs of surface damage in the cornea and conjunctiva, all leading to detrimental visual performance.1, 2, 3, 4 DES is a common problem worldwide and can reduce the working efficiency of an individual. Dry eye is therefore a frequent complaint that patient present to eye care clinics. Common patient's complaints related to dry eye include reduced vision, difficulty reading, difficulty driving at night and difficulty doing computer work.5A key principle for the management of dry eye disease is augmentation of the tear film through the topical istration of artificial tear substitutes. These products enhance tear stability thus reducing loss by evaporation; this, in turn, helps to retain moisture in the eye and relieve the chronic ocular inflammation associated with dry eyes. Artificial tear substitutes help to reduce patient discomfort, improve quality of life and reduce the risk of damage to the corneal epithelium.6 Artificial tears are among the first line of therapy in management of DES.8 They may be used along with other treatments such oral omega-3 essential fatty acid supplements, mucin secretagogues, short term

steroids and daily cyclosporine A, to combat the inflammatory nature of the disease.9 Frequent eye care visits and different treatment options impose high costs to patients and health care systems.10 Due to their non-invasive nature and low side effect profile, artificial tears have remained the main stay of therapy for DES.11 Almost all tear substitutes rapidly replace the moisture layer of tears12 and quickly reduce the symptoms. In USA, approximately 7 to 10 million Americans spend 320 million dollars per year on artificial tear products.13 In USA, many clinical trials have been conducted to evaluate their efficacy and to compare them with each other.14 In report of Dry Eye WorkShop (DEWS) was concluded that although many topical lubricants with various viscosities improve symptoms there is no evidence to suggest that any one agent is superior to another.7 However, ocular surface inflammation can be exacerbated by the presence of preservatives. Benzalkonium chloride (BAK) is a preservative frequently used in ophthalmic preparations. In patients with mild dry eye, benzalkonium chloride containing products may be well tolerated when used four to six times a day or less. Preservative free formulations are also indicated for those with a known history of allergy to preservatives and those who wear lenses.22 Preservative-free formulations are available in a variety of delivery systems. Many are supplied as single-dose units. These are often small tubes or plastic ampoules designed to ister one drop and to be discarded. These can usually be used to ister a drop into both eyes before discarding. In addition to the presence or absence of lipid, artificial tear formulations may be available in multidose bottles containing a preservative, or alternatively provided as preservative-free formulations in unit-dose packaging.20 Multi-dose bottle preparations of ocular lubricants are convenient to store and transport. Those licensed as medicinal products must have a 28 day expiry after opening but many ocular lubricants ed as medical devices have extended shelf lives of up to six months after first opening. Single dose units are bulky to store, particularly if several different eye drops are used. They are less convenient for the patient to carry, especially if they are being used many times a day. They have a greater unopened shelf-life than multidose vials but generate more waste.7, 20 A large number of artificial tear drops are available in the market. Selecting the proper product that suits the patient, with reduced costs remains a challenge for the clinician and the patients. The present study aimed to compare the clinical efficacy of two different products of hydroxypropyl methylcellulose (HPMC) based artificial tear drops on the improvement of dry eye syndrome after four weeks. Go to:ﾧ Patients and methods This is a randomized patient-masked clinical trial. The subjects for this study were recruited from patients with dry eye syndrome in Tehran, Iran. At first, the subjects completed the ocular surface disease index (OSDI) questionnaire. The examination of the ocular surface and the eyelids was performed with a slit lamp biomicroscope to rule out any other ocular diseases. The inclusion criteria were: having a score >20 in OSDI questionnaire and no use of any types of artificial tears during the previous three months. The exclusion criteria were as follows: patients with an allergy, infection, or eye surface problems (e.g. pterygium); patients using lenses; patients using ophthalmic drugs, such as steroidal or non-steroidal anti-inflammatory, antihistamines, and glaucoma

