Acupuncture and dry eye: current perspectives. A double-blinded randomized controlled trial and review of the literature.

Purpose: Dry eye disease (DED) is a common disorder that negatively impacts quality of life and vision. Prior studies have shown some benefit of acupuncture for dry eye, but very few have included control group to mitigate placebo effect. This study was designed with a sham acupuncture control group to evaluate true acupuncture treatment effect. Methods: This is a prospective, randomized, double-blinded, sham-acupuncture-controlled trial. Acupuncture treatment for dry eye was performed as per the Niemtzow Protocol. Twenty-four patients received true acupuncture and twenty-five received sham acupuncture. Treatment efficacy was assessed by the Ocular Surface Disease Index (OSDI) Questionnaire, ocular surface staining, tear flow, tear film break-up time (TBUT), and a general questionnaire. Atmospheric data were collected to control for the effect of atmospheric conditions on symptoms of dry eye. Results: OSDI scores in the treatment group improved compared to baseline (1 week, p<0.01, 1 month p<0.05, 3 months p<0.05, and 6 months p<0.01). OSDI scores in the control group improved, but did not reach significance (p=0.09). Secondary outcome measures showed no significant improvement in TBUT, Schiermer's Test, ocular surface grading, or artificial tear application. However, at 3 months, a significant reduction in the frequency of eye closing was observed among participants receiving true acupuncture treatment when compared to baseline (p=0.002). Furthermore, intragroup analysis showed significant reduction in symptoms of discomfort (p=0.01), dryness (p=0.001), scratchiness (p=0.001), and redness (p=0.01) in the true acupuncture group at 3 months. Conclusion: Both true and sham acupuncture improved OSDI at 1 week after treatment, however, the improvement in OSDI was significantly greater in the true treatment groups than the sham group at 6 months after acupuncture. True acupuncture treatment improved many subjective assessments of dry eye symptoms, however, other common indicators used to objectively assess dry eye (tear flow, corneal staining, TBUT) remained unchanged. While there were trends towards improvement in the sham acupuncture group, this did not reach statistical significant during the study period. This suggests a true treatment effect of acupuncture rather than a placebo effect. Acupuncture can, therefore, be an effective adjunct to routine clinical treatment of dry eye.

Effect of loteprednol etabonate 0.5% on initiation of dry eye treatment with topical cyclosporine 0.05%.

OBJECTIVE: The purpose of this work was to evaluate the effect of loteprednol etabonate (LE) before the initiation of topical cyclosporine A (tCsA) therapy in patients with mild-to-moderate dry eye disease. Prospective, multicenter randomized double-masked parallel group clinical study (NCT00407043). METHODS: Hundred and eighteen patients with dry eye disease were randomized to receive either LE and tCsA (n=61) or artificial tears (AT) and tCsA (n=57). Hundred and twelve patients completed the study (LE: n=57, AT: n=55) and are included in the data analysis. Patients self-administered either LE or AT for 2 weeks 4 times per day, followed by tCsA twice per day accompanied by either LE twice per day or AT twice per day for an additional 6 weeks of treatment. Primary outcome measures included the Ocular Surface Disease Index (OSDI) questionnaire, the Likert scale using standardized facial expressions, lissamine green staining, fluorescein staining, and the Schirmer test. Additional measures included global self-assessment, and safety outcomes included slitlamp examination, intraocular pressure, and assessment of visual acuity. RESULTS: Loteprednol etabonate pretreatment significantly reduced tCsA stinging (P<0.05). Both groups showed significantly improved OSDI scores at the 14-, 30-, and 60-day visits. Loteprednol etabonate showed significantly more OSDI improvement than AT. Both pretreatment strategies improved global self-assessment scores, Schirmer test, fluorescein staining, lissamine staining, and adjunctive AT use. Loteprednol etabonate showed superior improvement in Schirmer test, fluorescein staining, and lissamine staining. Intraocular pressure did not increase in either group. CONCLUSIONS: Loteprednol etabonate induction therapy 2 weeks before the initiation of long-term tCsA treatment for chronic dry eye disease provides more rapid relief of dry eye signs and symptoms with greater efficacy than tCsA and AT alone.

Efficacy of a phosphorodiamidate morpholino oligomer antisense compound in the inhibition of corneal transplant rejection in a rat cornea transplant model.

