Ketorolac eye drops reduce inflammation and delay re-epithelization in response to corneal alkali burn in rabbits, without affecting iNOS or MMP-9

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A New Method to Predict the Epidemiology of Fungal Keratitis by Monitoring the Sales Distribution of Antifungal Eye Drops in Brazil

Purpose: Fungi are a major cause of keratitis, although few medications are licensed for their treatment. The aim of this study is to observe the variation in commercialisation of antifungal eye drops, and to predict the seasonal distribution of fungal keratitis in Brazil. Methods: Data from a retrospective study of antifungal eye drops sales from the only pharmaceutical ophthalmologic laboratory, authorized to dispense them in Brazil (Opthalmos) were gathered. These data were correlated with geographic and seasonal distribution of fungal keratitis in Brazil between July 2002 and June 2008. Results: A total of 26,087 antifungal eye drop units were sold, with a mean of 2.3 per patient. There was significant variation in antifungal sales during the year (p < 0.01). A linear regression model displayed a significant association between reduced relative humidity and antifungal drug sales (R-2 = 0.17, p < 0.01). Conclusions: Antifungal eye drops sales suggest that there is a seasonal distribution of fungal keratitis. A possible interpretation is that the third quarter of the year (a period when the climate is drier), when agricultural activity is more intense in Brazil, suggests a correlation with a higher incidence of fungal keratitis. A similar model could be applied to other diseases, that are managed with unique, or few, and monitorable medications to predict epidemiological aspects.

Clinical Treatment of Dry Eye Using 0.03% Tacrolimus Eye Drops

Purpose: To report the clinical outcome of the treatment of dry eyes using 0.03% tacrolimus eye drops (olive oil + tacrolimus 0.03%) (Ophthalmos, Sao Paulo, Brazil). Methods: Sixteen eyes of 8 patients with Sjogren syndrome dry eyes (age, 51.13 +/- 9.45 years) were enrolled in this study (prospective noncontrolled interventional case series). Patients were instructed to use topical 0.03% tacrolimus eye drops twice a day (every 12 hours) in the lower conjunctival sac. Schirmer I test, break-up time, corneal fluorescein, and rose bengal staining score were performed in all patients 1 day before, and 14, 28, and 90 days after treatment with 0.03% tacrolimus eye drops. Results: The average fluorescein staining and rose bengal staining scores improved statistically significantly after 14 days of treatment and improved even more after 28 and 90 days. The average Schirmer I test did not improve statistically significantly after 28 days of treatment, although we did observe a significant improvement after 90 days of treatment with 0.03% tacrolimus eye drops. The average break-up time did not improve statistically after 14 days of treatment, although we observed a significant improvement after 28 and 90 days of treatment with 0.03% tacrolimus eye drops. Conclusions: Topical 0.03% tacrolimus eye drops successfully improved tear stability and ocular surface status in patients with dry eyes.

Controlled transscleral drug delivery formulations to the eye: establishing new concepts and paradigms in ocular anti-inflammatory therapeutics and antibacterial prophylaxis

Importance of the field: The use of topical agents poses unique and challenging hurdles for drug delivery. Topical steroids effectively control ocular inflammation, but are associated with the well-recognized dilemma of patient compliance. Although administration of topical antimicrobials as prophylaxis is acceptable among ophthalmologists, this common practice has no sound evidence base Developing a new antimicrobial agent or delivery strategy with enhanced penetration by considering the anatomical and physiological constraints exerted by the barriers of the eye is not a commonly perceived strategy. Exploiting the permeability of the sclera, subconjunctival routes may offer a promising alternative for enhanced drug delivery and tissue targeting.Area covered in this review: Ocular drug delivery strategies were reviewed for ocular inflammation and infections clinically adopted for newer class of antimicrobials, which use a multipronged approach to limit risks of endophthalmitis.What the reader will gain: The analysis substantiates a new transscleral drug delivery therapeutic approach for cataract surgery.Take home message: A new anti-inflammatory and anti-infective paradigm that frees the patient from the nuisance of topical therapeutics is introduced, opening a large investigative avenue for future improved therapies.

