Dry Eye Therapy Research Articles

Challenges and Pitfalls in Clinical Trials of Treatments for Dry Eye

Clinical trials to evaluate the effectiveness of therapy for dry eye disease are challenging because of the nature of the disease, the multiple palliative methods used by patients to control their symptoms, and the potential limitations of the techniques available to evaluate therapeutic outcomes. This review identifies some of the pitfalls encountered in recent clinical trials in dry eye disease. The peculiarities of dry eye disease with respect to symptoms, signs, and pathophysiological changes are discussed. Potential problems that apply to all clinical trials, including patient selection, randomization in small populations, and assessment of the placebo effect, are presented with respect to dry eye clinical trials. Considerations regarding study design address inclusion/exclusion criteria and selection of outcome measures. Special attention is given to methods of symptom analysis, techniques of staining of the ocular surface, and grading systems for surface staining. Alternative methods to the standard clinical trial are mentioned to place them in perspective for overall evaluation of dry eye disease therapy. Finally, caveats are provided to encourage investigators to vigorously conduct future clinical trials in dry eye therapy.

Anti-inflammatory Therapy of Dry Eye

As tear secretion and tear clearance decrease in the dry eye, an inflammatory response is initiated on the ocular surface that appears to involve both soluble and cellular mediators. Although the traditional approach to treating dry eye is to hydrate and lubricate the ocular surface with artificial tears, symptoms and/or sight-threatening corneal disease may persist in some patients on such aqueous enhancement therapies. In these patients, treatment with anti-inflammatory agents, such as cyclosporin A, corticosteroids, tetracyclines, or autologous serum, may be considered. Results of studies investigating the use of these agents are discussed. During treatment, patients should be conscientiously monitored for adverse effects.

Diquafosol: DE 089, diquafosol tetrasodium, INS 365, INS 365 Ophthalmic, INS 365 Respiratory, KPY 998.

Diquafosol [INS 365, KPY 998, diquafosol tetrasodium, DE 089, INS 365 Respiratory, INS 365 Ophthalmic] is a mucolytic compound that stimulates mucociliary clearance and also hydrates the mucosal surface of the lung. It is an activator of the P2Y2 receptor, which appears to be a key regulator of mucociliary clearance. Unlike the earlier P2Y2 receptor agonists such as uridine 5'-triphosphate, diquafosol is very stable chemically and does not require refrigeration or special handling. This makes diquafosol suitable for the treatment of chronic conditions. Diquafosol was originally developed at the University of North Carolina in the US. In September 2003, the US FDA announced that it accepted Inspire Pharmaceuticals' NDA filing for diquafosol tetrasodium ophthalmic solution for the treatment of dry eye. Additionally, FDA has completed a preliminary review of the NDA and issued the Filing Review Letter stating that no potential filing review issues were found during the review period. Inspire Pharmaceuticals' NDA for diquafosol has been granted priority review status, with initial FDA action expected at a target of 6 months after NDA submission. The first launch of diquafosol could potentially occur in the first quarter of 2004. Previously in January 2002, preliminary results from one of the US trials (study 104) revealed that the primary efficacy objectives of the study were not met. Data were re-evaluated and resubmitted in March 2002. Inspire Pharmaceuticals received a milestone payment from Allergan, which was not dependent on the study outcome, following the completion of study 104 and the submission of these study data. Phase II trials of diquafosol for dry eye are being conducted in Japan by Santen Pharmaceuticals. Santen projects that the compound will be launched in Japan during 2008-9. Phase I trials are also being conducted in the UK. Diquafosol eye drops activate P2Y2 receptors on the surface of the eye and inner eyelids, enhancing the natural process of tear secretion. Stimulation of tear secretion with diquafosol causes the release of salt, water, mucin and other components of the tear film, resulting in hydration of the surface of the eye. As there are no approved pharmacological therapies for dry eye, diquafosol is a potential breakthrough treatment for this disorder.

Outcome of Punctal Plug Occlusion Therapy for Severe Dry Eye Syndrome

Punctal occlusion using a silicone plug is one way of treating tear-deficient dry eye and it has been reported to be effective. We studied the outcome of punctal plug occlusion therapy for severe dry eye syndrome at our dry eye clinic. Subjects were 76 eyes of 51 patients [6 eyes of 5 males, 70 eyes of 46 females, mean age: 58.6 +/- 13.4 (mean +/- standard deviation), 49 eyes of 30 patients with Sjögren's syndrome, 27 eyes of 21 patients without Sjögren's syndrome] with severe tear-deficient dry eye who underwent punctal occlusion using a silicone plug (Punctal plug, FCI Co. Ltd, France) during the period of Nov. 1996 to Mar. 2000 at our dry eye clinic. They were under observation for 632 +/- 405 days (mean +/- standard deviation). We studied if there is difference in tolerance between the sizes of punctal plug, compared epithelial damage before and after plug insertion, and studied relief in symptoms using self-assessment. In tolerance of punctal plugs, 55.9% of all plugs were lost during our follow up, but there was no difference in time to loss between the sizes. Epithelial damage was reduced (p < 0.001). Dryness was the most reduced symptom: 26 patients (79%) got better, and only epiphora was increased, with 12 patients (36%) complaining slightly. Punctal plug occlusion therapy for tear-deficient dry eye is conclusively very effective.

Serum- and serum deprivation-induced transcriptional profiles of cultured conjunctival epithelial cells.