medications during the previous month, or systemically using drugs influencing tear production, such as antihistamines, cortisones, hormones, beta-blockers, antidepressants, and chemotherapy drugs; patients with a history of ophthalmic surgical operations; patients undergoing radiotherapy; patients allergic to hydroxypropyl methylcellulose; and pregnant or breastfeeding patients. For the patients who met the above criteria, the purpose of the study was explained. If they were willing to participate, they were asked to sign the informed consent form which was prepared based on the Declaration of Helsinki. The patients were examined in two visits; one before the intervention and one after 30 ± 2 days of using the specified artificial tear. To assess patients’ DES-related symptoms, a validated OSDI questionnaire was used. The OSDI, is a 12-question survey, with a five point scale answers (0 = none of time and 4 = all of the time), with higher scores representing greater disability. The total OSDI score is calculated based on the following formula = 100 (sum of severity for all questions answered)/4 (Total number of questions answered), where the severity was graded on a scale of: 0 = none of the time, 1 = some of the time, 2 = half of the time, 3 = most of the time, 4 = all of the time. A score of 100 corresponds to complete disability while a score 0 corresponds to no disability. Following the completion of the questionnaire, the tear break up time (TBUT) assessment was performed using Lowther's method15 (A method for use of fluorescein strip in which the portion of the fluorescein strip which is designed to be wetted, is approximately 5 mm wide by 15 mm long to deliver a limited dose of from 0.5 to 1.0 μl of liquid to the surface of the cornea) in right eye. A sterile fluorescein strip (Indicator, Tuba Teb Co., Iran) was moistened using non preserved saline and excessive solution was shaken off. The strip was touched gently to the superior bulbar conjunctiva or lid margin taking care not to instill too much solution or cause excessive reflex tearing. The patients were asked to blink two or three times naturally and then after one closure try to keep the eyes open. The time from the opening until the appearance of first dry spot was measured in seconds. The measurements were taken two times by stopwatch. For each subject, the TBUT were averaged and the average values were compared before and after the intervention. The subjects with TBUT < 10 s meeting the criteria for dry eye were enrolled into the study. The conjunctiva and the cornea were examined after instillation of fluorescein, with cobalt blue filter of SL-1E biomicroscope (Topcon, Japan). Punctuate staining was recorded using a standardized grading system of 0-3 for each of the five area on the corneal diagram.16 The Schirmer test was performed in right eye, with anesthetic, measuring the basic tear secretion; a drop of Tetracaine 0.5% (Anestocaine, Sina Darou, Iran) was applied to the eye. 5 min after instilling one drop of tetracaine 0.5% into the conjunctival sac for test, the paper strips (Tuba Teb Co., Iran) were placed over the junction of the temporal and medial one-third of the lower eyelid margin. The eyes were closed during the test, and the length of the wet portion was measured in millimeters.17 The wetting strip counted <10 mm per 5 min were enrolled into the study. The subjects meeting the inclusion criteria were divided into two groups based on their score in OSDI. Artificial tears drops used into two groups were as follows: Group (A) Tear Naturale® single dose eye drops from England, Alcon company, containing dextran 70, 1 mg/ml and hypromellose, 3 mg/ml hydroxypropyl methylcellulose, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, zinc chloride, sodium hydrogen carbonate, carbon dioxide (to adjust pH) and purified water as non-preservative. Group B) Tearlose® multidose eye drops from Iran, Sina Darou company, containing