Management of dry eye in UK pharmacies

Purpose - To investigate the ability of pharmacy staff in the United Kingdom (UK) to diagnose and treat dry eye. Methods - A mystery shopper technique to simulate a patient with presumed dry eye was used in 50 pharmacy practices in major towns and cities across the UK. Pharmacies were unaware of their involvement in the study. With the exception of a predetermined opening statement to initiate the consultation, no further information was volunteered. Questions asked, diagnoses given, management strategy advised and staff type was recorded immediately after the consultation. Results - The mean number of questions was 4.5 (SD 1.7; range 1–10). The most common question was the duration of symptoms (56%) and the least common was whether the patient had a history of headaches (2%). All pharmacy staff gave a diagnosis, but the majority were incorrect (58%), with only 42% correctly identifying dry eye. Treatment was advised by 92% of pharmacy staff, with the remaining 8% advising referral directly to the patient's GP or optometrist. Dry eye treatments involved topical ocular lubrication via eye drops (90%) and lipid based sprays (10%). However, only 10% gave administration advice, 10% gave dosage advice, 9% asked about contact lens wear, and none offered follow up although 15% also advised GP or optometrist referral. Conclusions - There is a need for improved ophthalmological training amongst pharmacists and pharmacy staff and establishment of cross referral relationships between pharmacies and optometry practices.

What is the optimum artificial treament for dry eye?

Dry eye disease is a common clinical condition whose aetiology and management challenges clinicians and researchers alike. Practitioners have a number of dry eye tests available to clinically assess dry eye disease, in order to treat their patients effectively and successfully. This thesis set out to determine the most relevant and successful key tests for dry eye disease diagnosis/ management. There has been very little research on determining the most effective treatment options for these patients; therefore a randomised controlled study was conducted in order to see how different artificial treatments perform compared to each other, whether the preferred treatment could have been predicted from their ocular clinical assessment, and if the preferred treatment subjectively related to the greatest improvement in ocular physiology and tear film stability. This research has found: 1. From the plethora of ocular the tear tests available to utilise in clinical practice, the tear stability tests as measured by the non-invasive tear break (NITBUT) up time and invasive tear break up time (NaFL TBUT) are strongly correlated. The tear volume tests are also related as measured by the phenol red thread (PRT) and tear meniscus height (TMH). Lid Parallel Conjunctival Folds (LIPCOF) and conjunctival staining are significantly correlated to one another. Symptomology and osmolarity were also found to be important tests in order to assess for dry eye. 2. Artificial tear supplements do work for ocular comfort, as well as the ocular surface as observed by conjunctival staining and the reduction LIPCOF. There is no strong evidence of one type of artificial tear supplement being more effective than others, and the data suggest that these improvements are more due to the time than the specific drops. 3. When trying to predict patient preference for artificial tears from baseline measurements, the individual category of artificial tear supplements appeared to have an improvement in at least 1 tear metric. Undoubtedly, from the study the patients preferred artificial tear supplements’ were rated much higher than the other three drops used in the study and their subjective responses were statistically significant than the signs. 4. Patients are also willing to pay for a community dry eye service in their area of £17. In conclusion, the dry eye tests conducted in the study correlate with one another and with the symptoms reported by the patient. Artificial tears do make a difference objectively as well as subjectively. There is no optimum artificial treatment for dry eye, however regular consistent use of artificial eye drops will improve the ocular surface.

