Shigeki Okamoto

A Randomized, Placebo-Controlled Clinical Trial of Tacrolimus Ophthalmic Suspension 0.1% in Severe Allergic Conjunctivitis

AIMS To examine the efficacy of tacrolimus ophthalmic suspension 0.1% in treating severe allergic conjunctivitis. METHODS This was a multicenter, randomized, double-masked, placebo-controlled clinical trial. Fifty-six patients with severe allergic conjunctivitis in whom topical antiallergic agents and corticosteroids had been ineffective were randomized to tacrolimus or placebo treatment. Patients were treated either with tacrolimus or placebo twice-daily for 4 weeks. Severity of objective signs in palpebral and bulbar conjunctiva, limbus, and corneal involvement was assessed using 4 grades. Seven subjective symptoms were evaluated by visual analog scale (VAS) assessment. The primary efficacy endpoint was change in the total score of objective signs at the end of treatment. The secondary efficacy endpoints included change in the score for each objective sign and change in the VAS for each subjective symptom. Safety was assessed based on the severity and the incidence of adverse events. RESULTS Mean change from baseline in total score for objective signs was significantly greater in the tacrolimus (-5.6 + or - 5.1) than in the placebo group (-0.1 + or - 4.5; P < 0.001). Tacrolimus significantly improved giant papillae (P = 0.001) and corneal involvement (P = 0.005). Five subjective symptoms (itching, discharge, hyperemia, lacrimation, and foreign body sensation) were significantly better in the tacrolimus than in the placebo group. The most frequent treatment-related adverse event in the tacrolimus group was mild ocular irritation upon topical instillation, which was well-tolerated. CONCLUSION Tacrolimus ophthalmic suspension 0.1% is effective in treating severe allergic conjunctivitis.

A Large Prospective Observational Study of Novel Cyclosporine 0.1% Aqueous Ophthalmic Solution in the Treatment of Severe Allergic Conjunctivitis

PURPOSE To evaluate the effectiveness and safety of a novel cyclosporine 0.1% aqueous ophthalmic solution in a large population with vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). METHODS A prospective observational postmarketing study was initiated in Japan. A total of 594 patients with VKC or AKC were started on this drug within 1 year after market launch (January 2006) and completed a 6-month follow-up. These patients were observed clinically, and subjective ocular symptoms (itching, discharge, tearing, photophobia, foreign body sensation, and pain), objective signs (hyperemia, swelling, follicle, papillae, and giant papillae for the tarsal conjunctiva; hyperemia and edema for the bulbar conjunctiva; Trantas dots and swelling for the limbus; and corneal involvement), and adverse events were recorded. RESULTS All scores for symptoms and signs significantly decreased from Month 1 through Month 6 of treatment in both VKC and AKC. Median total symptom scores at baseline, Month 1, and Month 6 were 6, 2, and 1, respectively, for VKC, and 7, 3, and 2, respectively, for AKC. Similarly, median total sign scores were 12, 7, and 5, respectively, for VKC, and 14, 10, and 7, respectively, for AKC. The percentage of patients able to complete topical cyclosporine 0.1% therapy within 6 months due to alleviation of symptoms was higher for VKC (44.4%) than for AKC (21.9%). In both VKC and AKC, approximately 30% of steroid users were able to discontinue topical steroids. Adverse drug reactions (ADRs) were found in 12.0% of patients, and the most common ADR was eye irritation (4.4%). Infectious corneal complications were observed in five AKC patients, including two cases of bacterial corneal ulcer and three cases of herpetic keratitis; all of these patients were concomitantly using topical steroids. CONCLUSIONS Topical cyclosporine 0.1% is an effective and safe treatment for VKC and AKC.

Tear film stability analysis system: introducing a new application for videokeratography.

Purpose To review our previous studies regarding the development of a tear stability analysis system (TSAS) using videokeratography and the clinical application of TSAS for evaluation of tear film stability in patients subject to laser in situ keratomileusis (LASIK). Methods New software, namely TSAS, was developed for the videokeratography system TMS-2N (topographic modeling system). TSAS automatically captures consecutive corneal surface images every second for 10 seconds. Corneal topographs were analyzed for tear breakup time (TMS-BUT) and tear breakup area (TMS-BUA, the ratio of breakup area to entire color-code area). First, we recruited volunteers to test the sensitivity and specificity of this new system in comparison with the routine method for tear stability analysis, tear film breakup time evaluation by slit-lamp microscope (SLE-BUT), with fluorescence staining. Second, we investigated the practicability of TSAS in dynamic evaluation of tear film stability before and after LASIK. Results TMS-BUT had a positive correlation with SLE-BUT, whereas TMS-BUA showed a negative correlation. Although they showed similar rates of specificity as SLE-BUT, the sensitivity rates of TMS-BUT and TMS-BUA were 97.5% and 95%, respectively, significantly higher than that of SLE-BUT (75%). The study on patients subject to LASIK showed that tear film stability significantly decreased during the early time period following LASIK and resolved at 6 months after surgery. Eyes that had abnormal TSAS evaluation tended to have higher risk of developing superficial punctuate keratitis and dry eye symptoms after LASIK, and their responses to treatment were slow. Conclusions TSAS is a noninvasive and objective method with higher sensitivity for tear film stability analysis than SLE-BUT.