PURPOSE: The cornea is one of the most commonly transplanted tissues. The morpholino-oligomer antisense compound AVI-5126 suppresses expression of proto-oncogene c-myc, a key factor in transplant rejection. AVI-5126 was evaluated in a rat cornea transplant model. METHODS: Donor corneas obtained from August x Copenhagen Irish rats were stored in Optisol™ containing 1.0 or 0.5 mg/mL AVI-5126 or Optisol alone for 24 h before transplant. Recipient Lewis rats were treated topically 3x/d with TobraDex™ and with 1.0 or 0.5 mg/mL of AVI-5126 or saline with daily monitoring for rejection using a modified McDonald-Shadduck Slit Lamp Scale. Using the high-performance liquid chromatography technique, the stability of AVI-5126 (0.5 mg/mL) in Optisol was evaluated for 30 days. AVI-5126 corneal transport was measured using Ussing chamber mounted rabbit corneas. The potential ocular toxicity of AVI-5126 (0.5 mg/mL) was evaluated after 8 days of 3x/d topical application in rats and in-vitro by incubation of human corneas for 8 days. RESULTS: Cornea storage in Optisol containing 1.0 mg/mL AVI-5126 plus post-transplant topical tid AVI-5126 (1.0 mg/mL) application significantly increased graft survival (7.0±1.6 days) versus 5.0±0.8 days for Optisol alone storage plus post-transplant topical tid saline application (P<0.001). After 30 days of storage, no significant degradation of AVI-5126 in Optisol was noted by high-performance liquid chromatography analysis. After 24 h, 5 µg/mL (1% of total dose) crossed the corneas mounted in Ussing chambers. Neither extended topical application of AVI-5126 to rats nor incubation of human corneas in AVI-5126 decreased endothelial cell density. CONCLUSIONS: Graft rejection was significantly delayed after pretransplantation storage of graft corneas in Optisol containing AVI-5126 followed by topical application of AVI-5126 post-transplantation. AVI-5126 was well tolerated, stable, and effectively penetrated the cornea.

Topical loteprednol pretreatment reduces cyclosporine stinging in chronic dry eye disease.

PURPOSE: This retrospective, clinical comparative analysis describes differences in clinical signs and symptoms and medication tolerability between those patients who receive topical corticosteroids prior to initiation of topical cyclosporine 0.5% emulsion (tCSA) therapy for chronic dry eye disease (CDED) and those who received tCSA and were not first induced with corticosteroid drops. tCSA is the only approved medication for CDED. Stinging is the most common side effect of tCSA and reason for tCSA discontinuation. This analysis describes an effective pharmacologic means to reduce tCSA stinging and subsequent discontinuation. METHODS: Thirty-six consecutive patients were initially treated with loteprednol etabonate (LE) 0.5% (Lotemax; Bausch & Lomb) for a period ranging from 2 to 16 months prior to institution of concomitant tCSA (Restasis™; Allergan). Clinical parameters (fluorescein staining, conjunctival redness, tear meniscus) were compared over a period of 6 months to a second cohort of 36 consecutive patients who were initially prescribed continuous tCSA without concomitant LE pretreatment. Patients in the LE pretreatment group discontinued LE after 3-6 months of concomitant therapy while continuing tCSA therapy. RESULTS: Of the 36 LE pretreatment patients, only 2 developed significant stinging (5.5%) and 1 discontinued the use of tCSA because of stinging (2.8%). Of the patients without LE pretreatment, 8 developed stinging (22%) and 3 discontinued tCSA as a result (8.3%). The intergroup P value was significant for severe stinging (<0.02) and for tCSA discontinuation because of severe stinging (<0.04). Patients in the LE pretreatment group had no statistically significant differences in preenrollment disease severity or demographics (P range from 0.19 to 0.59) compared with the group without pretreatment. CONCLUSION: Topical corticosteroid preparation of the ocular surface in CDED with LE induction therapy may reduce discomfort from subsequent long-term maintenance topical medications, particularly tCSA. This analysis describes a readily available induction and maintenance pharmacologic strategy to reduce tCSA stinging and subsequent discontinuation.

Lacritin, a novel human tear glycoprotein, promotes sustained basal tearing and is well tolerated.

PURPOSE: Lacritin is a novel human tear glycoprotein that promotes basal tear peroxidase secretion by rat lacrimal acinar cells in vitro. This study investigates whether lacritin is prosecretory when added topically to the ocular surface of normal living rabbits, and if so, what is its efficacy and tolerability versus cyclosporine and artificial tears. METHODS: Purified recombinant human lacritin (1, 10, 50, or 100 µg/mL), inactive lacritin truncation mutant C-25 (10 µg/mL), cyclosporine (0.05%), or artificial tears were topically administered to eyes of normal New Zealand White rabbits either as a single dose or three times daily for 14 days with monitoring of basal tear production. Basal tearing under proparacaine anesthesia was repeatedly assessed throughout and 1 week after chronic treatment ceased. Eyes were examined weekly by slit-lamp biomicroscopy. RESULTS: Lacritin acutely increased basal tearing to 30% over vehicle at 240 minutes. Three times daily treatment with 10-100 µg/mL lacritin was well tolerated. Basal tearing became progressively elevated 4, 7, and 14 days later and was 50% over baseline (50 µg/mL lacritin) 1 week after treatment had ceased. Cyclosporine elevated tearing to a similar level on days 4 and 7 but had little or no effect on day 14 and had returned to baseline 1 week after ending treatment. C-25 and artificial tears had no effect. CONCLUSIONS: Lacritin acutely stimulates basal tear flow that is sustained for at least 240 minutes. Two weeks of lacritin treatment three times daily was well tolerated and progressively elevated the basal tear flow. One week after treatment ended, basal tearing was still 50% over baseline. In contrast, cyclosporine triggered mild to moderate corneal irritation and a temporary elevation in tearing.

