Based on a lecture given before the Annual Meeting of AAO. Published in Contact Lens Spectrum, May, 1990. Reprinted in other journals.

Introduction

  Tear film abnormalities characterizing a dry eye state invariably lead to surface epithelial damage.¹ Such a surface damage, however, can also directly result from systemic diseases or excessive contact lens wear.² No matter what its cause, the affected ocular surface will adversely influence the tear film stability. Hence, cellular surface damage can be secondary to tear film abnormality, such as in the classical dry eye, and vice versa, a pathological ocular surface can adversely affect tear film stability, a condition that may be called a secondary dry eye. Both types of cases are characterized by an abnormal tear film and damaged ocular surface epithelium (Figure 1). Hence, it may be hard to assess whether the initial cause is pathological tear film instability that can be caused by several factors or primary ocular surface disease that again can result from various causes. The end result is epithelial damage that can be assessed by vital staining.

There is more than academic interest to such a distinction based on different mechanisms. This argument basically boils down to the adage: "what came first, the hen or the egg?" The difference is subtle but it could influence the type of treatment the patient receives.

If tear film instability is the primary cause of the "dry eye state", then artificial tears used in the treatment should enhance tear film stability by biophysical means such as increased wetting and the dehydration of the affected tissue. The obstruction of the puncta, especially in case of low tear volume, would also be indicated. The re-established continuous tear film then would create the milieu for the maintenance of a normal epithelial surface.

However, if the surface epitheliopathy is the primary event, then the topically used drops should be able to heal the surface epithelium, possibly by the virtue of their nutrient content or other biochemically active component. Over the healed surface, then, a continuous tear film would form. Hence, the biophysical factors in such a case would only play a role in the maintenance of a stable tear film.

Artificial Tears

The mainstay of "dry eyes" and, in a broader sense, ocular surface disease, has been traditionally the topical use of artificial tear formulations.³ Generally speaking, such tear substitutes consist of electrolytes at either isotonic or hypotonic levels, water-soluble polymers to increase viscosity, and preservatives if the tear substitute is packaged in multi-dose units. Quite recently, tear substitutes containing nutrients have become commercially available. Some of these preparations also contain polymers for purposes other than that of viscosity enhancement.⁴

 Effect on Tear Film Stability

It has been known for more than two decades that tear film instability in the eye is related to wetting, i.e. the inability of the tears to completely wet the ocular surface.⁵ Despite this fact, most of the commercial tear substitutes are unable to form a continuous film over a hydrophobic surface.⁶

Compromised Epithelial Integrity

In ocular surface disease the corneal epithelium often becomes waterlogged (microcystic edema). This condition not only affects its barrier properties but also interferes with its adherence to the underlying basement membrane.⁷ Hypertonic salt solutions are not effective in remedying this situation as the epithelium becomes quite leaky to electrolytes. On the other hand, high colloidal osmolality, i.e. high oncotic pressure will dehydrate such tissue provided that the magnitude of the pressure is higher than the imbibition pressure of the deturgescent stroma.⁸

NUTRIENTS IN THE TREATMENT OF OCULAR SURFACE DISEASE

 Topically Applied Vitamin A

The role and possible efficacy of vitamin A in eye drops have been very much in the news in the last five years and as a result, this topic is quite controversial. It has been shown that normal tears contain certain forms of vitamin A which are solubilized by a protein carrier namely the prealbumin factor.⁹ It has also been suggested that certain forms of vitamin A, specifically trans-retinoic acid and retinyl palmitate have a healing effect on ocular surface disease especially if squamos metaplasia is present.¹⁰ On the other hand, vitamin A used excessively is known to cause dry eye conditions. Such a side effect of Accutane®, an oral medication containing tretinoin and used for the treatment of acne vulgaris is well known.
 

The positive effect of vitamin C in alkali burns of the eye has been demonstrated by several authors but some questions still remain.¹¹ At least one author suggests that vitamin B₆ may also have beneficial effects on the eye.¹²

  Vitamin B₁₂ and the Eye
 

Vitamin B₁₂-containing eye drop has become commercially available only in the last few months.¹³ The role of this nutrient is not well know, especially in the eye, so that it should be discussed in more detail (Table I).

  Table I.