The effect of ocular surface conditions on blink rate and completeness

A healthy human would be expected to show periodic blinks, making a brief closure of the eyelids. Most blinks are spontaneous, occurring regularly with no external stimulus. However a reflex blink can occur in response to external stimuli such as a bright light, a sudden loud noise, or an object approaching toward the eyes. A voluntary or forced blink is another type of blink in which the person deliberately closes the eyes and the lower eyelid raises to meet the upper eyelid. A complete blink, in which the upper eyelid touches the lower eyelid, contributes to the health of ocular surface by providing a fresh layer of tears as well as maintaining optical integrity by providing a smooth tear film over the cornea. The rate of blinking and its completeness vary depending on the task undertaken during blink assessment, the direction of gaze, the emotional state of the subjects and the method under which the blink was measured. It is also well known that wearing contact lenses (both rigid and soft lenses) can induce significant changes in blink rate and completeness. It is been established that efficient blinking plays an important role in ocular surface health during contact lens wear and for improving contact lens performance and comfort. Inefficient blinking during contact lens wear may be related to a low blink rate or incomplete blinking and can often be a reason for dry eye symptoms or ocular surface staining. It has previously been shown that upward gaze can affect blink rate, causing it to become faster. In the first experiment, it was decided to expand on previous studies in this area by examining the effect of various gaze directions (i.e. upward gaze, primary gaze, downward gaze and lateral gaze) as well as head angle (recumbent position) on normal subjects’ blink rate and completeness through the use of filming with a high-speed camera. The results of this experiment showed that as the open palpebral aperture (and exposed ocular surface area) increased from downward gaze to upward gaze, the number of blinks significantly increased (p<0.04). Also, the size of closed palpebral aperture significantly increased from downward gaze to upward gaze (p<0.005). A weak positive correlation (R² = 0.18) between the blink rate and ocular surface area was found in this study. Also, it was found that the subjects showed 81% complete blinks, 19% incomplete blinks and 2% of twitch blinks in primary gaze, consistent with previous studies. The difference in the percentage of incomplete blinks between upward gaze and downward gaze was significant (p<0.004), showing more incomplete blinks in upward gaze. The findings of this experiment suggest that while blink rate becomes slower in downward gaze, the completeness of blinking is typically better, thereby potentially reducing the risk of tear instability. On the other hand, in upward gaze while the completeness of blinking becomes worse, this is potentially offset by increased blink frequency. In addition, blink rate and completeness were not affected by lateral gaze or head angle, possibly because these conditions have similar size of the open palpebral aperture compared with primary gaze. In the second experiment, an investigation into the changes in blink rate and completeness was carried out in primary gaze and downward gaze with soft and rigid contact lenses in unadapted wearers. Not surprisingly, rigid lens wear caused a significant increase in the blink rate in both primary (p<0.001) and downward gaze (p<0.02). After fitting rigid contact lenses, the closed palpebral aperture (blink completeness) did not show any changes but the open palpebral aperture showed a significant narrowing (p<0.04). This might occur from the subjects’ attempt to avoid interaction between the upper eyelid and the edge of the lens to minimize discomfort. After applying topical anaesthetic eye drops in the eye fitted with rigid lenses, the increased blink rate dropped to values similar to that before lens insertion and the open palpebral aperture returned to baseline values, suggesting that corneal and/or lid margin sensitivity was mediating the increased blink rate and narrowed palpebral aperture. We also investigated the changes in the blink rate and completeness with soft contact lenses including a soft sphere, double slab-off toric design and periballast toric design. Soft contact lenses did not cause any significant changes in the blink rate, closed palpebral aperture, open palpebral aperture and the percentage of incomplete blinks in either primary gaze or downward gaze. After applying anaesthetic eye drops, the blink rate reduced in both primary gaze and downward gaze, however this difference was not statistically significant. The size of the closed palpebral aperture and open palpebral aperture did not show any significant changes after applying anaesthetic eye drops. However it should be noted that the effects of rigid and soft contact lenses that we observed in these studies were only the immediate reaction to contact lenses and in the longer term, it is likely that these responses will vary as the eye adapts to the presence of the lenses.

Standardised antibacterial Manuka honey in the management of persistent post-operative corneal oedema: A case series

Background Corneal oedema is a common post-operative problem that delays or prevents visual recovery from ocular surgery. Honey is a supersaturated solution of sugars with an acidic pH, high osmolarity and low water content. These characteristics inhibit the growth of micro-organisms, reduce oedema and promote epithelialisation. This clinical case series describes the use of a regulatory approved Leptospermum species honey ophthalmic product, in the management of post-operative corneal oedema and bullous keratopathy. Methods A retrospective review of 18 consecutive cases (30 eyes) with corneal oedema persisting beyond one month after single or multiple ocular surgical procedures (phacoemulsification cataract surgery and additional procedures) treated with Optimel Antibacterial Manuka Eye Drops twice to three times daily as an adjunctive therapy to conventional topical management with corticosteroid, aqueous suppressants, hypertonic sodium chloride five per cent, eyelid hygiene and artificial tears. Visual acuity and central corneal thickness were measured before and at the conclusion of Optimel treatment. Results A temporary reduction in corneal epithelial oedema lasting up to several hours was observed after the initial Optimel instillation and was associated with a reduction in central corneal thickness, resolution of epithelial microcysts, collapse of epithelial bullae, improved corneal clarity, improved visualisation of the intraocular structures and improved visual acuity. Additionally, with chronic use, reduction in punctate epitheliopathy, reduction in central corneal thickness and improvement in visual acuity were achieved. Temporary stinging after Optimel instillation was experienced. No adverse infectious or inflammatory events occurred during treatment with Optimel. Conclusions Optimel was a safe and effective adjunctive therapeutic strategy in the management of persistent post-operative corneal oedema and warrants further investigation in clinical trials.

