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With the array of dry eye drops currently on the market, it can be confusing and difficult to select the most appropriate drop for the various forms of dry eye.
A universal definition
Many practitioners are familiar with the definition of dry eye developed by the international Dry Eye Workshop (DEWS) report: 'Multi-factorial disease of the tears and ocular surface that results in symptoms and discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.'1
Identification of the underlying cause of dry eye aids in the successful treatment of the disease. However, its multi-factorial nature makes it very complicated for practitioners to identify a single cause in a particular patient. The diagnostic challenge is further increased because no single test can correctly diagnose its various forms. Research suggests surface inflammation has an important role in the pathogenesis of dry eye.2
The multi-factorial nature also means there are numerous contributing factors, many of which are impossible to control. All of these factors add to the vicious cycle of events, which result in dry eye and inflammation of the ocular surface, (Figure 1).3
Typical presentation
Dry eye is either a result of increased evaporation from the tear film or reduced tear secretion. Both produce ocular dryness and hyperosmolarity is believed to be a feature common to all cases of dry eye disease.
Hyperosmolarity stimulates a cascade of inflammatory events in the epithelial surface cells. These inflammatory markers lead to apoptotic death of epithelial cells and goblet cells. This damage occurs because ocular surface cell membranes are permeable. When they are exposed to hyperosmotic tears, water flows out of the cells in an attempt to balance the osmolarity of the intracellular fluid with the osmolarity of the surrounding tears. When this happens, ocular surface cells can become dehydrated which damages the cell membranes, leading to desiccation and death.
The conventional approach
The conventional approach to dry eye treatment is tear supplementation. However, it is of paramount importance to identify any associated lid margin disease and manage this. There is very little benefit to these patients in supplying tear supplementation without also treating the root cause of their dry eye.
Why preservative free?
Most practitioners are aware these days that patients who require regular therapy over prolonged periods of time should be advised about avoiding most of the standard detergent-type preservatives such as benzalkonium chloride (BAK). Studies show the effect of regular use of BAK results in loss of goblet cells.4 These are vital to the production of mucous, the main role of which is to adhere the aqueous phase of the tear film to the epithelial microvilli.
It has also been shown that BAK use, over time, results in loss of cell-to-cell adhesions, the break down of cell walls and encourages inflammation of the conjunctiva.5 With a chronically dry eye, the last thing we want to do is give patients a therapy that has the potential to actually reduce tear quality and cell adhesion. It is also widely accepted that this toxic effect builds up over time.
A novel concept
Spectrum Thea has developed a dry eye drop called Thealoz. Following on from the success of its preservative-free Hyabak, Thealoz also uses Spectrum Thea's Abak system.
The Abak system uses a nozzle with a sterilising and filtering membrane to maintain a sterile solution in the bottle and avoid contamination. The solution remains sterile for up to eight weeks after opening. The bottle produces a metered volume of drop to avoid wastage.
Thealoz uses a novel active ingredient called trehalose. This is a natural disaccharide found in plants and non-mammalian animals and has some interesting properties. It is known to improve the hydration of cells as well as avoiding cell membrane lipid oxidation and protein denaturation under stress conditions.
These protective cellular properties result from anhydrobiosis, which is a resistance to dryness and in nature helps plants to survive in dry conditions, where trehalose is synthesised as a stress responsive factor.
Under stress conditions - in plants, when they are dried - trehalose is synthesised, which protects the cells and prevents denaturation of proteins. This allows the plant to retain its cellular integrity, so when it is re-hydrated the cells remain undamaged.
Trehalose stabilises lipid bilayers in cell membranes by replacing water and forming stable hydrogen bonds between hydroxyl (trehalose) and phosphate (phospholipid) groups. These stabilising groups decrease the water leakage that results from the osmotic gradients that occur due to the hyperosmolarity found in the tears of dry eye sufferers. Preventing this water leakage allows the cell membrane to retain its contents and properties.