Role of vitamin B₁₂ in the Eye

Vitamin B₁₂ is an essential product for mammalian life and cannot be synthesized by the body. Its role in pernicious anemia is well known.¹⁴ It is less known that this vitamin appears to play an indispensable role in the growth of the epithelial cells especially of the mucous membranes. Hence, vitamin B₁₂ may be considered vital for the maintenance of healthy ocular surface.^15,16

  Vitamin B₁₂ is a vital co-enzyme in the production of DNA from RNA and is therefore an essential component for normal cell growth and division.¹⁷ This vitamin also helps to maintain one of the body's vital antioxidant systems, i.e. glutathione. This system protects cells from damaging oxidative free radicals.¹⁸ Since this protective system has been identified in the eye we may assume that vitamin B₁₂ is also involved in protecting ocular tissues.

Laboratory tests in rabbits have shown that local application of vitamin B₁₂ solution more than triples the rate of healing of the cornea.¹⁹ There is some evidence to suggest that the eye's normal requirement for vitamin B₁₂ is provided via the tears. This nutrient binds to certain tear proteins to a larger extent than to either proteins in the saliva or gastric juice.^20,21

  The ability to absorb vitamin B₁₂ is reduced with aging and thus local supplementation may be desirable.²²

  Direct topical application of vitamin B₁₂ to the eye thus may be useful in replacing locally low levels of the vitamin in tear film deficiency, in eyes stressed by atmospheric conditions, intense and prolonged stare (e.g. computer screen, excessive T.V. viewing), or contact lens wear, and may offer an effective way of ameliorating these conditions and of re-vitalizing the exposed ocular tissues.

Lacrophilic Artificial Tears

  There are several commercially available eye drops that are able to wet hydrophobic surfaces, have high oncotic pressure and/or contain nutrients which thus are expected to be efficacious and may be called lacrophilic. We shall briefly discuss these products according to their features.

Elevated Oncotic Pressure/Complete Wetting

  The magnitude of the oncotic pressure of various, commercially available, artificial tear substitutes have been directly measured by the means of a Wescor Colloid Osmometer.⁸ One artificial tear, Hypotears® [IOLAB Pharmaceuticals], appeared to create an initial oncotic pressure high enough to supersede the imbibition pressure of the deturgescent corneal stroma. The authors⁸ assigned the exceptional patient acceptance and apparent efficacy of HypoTears® to its high oncotic pressure even though the relatively low polymeric content of the formulation should not result such a high oncotic pressure at a thermodynamic equilibrium.

Since then, another artificial tear formulation, formulated for the primary dry eye, has been introduced to the market. Dwelle® [Aqueous Pharma] is an artificial tear that has unique wetting properties and a high enough polymer concentration to create a thermodynamically stable high oncotic pressure (65mmHg). The formulation contains three different polymers. Two polymers form a synergistic mixture that is capable of wetting even an intensely hydrophobic surface. The third polymer is present at a high concentration.

In a double-blind cross-over clinical trial against Tears Naturale® [Alcon Laboratories],⁴ Dwelle® has healed the ocular surface in twice as many patients as the control drop. In an open clinical trial involving a large number of patients, two-thirds of all patients treated with Dwelle® demonstrated complete healing of the epithelium. The remaining one-third also showed a significant decrease in Rose Bengal staining after two to four weeks of treatment.⁴ The patients also noticed that they could use the drop less often than other tear substitutes. Despite the high polymeric content, Dwelle® has a relatively low viscosity, about 3 centipoises. However, due to the high polymer (solid) content of the formulation, patients occasionally complain of the stickiness or crusting of the eye lids, especially if their dry eye condition is mild. However, when the ocular surface damage is considerable (Rose bengal staining is above 2+), the use of Dwelle® is justified and the patients will tolerate it well.

Vitamin A-containing Artificial Tears

It is difficult to include vitamin A in an aqueous artificial tear due to its lack of solubility in water and the poor stability of the resulting formulations.

Hence, there are only two artificial tear formulations on the market that contain vitamin A, both in the palmitate form. In the product Viva-Drops® [Vision Pharmaceuticals], the ester form of this lipid-soluble nutrient is solubilized in saline by a nonionic surfactant, Tween 80. The patient acceptance of this formulation has been quite good. In Dakrina® [Aqueous Pharma], vitamin A palmitate is complexed by a polymer which is present at high enough concentration to convey a high oncotic pressure (>70 mmHg) to the formulation. This polymer carrier stabilizes the vitamin A and apparently also makes it bio-available.

