アレルギー性結膜疾患診療ガイドライン作成委員会：アレルギー性結膜疾患診療ガイドライン（第3版）．⽇眼会誌125（8）741－785、2021.
秦野 寛： 眼脂を見分ける、眼科診療クオリファイ2 結膜炎オールラウンド（大橋裕一 編）、 6-9 ,中山書店、東京 2010.
高村悦子：内科学（第11版）、朝倉書店、東京 2017.
高村悦子：抗アレルギー点眼薬（Ⅳ 治療総論・内科的治療 C薬剤処方） 眼科学 第3版（大鹿哲郎、園田康平、近藤峰生、稲谷大編集） p.1032-1036, 文光堂、東京、2020.
Etsuko Takamura, Keiko Nomura, Hiroshi Fujishima, Kazumi Fukagawa, Yoshiyuki Satake, Yuka Fukada, Mitsuru Sawa, Eiji Uchida
Efficacy of levocabastine hydrochloride ophthalmic suspension in the conjunctival allergen challenge test in Japanese subjects with seasonal allergic conjunctivitis.
Allergol Int. 2006 Jun;55(2):157-65. doi: 10.2332/allergolint.55.157.
Abstract/Text
BACKGROUND: This study was conducted to investigate the efficacy and safety of 0.025% levocabastine hydrochloride in Japanese subjects with seasonal allergic conjunctivitis and its duration of action using the conjunctival allergen challenge (CAC) test.
METHODS: Twenty-four asymptomatic subjects were randomized to instill 0.025% levocabastine ophthalmic suspension in one eye and vehicle in the other eye 10 minutes before the CAC test. Signs and symptoms of allergic conjunctivitis were scored 10, 15, and 25 minutes after the CAC test. The duration of drug effects was also evaluated by allergen rechallenge 4 hours after levocabastine administration. The itching score for each eye as the primary efficacy endpoint was assessed 15 minutes after the CAC test using a 5-point scale.
RESULTS: The mean itching score in the levocabastine-treated group was 0.08 +/- 0.06, which was significantly lower than the mean score of 1.98 +/- 0.16 in the vehicle group (P < 0.0001). The redness and chemosis of the conjunctiva were also improved significantly compared with the vehicle group. Levocabastine showed prolonged efficacy in inhibiting itching (0.42 +/- 0.12 vs 0.94 +/- 0.17, P < 0.0002) and redness (1.04 +/- 0.18 vs 1.42 +/- 0.22, P < 0.01) of the conjunctiva upon the rechallenge test. No significant topical or systemic adverse safety findings were observed in the levocabastine group.
CONCLUSIONS: The results indicate that 0.025% levocabastine ophthalmic suspension is effective and safe in the treatment of allergic conjunctivitis with a duration of action of at least 4 h.
Hiroshi Fujishima, Yuichi Ohashi, Etsuko Takamura
Efficacy of epinastine hydrochloride ophthalmic solution in allergic conjunctivitis by conjunctival cedar pollen allergen challenge.
Ann Allergy Asthma Immunol. 2014 Oct;113(4):476-81. doi: 10.1016/j.anai.2014.07.007. Epub 2014 Aug 20.
Abstract/Text
BACKGROUND: Epinastine hydrochloride is a selective histamine H1 receptor antagonist that also inhibits IgE receptor-mediated histamine release from mast cells.
OBJECTIVE: To show the superiority of epinastine 0.05% ophthalmic solution (epinastine) to placebo ophthalmic solution (placebo) and noninferiority to olopatadine 0.1% ophthalmic solution (olopatadine) for cedar pollen antigen-induced ocular itching and conjunctival hyperemia.
METHODS: The study was conducted in ophthalmologically asymptomatic adult volunteers with seasonal allergic conjunctivitis using a conjunctival allergen challenge test. Subjects were randomized into 3 groups (n = 87) to evaluate superiority to placebo (visits 4 to 6) and 2 groups (n = 86) to evaluate noninferiority to olopatadine (visit 7). At each visit, a single administration of the study medication was instilled at 15 minutes (visit 4), 4 hours (visit 5), 8 hours (visit 6), and 4 hours (visit 7) before the conjunctival allergen challenge test. Ocular itching and conjunctival hyperemia of allergic conjunctivitis were assessed after the conjunctival allergen challenge test.
RESULTS: For the primary end point, epinastine showed superiority to placebo for the inhibition of ocular itching and conjunctival hyperemia induced at 4 hours after the dose (equivalent to 4-times-daily dosing). For the secondary end points, epinastine significantly inhibited itching and conjunctival hyperemia induced at 15 minutes and 8 hours after the dose (equivalent to 2-times-daily dosing) compared with placebo. In addition, epinastine demonstrated noninferiority to olopatadine for ocular itching and conjunctival hyperemia. No adverse drug reactions or serious adverse events were reported throughout the study, indicating that epinastine has a good safety profile.