Expression of cytochrome P450 enzymes and metabolism of timolol in human ocular tissue

Glaucoma is a group of progressive optic neuropathies causing irreversible blindness if not diagnosed and treated in the early state of progression. Disease is often, but not always, associated with increased intraocular pressure (IOP), which is also the most important risk factor for glaucoma. Ophthlamic timolol preparations have been used for decades to lower increased intraocular pressure (IOP). Timolol is locally well tolerated but may cause e.g. cardiovascular and pulmonary adverse effects due to systemic absorption. It has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. However, only limited information is available on timolol metabolism in the liver or especially in the human eye. The aim of this work was to investigate metabolism of timolol in human liver and human ocular tissues. The expression of drug metabolizing cytochrome P450 (CYP) enzymes in the human ciliary epithelial cells was studied. The metabolism of timolol and the interaction potential of timolol with other commercially available medicines were investigated in vitro using different liver preparations. The absorption of timolol to the aqueous humor from two commercially available products: 0.1% eye gel and 0.5% eye drops and the presence of timolol metabolites in the aqueous humor were investigated in a clinical trial. Timolol was confirmed to be metabolized mainly by CYP2D6 as previously suggested. Potent CYP2D6 inhibitors especially fluoxetine, paroxetine and quinidine inhibited the metabolism of timolol. The inhibition may be of clinical significance in patients using ophthalmic timolol products. CYP1A1 and CYP1B1 mRNAs were expressed in the human ciliary epithelial cells. CYP1B1 was also expressed at protein level and the expression was strongly induced by a known potent CYP1B1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The CYP1B1 induction is suggested to be mediated by aryl hydrocarbon receptor (AHR). Low levels of CYP2D6 mRNA splice variants were expressed in the human ciliary epithelial cells and very low levels of timolol metabolites were detected in the human aqueous humor. It seems that negligible amount of CYP2D6 protein is expressed in the human ocular tissues. Timolol 0.1% eye gel leads to aqueous humor concentration high enough to achieve therapeutic effect. Inter-individual variation in concentrations is low and intraocular as well as systemic safety can be increased when using this product with lower timolol concentration instead of timolol 0.5% eye drops.

Stir bar sorptive extraction of diclofenac from liquid formulations: A proof of concept study

A new stir bar sorptive extraction (SBSE) technique coupled with HPLC-UV method for quantification of diclofenac in pharmaceutical formulations has been developed and validated as a proof of concept study. Commercially available polydimethylsiloxane stir bars (Twister (TM)) were used for method development and SBSE extraction (pH, phase ratio, stirring speed, temperature, ionic strength and time) and liquid desorption (solvents, desorption method, stirring time etc) procedures were optimised. The method was validated as per ICH guidelines and was successfully applied for the estimation of diclofenac from three liquid formulations viz. Voltarol (R) Optha single dose eye drops, Voltarol (R) Ophtha multidose eye drops and Voltarol (R) ampoules. The developed method was found to be linear (r=0.9999) over 100-2000 ng/ml concentration range with acceptable accuracy and precision (tested over three QC concentrations). The SBSE extraction recovery of the diclofenac was found to be 70% and the LOD and LOQ of the validated method were found to be 16.06 and 48.68 ng/ml, respectively. Furthermore, a forced degradation study of a diclofenac formulation leading to the formation of structurally similar cyclic impurity (indolinone) was carried out. The developed extraction method showed comparable results to that of the reference method, i.e. method was capable of selectively extracting the indolinone and diclofenac from the liquid matrix. Data on inter and intra stir bar accuracy and precision further confirmed robustness of the method, supporting the multiple re-use of the stir bars. (C) 2010 Elsevier B.V. All rights reserved.

Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial

Background
Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo.

Methods
In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0·005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140.

Findings
We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19·6 mm Hg (SD 4·6) in 258 patients in the latanoprost group and 20·1 mm Hg (4·8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3·8 mm Hg (4·0) in 231 patients assessed in the latanoprost group and 0·9 mm Hg (3·8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0·44 (95% CI 0·28–0·69; p=0·0003). We noted 18 serious adverse events, none attributable to the study drug.

Interpretation
This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period