JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 30, Number 7, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2013.0248
Effects of Polyquaternium- and BenzalkoniumChloride-Preserved Travoprost on Ocular Surfaces: An Impression Cytology Study Betu¨l _Ilkay Sezgin Akc¸ay,1 Esra Gu¨ney,1 Tahir Kansu Bozkurt,1 Cumhur Selc¸uk Topal,2 ¨ nlu¨1 Ju¨lide Canan Umurhan Akkan,3 and Cihan U
Abstract
Purpose: To compare the toxicity effect of polyquaternium (PQ) and benzalkonium chloride (BAK) preservation of travoprost on the ocular surface. Methods: This prospective study included 44 eyes of 44 patients with newly diagnosed glaucoma. Twenty-two patients used PQ-preserved travoprost (PQ group) and 22 patients used BAK-preserved travoprost (BAK group). To investigate the effect on the ocular surface, conjunctival impression cytology (IC) was performed at baseline and the 1- and 6-month follow-up visits. Additionally, the ocular surface disease index (OSDI) questionnaire, Schirmer I test, and tear break-up time (TBUT) measurement were administered at baseline, and at 1-, 3-, and 6-month follow-up visits. Results: While both groups showed statistically significant IC grade increases at 1 and 6 months when compared with baseline measurements, IC grades were significantly higher for patients using PQ-preserved travoprost compared with patients using BAK-preserved travoprost. The Schirmer I test and TBUT scores were not statistically significant between group 1 and BAK group at baseline and at 1-, 3-, and 6-month visits (P > 0.05). OSDI scores did not statistically differ at baseline and the 1-month measurements between the 2 groups (P > 0.05), but the 3- and 6-month OSDI scores were significantly higher for BAK group (P = 0.001). Differences in OSDI and Schirmer I test scores were statistically significant at 1, 3, and 6 months in both groups as compared with baseline values (P < 0.05). Statistically significant differences in the TBUT scores were seen for both groups at 3 and 6 months, while BAK group, but not PQ group, had insignificant score differences at 1 month as compared with baseline values of PQ group (P = 0.083). Conclusion: PQ-preserved travoprost was found to be safer and better-tolerated than BAK-preserved travoprost. PQ-preserved travoprost provided better ocular surface comfort, and therefore a better patient experience, which would likely result in higher treatment compliance.
Introduction
G
laucoma is the leading cause of irreversible blindness throughout the world and has become the second most common cause of bilateral blindness.1 While medical therapy involving topical eye drops is a mainstay for treating glaucoma patients, this treatment must be continued for the remainder of the patient’s life and can be discontinued because of drug side effects and compliance problems. Drug side effects can be caused by active components or preservatives. Multidose packaging requires the
inclusion of antimicrobial preservatives and most topical antiglaucomatous drugs are preserved with benzalkonium chloride (BAK), which has been reported to be especially toxic to the ocular surface.2–13 BAK is well-documented to decrease tear film stability, increase inflammatory cell infiltration, and induce dry eye, superficial punctate keratitis, blepharitis, and eyelid eczema.8–12 Therefore, reducing BAK exposure in patients who have been using antiglaucoma eye drops over the long term may improve ocular surface health. Travoprost 0.004% ophthalmic solution (Travatan; Alcon, Fort Worth, TX) is one of the most successful intraocular
_ Umraniye Research and Training Hospital, Eye Clinic, Istanbul, Turkey. _ Umraniye Research and Training Hospital, Pathology Clinic, Istanbul, Turkey. 3 _ Department of Ophthalmology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey. 1 2
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EFFECTS OF POLYQUATERNIUM- AND BENZALKONIUM-CHLORIDE-PRESERVED TRAVOPROST
pressure (IOP)–lowering agents, and is therefore frequently prescribed. Travoprost also contains 0.015% BAK. To decrease ocular surface toxicity, travoprost was reformulated with the preservative polyquaternium-1 0.001% (Polyquad, PQ) instead of BAK. PQ is a polymeric quaternary ammonium mixture that has cationic antimicrobial properties and is commonly used in contact lens solutions as well as in artificial tear eye drops.14 In the current study, we compared ocular surface toxicity effects of travoprost containing BAK and PQ using impression cytology (IC) in patients with newly diagnosed glaucoma.
