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Abstract

Purpose: To compare the efficacy and safety of 0.3% hydroxypropyl methylcellulose/dextran (HPMC/dextran) and 0.18% sodium hyaluronate (SH) in the treatment of ocular surface disease in patients using antiglaucoma drugs containing preservatives.

Methods: This was a double-blind, randomized, parallel-group study in 70 glaucoma patients with Ocular Surface Disease Index (OSDI) score greater than 20 points and/or presence of ocular signs. Patients were randomized to receive either preservative-free 0.3% HPMC/dextran (n=35) or preservative-free 0.18% SH (n=35). Treatment was 1 drop in each eye, 4 times a day. Data were collected at baseline, at day 7 and day 28.

Results: The groups were homogeneous at baseline. At day 28, both treatments showed significant improvements (P<0.05) in the mean OSDI score, lid skin and lid margin inflammation, conjunctival injection, and expressibility of meibomian glands, corneal staining score, fluorescein tear breakup time (FBUT), and Schirmer I test. However, the mean OSDI score, lid margin inflammation and conjunctival injection showed significant improvements (P<0.05) in the SH group at days 7 and 28, compared to the HPMC/dextran group. FBUT and the Schirmer I test also showed significant improvements (P<0.05) in the SH group compared to the HPMC/dextran group, at day 28. No adverse reactions were observed in either group.

Conclusions: Preservative-free artificial tear, 0.3% HPMC/dextran, and 0.18% SH, caused a significant relief of the ocular surface disease in glaucoma patients. However, 0.18% SH led to a greater improvement in ocular signs and symptoms than 0.3% HPMC/dextran.

Introduction

Glaucoma is the second leading cause of blindness in Thailand, and more generally worldwide.1,2 Nowadays, various medications are mandatory for the treatment of glaucoma to prevent blindness from hypertensive optic nerve damage. Eye drops usually containing preservatives, are the mainstay of treatment. However, the long-term duration of such treatments can also cause ocular surface disease, especially dry eye. Several previous studies3–9 have shown that the presence of preservatives in antiglaucoma medications is a main cause of ocular surface problems such as keratopathy, conjunctival inflammation, abnormal tear film production, tear film instability, and meibomian gland dysfunction. These adverse effects can lead to poor adherence to treatment.

Thus, given the need to continue glaucoma treatments and concern for the ocular surface damage they cause, it is important to find a medication that would decrease these ocular surface side effects. Previous reports have demonstrated the efficacy of nonpreserved artificial tears in increasing tear film production, tear film stability, and improving ocular surface in dry eye patients.10–14 Sodium hyaluronate (SH) was shown in vitro to reduce ocular toxicity due to benzalkonium chloride (BAK), a preservative often used in antiglaucoma drugs.15 Hydroxypropyl methylcellulose (HPMC) is a conventional therapy for tear film disturbances13,14 and is included in the essential drug list in Thailand.

The purpose of this study was to investigate the efficacy and safety of these 2 preservative-free artificial tears (0.3% HPMC and 0.18% SH) in reducing ocular surface toxicity induced by preserved antiglaucoma medication. To the best of our knowledge, this is the first study comparing the efficacy of these 2 artificial tears in the treatment of ocular surface disease in glaucoma patients.

Methods

Study design

This was a double-blind, randomized, parallel-group study carried out at a single center in Thailand. The treatment duration was 4 weeks and the study was divided into 3 visits for assessments (baseline, D7, and D28). After a washout period of 7 days for patients who were using artificial tears at the time of study inclusion, treatment was 1 drop in each eye, 4 times a day. No artificial tears were given during the washout period. Ethics committee approval was obtained from the Committee for the Protection of Human Participants in Research at the Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand [655/2553(EC4)]. The trial was registered with the following identification number: {"type":"clinical-trial","attrs":{"text":"NCT 01284439","term_id":"NCT01284439"}}NCT 01284439 (www.clinicaltrials.gov). All subjects were recruited from an outpatient department in the Siriraj hospital during the period from October 2009 to December 2011. Informed consent was obtained from all patients before they were subjected to any study-specific examination. This study was conducted in accordance with the Helsinki Declaration and Good Clinical Practice.

Study population

Male and female patients were eligible for the study if they were over 18 years of age, diagnosed with glaucoma, that is, primary open angle glaucoma or primary angle closure glaucoma, and receiving topical antiglaucoma medications. All eligible patients must have an ocular surface disease index (OSDI; with the permission of Allergan, Inc., Irvine, CA) score equal to or greater than 20 and/or ocular surface diseases presenting any of the following: erythematous rash at eyelid skin/lid margin, signs of meibomian gland dysfunction, bulbar/tarsal conjunctival hyperemia, follicle at tarsal conjunctiva, fluorescein staining score using the National Eye Institute (NEI) system score equal to or greater than 3 points, Rose Bengal staining score (NEI system score) equal to or greater than 3 points, Schirmer's test equal to or less than 5 mm, and/or fluorescein tear breakup time (FBUT) equal to or less than 8 s.