hydroxypropyl methylcellulose 0.3 g and 0.1 g of dextran 70, with 0.01% benzalkonium chloride (BAK) as preservative which are available in 10 mL plastic bottles with nozzle droppers and pilferproof caps. Using random blocks, the first group and the second group received Tear Naturale® and Tearlose® eye drops, respectively. The patients were blind to the names of the medication and were instructed to use the eye drops 2 times a day for 4 weeks. In addition, lid hygiene was recommended in the mornings; the base of lashes had to be cleaned at the lid margins by Eyesol Ophthalmic Cleansing Shampoo, (Livar Co, Iran). The patients were asked to return to the clinic for a follow-up visit in thirty days. Before using a statistical procedure, the preconditions for its use were verified (e.g. the normal distribution of the variables). If the preconditions were largely fulfilled, parametric methods were used for the evaluation. If the preconditions were not fulfilled, a non-parametric method was selected. Statistical analysis was performed using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). Kolmogorov–Smirnov test was performed to assess normality for continuous variables. The outcomes were compared between the two groups using an independent t-test for continuous variables or the Chi-square test for categorical variables. The comparisons of outcome measures between the baseline and 4week after intervention in each group were performed using a paired t-test and the differences in the degree of change were compared between the two groups using an independent t-test. To compare changes in Group A and B, repeated-measures analysis of variance was used. A value of p < 0.05 was considered significant. Go to:ﾧ Results A total of 100 participants were recruited into the trial, 88 patients (41 patients in the Group A and 47 patients in the Group B) completed the entire protocol. A total of 12 subjects (9 patients in the Group A and 3 patients in the Group B) failed to complete the trial. The difference between the two groups in of sex distribution was not significant (p = 0.135). The mean age of the participants in the Group A and the Group B was 44.08 ± 6.29 years (range, 33–58 years) and 45.83 ± 8.42 years (range, 31–60 years), respectively, and there was no significant difference between the groups (p = 0.379). Demographic features of patients in the Group A and B are stated in Table 1. The means and standard deviations of OSDI scores, TBUT, conjunctival and corneal staining scores, Schirmer test scores of Groups A and B, before and after the intervention are presented in Table 2. The OSDI scores after the intervention showed a significant decrease compared to those before the intervention in both groups (p < 0.001). However, there was no significant difference in the efficacy of the two artificial tear products (p = 0.440), and repeated-measures analysis of variance did not demonstrate significant interaction between type of product and change over time in the trend of mean OSDI in the Group A and B (p = 0.468). The TBUT results after the intervention showed a significant increase compared to those before the intervention, although not statistically significant (Group A; p = 0.027 and Group B; p = 0.013). Also, in comparing the mean results of each tests carried out, there was no significant difference in the efficacy of the two products (p = 0.497). The difference of interaction between the two groups and change over time in the trend of mean TBUT was not statistically significant (p = 0.834). The conjunctival staining scores 4-week after the intervention showed a significant decrease compared to

those before the intervention (p < 0.001). The two artificial tear products compared in two groups showed similar effects (p = 0.822). Furthermore, the interaction of product type and change over time in the trend of conjunctival staining score between the Group A and B was not significant (p = 0.080). The corneal staining scores after the intervention also showed a significant decrease compared to those before the intervention (p < 0.001). However, two products of artificial tear drops did not show different effects (p = 0.793), and the interaction the type of artificial tear and change over time in the trend of corneal staining score was not statistically significant (p = 0.894). The Schirmer test scores, after the intervention showed an increase compared to those before the intervention, but the differences were not significant in either group (Group A; p = 0.129 and Group B; p = 0.115). Both products showed similar effects (p = 0.441), and the interaction between type of artificial tear and change over time in the trend of Schirmer test was not significant (p = 0.475). Table 1 Demographic features of patients. Group A (N = 41)

Group B (N = 47)

p Value

Mean age ± SD

44.08 ± 6.29 (range: 33–58 years)

45.83 ± 8.42 (range: 31–60 years)

0.379

Male/Femal e

19/22

21/26

0.135

Group A: patients assigned to use of the product of Tear Natural® single dose eye drops. Group B: patients assigned to use of product of Tearlose® multidose eye drops. p value: p values were derived from an independent t-test for continuous data and the Chi-square test for categorical data. N: number of patients. Table 2 Comparison of the clinical characteristics of the two groups. Group A

Type of test

Baselin 4-Week pValue e visit (1)

Group B

Baselin 4-Week pValue e visit (1)

pValue (2)

pValue (3)

OSDI score

43.58 ± 31.92 ± <0.001 16.96 15.21

39.51 ± 29.97 ± <0.001 15.77 16.18

0.339

0.440

TBUT (sec)

7 ± 2.2

7.64 ± 2.60

0.027

7.15 ± 2.25

8.09 ± 2.74

0.013

0.640

0.497

Conjuncti val score

6.67 ± 2.88

5.53 ± 2.27

<0.001

7.34 ± 2.20

5.09 ± 1.67

<0.001

0.334

0.822

Corneal score

1.23 ± 1.33

0.49 ± 0.78

<0.001

1.15 ± 1.07

0.44 ± 0.57

<0.001

0.807

0.793

Schirmer test (mm)