The utility of bedside ultrasound in the detection of a ruptured globe in a porcine model.

BACKGROUND: Recent case reports have shown that ultrasonography can be used to diagnose ocular pathology in an emergency setting. Ultrasound may be especially useful when periorbital edema and pain interfere with the examination of the post-traumatic eye. OBJECTIVE: This study evaluated the ability of emergency physicians to detect a ruptured globe in an ex-vivo porcine model. METHODS: Following a brief training lecture, 15 emergency medicine residents and 4 emergency medicine attending physicians used ultrasonography to evaluate 18 porcine eyes, randomized as normal, ruptured, or completely devoid of vitreous humor. The consequences of ultrasound applanation with this method were evaluated by measuring intraocular pressure changes with and without a 1mm clear plastic shield. RESULTS: Our study participants were able to identify abnormal eyes with a sensitivity of 79% (95% CI 73% to 84%) and a specificity of 51% (95% CI 41% to 61%). Intraocular pressure increased 5% with ultrasound applanation, though with a 1mm thick plastic shield there was no measurable change. CONCLUSIONS: Ultrasound imaging may be a future modality to be used by trained emergency physicians to expedite the identification of a rupture globe, but it is unlikely to replace more definitive imaging techniques. The use of a clear plastic barrier in this porcine model prevents an increase in intra-ocular pressure without affecting image quality, and should be used in any future studies on this method.

Comparison of topical and intravenous administration of WIN 55-212-2 in normotensive rabbits.

OBJECTIVE: This study compares the effect of topical versus intravenous (IV) administration of synthetic WIN 55-212-2 (WIN) or timolol on intraocular pressure (IOP). METHODS: WIN or timolol were administered either topically or by IV in normotensive New Zealand white rabbits. IOP was measured at baseline and 30, 60, and 120 min after administration (n = 4 per group). Blood pressure (BP) and heart rate (HR) were measured concomitantly with IOP. RESULTS: IV administration of 0.1 mg/kg WIN reduced IOP by 30% after 30 min, which continued to decline for up to 120 min. Timolol injection (25 mu g/kg) also reduced IOP by 25% after 30 min but was not sustained. In comparison, both topical WIN (1.0%) and timolol (0.5%) reduced IOP by 20% from baseline after 30 min. IV injection of either WIN or timolol significantly reduced HR to 155.4 +/- 11.4 bpm and 165.9 +/- 11.1 bpm, respectively, from a baseline of 256.3 +/- 9.9 bpm. Topical administration was well tolerated and did not affect behavior, BP, or HR. CONCLUSION: Topical administration of either WIN or timolol did not decrease IOP as much as IV administration, but the lack of systemic or local toxicity could make it the safer alternative.

Topical WIN55212-2 alleviates intraocular hypertension in rats through a CB1 receptor mediated mechanism of action.

INTRODUCTION: Systemically administered cannabinoids can reduce intraocular pressure (IOP), but produce undesirable cardiovascular and central nervous system effects. In a chronic model of ocular hypertension, we examined the efficacy of acute topical administration of WIN55212-2 (WIN) in a novel commercially available vehicle and in combination with timolol. METHODS: IOP was chronically elevated by the surgical ligature of vortex veins in Sprague Dawley rats. IOP was measured by using Goldmann applanation tonometry. IOP, blood pressure (BP), and heart rate (HR) were measured at baseline and 30, 60, 90, and 120 min after the topical administration of WIN 1.0%, 0.25%, 0.06%, or 0.015%, the commercially available vehicle, timolol 0.5%, or a combination of WIN and timolol. SR141716 (CB1 antagonist) or SR144528 (CB2 antagonist) was administered topically 30 min before WIN to determine receptor specificity. To determine ocular and systemic penetration, 3H WIN 55212-2 was administered topically and tissues were collected at 60 and 120 min. Ocular irritation was evaluated by slit-lamp examination (SLE) at baseline and 120 min. RESULTS: WIN significantly decreased IOP in the hypertensive eye, with no BP or HR effects. SR141716 pretreatment significantly inhibited the IOP effects of WIN 1.0% in a dose-dependent manner, while SR 144528 was not as effective. No significant additive effects were observed by combining WIN (0.5% or 1.0%) with timolol 0.5%. WIN was retained in ocular tissue with a t1/2 of 80-100 min. SLE at 120 min revealed no solvent or drug-related toxic effects. CONCLUSIONS: In a chronic ocular hypertensive rat model, topically applied WIN is an effective, nontoxic ocular hypotensive agent with no hemodynamic side-effects. This effect was predominantly CB1 receptor mediated, but some CB2 contribution could not be ruled out.