Severe dry eye is caused not only by the dryness of the ocular surface, but also by lack of tear components, which are essential to maintain the ocular surface.1 Artificial tears are useful as a therapy for dry eye, but the efficiency of artificial tears is not comparable to human tears. We have used autologous serum as a substitute for tears in severe dry eye patients, and have observed dramatic improvements to the ocular surface.2 This serum effect suggests that serum includes similar components to tearsKeywordsHerpes ZosterOcular SurfaceAmniotic MembraneLacrimal GlandSecretory Leukocyte Protease InhibitorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The now and future therapy of the non-Sjögren's dry eye.

The National Eye Institute/Industry Workshop Classification for Dry Eye was developed to coordinate clinical research in dry eye, but also provides a framework to consider the various therapeutic options for managing dry eye disease.1 This classification differentiates between evaporative and tear-deficient dry eye, although it is important to recognize that both mechanisms for development of dry eye may occur in any given patient. Traditional therapy for the dry eye has concentrated on tear replacement with a variety of topical solutions. As our understanding of the structure and function of the tearfilm has improved, so has our knowledge of the important interactions this tearfilm has with the eyelid and the ocular surface.2 We are able to appreciate the variety of ocular conditions that can produce or aggravate dry eye, and with this appreciation we can develop a practical strategy for its management.3 This discussion proposes some therapeutic principles for the treatment of dry eye, and summarizes the things we presently do to treat dry eye, and then identifies new strategies that should soon be available for dry eye therapy. An important caveat before any treatment is employed, however, is that the patient must be fully educated as to the nature and characteristics of his/her dry eye disorder in order to assure understanding of the goals of therapy and to stimulate compliance with the recommended treatment.KeywordsOcular SurfaceLacrimal GlandTreatment PrincipleMeibomian GlandOcular Surface DiseaseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Ocular surface cooling in dry eye — a pilot study

Infrared thermography was employed to measure the change in ocular surface temperature on eye opening within agroup of 11 dry-eye patients and seven control subjects. Qualitatively, the colour coded thermograms were found to be disorganised and irregular in the dry-eye group. Quantitatively, the decrease in temperature was found to be much more rapid in the dry-eye group (0.88 ± 0.23°C in 7s) compared with the control group (0.21 ± 0.27°C) (P<0.0001). This faster rate of cooling can be explained in terms of a greater evaporation rate and the increased ocular surface temperature on eye opening in a dry eye. This observation, if confirmed on a larger study group, potentially offers a new, objective, non-invasive system for analysis of the tear-film and dry-eye therapies.

The tear film in rheumatoid arthritis

Summary Dry eye (keratoconjunctivitis sicca, KCS) is thought to develop in approximately 10% of rheumatoid arthritic patients with the most severe examples being found in patients with Sjogren's syndrome (KCS, xerostomia and connective tissue disease). Dry eye is present to a lesser but significant extent in patients with rheumatoid arthritis not associated with Sjogren's syndrome and in a mild form in the ageing population. Diagnosis of dry eye depends on obtaining a careful clinical history from the patient and performing various clinical tests of tear function. Tear physiology in rheumatoid arthritis has received little attention in the literature. The aim of this study was to investigate differences in basic tear physiology between rheumatoid arthritic patients with and without the association of Sjogren's syndrome by evaluating tear production, stability, evaporation and osmolarity in order to gain more knowledge into the regulatory mechanism of the lacrimal apparatus in these conditions. This study could also prove useful in the long-term development and evaluation of therapies for dry eye. Tear production was assessed using Schirmer tear test strips. The Keeler Tearscope™ allowed observation of the lipid layer and evaluation of the non-invasive tear break-up time. A modified Servomed evaporimeter provided recordings of the tear evaporation rate and osmolarity was determined by the freezing point depression method. Rheumatoid arthritic patients with (n = 30) and without (n = 17) the association of Sjogren's syndrome were selected from those attending a rheumatology outpatient clinic. The same set of tests was performed on 25 age- and sex-matched normals. Diagnosis of dry eye for the purpose of this study was based on symptomatic evaluation and on ocular surface staining after instillation of rose bengal eye drops as determined by an independent observer. Results showed that there is a significantly greater degree of corneal and conjunctival staining in the Sjogren's group compared with the rheumatoid arthritic subjects without Sjogren's syndrome (P 0.05), but is significantly reduced in those with Sjogren's syndrome (P < 0.05). Tear evaporation and osmolality were found to increase significantly in both rheumatoid arthritic groups compared with normals (P < 0.05) but there was no significant difference between those with and without Sjogren's syndrome (P < 0.05). An abnormal coloured fringe pattern was detected in no normals, in 10% of subjects with rheumatoid arthritis alone and in 40% of those with Sjogren's syndrome. A mechanism for the development of dry eye in the rheumatoid arthritic subjects without Sjogren's syndrome is proposed. Reduced integrity of the lipid layer does not inhibit evaporation of the aqueous layer of the tears. This increased evaporation rate leads to increased tonicity of the tears and is though to play a role in the damage to the ocular surface.

New Approaches to Dry-Eye Therapy

New Approaches to Dry-Eye Therapy

Survey of optometric opinion on dry eye topics

Optometrists attending conferences in Australia and the USA were surveyed to syndiesise clinical expertise on dry eye topics. Most respondents estimated the prevalence of dry eye in their practice to be two per cent or higher. Significandy higher estimates were obtained from respondents practicing in dry or high altitude environments. Symptoms of sandy/gritty or burning eyes were rated as valuable in diagnosing dry eye. Vital staining and breakup time tests were considered to have the highest diagnostic value of 14 specific procedures, followed by slitlamp signs, while the Schirmer and other special tests achieved the lowest ratings. Preferred treatments were artificial tears, ointments and, in the USA group, punctal closure. Implicit in the survey results were:(i) a requirement for reliable clinical diagnostic tests to offset practitioner reliance on symptomatology; and (ii) the need for Australian practitioners to consider temporary punctal occlusion for dry eye therapy.