Methods This article describes a prospective, single-masked, single-center clinical study that was reviewed and approved by the institutional ethics committee and conducted in accordance with the Declaration of Helsinki. All participating patients provided written informed consent. Inclusion and exclusion criteria were given in Table 1. Forty-four patients were recruited to the study; 26 (59.09%) were women and 18 (40.91%) were men. The average patient age was 53.55 – 4.10 years (range 47–61 years). Patients were randomly divided into 2 groups. Both groups were identical in terms of gender and age (no significant difference). Twenty-two patients used PQ-preserved travoprost (PQ group) and 22 patients used BAK-preserved travoprost (BAK group). Patients were instructed to use the drops once daily at the same time of the day (8 P.M.). All study participants underwent a detailed ophthalmologic examination that included best-corrected visual acuity, slit-lamp biomicroscopy, IOP measurement with Goldmann applanation tonometry, and funduscopy. The diagnosis of glaucoma was made by experienced glaucoma specialists (B.A. and E.G.) on the basis of the Humphrey Field Analyzer (Humphrey-Zeiss Systems, Dublin, CA) Swedish Interactive Threshold Algorithm (SITA) 30-2 test. To investigate the effect the different travoprost preservatives on the ocular surface, conjunctival IC was performed at baseline and at 1- and 6-month follow-up visits. Schirmer I test, tear break-up time (TBUT) measurement, and ocular surface disease index (OSDI) questionnaire were administered at baseline and at 1-, 3-, and 6-month followup visits.
Impression cytology One drop of local anesthetic proparacaine HCl 0.5% ophthalmic solution (Alcaine; Alcon) was instilled into the eye and excess tear fluid and medication were wiped away. A 4 · 5 mm2 Whatman nitrocellulose filter paper strip was
Table 1.
applied to the superior bulbar conjunctiva and smoothed onto the ocular surface by applying gentle pressure with a Goldmann Applanation Tonometer Headpiece held between the thumb and forefinger by the same investigator (B.A). The paper was allowed to remain in contact with the eye for *5–10 s and then peeled off with forceps. During the contact period it was important that the eyelids be held away from the paper and not allowed to be wetted by tear fluid that might appear as a result of lacrimation stimulation, since undue wetness of the filter paper would produce poor cell yields. The paper was immediately transferred into a well of a 24-well plate containing fixative solution (95% ethanol). The specimens were stained with both Papanicolaou’s modification of Gill’s technique and periodic acid– Schiff method (Fig. 1). The examination was performed according to Nelson’s method15 under a light microscope by C.S.T. (Table 2). At each visit, the same afore mentioned procedure was repeated by the same investigators.
Ocular surface disease index The OSDI includes a 12-item questionnaire, which evaluates ocular complaints and their impact on a patient’s daily life. There are 5 different levels of symptoms that are scored from 0 (none of the time) to 4 (all of the time).16 The OSDI overall score ranges from 0 to 100 with 100 representing the presence of worse OSD and 0 representing absence of a problem. The total OSDI score was calculated as described previously17 as follows: OSDI score ¼ (sum of scores for all questions answered) · 25/total no. of questions answered A score ‡12 was considered as a marker of ocular surface disease.18
Schirmer I test A Schirmer I test was done after a 5-min waiting period following cornea staining evaluation. Schirmer’s test results were obtained at 5 min.
Tear break-up time Following the application of 2 drops of preservative-free 2% sodium fluorescein on the inferior bulbar conjunctiva, the TBUT was measured by a slit-lamp biomicroscope under a standard cobalt blue light between the last complete blink and first appearance of a growing micelle. Three TBUT measurements were obtained for each eye and the average of 3 measurements was used for statistical analysis.
Inclusion and Exclusion Criteria of the Patients
Inclusion criteria Age 18 years or older Diagnosis of open-angle glaucoma without any history of medication within 3 months No use of any other topical medication for the last 1 month IOP ‡ 21 mmHg in at least 1 eye on 2 eligibility visits without any hypotensive agent IOP, intraocular pressure.