Patients less than 18 years of age, those with secondary glaucoma from known causes, immunocompromised patients, those with an active or recent ocular infection, those with known allergies to any ingredient of study medications, pregnant or lactating women, contact lens wearers, and patients who were not able to follow the study instructions, were excluded from the study.

Study material

Vislube® (0.18% SH, molecular weight 1.2×106 Da; TRB Chemedica, Munich, Germany) and TearsNaturale® Free (0.3% HPMC/0.1% dextran; Alcon, FortWorth, TX) were used as study products. Vislube is a patented hypotonic (150 mOsm/kg) solution containing the electrolytes potassium, calcium, magnesium, sodium, and chloride. TearsNaturale Free is an isotonic (274 mOsm/kg) solution containing sodium, potassium, calcium, magnesium, zinc, chloride, and bicarbonate as electrolytes. Both products are preservative free. Both the patients and the evaluating investigator (PP) were blinded to the treatments received. The products were packed in their original monodose units, from which the label was removed. Therefore, the patients did not know which drug they were using. In addition, the evaluating investigator (PP) did not know which product was used.

Study proceedings

At the baseline visit (day 0), patients were assessed for the inclusion and exclusion criteria. Eligible patients were then randomized, by blocks of 4, into 2 groups using a computer-generated randomization list. The type of antiglaucoma products used was recorded.

Thereafter, all patients were classified as having either severe or nonsevere complications due to their antiglaucoma medications. If patients had any serious corneal complication, such as corneal epithelial defect, pseudodendritic corneal lesion, or conjunctival pseudomembrane, these patients were instructed to discontinue their current antiglaucoma medications and were switched to other systemic treatment modalities. However, no serious case occurred during the study.

All included patients underwent ocular examinations and completed 12 questions of the OSDI16 (Thai version) at baseline and at days 7 and 28. A detailed slit-lamp biomicroscopy was performed to evaluate and grade the severity of lid skin inflammation (Grade 0=no injection, Grade 1=lid skin injection/erythematous rash). Lid margin inflammation (hyperemia and telangiectasia) and bulbar conjunctival injection were graded as shown in our previous study17: (Grade 0=no injection, Grade 1=mild injection, Grade 2=moderate injection, and Grade 3=severe injection).17 The presence of follicles at the tarsal conjunctiva (Grade 0=none, Grade 1=presence of follicle) was assessed.

FBUT test was assessed with 2% fluorescein solution instilled into the lower fornix. FBUT recording was stopped when the first tear disruption spot was seen. This test was done 3 times and the mean time was used to calculate the FBUT.

Corneal and conjunctival staining with fluorescein and Rose Bengal was scored and recorded following the NEI system,18 in which the Rose Bengal staining score was recorded, after totally rinsing out the fluorescein solution with normal saline solution. The meibomian glands were evaluated in the next step to prevent pressure on the cornea from the observer's hand, which could interfere with the grading of corneal staining score. Grading of meibomian gland dysfunction was carried out according to the method reported in our previous study.17 In brief, the characteristics of meibomian gland secretions and meibomian gland expressibility were graded as in . Tear volume, measured by Schirmer I test, was performed in the last step. Additionally, the daily use of tear supplements was recorded by the patients.

Table

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In concordance with previous reports,8,19,20,29 the present study evidenced the relationship between the symptoms of a damaged ocular surface and the frequency of antiglaucoma eye drops administration ( ).

From this study, both preservative-free artificial tears (SH and HPMC/dextran) could improve the signs and symptoms of ocular surface disease in glaucoma patients within 1 month. The use of preservative-free artificial tears, concomitantly with antiglaucoma drugs, allowed counteracting their side effects onto the ocular surface. The study demonstrated that SH could improve ocular surface to a larger extent than HPMC/dextran, the following parameters: OSDI score, FBUT, conjunctival and lid inflammation as long as tear amount after 1 month of treatment with statistically significant difference (P<0.05). The viscoelasticity property of SH is probably its main asset to protect ocular surface damage.30 SH has also mucomimetic and mucoadhesive effects, which stabilized the precorneal tear film, and thus prolonged the residence time.31,32 Clinical studies comparing tear film stability in SH versus HPMC/dextran, supporting these results, demonstrated a significant improvement in SH than the HPMC group.10,33 Moreover, several studies reported that SH is able to promote epithelial migration,12 therefore, reducing punctate epitheliopathy.11,34 An in vitro study highlighted the positive effect of SH on oxidative stress, apoptosis, and necrosis of conjunctival and corneal epithelial cell line induced by BAK.15 Additionally, SH, in this study, is a hypotonic preservative-free artificial tear (150 mOsm/kg), which benefits the hyperosmolarity state of dry eye.35,36 This might explain the significantly improved result different from the previous study of Monaco et al.,37 which failed to demonstrate the advantage of using 0.2% isotonic (300 mOsm/kg) SH to treat ocular surface damage from glaucoma medications. However, in the Monaco study, carboxymethylcellulose with osmoprotection improved both OSDI and lissamine green staining score in patients having ocular surface disease (OSD) from glaucoma medications.