In a double blind clinical trial conducted against Dwelle® and Tears Naturale®, Dakrina® demonstrated the highest degree of improvement as measured by objective as well as subjective methods in moderate to severe dry eye patients including patients suffering from Sjögren syndrome.¹⁶ The difference was significant at the p<0.01 level. Again, this formulation has a high polymer content with a corresponding oncotic pressure of over 70 mmHg, so its use is not practical in marginal dry eye patients.

Artificial Tears Containing Other Nutrients

 Commercially available only recently, now there is one artificial tear formulation on the market, called NutraTear® (later re-named FreshKote™ ) that contains vitamin B₁₂. The nutrient, cyanocobalamine, attributes a rosy color to the formulation, but the solution does not stain either clothing or contact lenses.

In a subjective clinical trial conducted by an optometrist and an ophthalmologist, people reported prompt relief from allergic eyes, mild dry eyes, and overused, tired eyes after instillation of NutraTear®. In this study,²⁴ an overall 95% of subjects found the eye drop beneficial. Eighty-four per cent of this group stated that NutraTear® did not sting or only mildly stung upon instillation and that their eyes felt better afterwards. After using NutraTear® for a week, the majority of the subjects found that their eyes were more comfortable and looked better. (Table II).

Table II.

Summary of Subjective Responses by Users of NutraTear®
[20 patients]

1. Does the eye sting briefly upon instillation?

                        Not at all: 42% Mildly: 42% Definitely: 16%

2. Do your eyes feel better after instillation?

                        Immediately: 47% After 5-10 minutes: 37% No difference: 5%

3. Do the drops help after using them for several days?

                        Yes: 74% Not Sure: 21% No difference: 5%

4. Choose those statements that describe your experience with NutraTear®:

                        My eyes are more comfortable: 79%
                        My eyes look clearer and shinier: 53%

                        My eyes do not feel tired as often: 47%

                        Upon awakening my eyes feel cleaner: 42% 

CONCLUSIONS
 

In summary, while most artificial tear formulations do an adequate job of relieving discomfort experienced by dry eye patients, lacrophilic formulations are now available that are capable of significantly reversing or even eliminating epithelial damage that is the commonly observed factor in ocular surface diseases. With the accumulation of additional clinical data, the discerning use of the various types of lacrophile tear substitutes will become better delineated resulting in even more encouraging results in the treatment of dry eye conditions, ocular surface disorders, and poor contact lens tolerance. 

REFERENCES:

1. Lemp, M.A. Dohlman, C.H., and Holly, F.J.: Corneal desiccation despite normal tear volume, Ann.                Opthalmol. 2: 669-672, 1970.

2. Holly, F.J.: Tear film physiology and Contact Lens Wear. II. Contact Lens and Tear Film Interaction, Am. J. Optom. Phys. Optics, 58:331-341, 1981.

3. Holly, F.J. and Lemp, M.A.: Tear physiology and dry eyes, Survey of Opthalmol. 22: 27-33, 1977.

4. Holly, F.J.: Dry Eye and Artificial Tear Formulations, Contact Lens Forum, pp. 30-39, April, 1988.

5. Holly, F.J. and Lemp, M.A.: Wettability and wetting the corneal epithelium. Exp. Eye Res. 11:239-249, 1971.

6. Holly, F.J.: Aqueous tear substitutes, In Clinical Ophthalmic Pharmacology, D.W. Lamberts and D.E. Potter, eds. Boston, Little, Brown, 1987. pp. 497-518.

7. Holly, F.J.: Biophysical aspects of epithelial adhesion to stroma and its clinical implication, Invest. Opthalmol. 17: 552-557, 1978.

8. Holly, F.J. and Esquivel, E.D.: Colloidal osmotic pressure of artificial tears, J. Ocular Pharmacol. 1(4): 327-336, 1985.