Research
Studies conducted on trehalose-treated corneal epithelial cells in culture6 show the protective effect on corneal epithelial cells from desiccation when pre-treated with trehalose, (Figure 2) compared to other drops.
This effect under desiccation is different from the non-specific effect of fluid maintenance and lubrication from components such as hyaluronic acid (HA) and carboxymethylcellulose (CMC). Instead it uniquely promotes cell survival and is considered to have an anti-apoptotic effect on the cell.
Another study7 looked at the potential healing effect of drops by examining improvement in levels of corneal dessication induced by low humidity air velocity (to accelerate evaporation) in mice eyes, to compare the effect of trehalose-treated corneas with corneas treated with either saline or autologus serum every six hours for 14 days.
Trehalose treatment showed significantly less fluorescein staining and apoptosis compared with saline and serum. It is thought it might act as a signalling or regulatory molecule in some cells to suppress multiple types of apoptosis signals. Trehalose treatment showed less improvement in epithelial thickness and goblet cell density compared to autologus serum, but both were significantly better than saline.
A further study8 looked at the responses of 36 patients treated over four weeks with trehalose, compared with four weeks using commercially available hyaluronan or cellulose drops. Tear break-up times (TBUTs) were significantly higher in the trehalose group while fluorescein and rose bengal stain scores were significantly lower. A larger proportion of patients subjectively evaluated trehalose as a better treatment compared to either HA or cellulose.
Application in practice
The clinical data, along with the proposed mechanism of action of the drops, suggests Thealoz protects surface epithelial cells against dessication in the hyperosmotic conditions experienced in dry eyes. It seems to have implications for managing both aqueous-deficient and evaporative dry eye, due to its role in reducing cell dessication.
Having tried Thealoz on a number of my dry eye patients in practice, the initial feedback from patients seems positive. All patients given a trial of the Thealoz drop were suffering from a moderate level of dry eye. Some were existing over-the-counter drop users, and others were new to lubricant drops. All patients felt the drops were very comfortable and a number of existing drop users felt there was much less post-instillation blur with Thealoz.
With the way the active ingredient in Thealoz works, it could achieve an active cellular protection, regardless of the root cause of the dry eye, rather than a simple moisture barrier to the external environment. ?
References
1 The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the international Dry Eye WorkShop, 2007 5 (2):75-92.
2 McCabe E, Narayanan S. Advancements in anti-inflammatory therapy for dry eye syndrome. Optometry, 2009 in press.
3 C Baudoin. Un nouveau schéma pour mieux comprendre les maladies de la surface oculaire. JFO, 2007 30,3,239-246.
4 Malik Y. Kahook and Robert Noecker. Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Advances in Therapy, Volume 25, Number 8, 743-751.
5 Kahook, Malik Y MD, Noecker, Robert J MD, MBA. Comparison of Corneal and Conjunctival Changes After Dosing of Travoprost Preserved With sofZia, Latanoprost With 0.02% Benzalkonium Chloride, and Preservative-free Artificial Tears. Cornea: April 2008 - Volume 27 - Issue 3 - pp 339-343.
6 Matsuo T. Trehalose protects corneal epithelial cells from death by drying.
Br J Ophthalmol, 2001 May85(5):610-612.
7 Chen W, Zhang X, Liu M , Zhang J, Ye Y, Lin Y, Luyckx J, Qu J. Trehalose Protects against Ocular Surface Disorders in Experimental Murine Dry Eye through Suppression of Apoptosis. J Experimental Eye Research, 2009 89, 311-318.
8 Matsuo T. Trehalose versus hyaluronane or cellulose in eyedrops for the treatment of dry eye. Jpn J Ophthalmol, 2004 48 : 321-327.
9 Baudouin C. Un nouveau schema pour mieux comprendre les maladies de la surface oculaire (A new scheme to better understand ocular surface diseases). JFO. 2007 30, 3 239-246.
? Sarah Farrant works in private practice in the South West