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Exclusion criteria Any history or indication of ocular surface diseases Previous ocular surgery history Any systemic disease that may affect ocular surface health Pregnant or nursing females
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and P = 0.510, respectively), but the 3- and 6-month OSDI scores were significantly higher for BAK group (P = 0.001) (Table 3). For both groups, increases in OSDI scores relative to baseline were statistically significant at 1-, 3-, and 6-month follow-ups (PQ group: P = 0.008, P = 0.003, and P = 0.003, respectively; BAK group: P = 0.003, P = 0.003, and P = 0.003, respectively) (Table 4).
Schirmer scores
FIG. 1. Impression cytology (IC) of the conjunctival surface showing reddish pink goblet cells (GCs) and epithelial cells (ECs) ( · 20 periodic acid–Schiff staining). Color images available online at www.liebertpub.com/jop
Statistical analysis For statistical analysis, NCSS (Number Cruncher Statistical System) 2007 and PASS (Power Analysis and Sample Size) 2008 Statistical Software (Kaysville, UT) were used. For data evaluation, determinative statistical methods (mean standard deviation, median), Mann–Whitney U test, Friedman test, and Wilcoxon signed rank test were used. Results were evaluated with a 95% confidence interval and P < 0.05 was considered as significant.
Results IC grades In-group analysis of IC results showed that the IC grades were significantly higher than baseline measurements at 1- and 6month follow-up visits for both groups (PQ group: P = 0.039 and P = 0.004, respectively; BAK group: P = 0.003 and P = 0.003, respectively). When the 2 groups were compared, IC grades were significantly higher for BAK group (P = 0.001) (Fig. 2).
OSDI scores OSDI scores did not differ statistically between the 2 groups at baseline and for 1-month measurements (P = 0.489
Table 2. Grade 0 Grade 1 Grade 2 Grade 3
Schirmer scores were not statistically different between the 2 groups at baseline and at 1-, 3-, and 6-month measurements (P = 0.836, P = 0.301, P = 0.89, and P = 0.067, respectively) (Table 3). A significant decline in Schirmer scores for both groups relative to baseline scores was seen at 1, 3, and 6 months (PQ group: P = 0.011, P = 0.003, and P = 0.002, respectively; BAK group: P = 0.002, P = 0.003, and P = 0.003, respectively) (Table 4).
TBUT scores TBUT scores between the 2 groups did not differ statistically relative to baseline and for the 1-, 3-, and 6-month measurements (P = 0.476, P = 0.075, P = 0.051, and P = 0.142, respectively) (Table 3). A statistically significant decline in TBUT scores relative to the baseline was seen at 3- and 6-month follow-up for PQ group (P = 0.014 and P = 0.004, respectively). For BAK group, decline in TBUT scores was statistically significant at 1-, 3-, and 6-month follow-up (P = 0.024, P = 0.003 and P = 0.003, respectively) (Table 4).
Discussion While preservative-free ophthalmic drugs are known to be much safer and better-tolerated than preserved drugs,9 antimicrobial preservatives are required for most multidose packaging. The present study compared the effect of preservation of travoprost with BAK (most common preservative) and PQ (a more recently used preservative) on the ocular surface and found that PQ-preserved travoprost was safer and better-tolerated than BAK-preserved travoprost. In addition to the IOP-lowering effect of antiglaucomatous agents, for glaucoma management clinicians should take into account the deleterious effects of antiglaucoma drugs on the tear film and ocular surface. Changes in the ocular surface may cause ocular comfort problems that in turn lead to poor compliance. The fact that patients will likely use an
Impression Cytology Grading According to Nelson Classification
Epithelial cells are small and round with cytoplasmic eosinophilic staining. Nuclei are large, basophilic, with a nucleo–cytoplasmic ratio of 1:2. Goblet cells show intense PAS-positive staining with abundant, plump and oval cytoplasm. Epithelial cells are slightly larger and more polygonal and have eosinophilic staining in the cytoplasm. The nucleo–cytoplasmic ratio is 1:3. Goblet cells are decreased in number but maintain their plump oval shape, with intense PAS-positive cytoplasm staining. Epithelial cells are larger and polygonal, and occasionally multinucleated with variable cytoplasmic staining. Goblet cells are markedly decreased in number and are smaller with less-intense PAS-positive staining and poorly defined cellular borders. Epithelial cells are large and polygonal with basophilic staining of the cytoplasm. Nuclei are small, pycnotic, and completely absent in many cells. The nucleo–cytoplasmic ratio is > 1:6. Goblet cells are completely absent.