In serious cases such as severe lid edema, persistent epithelial defect, or severe keratitis, which were not included in this study, artificial tear supplement only may not be adequate. The treatment may require other modalities such as discontinue or change the medications, avoid toxic preservative such as BAK as demonstrated by Konstas,38 use nonpreservative drugs, add some more potent therapy such as nonpreservative steroid to reduce the inflammation, biological substance such as autologous serum which has growth factor39 to promote corneal integrity, or even switch to surgical treatment.

Different types of antiglaucoma medications may affect OSD differently. In this study, patients in beta-blocker monotherapy group had significantly more symptoms than prostaglandin group before the treatment. This finding was consistent with the Monaco study.37 However, OSDI score could be improved in both groups by artificial tears as previously mentioned.

The present randomized and controlled trial demonstrates the benefit of preservative-free artificial tears in a glaucoma patient, to reduce the ocular surface toxicity from glaucoma medication. However, the weakness of this study is the limitation in the number of patients. A larger or multicenter study may confirm the result.

In conclusion, ocular surface collateral damage or preservatives contained in antiglaucoma drugs are now well recognized. This study establishes that the concomitant use of preservative-free artificial tears, especially SH, may be helpful to relieve the patient's discomfort and improve the ocular surface health and could promote a reasonable compliance of the patient to antiglaucoma treatment.

Acknowledgments

The authors are grateful to Assistant Professor Chulaluk Komoltri, DrPH (Biostatistics) and Pimrapat Tengtrakulcharoen, MBH, from the Office for Research and Development, for their assistance with statistical analysis, and to Mathuwan Srikong from the Medical Education Technology Center, Faculty of Medicine Siriraj Hospital, Mahidol University, for preparing the figures.

Author Disclosure Statement

No competing financial interests exist.

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Hydroxypropyl Methylcellulose

Generic name: Hydroxypropyl Methylcellulose [ hye-droks-ee-PROE-pil-meth-il-SEL-yoo-lose ]
Brand names: GenTeal Mild to Moderate, GenTeal Mild, GenTeal Severe, Gonak, Goniosoft, ... show all 15 brands Goniosol, Goniotaire, Goniovisc, ImproVue, Isopto Tears, Natural Balance Tears, Natures Tears, OcuCoat Viscoadherent, Pure & Gentle Lubricant, Systane Overnight Therapy
Drug class: Ophthalmic lubricants and irrigations

Medically reviewed by Drugs.com. Last updated on Jun 23, 2023.

Uses of Hydroxypropyl Methylcellulose:

• It is used to treat dry eyes.
• It is used to treat eye irritation.

What do I need to tell my doctor BEFORE I take Hydroxypropyl Methylcellulose?

• If you are allergic to hydroxypropyl methylcellulose; any part of hydroxypropyl methylcellulose; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take hydroxypropyl methylcellulose with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take Hydroxypropyl Methylcellulose?

• Tell all of your health care providers that you take hydroxypropyl methylcellulose. This includes your doctors, nurses, pharmacists, and dentists.
• Do not take hydroxypropyl methylcellulose by mouth. If hydroxypropyl methylcellulose is put in the mouth or swallowed, call a doctor or poison control center right away.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using hydroxypropyl methylcellulose while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

How is this medicine (Hydroxypropyl Methylcellulose) best taken?

Use hydroxypropyl methylcellulose as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• For the eye only.
• Some of these products are not for use if you are wearing contact lenses. Be sure you know if you need to avoid wearing contact lenses while using this product.
• Do not touch the container tip to the eye, lid, or other skin.
• Put the cap back on after you are done using your dose.
• Wash hands before and after use.
• Tilt your head back and drop drug into the eye.
• After use, keep your eyes closed. Put pressure on the inside corner of the eye. Do this for 1 to 2 minutes. This keeps the drug in your eye.
• Some of these drugs need to be shaken before use. Be sure you know if this product needs to be shaken before using it.
• Do not use if the solution is cloudy, leaking, or has particles.
• Do not use if solution changes color.

What do I do if I miss a dose?

• If you use hydroxypropyl methylcellulose on a regular basis, use a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not use 2 doses or extra doses.
• Many times hydroxypropyl methylcellulose is used on an as needed basis. Do not use more often than told by the doctor.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Change in eyesight, eye pain, or very bad eye irritation.

What are some other side effects of Hydroxypropyl Methylcellulose?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-332-1088. You may also report side effects at https://www.fda.gov/medwatch.

If OVERDOSE is suspected:

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

How do I store and/or throw out Hydroxypropyl Methylcellulose?

• Store at room temperature.
• Be sure you know how long you can store hydroxypropyl methylcellulose before you need to throw it away.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

Consumer Information Use and Disclaimer

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about hydroxypropyl methylcellulose, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

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