CONCLUSION: Epinastine is effective and safe for the treatment of allergic conjunctivitis.
TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01363700.
Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
高村悦子ほか：アレルギー性結膜炎の治療―初期療法、季節前投与.アレルギーの臨床 14：650－654、1994.
海老原伸行ほか：季節性アレルギー性結膜炎におけるイブジラスト点眼予防投与の効果．あたらしい眼科20：259－262、2003.
齋藤圭子：アレルギー性結膜炎に対する予防的治療法．あたらしい眼科 17：1199－1204、2000.
深川和己ほか. 季節性アレルギー性結膜炎に対するエピナスチン塩酸塩点眼薬による初期療法の効果．アレルギー・免疫. 22 （9）, 110-120, 2015.
Hiroshi Fujishima, Kazumi Fukagawa, Yoji Takano, Shigeki Okamoto, Yayoi Nakagawa, Eiichi Uchio, Norihiko Yokoi, Atsuki Fukushima, Etsuko Takamura
The early efficacy of topical levocabastine in patients with allergic conjunctivitis.
Allergol Int. 2006 Sep;55(3):301-3. doi: 10.2332/allergolint.55.301.
Abstract/Text
BACKGROUND: We investigated the early efficacy of topical levocabastine, an H(1) histamine-receptor antagonist, in improving the clinical symptoms of allergic conjunctivitis.
METHODS: Thirty-six patients with allergic conjunctivitis were enrolled. One drop of levocabastine was instilled in one eye and one drop of artificial tears in the contralateral eye. Clinical examinations were performed before, and 15 and 30 minutes after instillation. Symptoms of itching and signs of injection were assessed at each time point.
RESULTS: Both levocabastine and artificial tears resulted in a statistically significant reduction in ocular itching. However, levocabastine was significantly more effective.
CONCLUSIONS: Although artificial tears had a positive effect in reducing symptoms of allergic conjunctivitis, by the washing out of allergens, levocabastine was more effective than artificial tears in controlling acute symptoms of allergic conjunctivitis, demonstrating that the selective H1 histamine-receptor antagonist action of levocabastine is rapidly effective in a clinical setting.
福島敦樹ほか：スギ花粉以外の抗原によるアレルギー性結膜炎の薬物療法―ヒスタミンH1受容体拮抗点眼薬とメディエータ―遊離抑制点眼薬の効果についてーあたらしい眼科 22：225－229、2005.
J M Lewis, T Priddy, J Judd, M O Gordon, M A Kass, A E Kolker, B Becker
Intraocular pressure response to topical dexamethasone as a predictor for the development of primary open-angle glaucoma.
Am J Ophthalmol. 1988 Nov 15;106(5):607-12.
Abstract/Text
In a retrospective study we reviewed the records of 788 subjects who had been corticosteroid tested with 0.1% dexamethasone four times daily to one eye for six weeks. All subjects had normal kinetic visual fields and optic nerve heads in both eyes at the time of testing and were followed up for a minimum of five years. Some subjects had normal baseline intraocular pressures whereas others were considered to have ocular hypertension. Of 276 individuals who were high corticosteroid responders (intraocular pressure greater than 31 mm Hg during dexamethasone administration), 36 (13.0%) developed glaucomatous visual field loss during the follow-up period. Only nine of 261 individuals (3.4%) who were intermediate responders (intraocular pressure 20 to 31 mm Hg during dexamethasone administration) and none of 251 individuals who were low responders (intraocular pressure less than 20 mm Hg during dexamethasone administration) developed glaucomatous visual field loss. However, the ability of the intraocular pressure response to dexamethasone to predict the development of glaucomatous visual field loss was not as good as the predictive power of a multivariate model that included patient age, race, baseline intraocular pressure, baseline outflow facility, baseline cup/disk ratio, and systemic hypertension.
M Ohji, S Kinoshita, E Ohmi, Y Kuwayama
Marked intraocular pressure response to instillation of corticosteroids in children.
Am J Ophthalmol. 1991 Oct 15;112(4):450-4.
