Efficacy of Bromfenac Sodium Ophthalmic Solution for Treatment of Dry Eye Disease

Transcription

1 ORIGINAL CLINICAL STUDY Efficacy of Bromfenac Sodium Ophthalmic Solution for Treatment of Dry Eye Disease Hiroshi Fujishima, MD,* Miki Fuseya, MD,Þ Masarou Ogata, MD,Þ and Dogru Murat, MD, PhDþ Purpose: To evaluate the efficacy of bromfenac sodium ophthalmic solution (BF) in patients with dry eye disease (DED) inadequately controlled by monotherapy with artificial tears (ATs). Design: An investigator-oriented trial with a single-arm, nonrandomized, open-label design. Methods: Twenty-six patients, who showed no symptomatic improvement of DED after 1 month of AT treatment, were enrolled. Bromfenac sodium ophthalmic solution was administered adjunctively with AT for 1 month. The BF treatment was then discontinued, and AT treatment alone was continued for 3 months. The signs and symptoms were evaluated at the beginning of BF treatment (Pre), at the end of the combined BF and AT treatment (BF1M), and at 1 and 3 months after discontinuation of BF treatment (Po1M and Po3M, respectively). Results: The dryness scores at BF1M were significantly improved compared with Pre (P G 0.001) and significantly superior to Po3M (P G 0.001). No significant changes in the Schirmer scores were observed throughout the treatment period. The tear film breakup time was significantly improved at BF1M (4.4 T 2.3 seconds) compared with Pre (2.8 T 1.8 seconds; P G 0.001). Superficial punctate keratopathy showed significant improvements in the total score of area and density at BF1M compared with Pre (P G 0.001). However, these parameters had significantly worsened at Po3M compared with BF1M. No adverse events were observed. Conclusions: Bromfenac sodium ophthalmic solution has improved the dryness of the eye and signs of DED through its anti-inflammatory effects. Nonsteroidal anti-inflammatory drugs were suitable as anti-inflammatory ophthalmic solutions for patients with DED. Key Words: bromfenac sodium, dry eye disease, artificial tears, combined therapy (Asia Pac J Ophthalmol 2015;4: 9Y13) It has been reported that inflammatory cell infiltration and increased proinflammatory cytokines are well established in the conjunctiva of patients with severe dry eye disease (DED). 1 Dry eye disease is characterized by chronic dryness of the cornea and conjunctiva, 2 and patients with DED typically show symptoms of ocular discomfort, ranging from irritation to severe pain. Currently, administration of artificial tears (ATs) is the most common therapy available for lubricating a dry ocular surface. However, this palliative treatment provides only temporary and incomplete symptomatic relief and does not address the cause of From the *Department of Ophthalmology, Tsurumi University School of Dental Medicine, Kanagawa; and Department of Ophthalmology, Tokyo Saiseikai Central Hospital; and J&J Ocular Surface and Visual Optics Department, Keio University School of Medicine, Tokyo, Japan. Received for publication May 28, 2013; accepted December 13, The authors have no funding or conflicts of interest to declare. Reprints: Hiroshi Fujishima, MD, Department of Ophthalmology, Tsurumi University School of Dental Medicine, Tsurumi, Tsurumi-ku, Yokohama , Japan. fujishima117@gmail.com. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: DOI: /APO the symptoms, which may include immune-mediated inflammation of the ocular surface. Ophthalmic solutions of anti-inflammatory agents, such as steroids, cyclosporine, and nonsteroidal antiinflammatory drugs (NSAIDs), are expected to be effective for the disease. 3Y8 Inflammation was included in the new definition of dry eye given by the International Dry Eye Workshop. 9 Inflammatory mediators in the dry eye tear film are potential targets for molecules such as NSAIDs with lower adverse effects than topical corticosteroids. Bromfenac, an NSAID, has anti-inflammatory activity that is thought to be mediated by its ability to block prostaglandin (PG) synthesis through inhibition of cyclooxygenases (COXs), an important group of enzymes active in the inflammatory process that catalyze the biosynthesis of eicosanoids from arachidonic acid to produce PGs and thromboxanes. 10 Bromfenac sodium ophthalmic solution (BF) is a stronger COX-2 inhibitor than other NSAIDs such as diclofenac. 