6.04 ± 5.25

6.56 ± 5.46

0.129

6.64 ± 6.12

7.10 ± 6.40

0.115

0.676

0.441

OSDI: Ocular Surface Disease Index questionnaire; TBUT: tear break up time; Group A: patients assigned to use of the product of Tear Natural® single dose eye drops; Group B: patients assigned to use of product of Tearlose® multidose eye drops. p Value (1): indicates the significant level of paired t-test within A or B groups between baseline and four weeks after intervention. p Value (2): indicates the significant level of independent t-test for comparing between A and B groups before intervention. p Value (3): indicates the significant level of independent t test for comparing between A and B groups after four weeks. Go to:ﾧ Discussion In this study, hydroxypropyl methylcellulose (HPMC) as the active principle in Tear Naturale® and Tearlose® eye drops reduced the symptoms DES equally. The mean score of the OSDI questionnaire decreased significantly after the intervention in both groups. When Toda et al.18 studied the effect of 0.5% HPMC without any preservative on Sjögren and non-Sjögren dry eye patients, they observed that the symptoms were reduced in both groups. Nguyen et al.19 examined the effect of inserts containing HPMC on patients with DES and found that inserts were significantly effective in DES treatment. Lanz20 also compared preserved HPMC (GenTeal, 0.3% HPMC, with sodium perborate as preservative) vs nonpreserved HPMC (Tears Naturale, 0.3% HPMC, 0.1% dextran 70) and found no significant difference between the symptoms of two groups after the intervention. These findings agree with the result of this study. Lanz20 also found better improvement in the Schirmer test with the preserved Genteal. In this study, a slightly better improvement was observed with the preserved drop but the difference was not significant. This difference could be due different preservatives used (sodium perborate vs BAK) in two studies. In both groups, the conjunctival and corneal staining scores, after the intervention, were reduced significantly (p < 0.001). In study performed by Climent,23 GenTeal Tears® with preservative, and preservative-free Tears Naturale®

(Alcon Laboratories, Inc.) were compared. After 4 weeks of treatment, patients were evaluated with TBUT, Schirmer's test, and corneal staining as well as via a symptom questionnaire. A total of 37 patients completed the study. Both TBUT and Schirmer testing improved in the GenTeal group but not in the Tears Naturale® group (p = 0.27). These differences in two studies could be due to the preservative used in the group GenTeal Tears and the amount of HPMC used in formulation of artificial tear drops. Subjective symptoms were not different between the two treatments. In this study, the results of Schirmer test (with anesthetic) before the intervention did not differ significantly from those after the intervention. According to previous studies performed,30, 31, 32 an increase in the volume of baseline tear was expected after the use of artificial tears, but no change was observed. The increase in volume might have happened shortly after the application of the eye drops and at the time of testing, a long time might have ed since the instillation of the drop. In this study, a slightly better improvement was observed with the preserved drop but the difference was not significant. In both groups, the conjunctival and corneal staining scores, after the intervention, were reduced significantly (p < 0.001). The improvement of epithelial cells in the cornea and conjunctiva were in line with reduction of patients’ complaints. The absence of preservative does not appear to be advantageous in of reducing the corneal and conjuntival stains. Agents such as hydroxypropyl methylcellulose (HPMC), which decrease rose bengal staining in dry eye subjects,33 may either coat and protect the surface epithelium or help restore the protective effect of mucins. However, these results might be due to the short-term use of these eye drops. McCann et al.21 compared the efficacies of HPMC (Dacrisol unidose; Alcon, Italy), sodium hyaluronate (Lubristil 0.15% unidose, SIFI, Catania, Italy) and a new oil-in-water emulsion (Emustil unidose: SIFI) in the management of patients with DES caused by impaired lipid bilayer. They found that the symptoms and tear evaporation were reduced in the three groups, but the differences for sodium hyaluronate or the HPMC group statistically were not significant. This difference could be due to different preservatives used (sodium perborate vs BAK) in two studies. Peter et al.24 demonstrated that both unit-dose and multi-dose artificial tear drops are similar in of efficacy. Peter study observed statistically significant improvements in OSDI scores from baseline at 30 days. There were no clinically significant differences in performance in TBUT, corneal staining, conjunctival staining, and Schirmer's test among the artificial tear formulations. In Peter et al. study, subjects used artificial tears a median of three times a day, thus there may have been a difference between the adverse effects observed with preservative vs non-preservative formulations in subjects who used the eye drops more frequently for treatment of more severe dry eye. Some studies have emphasized the side effects of preservatives on eye surface and tears, including corneal and conjunctival tissue damage, loss of goblet cells, preventing the growth of new cells, and accelerating cell death.25, 26, 27, 28 Benzalkonium chloride (BAK) is the most frequently used preservative in topical ophthalmic preparations, as well as in topical lubricants. Its epithelial toxic effects have been well established.11, 29The toxicity of BAK is related to its concentration, the frequency of dosing, the level or amount of tear secretion, and the severity of the ocular surface disease. In the patient with mild dry eye, BAK-preserved drops are usually well tolerated when used 4–6 times a day or less. In patients with moderate-to-severe dry eye, the potential for BAK toxicity is high, due to decreased tear secretion and decreased turnover.25, 26, 28, 29 The

