Download VITAPOS

Vitamins and Polymers in the Treatment of
Ocular Surface Disease
Author: Dr. Frank J. Holly
Based on a lecture given before the Annual Meeting of AAO. This work was also published in the Contact Lens Spectrum and later
reprinted in several journals and various languages. Revised in February, 2004.
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. 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 reestablished 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
available through as they are now prepared now by a compounding pharmacy. Some of these preparations
(Aqueous Pharma drops) also contain polymers for purposes other than that of viscosity enhancement.4
Actually, the viscosity of these drops are kept purposefully low in order to achieve proper lid lubrication.5
Effect on Tear Film Stability
It has been known for almost 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.6 Despite this fact, most of the commercial tear
substitutes are unable to form a continuous film over a hydrophobic surface.7
Compromised Epithelial Integrity
In ocular surface disease the corneal epithelium often becomes waterlogged (micro-cystic edema). This
condition not only affects its barrier properties but also interferes with its adherence to the underlying
basement membrane.8 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.9
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.10 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 squamous metaplasia is present.11 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.12 At least one author suggests that vitamin B6 may also have beneficial effects on the
eye.13
Vitamin B12 and the Eye
Vitamin B12-containing eye drop has become commercially available only in the last few months.14 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 essential for life and normal cell growth.
Cannot be synthesized by the body.
Increases growth rate of corneal epithelium.
May protect the eye from oxidative free radicals.
Is highly bound by tear proteins.
Is absorbed poorly in the elderly.
Vitamin B12 is an essential product for mammalian life and cannot be synthesized by the body. Its role in
pernicious anemia is well known.15 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.16,17
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.18 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.19 Since this
protective system has been identified in the eye we can 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.20 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.21,22
The ability to absorb vitamin B12 is reduced with aging and thus local supplementation may be desirable.23
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 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.
Complete Wetting of Ocular Surface
It is important that the artificial tears make the ocular surface completely wettable by water (tears). There are
certain formulation (all the tears substitutes of Aqueous Pharma: Dwelle, Dakrina, RedKote, and FreshKote
contain a synergistic polymer mixture which in aqueous solution exhibit a zero receding wetting angle on a
hydrophobic solid surface. Such a formulation stabilizes the tear film and thus enhances the tear film break-up
time.
Elevated Oncotic Pressure
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 3-4 centipoises. However, due to the high
polymer 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 such patients 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, although the efficacy of this formulation was not remarkable due to the apparent biounavailability of vitamin A palimitate solubilized by a nonionic surfactant.
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. 24 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 that contains
vitamin B12, RedKote (Aqueous Pharma). 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 RedKote®. In this study,25 an overall 95% of subjects
found the eye drop beneficial. Eighty-four per cent of this group stated that RedKote® did not sting or only
mildly stung upon instillation and that their eyes felt better afterwards. After using RedKote ® for a week, the
majority of the subjects found that their eyes were more comfortable and looked better.
Artificial Tears Containing Emulsified Lipid Components
Such tears are fairly new to the market. They supposed to stabilize the superficial lipid layer of the tear film
thereby contributing to its stability. They are especially useful in eyes suffering from meibomian gland
dysfunction. Such a formulation is FreshKote™ (Aqueous Pharma).
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 Holly T.F.: Advances in ocular tribology. In: Lacrimal Gland, Tear Film, and Dry Eye
Syndromes, ed. by D.A. Sullivan, Plenum Press, New York, 1994, pp. 275-283.
6. Holly, F.J. and Lemp, M.A.: Wettability and wetting the corneal epithelium. Exp. Eye Res. 11:239-249,
1971.
7. 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.
8. Holly, F.J.: Biophysical aspects of epithelial adhesion to stroma and its clinical implication, Invest.
Opthalmol. 17: 552-557, 1978.
9. Holly, F.J. and Esquivel, E.D.: Colloidal osmotic pressure of artificial tears, J. Ocular Pharmacol. 1(4): 327336, 1985.
10 . 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.
11. 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
12. 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)
13. Caffery, B.: Nutrition and the Eye. (to be published).
14. Dakryon Pharmaceuticals, 2579 S. Loop 289, Lubbock, TX 79423.
15. Silver, R. & Moldow, C.F.: The biochemistry of B12 -mediated reactions in man. Am. J. Med. 48: 549-554,
1970.
16. 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.
17. 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.
18. Silbor, R., Fujioka, S., Moldow, C.F. & Cox, R.: Altered regulation of deoxyribonucleotide synthesis in B12
or folate deficiency. Clin. Res. 18:416, 1970.
19. 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.
20. 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.
21. Grasbeck, R. & I.T. Takki-Luukkainen, : Vitamin B12-binding substance in human tear fluid. Acta
Opthalmol. 36: 860-864, 1958.
22. Phillips et al., Nature. 217: 67 1968.
23. 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.
24. Foulks, G.N.: Update on Artificial Tears, American Academy of Ophthalmology, Annual Meeting, New
Orleans, October, 1989.
25. Ginter, J., Lamberts, D.W., and Holly, F.J.: Evaluation of an Artificial Tear containing Cyanocobalamine:
An open clinical trial. Data on file, Dakryon Pharmaceuticals, Lubbock, TX 79416.