11 COX-2 is often induced at sites of inflammation. Animal models have shown that COX-2 is the primary mediator of ocular inflammation. 12 Therefore, COX-2 inhibition is thought to be the most important therapeutic mechanism of ophthalmic NSAIDs. Bromfenac sodium ophthalmic solution has been shown to be the most potent ophthalmic NSAID for inhibiting COX-2 enzyme activity 13 and was found to be approximately 32 times more active against COX-2 than COX-1 in a rabbit model and 18 times more potent than ketorolac for inhibiting COX Twice-daily administration of BF shows excellent anti-inflammatory effects and good tolerability. Based on these findings, the clinical efficacy of BF was evaluated in patients with DED inadequately controlled by monotherapy with AT. There are some limited reports on NSAID application for dry eyeylike symptoms. Avisar et al 15 reported the administration of diclofenac eye drops to patients with filamentary keratitis and showed improvements in subjective symptoms including itching, ocular pain, and foreign-body sensation. However, Aragona et al 16 suggested that corneal problems arising from topical treatment with NSAIDs should be of concern in patients with Sjögren syndrome, although their subjective symptoms were improved by NSAIDs. In fact, we were unable to find any reports describing the effects of NSAIDs on mild to moderate dry eyes, which are frequently encountered in routine medical practice. The cited reports strongly suggest that topical treatment with NSAIDs should be effective for the improvement of dry eye symptoms, as long as the severity of the corneal problems is mild. At this time, we planned a clinical study in patients with mild to moderate DED to evaluate the efficacy and safety of BF with a twice-a-day dosage regimen. MATERIALS AND METHODS This study was an investigator-oriented trial with a singlearm, nonrandomized, open-label design. Before conduction of the study, the internal review board of Tokyo Saiseikai Central Hospital (Tokyo, Japan) evaluated and approved the study protocol. All procedures were conducted in accordance with the principles of the Declaration of Helsinki. Asia-Pacific Journal of Ophthalmology & Volume 4, Number 1, January/February

2 Fujishima et al Asia-Pacific Journal of Ophthalmology & Volume 4, Number 1, January/February 2015 FIGURE 1. Flowchart showing enrolment and the study methodology. Pre, at the beginning of BF treatment; BF1M, at the end of the combined BF and AT treatment for 1 month; Po1M, at 1 month after discontinuation of BF treatment; Po3M, at 3 months after discontinuation of BF treatment. The main inclusion criteria were (1) tear film breakup time (BUT) of 5 seconds or less or Schirmer I test measurement of 5 mm or less; (2) patients who had or were suspected to have DED with a subjective symptom (dryness of eyes); and (3) no symptomatic improvement after 1 month of AT treatment or longer (Soft Santear [Santen pharmaceutical, Japan], a widely used benzalkonium-free product in Japan). The main exclusion criteria were (1) severe DEDs such as Sjögren syndrome; (2) symptoms of allergic conjunctivitis in the last 1 year; (3) apparent eye diseases other than DED; (4) treatment history of systemic drugs or ophthalmic solutions including corticosteroids, NSAIDs, anticholinergics, or immunosuppressants that may possibly affect the efficacy assessment of BF; (5) pregnant or possibly pregnant women; (6) patients who had worn or wished to wear contact lenses during the study period; (7) patients who worked in an environment where they were exposed to and affected by exhaust gases; (8) smokers; and (9) patients who could not explain their symptoms. Bromfenac sodium ophthalmic solution (Bronuck; 0.1% solution; Senju Pharmaceutical, Osaka, Japan) was administered to both eyes (twice a day: morning and evening) for 1 month adjunctively with AT in patients who had shown no improvement in their DED symptoms after use of AT (Soft Santear; 4 times a day [morning, noon, evening, and bedtime]) for 1 month. Treatment with BF was discontinued to evaluate the efficacy, and treatment with AT alone was continued for 3 months (Fig. 1). The evaluation points were at the beginning of BF treatment (baseline; Pre), at the end of the combined BF and AT treatment (BF1M) and at 1 and 3 months after discontinuation of BF treatment (Po1M and Po3M, respectively). Dryness, a