Abstract/Text
We examined intraocular pressures of patients with strabismus whose eyes were instilled with corticosteroid eyedrops after a strabismus operation. Group A consisted of 11 children under 10 years of age whose eyes were instilled with 0.1% dexamethasone; Group B consisted of nine patients 10 years old or older whose eyes were instilled with 0.1% dexamethasone; and Group C consisted of 13 children under 10 years of age whose eyes were instilled with 0.1% fluorometholone. In Group A, four patients had intraocular pressures greater than 30 mm Hg, five had intraocular pressures from 21 to 30 mm Hg, and two had intraocular pressures under 21 mm Hg one or two weeks postoperatively. The intraocular pressure decreased to less than 21 mm Hg one week after discontinuation of dexamethasone treatment in all nine patients. No patients in Groups B or C had intraocular pressures greater than 20 mm Hg. Our results suggest that marked ocular hypertensive response to 0.1% dexamethasone treatment occurs frequently in children under 10 years of age.
アレルギー性結膜疾患診療ガイドライン編集委員会：アレルギー性結膜疾患診療ガイドライン（第2版）第5章 診断と鑑別診断：日眼会誌 114：847－849、2010.
中川やよい ほか：アレルギー性結膜疾患における結膜分泌物中好酸球陽性率．アレルギーの臨床 16：968－971、1996.
庄司純ほか：アレルギー性結膜疾患診断における自覚症状、他覚所見および涙液総IgE検査キットの有用性の検討．日眼会誌 116：485－493、2012.
J F Elliott, Y Lin, S B Mizel, R C Bleackley, D G Harnish, V Paetkau
Induction of interleukin 2 messenger RNA inhibited by cyclosporin A.
Science. 1984 Dec 21;226(4681):1439-41.
Abstract/Text
Cyclosporin A blocked production of the lymphokine interleukin 2 by activated T lymphocytes. In a human and a murine cell line this inhibition reflected an absence of interleukin 2 messenger RNA. Under conditions in which these cells are normally stimulated to secrete high levels of interleukin 2, they failed to do so in the presence of cyclosporin A. In both cell lines this failure was accompanied by an absence of interleukin 2 messenger accumulation.
Daisuke Shii, Tomoko Oda, Katsuhiko Shinomiya, Osamu Katsuta, Masatsugu Nakamura
Cyclosporine A eye drops inhibit the early-phase reaction in a type-I allergic conjunctivitis model in mice.
J Ocul Pharmacol Ther. 2009 Aug;25(4):321-8. doi: 10.1089/jop.2009.0009.
Abstract/Text
PURPOSE: The effects of cyclosporine A eye drops on the early-phase reaction were investigated in a type-I allergic conjunctivitis model.
METHODS: Mice were actively sensitized with ragweed (RW) absorbed on aluminium hydroxide gel and challenged with RW for 10 days (single challenge model) or 10-14 days (repetitive challenge model) after the first sensitization. For the evaluation of itching, ovalbumin was used as an antigen instead of RW. The effects of cyclosporine A eye drops on increased vascular permeability, mast cell degranulation, and itching were evaluated and compared with those of other anti-allergic eye drops.
RESULTS: In the single challenge model, cyclosporine A eye drops significantly inhibited the increase in vascular permeability and histological evaluations showed suppressed degranulation of mast cells. Disodium cromoglycate (DSCG) eye drops showed only a slight tendency to inhibit the increase in both pathophysiological parameters. Ketotifen or betamethasone eye drops significantly inhibited the increase in vascular permeability. The order of potency in the single challenge model was ketotifen > cyclosporine A > betamethasone. In the repetitive challenge model, cyclosporine A eye drops significantly inhibited the increase in vascular permeability and DSCG eye drops showed only slight inhibition. Ketotifen or betamethasone significantly inhibited the increase in vascular permeability. The order of potency in the repetitive challenge model was cyclosporine A > betamethasone > ketotifen. The effect of cyclosporine A eye drops on the itch-scratch response was studied. Cyclosporine A and DSCG significantly reduced the itch-scratch response in the single and repetitive challenge models; the effect of cyclosporine A in the repetitive challenge model was more potent than in the single challenge model.
CONCLUSIONS: Those results suggest that administration of cyclosporine A eye drops inhibit the early-phase reaction in type-I allergic conjunctivitis, which may be mediated by the suppression of mast cell degranulation. This action of cyclosporine A eye drops may be involved in the therapeutic effect of cyclosporine A on allergic conjunctivitis.
Nobuyuki Ebihara, Yuichi Ohashi, Eiichi Uchio, Shigeki Okamoto, Naoki Kumagai, Jun Shoji, Etsuko Takamura, Yayoi Nakagawa, Kenichi Nanba, Atsuki Fukushima, Hiroshi Fujishima
A large prospective observational study of novel cyclosporine 0.1% aqueous ophthalmic solution in the treatment of severe allergic conjunctivitis.
J Ocul Pharmacol Ther. 2009 Aug;25(4):365-72. doi: 10.1089/jop.2008.0103.
Abstract/Text
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.