9. Ubels, J.L.: The relationship of vitamin A to the ocular surface, In Preocular Tear Film in

Health, Disease, and Contact Lens Wear. Ed. By Holly, F.J., Lamberts, D.W., and MacKeen, D.L., Dry Eye Institute, Lubbock, TX 1986, pp. 319-330.

10. Tseng, S.C.-G.: Cytological evidence of the effect of topical vitamin A on dry eye disorders, Preocular Tear Film in Health, Disease, and Contact Lens Wear. Ed. By Holly, F.J., Lamberts, D.W., and MacKeen, D.L., Dry Eye Institute, Lubbock, TX 1986, pp. 253-270

11. Tuyet-Mai M. Phan et al.: Ascorbic acid therapy in a thermal burn model of corneal ulceration in rabbits. Am. J. Ophthalmol. 99: 74-82 (1985)

12. Caffery, B.: Nutrition and the Eye. (to be published).

13. Aqueous Pharma,  Birmingham, AL.

14. Silver, R. & Moldow, C.F.: The biochemistry of B₁₂ -mediated reactions in man. Am. J. Med. 48: 549-554, 1970.

15. Liotet, S., van Bijsterveld, O.P., Bletry, O., Chomette, G., Moulias, R. & Arrata, M.: Anatomical physiology of the tear film. Chapter 5 in The Dry Eye. Publ. Masson, Paris. 1987. P. 188.

16. Yudilevich, D.L. & Mann, G.E.: Unidirectional uptake of substrates at the blood side of secretory epithelia; stomach, salivary gland, pancreas. Fed Proc. 41(14): 3045-3053, 1982.

17. Silbor, R., Fujioka, S., Moldow, C.F. & Cox, R.: Altered regulation of deoxyribonucleotide synthesis in B₁₂ or folate deficiency. Clin. Res. 18:416, 1970.

18. Larsson, A. & Reichard, P.: Enzymatic reduction of ribonucleotides. Progress in Nucleic Acid research and Molecular Biology. Vol 7. New York. Academic Press. 1967. p.303.

19. Lapalus. P., Fredj-Reygrobellet.D. & Delayre.T. Effect of vitamin B₁₂ on the healing of corneal wounds in the rabbit. Contactologia, 10D: 73-75., 1988.

20. Grasbeck, R. & I.T. Takki-Luukkainen, : Vitamin B₁₂-binding substance in human tear fluid. Acta Opthalmol. 36: 860-864, 1958.

21. Phillips et al., Nature. 217: 67 1968.

22. Toyoshima.M., Inada.M. & Kameyama.M. Effect of aging on intracellular transport of vitamin B₁₂ in rat enterocytes. J. Nutr. Sci. Vitaminol. 29: 1-10, 1983.

23. Foulks, G.N.: Update on Artificial Tears, American Academy of Ophthalmology, Annual Meeting, New Orleans, October, 1989.

24. Ginter, J., Lamberts, D.W., and Holly, F.J.: Evaluation of an Artificial Tear containing Cyanocobalamine: An open clinical trial. Data on file, Aqueous Pharma, Birminhgam, AL.

The following is based on a true story. The name of the patient has been changed to protect his privacy. His E-mail address, however, is available from the author to those interested.

Mr. A glanced in the rear-view mirror of his car as he was driving carefully to work through a country road surrounded by the steamy jungle of Southern Thailand. The cicadas made a terrible racket as huge, colorful dragon flies and butterflies were fluttering around the dense bushes and bamboo shoots lining the road. Mr. A was a highly-placed executive in an industrial firm, owned by an international Asian company, located several hours of drive from Bangkok, the capital. A frown contorted his otherwise expressionless, handsome face.

"Darn it," he thought. "My eyes look terrible again this morning. All blood shot! My colleagues and superior will think that either I never sleep, or I am a dope addict!"

After pulling into the parking lot, Mr. A took a small plastic bottle out of his brief case and put one drop of liquid in each of his eyes. He blinked several times, held his eye lids closed then looked into the mirror again. "Well, it's an improvement, anyhow." By the time he had to visit the men's room later on in the morning, his eyes looked quite red again much to his chagrin.

Without realizing it, Mr. A was a "junkie." He had too much integrity to get hooked on cocaine or heroine which is readily obtainable in the country. Still, he was a junkie with the unwitting help of his eye doctor in Bangkok.