subjective symptom, was assessed using 5 grades (0: none, 1: mild, 2: moderate, 3: severe, 4: very severe). Corneal staining with 1% fluorescein sodium (AD. classification), 17 measurements of BUT, and tear function testing with the Schirmer I test were performed to evaluate the objective symptoms. A patient questionnaire, comprising a newly designed dry eye questionnaire 18 on a scale from 0 to 4 (0: very good, 1: good, 2: unchanged, 3: dryness not severe enough to interfere with daily life, 4: severe dryness interferes with daily life), was performed as an overall evaluation. Dry eye questionnaire was utilized instead of OSDI. RESULTS Because this study was a single-arm, open-label design, it was an investigator-oriented study, and it was very difficult to prepare a placebo for BF because of the color of the solution and the container preparation, as well as financial conditions. A total of 72 patients were enrolled in the study. Of these, 26 patients showed no symptomatic improvement of their DED within the last 1 month of AT treatment. All of the nonimproved patients (3 men, 23 women; mean age, 67.5 T 11.9 years) were administered AT 4 times a day plus BF twice a day for 1 month and subsequently administered AT alone for 3 months. The dryness scores were evaluated in the 26 patients at Pre, BF1M, Po1M, and Po3M (Fig. 2). In the baseline scores at Pre, the most frequent score was 3: severe (11/26 patients, 42.3%) as the median and 75th percentile, followed by 2: moderate (7/26 patients, 26.9%) as the 25th percentile. No patients had a score of 0: none, and 4 patients (15.4%) had a score of 4: very severe. At BF1M, the most frequent score was 1: mild (11/26 patients, 42.3%) as the median and 25th percentile, followed by 2: moderate (8/26 patients, 30.8%) as the 75th percentile. No patients had a score of 4: very severe, whereas 5 (19.2%) of 26 patients had a score of 0: none. At Po1M, the most frequent score was 1: mild (10/26 patients, 38.5%) including the median (the 50th percentile), followed by 0: none (7/26 patients, 26.9%) including the 25th percentile. No patients had a score of 4: very severe, but 4 patients had a score of 3: severe. At Po3M, the most frequent score had shifted to 3: severe (11/26 patients, 42.3%) including the 75th percentile, followed by 2: moderate (10/26 patients, 38.5%) including the median and 25th percentile. Statistical comparisons among the evaluation points by the Wilcoxon matched-pairs signedrank sum test revealed that the scores were significantly improved at BF1M compared with Pre (P G 0.001), and because the scores at BF1M did not differ greatly from those at Po1M (P = 0.875), they were significantly superior to Po3M (P G 0.001). There was no significant difference between Pre and Po3M. The Schirmer scores were evaluated in the 26 patients at Pre, BF1M, Po1M, and Po3M (Fig. 3A). While no significant changes were observed throughout the treatment period by the paired t test (BF1M vs Pre: P = 0.294, Po1M vs BF1M: P = 0.805, Po3M vs BF1M: P = 0.337), the scores tended to decrease monotonically during the study period. This trend of the score changes was not attuned to that of the dryness scores. FIGURE 2. Patient symptoms (dryness of eye). Dryness score significantly improved at BF1M compared with those at Pre, but was significantly worsened at Po3M compared with BF1M (P G 0.001, respectively). Pre, at the beginning of BF treatment; BF1M, at the end of the combined BF and AT treatment for 1 month; Po1M, at 1 month after discontinuation of BF treatment; Po3M, at 3 months after discontinuation of BF treatment * 2014 Asia Pacific Academy of Ophthalmology

3 Asia-Pacific Journal of Ophthalmology & Volume 4, Number 1, January/February 2015 Efficacy of Bromfenac for Dry Eye Disease the Wilcoxon matched-pairs signed-rank sum test showed significant improvements in the total score of area and density at BF1M compared with Pre (P G 0.001) and significant worsening at Po3M compared with BF1M (P G 0.001). There was no significant difference between Pre and Po3M. This trend of the score changes was attuned to that of the dryness scores. Reflecting these results, the overall evaluations by the patient questionnaire were assessed in the 26 patients at Pre, BF1M, Po1M, and Po3M (Fig. 5). The scores were significantly improved at BF1M compared with Pre (P = 0.005), but