Therapeutic effects of 0.1% tacrolimus eye drops for refractory allergic ocular diseases with proliferative lesion or corneal involvement

Background The objective of this study was to investigate the efficacy of topical 0.1% tacrolimus in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement. Methods This prospective observational study included 1436 patients with refractory allergic conjunctivitis whose condition had responded poorly to conventional antiallergic drugs and/or topical steroids and/or topical cyclosporine. All patients received tacrolimus eye drops twice daily during the study period. Ten clinical signs and six clinical symptoms were rated on a four-grade scale. The primary endpoint was the change from baseline in total clinical signs and symptoms score at the last observation or following 6 months of treatment. Results Total signs and symptoms score significantly decreased after 1 month of treatment (p<0.001). Giant papillae and corneal lesions were also reduced by tacrolimus eye drop use (p<0.001). The drug proved effective in patients whose condition did not respond well to topical cyclosporine therapy. About 50% of all patients using topical steroids were weaned. The most common adverse reaction was a transient burning sensation (3.20%). Conclusions Tacrolimus eye drops are highly effective in treating refractory allergic conjunctivitis with proliferative lesions and/or corneal involvement, and may reduce or replace topical steroid use. Trial registration number UMIN 000008640.

Blood Level of Tacrolimus in Patients with Severe Allergic Conjunctivitis Treated by 0.1% Tacrolimus Ophthalmic Suspension

BACKGROUND To estimate the efficacy and safety of 0.1% tacrolimus ophthalmic suspension based on the blood level of tacrolimus in patients with severe allergic conjunctivitis. METHODS Fifty-two patients in whom topical anti-allergic agents had been ineffective were treated with 0.1% tacrolimus ophthalmic suspension twice daily for 12 weeks. Adverse drug reactions were monitored, as well as ocular symptoms and signs. The blood concentration of tacrolimus was measured before the initiation of treatment and 4 and 12 weeks later. RESULTS About 75% of the patients without concomitant using of tacrolimus ointment had blood levels of tacrolimus below the detection limit of the assay (0.5ng/mL). On the other hand, 71% (week 4) and 57% (week 12) of patients with concomitant using of tacrolimus ointment had blood levels above the detection limit of the assay. However, the maximum blood concentration was less than 2ng/mL. Adverse drug reactions occurred in 16 patients. These were disorders of the eye such as warmness, irritation, and a burning sensation. However, all of the patients could continue treatment with tacrolimus for 12 weeks. There were no serious adverse events such as increased intraocular pressure or ocular infection during the study. All symptoms and signs improved over time. CONCLUSIONS The good safety profile of 0.1% tacrolimus ophthalmic suspension based on the low blood concentration of tacrolimus, coupled with demonstrated efficacy, make it an important tool for treating severe allergic conjunctivitis.

Suppression of experimental immune-mediated blepharoconjunctivitis in Brown Norway rats by topical application of FK506

Abstract.Background: Experimental immune-mediated blepharoconjunctivitis (EC) in Brown Norway (BN) rats, which is inducible by transfer of antigen-specific T cells, is a model for human allergic conjunctivitis. We investigated the possible inhibition of EC in BN rats by topical application of FK506, which is an immunosuppressive agent that mainly targets T cells. Methods: To induce EC by active immunization, ovalbumin (OVA) adsorbed to alum was injected into the hind footpads of BN rats. Three weeks after the initial immunization, rats were challenged with OVA by eye drops. Twenty-four hours later, lids including conjunctivas, lymph nodes (LNs), and sera were harvested for histology or reverse transcriptase PCR, proliferation assays, and measurement of IgE titer, respectively. For passive immunization, rats were intravenously injected with 10 million of in vitro-stimulated OVA-primed LN cells. Four days after the transfer, rats were challenged with OVA and evaluated as above. The rats were divided into two groups. One group received topical FK506 treatment three times per day from 15 to 21 days after active immunization or from 1 to 4 days after transfer. The other group was treated with vehicle as above. Results: FK506 treatment suppressed infiltration of both lymphocytes and eosinophils in the conjunctiva either by active or passive immunization (P<0.002). No differences were noted in antigen-specific cellular and humoral immune responses. Concerning cytokine expression in the conjunctiva, a prominent difference was noted only with IL-4, which was more abundantly detected in the vehicle-treated group. Conclusion: Topical FK506 treatment suppressed EC in BN rats, possibly by inhibition of IL-4 in the conjunctiva.