incidence of most of the side effects depends on concentration of preservatives and long duration of their use. Although other preservatives have shown better safety profile than BAK,11but we did not observe any side effects for short time about the drop containing BAK. Preservative-free formulations are absolutely necessary for patients with severe dry eye with ocular surface disease and impairment of lacrimal gland secretion, or for patients on multiple, preserved topical medications for chronic eye disease. Therefore, artificial tears without preservatives are still recommended for patients with persistent symptoms or those who require higher doses of the drops. Nonpreserved, single unit-dose tear substitutes are more costly for the manufacturer to produce, more costly for the patients to purchase, and less convenient to use than bottled artificial tear drops.22, 23 Go to:ﾧ Conclusion The two artificial tears compared in this study, equally reduced the signs and symptoms of dry eye syndrome in four weeks. Go to:ﾧ Funding This project is funded by department of ophthalmology, Bahman Hospital, Tehran, Iran. Go to:ﾧ Conflict of interest The authors have no financial interest in the products discussed in this article. Go to:ﾧ Acknowledgements This article is the result of a clinical research prepared by the research committee at department of ophthalmology, Bahman Hospital, Tehran, Iran. Go to:ﾧ References 1. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye Workshop (2007) Ocul Surf. 2007;5:75–92. [PubMed] 2. Gumus K., Crockett C.H., Rao K. Noninvasive assessment of tear stability with the tear stability analysis system in tear dysfunction patients. Invest Ophthalmol Vis Sci. 2011;52:456–461. [PubMed] 3. Versura P., Profazio V., Campos E.C. Performance of tear osmolarity compared to previous diagnostic tests for dry eye diseases. Curr Eye Res. 2010;35:553–564.[PubMed] 4. Savini G., Prabhawasat P., Kojima T., Grueterich M., Espana E., Goto E. The challenge