PAS, periodic acid-Schiff.
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FIG. 2. Comparison of IC grades within and between groups relative to baseline values. PQ, polyquaternium; BAK, benzalkonium chloride.
antiglaucoma drug for the remainder of their life makes the association between drug properties and ocular surface effects even more important. Continuing low-grade inflammation that originates from drug use may cause subsequent damage, including fibrosis and/or scarring, to the ocular surface that may lead to the failure of future surgical interventions such as trabeculectomies.19 BAK toxicity is a well-known side effect
Table 3.
Comparison of Ocular Surface Disease Index, Schirmer I Test, and Tear Break-Up Time Scores Between Groups PQ Group
OSDI (unit) Baseline 1 month 3 months 6 months Schirmer I test (mm) Baseline 1 month 3 months 6 months TBUT(s) Baseline 1 month 3 months 6 months
of topical eye drops.20 Recently, a newer preservative was developed to reduce these toxicity problems: PQ-1.21 Both BAK and PQ are quaternary ammonium compounds that act as surfactants to disrupt bacterial cell membranes and ultimately induce bacterial cell death. Although PQ and BAK are both classified as detergent-type preservatives, compared with BAK, PQ is less likely to cause cytotoxic effects due to its
BAK Group
Mean – SD
Median
Mean – SD
Median
P
7.10 – 0.82 7.40 – 0.77 7.96 – 0.79 10.07 – 1.23
7.10 7.30 8.00 10.00
6.88 – 0.68 7.61 – 0.67 9.76 – 1.10 12.60 – 1.34
7.10 7.60 9.90 12.80
0.489 0.510 0.001** 0.001**
14.00 – 1.00 13.27 – 1.10 12.82 – 1.17 12.55 – 0.82
14.00 13.00 13.00 13.00
13.91 – 1.04 12.73 – 0.90 11.91 – 1.14 11.77 – 1.10
14.00 13.00 12.00 11.00
0.836 0.301 0.089 0.067
14.45 – 0.93 14.18 – 0.75 13.55 – 0.93 12.91 – 0.94
15.00 14.00 13.00 13.00
14.18 – 1.47 13.36 – 1.12 12.55 – 1.13 12.27 – 0.90
14.00 13.00 12.00 12.00
0.476 0.075 0.051 0.142
**, statistically highly significant. BAK, benzalkonium chloride; OSDI, ocular surface disease index; PQ, polyquaternium; SD, standard deviation; TBUT, tear break-up time.
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Table 4. Difference in Ocular Surface Disease Index, Schirmer I Test, and Tear Break-Up Time Scores Relative to Baseline Values for Each Group PQ group
OSDI unit Baseline—1 month Baseline—3 months Baseline—6 months Schirmer I test (mm) Baseline—1 month Baseline—3 months Baseline—6 months TBUT(s) Baseline—1 month Baseline—3 months Baseline—6 months
BAK group
Mean – SD
P
Mean – SD
P
- 0.30 – 0.24 - 0.86 – 0.22 - 2.97 – 0.72
0.008** 0.003** 0.003**
- 0.73 – 0.15 - 2.88 – 1.22 - 5.72 – 1.63
0.003** 0.003** 0.003**
0.73 – 0.65 1.18 – 0.75 1.45 – 0.69
0.011* 0.003** 0.002**
1.18 – 0.40 2.00 – 0.77 2.14 – 0.92
0.002** 0.003** 0.003**
0.27 – 0.14 0.91 – 0.94 1.55 – 0.93
0.083 0.014* 0.004**
0.82 – 0.87 1.64 – 1.03 1.91 – 1.22
0.024* 0.003** 0.003**
*, statistically significant. **, statistically highly significant.