Comparison of Efficacy of Bromfenac Sodium 0.1% Ophthalmic Solution and Fluorometholone 0.02% Ophthalmic Suspension for the Treatment of Allergic Conjunctivitis

AIMS Bromfenac sodium (BF) 0.1% was compared with fluorometholone (FML) 0.02% for the treatment of seasonal allergic conjunctivitis when concomitantly used with disodium cromoglycate (DSCG) 2.0%. METHODS Eighty-six patients with seasonal allergic conjunctivitis were treated with DSCG four times a day, and BF was concomitantly administered twice a day in one eye and FML was administered four times a day in the contralateral eye for 1 week. Ocular signs were scored on a four-graded severity. Patients recorded symptoms using visual analog scale. Patients were asked which concomitant treatment was more suitable for them and scored global evaluation. RESULTS All subjective symptom scores were decreased in both concomitant treatment groups compared with baseline (P < 0.05). Objective signs were significantly improved with the concomitant use of BF or FML with DSCG (P < 0.05). Neither symptoms nor signs differed significantly between the concomitant use of BF and FML. Fifteen patients selected BF and 29 patients selected FML as the more preferred concomitant eye drops, 42 patients judged no difference in efficacy between the groups. No significant difference was observed in patients global evaluation between the groups. CONCLUSIONS Bromfenac sodium for allergic conjunctivitis was effective, with efficacy equivalent to that of FML when used with DSCG.

Multicentre clinical study of the herpes simplex virus immunochromatographic assay kit for the diagnosis of herpetic epithelial keratitis.

Background/aims The novel immunochromatographic assay (ICGA) kit was recently developed to diagnose herpes simplex virus (HSV) infection. This multicentre study aimed to evaluate the value of the ICGA kit for the diagnosis of herpetic epithelial keratitis by comparing it with immunofluorescence assay (IFA) and real-time PCR. Methods Corneal scrapings were collected from 117 patients, including 77 with herpetic keratitis as their final clinical diagnosis as well as 40 others at 21 facilities. These samples were tested by the ICGA kit, IFA and real-time PCR. Results The positive concordance between final clinical diagnosis and ICGA was 46.7% (35/75 cases) and the negative concordance was 100% (39/39). The positive and negative concordance between real-time PCR and ICGA were 57.4% (35/61 cases) and 100% (53/53), respectively. The positive and negative concordance between IFA and ICGA were 61.1% (22/36 cases) and 83.3% (55/66), respectively. In 92 cases where anti-HSV drugs were not prescribed prior to corneal scraping, the positive and negative concordance between final clinical diagnosis and ICGA were 55.0% (33/60 cases) and 100% (32/32), respectively. Conclusions The ICGA kit has moderate sensitivity and high specificity, indicating clinical utility in the diagnosis of herpetic epithelial keratitis.

The Effect of a Combined Therapy with a Histamine H1 Antagonist and a Chemical Mediator Release Inhibitor on Allergic Conjunctivitis

Purpose: To evaluate the efficacy of a combined therapy with levocabastine hydrochloride ophthalmic suspension and pemirolast potassium ophthalmic solution compared to single therapy with levocabastine hydrochloride ophthalmic suspension alone. Methods: Thirty-two allergic conjunctivitis patients were randomized to combined-treatment (n = 15) or single-treatment groups (n = 17). The improvement of subjective symptoms as well as objective findings were evaluated. Results: The degree of improvement was significantly higher in the combined-treatment group for lacrimation (p = 0.008) among the subjective symptoms, for conjunctival edema (p = 0.030), eyelid edema (p = 0.032) and conjunctival papilla formation(p = 0.040) among the objective findings. Conclusions: Both objective assessments and subjective symptoms of allergic conjunctivitis showed the greatest improvements when patients were treated with combined therapy as compared to single-agent therapy. The enhanced benefits of combined therapy may result from these agents having different mechanisms of action.