of dry eye diagnosis. Clin Ophthalmol. 2008;2:31–55. [PubMed] 5. Pouyeh B., Viteri E., Feuer W. Impact of ocular surface symptoms on quality of life in a United States veterans affairs population. Am J Ophthalmol. 2012;153:1061–1066. [PubMed] 6. Sullivan B.D., Crews L.A., Sonmez B. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea. 2012;31:1000–1008. [PubMed] 7. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop. Ocul Surf. 2007;5:75–92. [PubMed] 8. Aragona P., Papa V., Micali A., Santocono M., Milazzo G. Long term treatment with sodium hyaluronate containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol. 2002;86:181–184. [PubMed] 9. Lin H., Yiu S.C. Dry Eye Disease: a review of diagnostic approaches and treatments. Saudi J Ophthalmol. 2014;28:173–181. [PubMed] 10. Waduthantri S., Yong S.S., Tan C.H. Cost of dry eye treatment in an Asian clinic setting. PLOS One. 2012;7:e37711. [PubMed] 11. Moshirfar M., Pierson K., Hanamaikai K., Santiago-Caban L., Muthappan B., i S.F. Artificial tears potpourri: a literature review. Clin Ophthalmol. 2014;8:1419–1433. [PubMed] 12. Lemp M.A., Goldberg M., Roddy M.R. The effect of tear substitutes on tear film break up time. Invest Ophthalmol. 1975;14:255–258. [PubMed] 13. Gayton J.L. Etiology, prevalence, and treatment of dry eye disease. Clin Ophthalmol. 2009;3:405–416. [PubMed] 14. Schiffman R.M., Christianson M.D., Jacobsen G., Hirsch J.D., Reis B.L. Reliability and validity of the ocular surface disease index. Arch Ophthalmol. 2000;118:615–621. [PubMed] 15. Donald R., Korb J.C., Doughty M., Guillon J.P., Smith G., Tomlinson A. ButterworthHeinemann; 2002. The Tear Film: structure, function and clinical examination. pg138. 16. Lemp M.A. Report of the National EYE Institution/Industry. Workshop on Clinical Trials In dry Eyes. CLAO J. 1995;21:221–232. [PubMed] 17. Donald R., Korb J.C., Doughty M., Guillon J.P., Smith G., Tomlinson A. ButterworthHeinemann; 2002. The Tear Film: structure, function and clinical examination; p. 114. 18. Toda I., Shinozaki N., Tsubutak Hydroxypropylmethyl cellulose for the treatment of severe dry eye associated with sjogren syndrome. Cornea. 1996;15:120–128. [PubMed] 19. Nguyen T., Lutkeny R. Review of hydroxypropylmethyl cellulose inserts for treatment of dry eye. Clin Ophthalmol. 2011;5:587–591. [PubMed] 20. Lanz R. Comparison of Genaqua-Preserved Genteal in multidose bottles vs

Preservative-Free Tears Naturale in single dose units in patients with moderate to severe Dry Eye. Invest Ophthalmol Vis Sci. 2006:47. E-Abstract 259. 21. McCann L.C., Tomilsone A., Pearce E.I., Papa V. Effectiveness of artificial tears in the management of evaporative dry eye. Cornea. 2012;31:1–5. [PubMed] 22. Murube J., Murube A., Zhuo C. Classification of artificial tears. II: additives and commercial formulas. Adv Exp Med Biol. 1998;438:705–715. [PubMed] 23. Climent A.O. Comparison of GenAqua-preserved GenTeal in multidose bottles vs preservative-free tears naturale in single dose units in patients with moderate to severe dry eye. Invest Ophthalmol Vis Sci. 2006:47. E-Abstract 261-B439. 24. Peter A. Simmons, Carlisle-Wilcox Cindy, Joseph G. Vehige. Comparison of novel lipid-based eye drops with aqueous eye drops for dry eye: a multicenter, randomized controlled trial. Clin Ophthalmol. 2015;9:657–664. [PubMed] 25. Baudouin C., Labbe A., Liang H., Paul A., Brignole-Baudouin E. Preservatives in eye drops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312–334.[PubMed] 26. Herrero Vanrell R. Preservatives in ophthalmic formulations. Arch Soc Esp Ophthalmol. 2007;82:531–532. [PubMed] 27. Noecker R. Ophthalmic preservatives: considerations for long term use in patients with dry eye or glaucoma. Rev Ophthalmol. 2001;8:73–79. 28. Noecker R. Effect of common ophthalmic preservatives in ocular health. Adv Ther. 2001;18:205–215. [PubMed] 29. Furrer P., Mayer J.M., Gurny R. Ocular tolerance of preservatives and alternatives. Eur J Pharma Biopharma. 2002;53:263–280. [PubMed] 30. Yokoi N., Kato H., Kinoshita S. Facilitation of tear fluid secretion by 3% diquafosol ophthalmic solution in normal human eyes. Am J Ophthalmol. 2014;157:85–92. [PubMed] 31. Matsumoto Y., Ohashi Y., Watanabe H., Tsubota K. Efficacy and safety of diquafosol ophthalmic solution in patients with dry eye syndrome: a Japanese phase 2 clinical trial. Ophthalmology. 2012;119:1954–1960. [PubMed] 32. Akiyama-Fukuda R., Usui T., Yoshida T., Yamagami S. Evaluation of tear meniscus dynamics using anterior segment swept-source optical coherence tomography after topical solution instillation for dry eye. Cornea. 2016;35:654–658. [PubMed] 33. Versura P., Maltarello M., Stecher F. Dry eye before and after therapy with hydrox ypropylmethylcellulose. Ophthalmologica. 1989;198:152–162. [PubMed]