much greater molecular weight and lower capacity to penetrate mammalian cells. Moreover, BAK increases corneal permeability, which significantly increases its cytotoxic effect on cells as compared with PQ.22,23 In concordance with the aforementioned reports, the present study indicates that IC grades were significantly higher at 1- and 6-month follow-up for patients who used BAK-preserved travoprost. On the other hand, no significant difference was observed in Schirmer’s test and TBUT scores between the 2 groups at 1-, 3-, and 6-month visits. However, OSDI scores were found to be significantly higher at 3- and 6-month followup visits for patients treated with BAK-preserved travoprost. In addition, when evaluated separately (in-group analysis), each preservative caused significant goblet cell loss compared with baseline, together with the significant changes seen for Schirmer I, TBUT, and OSDI scores. This reduction in goblet cells may represent an early indication of ocular surface toxicity, which may occur before a patient experiences pain and effects are seen in clinical tests. The only observed difference was for the TBUT score for PQ group at 1-month follow-up visit relative to the baseline, although this difference was statistically insignificant. In support of our data, some authors reported similar results for in vitro studies that evaluated the effects of BAKand/or PQ-preserved medications. Liang et al.24 investigated the toxicological profile of BAK- and PQ-preserved travoprost on rabbit eye and reported that BAK-preserved travoprost induced diffuse conjunctival hyperemia and chemosis with significant total ocular surface toxicity accompanied by a decrease in goblet cell density. Such negative effects were not observed for PQ-preserved travoprost, thus indicating that PQ-travoprost has a greater safety advantage for the ocular surface of patients receiving chronic glaucoma treatment. Brignole-Baudouin et al.14 compared the toxicological profile of PQ-preserved travoprost, BAK-preserved travoprost, and BAK-preserved latanoprost ophthalmic solutions on human conjunctival epithelial cells in vitro and concluded that travoprost PQ produced better cell viability and reduced apoptosis relative to travoprost with BAK. Similarly, Ammar et al.25 evaluated the effect of the BAK-
and PQ-preserved combination glaucoma medications on cultured human ocular surface cells and reported significant in vitro cytotoxicity of BAK toward cultured ocular epithelial cells. Replacement of BAK with PQ yielded a significantly higher percentage of live conjunctival and corneal cells. Aihara et al.26 assessed the long-term effect of BAKfree travoprost on ocular surfaces and IOP in glaucoma patients after they transitioned from latanoprost and found a reduced prevalence of superficial punctate keratopathy and decreased hyperemia with BAK-free travoprost. Gandolfi et al.27 compared travoprost BAK-free formulation preserved with PQ-1 with BAK-preserved travoprost and concluded that travoprost BAK-free safely and effectively lowers IOP in eyes with open-angle glaucoma or ocular hypertension. Paimela et al.28 reported that although PQ-1 was less cytotoxic than BAK, both of the preservatives evoked an inflammatory reaction in human corneal epithelial cells. However, in vitro results have their limitations because the duration of exposure to a drug is continuous in vitro whereas in vivo kinetics are different because the drug is only present for a shorter time. In conclusion, the present study aimed to compare effects of PQ- and BAK-preserved travoprost in newly diagnosed glaucoma patients. PQ-preserved travoprost provides better ocular surface comfort, which would likely translate into better patient experiences and increased treatment compliance. Long-term studies with a greater number of patients will be required to further validate these comparisons in glaucoma patients.
Author Disclosure Statement No competing financial interests exist.
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Received: February 2, 2014 Accepted: April 21, 2014 Address correspondence to: _ Dr. Betu¨l Ilkay Sezgin Akc¸ay Umraniye Research and Training Hospital, Elmalıkent Mahallesi Adem Yavuz Cad. No:1 Umraniye _ Istanbul 34766 Turkey E-mail:
[email protected]