significantly worsened at Po3M compared with BF1M (P G 0.001). There was no significant difference between Pre and Po3M. The trend of the score changes was comparable to that of the dryness scores. Regarding safety, no adverse events were observed, and no patients with immature termination caused by drug reactions were reported. FIGURE 3. A, Schirmer test results (mean T SD). There were no significant changes in Schirmer scores throughout the entire treatment period. Pre, at the beginning of BF treatment; BF1M, at the end of the combined BF and AT treatment for 1 month; Po1M, at 1 month after discontinuation of BF treatment; Po3M, at 3 months after discontinuation of BF treatment. B, The tear film BUT results (mean T SD). Breakup time significantly improved at BF1M compared with those at Pre, but was significantly worsened at Po3M compared with BF1M (P G 0.001, respectively). Pre, at the beginning of bromfenac (BF) treatment; BF1M, at the end of the combined BF and AT treatment for 1 month; Po1M, at 1 month after discontinuation of BF treatment; Po3M, at 3 months after discontinuation of BF treatment. The BUT values were evaluated in the 26 patients at Pre, BF1M, Po1M, and Po3M (Fig. 3B). The BUT was significantly improved at BF1M (mean T SD: 4.4 T 2.3 seconds) compared with Pre (2.8 T 1.8 seconds; P G 0.001), but significantly worsened at Po3M (2.9 T 1.2 seconds) compared with BF1M (P G 0.001). There was no significant difference between Pre and Po3M, and this trend of the score changes was attuned to that of the dryness scores. Evaluation of superficial punctate keratopathy (SPK) in the 26 patients at Pre, BF1M, Po1M, and Po3M showed similar results (Fig. 4). In the baseline scores at Pre, the most frequent score was score 2 (14/26 patients, 53.8%) including the median and 25th percentile. Two patients (7.7%) had the worst score of score 6. At BF1M, the most frequent score was score 0 (14/26 patients, 53.8%) including the median and 25th percentile dominantly, followed by score 2 (8/26 patients, 30.8%) including the 75th percentile. No patients had the worst score of score 6. At Po1M, the most frequent score was score 2 (13/26 patients, 50.0%) including the median, followed by score 0 (9/26 patients, 34.6%) including the 25th percentile. No patients had worse scores than score 3. Apparently, SPK showed the most improvement at Po1M. At Po3M, the most frequent score had shifted to score 2 (15/26 patients, 57.7%) including the median and 25th percentile dominantly. Statistical comparisons among the evaluation points by DISCUSSION COX inhibitors can improve conjunctival inflammations induced by dry eye, with subsequent improvement in BUT accompanied by recovery of goblet cells. Nonsteroidal antiinflammatory drugs act by inhibiting COXs, 19 of which COX- 1 responds acutely to direct mechanical stimuli in the eyes, and COX-2 is associated with eye pain caused by moderate to severe inflammation and chemical burns. 20 COX-1 and COX-2 have been cloned and characterized. 21,22 Their activities and expressions are differentially regulated, and they can function independently within the same cell type. 23 COX-1 is important for homeostatic functions, and COX-2 is often induced at sites of inflammation. The anti-inflammatory effects of NSAIDs are produced by inhibition of COX-2, whereas their adverse effects are induced by inhibition of COX-1. 24,25 A desirable COX-2/ COX-1 inhibitory activity ratio is expected to have stronger anti-inflammatory effects and fewer adverse effects than a low COX-2/COX-1 inhibitory ratio. COX-2Yselective inhibitors in medical practice can lead to better treatments. Because BF has a strong COX-2 inhibitory action with a weak COX-1 inhibitory action, 14 it is applicable to the treatment of various mild to severe inflammation of the eyes and disorders involving eye pain. Studies evaluating the pharmacokinetic profile of topical BF 0.09% revealed a maximum concentration of 95.3 ng/g in the aqueous humor after instillation of a single dose in rabbits. 26 FIGURE 4. Results of the evaluation for the SPK [area score + density score (AD score)]. AD score significantly improved at BF1M compared with those at Pre (P G 0.001), but was significantly worsened at Po3M compared with BF1M (P G 0.001).Pre,atthe beginning of BF treatment; BF1M, at the end of the combined BF and AT treatment for 1 month; Po1M, at 1 month after discontinuation of BF treatment; Po3M, at 3 months after discontinuation of BF treatment. * 2014 Asia Pacific Academy of Ophthalmology 11