高村悦子ほか：春季カタルに対するシクロスポリン点眼液0.1％の全例調査．日眼会誌 115：508－515、2011.
T Kino, H Hatanaka, S Miyata, N Inamura, M Nishiyama, T Yajima, T Goto, M Okuhara, M Kohsaka, H Aoki
FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro.
J Antibiot (Tokyo). 1987 Sep;40(9):1256-65.
Abstract/Text
The immuno-pharmacological profile of a novel immunosuppressive agent, FK-506 produced by a streptomycete, is presented here. We proceeded to test the effect of the agent on various in vitro immune systems. It showed that mixed lymphocyte reaction, cytotoxic T cell generation, the production of T cell-derived soluble mediators such as interleukin 2 (IL-2), interleukin 3 and gamma-interferon and the expression of the IL-2 receptor were suppressed by this agent. The IC50 values of FK-506 and ciclosporin (CS) in all tests were approximately 0.1 nM and 10 nM, respectively. Therefore, the novel agent, FK-506 suppressed in vitro immune systems at about hundred times lower concentration than CS.
Yuichi Ohashi, Nobuyuki Ebihara, Hiroshi Fujishima, Atsuki Fukushima, Naoki Kumagai, Yayoi Nakagawa, Kenichi Namba, Shigeki Okamoto, Jun Shoji, Etsuko Takamura, Kunihiko Hayashi
A randomized, placebo-controlled clinical trial of tacrolimus ophthalmic suspension 0.1% in severe allergic conjunctivitis.
J Ocul Pharmacol Ther. 2010 Apr;26(2):165-74. doi: 10.1089/jop.2009.0087.
Abstract/Text
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.
Dai Miyazaki, Atsuki Fukushima, Yuichi Ohashi, Nobuyuki Ebihara, Eiichi Uchio, Shigeki Okamoto, Jun Shoji, Etsuko Takamura, Yayoi Nakagawa, Kenichi Namba, Hiroshi Fujishima
Steroid-Sparing Effect of 0.1% Tacrolimus Eye Drop for Treatment of Shield Ulcer and Corneal Epitheliopathy in Refractory Allergic Ocular Diseases.
Ophthalmology. 2017 Mar;124(3):287-294. doi: 10.1016/j.ophtha.2016.11.002. Epub 2016 Dec 22.
Abstract/Text
PURPOSE: To evaluate the effects of 0.1% topical tacrolimus alone or in combination with steroids for the treatment of shield ulcers and corneal epitheliopathy in patients with refractory allergic ocular diseases.
DESIGN: Open cohort study.
PARTICIPANTS: Patients with refractory allergic conjunctivitis epitheliopathy, shield ulcers, or corneal plaques (N = 791).
METHODS: The 791 patients were treated with topical tacrolimus alone or in combination with topical or oral steroids. The effectiveness of the treatments was determined by a corneal epitheliopathy score during the 3-month follow-up period. The clinical signs were rated on a 4-grade scale. Corneal epitheliopathy with no corneal staining was graded as 0, and shield ulcers or plaques were graded as 3, the highest grade. The effects of tacrolimus with and without topical steroids on the epitheliopathy scores were assessed after adjustments for the severity of the clinical signs and characteristics.
MAIN OUTCOME MEASURES: Changes in the corneal epitheliopathy score.
RESULTS: Adjusted mean epitheliopathy score at the baseline was 1.73 (95% confidence interval [CI], 1.65-1.81) for patients treated with tacrolimus alone, and this was significantly reduced by -0.93 at 1 month. The reduction of the score by topical and oral steroids was -0.02 for fluorometholone, 0.02 for betamethasone, and -0.02 for oral steroids, and these reductions were not significant compared with the reduction effect of topical tacrolimus alone at -0.93. The 238 patients with shield ulcer (score 3) were analyzed with adjustments, and the mean epitheliopathy score at 1 month was reduced to 1.38 with tacrolimus alone (95% CI, 1.24-1.51), 1.41 (95% CI, 1.26-1.56) with adjuvant fluorometholone, and 1.46 (95% CI, 1.32-1.61) with adjuvant betamethasone. No significant difference was observed in the adjunctive topical steroids. The presence of severe palpebral conjunctival symptoms, including giant papillae, was a significant resisting factor for topical tacrolimus.
CONCLUSIONS: The significant effects of topical tacrolimus alone on shield ulcers and corneal epitheliopathy suggest that it may be used without the need for steroids.
Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
アレルギー性結膜疾患診療ガイドライン編集委員会：アレルギー性結膜疾患診療ガイドライン（第2版）第7章 セルフケア ：日眼会誌 114：850－852、2010.
佐野研二：イオン性素材―何が問題なのか。あたらしい眼科 17：917－921、2000.