Go to:ﾧ 3. Historical Treatment of Dry Eye Related to Lacrimal Gland Dysfunction

Regrettably, the treatment of dry eye related to tear film insufficiency has made little progress in recent years. Most current therapies aim to reduce drainage of tears from the eye, that is, punctual occlusion with cautery or plugs, or to replace insufficient aqueous production from the lacrimal gland with artificial tears. Each of these therapies reduces dry eye symptoms but each has significant drawbacks. For example, punctal plugs have poor retention rates; can migrate into the lacrimal system; predispose the eye to infection; and cause epiphora [86]. Punctal cautery can cause similar issues but is much more difficult to reverse with patient intolerance. Artificial tears are a more benign therapeutic option but the preservatives within them can be toxic to the cornea with frequent dosing [87]. This issue has been circumvented by the production of preservative-free preparations. While the ingredients have significantly changed, artificial tears were first described nearly 3,500 years ago and are unfortunately rapidly removed from the ocular surface [88]. It was not until the 1980s that natural or synthetic polymers were added to preparations increasing viscosity and retention time. Such compounds as 1% glycerin have shown prolonged benefit compared to propylene and polyethylene glycol are one such example [89]. Even with these advancements, artificial tears are only a temporary measure and do not provide important proteins produced by the lacrimal gland for ocular health as previously discussed and are short-lived. As such, artificial tears and punctal occlusion remain viable options for dry eye treatment but do not address the underlying lacrimal gland dysfunction. Further advancements have been made with the introduction of cyclosporine. The compound was initially isolated from the fungus Tolypocladium inflatum, a potent inhibitor of T cell activity [90, 91]. Therapy with this medication has shown great effect by increasing goblet cell density and TGF-β. It has also been shown in mice to better reduce epithelial staining compared to prednisone in an inflammatory dry eye model [92]. However, this therapy is presumably most effective in an inflammatory dry eye minimizing its therapeutic use to these specific conditions. Additionally, poor patient compliance further reduces its widespread application due to ocular irritation and prolonged use necessary to see any appreciable benefit frustrating even the most compliant patients. Multiple surgical attempts have been made to by the lacrimal gland altogether by transposing the parotid gland duct onto the lower conjunctiva, a technique developed in the 1950s [93]. This has shown great promise in dogs with keratoconjunctivitis sicca with a success rate as high as 92% [94], but the results are difficult to interpret in animals unable to voice complaints of dry eye or excessive tearing. We, as well as others, have all but abandoned the technique due to lack of any appreciable benefit, excessive tear secretion, and high rates atrophy of the gland following surgery [95]. Consequently, this technique is rarely used today except in animals due to inconsistent results and significant side effects. Go to:ﾧ 4. Emerging Therapies for Dry Eye There are several emerging modalities that have shown at least some promise in the basic science realm. These emerging therapies can be divided into two categories: exogenous