Mr. A's troubles started seven years before, when he was still living and working in his homeland. Being a self-motivated person always willing to go the extra mile, he worked days and late into the nights often over 100 hours a week. After the third month working at such a furious pace, his eyes became chronically red, but they did not hurt. Being young and energetic, he kept up the extraordinary effort for six more months.

Even after he decided to slow down, his eyes did not improve. Finally, after two years of putting up with his red eyes, he visited several eye doctors in the capital. The physicians could not find any obvious problem. When Mr. A kept complaining of a gritty sensation, one of the doctors even tried to remove the "gritty substance" by forceps. However, the problem persisted.

When Mr. A was promoted and transferred to Thailand, he wasted no time but went to see a famous lady physician in Bangkok. She diagnosed chronic conjunctivitis, a medical term for chronically red, inflamed eyes without indicating the cause. She advised the use of baby shampoo to clean the eye lids and also an American-made eye drop that contains a decongestant (vasoconstrictor) and antihistamine.

To make a long story short, Mr. A's eyes remained red and his desperation grew. The vasoconstrictor did "take the red out of his eyes" at least partially, but only for a short period of time and the eye drops became less and less effective over time. Every morning he was dismayed to see that his eyes were very red and shuddered to think that the eye drops on which by now he completely depended, were helping less and less. He was worried for his eye sight, worried for his job, and for an energetic 36 year old in a responsible position, he was starting to get depressed.

The help came from an unexpected source and from many thousands mile away, from the Dry Eye Institute  located at that time in Lubbock, Texas. Mr. A was "surfing the Internet" on the World-Wide-Web one evening with his computer and found some reference to dry, irritable eyes and to the above institute.  He sent an electronic mail immediately asking for help.

After the exchange of many electronic messages and consultation with a corneal specialist from Lubbock and an internationally renown ophthalmologist from Amarillo, Mr. A's major problem was tentatively recognized as iatrogenic, i.e. caused by the medication he was instilling in his eyes. Cleaning his eye lids with a "no tear" shampoo most likely contributed to his problems.

When Mr. A was advised to discontinue his use of the decongestant eye drops, he panicked exclaiming that he could not exist without his eye medication, thereby emphasizing the extent he was addicted to the decongestant.

A strategy was worked out to "wean him away" from the decongestant that by now was making him wake up with blood-red eyes. The Institute rushed him two drug-free eye drops, Dakrina® and NutraTear®  (later renamed REDKOTE™), both of which help to re-stabilize the tear film and nourish the ocular surface, without the use of drugs. Mr. A was advised to take a few days of vacation to weather the worst period of withdrawal. He was given an exact schedule to use his new eye drops and warned to stay away from any type of the decongestant eye drops. He faithfully E-mailed every day the degree of redness and of irritation in his eyes, which he monitored every hour of the day.

The story has a happy ending . Mr. A adhered faithfully to the new regimen and successfully resisted the temptation to use the decongestant. Within ten days the redness of his eyes decreased to barely noticeable levels. In two weeks his eyes were completely free of irritation. When a contingent of high officials arrived at the factory site from the headquarters of the company back home, a visit Mr. A dreaded because of his eyes, a self-assured and clear-eyed executive greeted them at the Bangkok airport.
 

What can we learn from this story? When our eyes do not look at their best, we tend to quickly reach for a "quick fix," instilling a drop of heavily promoted eye drops to get rid of redness! We forget that frequent or prolonged use of adrenergic (decongestant) drugs may readily lead to over-congestion and increased eye irritation.

We must also remember that "red eye" or a "pink eye" is not a helpful diagnosis, since it does not indicate the cause. To temporarily alleviate the symptom by instilling a decongestant, especially when combined with antihistamine, results only in temporary cosmetic improvement at the cost of possibly grave consequences. In addition, the such eye drops do not cure but only mask the underlying cause, which could be something dangerous and vision-threatening such as a bacterial or viral infection.

Furthermore, the dilation of blood vessels is also part of the defense mechanism of the eye which is impeded by the use of decongestant. Once, infection or other serious eye disease is ruled out by a competent eye doctor it makes much more sense to soothe irritated eyes with a drug-free, well-formulated artificial tear that supports, rather than adversely affects, the preocular tear film and the ocular surface.


 

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