4 Fujishima et al Asia-Pacific Journal of Ophthalmology & Volume 4, Number 1, January/February 2015 FIGURE 5. Overall evaluation by patient questionnaire. Overall evaluation score significantly improved at BF1M compared with those at Pre (P = 0.005), but was significantly worsened at Po3M compared with BF1M (P G 0.001). Pre, at the beginning of BF treatment; BF1M, at the end of the combined BF and AT treatment for 1 month; Po1M, at 1 month after discontinuation of BF treatment; Po3M, at 3 months after discontinuation of BF treatment. The half-life was 2.2 hours, but the drug remained detectable at 24 hours. 26,27 Human studies revealed that the drug concentration required to reduce human COX-2 activity to half-maximal (IC 50 ) was achieved after administration of a single dose of BF, 28 and the BF concentration in the aqueous humor of patients undergoing cataract surgery after instillation of 1 drop of BF at 12 hours before surgery was in excess of the IC 50 value for COX-2, but not the IC 50 value for COX Quite a few clinical cases of DED show no improvements in symptoms with the use of AT, and it is supposed that these cases arise through not only tear fluid reduction, but also inflammatory effects. In this study, the efficacy of BF was evaluated in patients with mild to moderate DED inadequately controlled by the use of AT for 1 month, using a combined treatment of BF and AT. Comparisons of the improvements in DED achieved via the anti-inflammatory effects of BF between combined treatment with BF and AT and subsequent treatment with AT alone showed significant improvements in the dryness score, BUT, and SPK at BF1M, but not in the Schirmer score. Corneal sensitivity was also evaluated in some patients, and no changes were observed during the study period. We believe that these effects were induced not only by increasing the amount of eye drops, but also by the anti-inflammatory action of BF. In our study, significant improvements were observed in the dryness scores, an important index of subjective symptoms, as well as in BUT and SPK, although there was no improvement in the Schirmer score. Interestingly, the trend of the changes in the Schirmer scores was quite different from those of the other parameters, but the reason for the discrepancy remains to be clarified. The improvements were brought about by a sequence of events following administration of BF. The conjunctiva can return to a healthy condition through the anti-inflammatory effects of BF (blocking of PG production) such that the production of mucin can return to normal, and finally the corneal epithelium findings and subjective symptoms (dryness scores) improved. In addition, significant improvements were maintained at Po1M, but not at Po3M, where the symptoms returned to baseline. Although we did not prepare any control groups in the study, the Po3M conditions with AT monotherapy had completely returned to the baseline Pre conditions, thereby indicating the adequacy of our study design. Moreover, the price of drug is a key factor in the selection of eye drops for DED. For example, cyclosporines are especially expensive but have similar effects to the costeffective BF on DED. Therefore, NSAIDs are more accessible and better suited anti-inflammatory ophthalmic solutions than steroids or cyclosporine. Corneal disorders, such as corneal ulcers, are occasionally reported as adverse drug reactions with use of ophthalmic NSAID solutions 30,31,32 and are often observed when corneal epithelium disorders are severe. Treatment of corneal epithelium disorders with NSAIDs is quite effective, 20 owing to the improved BUT in corneal epithelium disorder patients with persistent, but relatively mild, inflammation, similar to the patients enrolled in this study. Liu et al. 33 reported that a topical NSAID (pranoprofen 0.1%) significantly improved the ocular signs and symptoms of DED patients. Furthermore, Li et al. 34 demonstrated that topical pranoprofen is effective for management of chronic allergic conjunctivitis. However, further studies are required to determine whether long-term administration is appropriate. 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