compounds and gland regeneration/by. Unfortunately, many of these treatments are still in their infancy and have not made significant progress beyond the basic science realm. Exogenous compounds are delivered to host tissue through either topical or oral routes. Many of these new agents directly inhibit proinflammatory cascades. The list of targets includes vascular cell adhesion inhibitors, immune modulators, and immune suppressants [96–98]. These inhibitors have shown efficacy in mouse models of inflammatory dry eye but have not been used in humans. One of these agents is delivered in an adenoviral vector, which would theoretically reduce the need for reapplication but raises concerns for inducing an innate immune response that could worsen inflammation [35, 98]. Moreover, immune suppression of the ocular surface could result in frequent infectious complications. The recently described nonimmune compound, pituitary adenylate cyclase-activating polypeptide-derived peptide, has been shown to promote corneal wound healing and lacrimal gland secretion in mice [99]. With the adenoviral vector as the exception, these compounds would likely be an improvement from artificial tears but would reduce ocular immunity. Patient compliance as seen with other topical eye medications would also be an issue. Consequently, the untested role of these topical therapies may be of some benefit in few select populations. With increasing success in stem cell-based tissue regeneration, tissues and organs such as functioning photoreceptors and the liver can now be grown in vitro [100, 101]. Attempts of a bioengineered lacrimal gland have seen recent success in mouse models as well [102]. Stem cells are isolated using specific lacrimal cell markers, tissue grown ex vivo, and transplanted into the host resulting in increased tear production [102–104]. While promising, it remains to be seen whether these results can be reproduced in humans and provide a feasible, long lasting therapeutic option. There has also been some suggestion of using lacrimal gland xenografts as healthy tissue, but this theoretical idea remains untested [105]. Furthermore, these transplant models have not evaluated the effect of transplantation with ongoing diseases such as SS that may reduce graft transplantation rates and efficacy such as seen with a significantly higher rejection rate of herpes-infected corneas compared to noninflammatory corneal transplants [106]. While clinical promising and would address gland dysfunction and restore normal tear production, lacrimal gland regeneration or xenograph transplantation remains to be years from clinical use. More recently, sublingual, labial, and submandibular glands have been transplanted into the subconjunctival space as an additional means to treat severe dry eyes due to underlying basal secretion of these glands that does not require innervation [107, 108]. The transplanted glands have shown a reduction in dry eye symptoms for at least five years and reduce the need for tear supplementation [109]. In addition, saliva contains many of the same contents as the lacrimal gland including secretory IgA but the two have not been specifically compared [110]. Unfortunately, the long-term efficacy beyond 5 years is currently unknown. Furthermore, the transplantation rate is at best 72% and requires a difficult microsurgery including vascular anastomosis of the gland to the temporal artery and vein [111]. As such, the surgery has not gained widespread use at this point in time. The transplants can also cause chronic inflammation exacerbating dry eye symptoms, microcystic epithelial edema, and epiphora in approximately 40% of patients

within 3–6 months of surgery [112, 113]. While transplantation of these glands has shown great effect on dry eye and produce more natural tears than artificial instilled ones, the complicated surgery and risk of graft failure are staggering complications to overcome making them less than ideal. Lastly, there is ongoing work on an implantable device to that stimulates the lacrimal nerve to increase tear production within the lacrimal gland and this small animal study has shown promising results [114]. However, it remains to be seen whether this method of hyperstimulating the lacrimal gland can and/or will overcome gland dysfunction and whether it becomes a feasible clinical treatment option. Furthermore, will this device be able to stimulate a diseased gland enough such as in SS to overcome the symptoms of dry eye? In summary, there are several new modalities emerging for severe dry eye; however, many of these options remain unproven or require extensive, technically difficult microsurgery. Go to:ﾧ 5. Conclusion There are multiple disease entities that can affect the lacrimal gland and cause its dysfunction. Untreated pathologies and downstream effects of reduced production from the lacrimal gland can result in decompensation of the ocular surface and gross deterioration of visual acuity. The role of this gland cannot be overstated in ocular surface health and proper light refraction from the air-tear interface. Emerging therapies will hopefully alleviate the large dry eye burden worldwide by addressing the issue at its core, by attempting to regenerate a dysfunctional gland and/or controlling the proinflammatory state that ensues with severe dry eye. As such, new modalities and therapies need to be developed through collaborative/translational research to treat aqueous deficiency-related dry eye. It will be interesting to see if the untested, but promising, therapies discussed become viable treatment modalities in dry eye therapy beyond the temporary measures of ocular lubricants. Go to:ﾧ Acknowledgments The authors would like to thank Dr. Nick Mamalis for images of the lacrimal gland and Lane Bennion for the medical drawings. The authors would also like to thank Research to Prevent Blindness for their unrestricted grant to the Moran Eye Center.