Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Volume I -I Numhrr 3 Prednisolone phosphate 1.0% solution 18.2 ±7.1| 33.1 + 7.2 Reports Dcxamethasone alcohol 0.1% suspension Dexamethasone phosphate 0.1% solution 20.9 t 3.8 3.8 ± 2.2f 30.0 t 6.1 N.I ± 4.1 10. 255 Symposium on Glaucoma. Transactions of the New Orleans Academy of Ophthalmology, St. Louis, 1967, The C. V. Mosby Company, p. 123. Podos, S. M., Kolker, A. M., and Becker, B.: Topical corticosteroids: Dissociation of effects, in: Ocular Anti-Inflammatory Therapy, Kaufman, M. L\, editor. Springfield, III'., 1970, Charles C Thomas, Publisher, p. 108. The effect of lenr substitutes on tear film break-up time. MICHAEL A. LKMP, MICHAEL GOLDHEHC, AND MAMCAHKT R. RODDY. 46.0 ± 8.1 oxprcssi'tl us pi'iri'iit •11.8 + 7.1 ilillrri'iifc from 22.4 ± 6.1 tin." m e n u of 1 2 i m t r c i i t c i l truiilini-iit p r o t o c o l ( p < 0 . 0 5 ) . trc.itmcnt protocol ( p < 0 . 0 5 ). Leibowitz, Boston University School or Medicine, 80 E. Concord St., Boston, Mass. 02118. Key words: cornea, conical inflammation, corticosteioid, steroid, prednisolonc, dexaiiiethasone, polymorplionuclear leukocytes, cornea. KEFEKENCES 1. Leibowitz, II. M., and Kupferman, A,: Pharmacology of topically applied dcxamethasone, Trans. Amur. Acad. Ophthalmol. Otolaryngol. 79: 78, 1975. 2. Leibowitz, II. M., and K'upferman, A.: Antiinllammatory effectiveness in the cornea of topically administered prednisolone, INVEST. OI'IITIIALMOI.. i:J: 757, 1974. 3. Cox, W. V., Kupferman, A., and Leibowitz, II. M.: Topically applied steroids in conical disease. I. The role of inflammation in stronial absorption of dexaniethasone, Arch. Ophthalmol. 88: 308, 1972. 4. Cox, VV. V., Kupferman, A., and Leibowitz, II. M.: Topically applied steroids in cornea I disease. II. The role of drug vehicle in stronial absorption of devunethasone, Arch. Ophthalmol. 88: 549, 1972. 5. Leibowitz, II. M., Lass, |. H., and Kupferinan, A.: Oiiantitation of iiiHammation in the cornea, Arch. Ophthalmol. 92: 427, 1974. 6. Kupferman, A., and Leibowitz, II. M.: Topically applied steioids in corneal disease. IV. The role of drug concentration in the stronial absorption of prednisolone acetate, Arch. Ophthalmol. 9 1 : 377, 1974. 7. Kupfernian, A., and Leibowitz, II. M.: Topically applied steroids in conical disease. VI. Kinetics of prednisolone phosphate., Arch. Ophthalmol. 92: 331, 1974. 8 Kupferman, A., and Leibowitz, II. M.: Topically applied steroids in corneal disease. V. Dexametliasone alcohol, Arch. Ophthalmol. 92: 329, 1974. 7 9. Arnialy, M. I .: Steroids and glaucoma, in: Twelve commercial artificial tear solutions and a newly developed one were evaluated, as to their effect. O)i tear film breakup time (BUT) in ten normal subjects. Instillation of one drop of these solutions altered the BUT in such a way that serial BUT measurements could be used as an index of retention time. Results demonstrated significantly longer retention time for three related products (Adapt, Adapcttc, and Adsorbotear) and a newly developed product (Aleon 0413) [Tears Naturale (Alcon T")]. This method appears to be an accurate nonirritative way of assessing retention time of tear substitute/vehicles ami demonstrate values much longer than previously reported hi/ other miihods. Artificial tear solutions are used as replacement therapy in dry eye states: virtually identical lormulations form the vehicles for the delivery of locally instilled medications to the eye. These solutions contain water-soluble polymers incorporated with the intent of prolonging retention in the conjunctiva! sac. In practice, however, their elh'eaev is limited by their short duration. 1 Studies attempting to assess their stay in the conjnnctival sac (retention time, contact time) have employed visible markers, e.g., argyrol, nickel chloride,- and have shown retention times of about 3 to 10 minutes; alternatively, excretion of instilled solutions through the nasolacrinial duct has been studied and found to occur within minutes.' Other studies have measured intiaoeular penetration of dyes1' and uptake of radioactive substances, but are only an indirect indication of relative efficacy of dillcrent solutions in facilitating incorporation or substances into the cornea. If normal blinking is prevented, the precorneal tear film will break up, i.e., develop random dry spots. The interval between the last complete blink and the appearance of the first dry spot— breakup Mine (BUT)—lias been found to be abnormally rapid in dry eye states. 0 ' i; This is a reflection of decreased tear film stability. As part of a larger study of BUT in normal subjects, it was noted that after instillation of an artificial Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933293/ on 05/03/2017 256 Reports Ophthalmology March 1975 E fftC I O F IEAR SUBSTITUTES O N B U I i! I Bdseline BUI laveraqpi ^ B U I post instillation • I. ! I II . .I I I . I II II Ii I J I iI I I 1pIJ I II I 1I II ?0 Fig. 1. This graph illustrates the magnitude of the effect of the solutions on the BUT. tear solution, a subject's BUT was altered over a period of time. Since this might provide a convenient nonirritative marker for duration o\ tear substitutes in the conjunctival sac, this study was undertaken. Methods. Twelve subjects with no evidence of ocular disease and with normal BUT, between 15 and 25 seconds, were chosen for this study. Twelve commercially available artificial tear solutions were studied; in addition, a new tear substitute developed in our laboratory with the cooperation of Alcon Laboratories was studied. These solutions were studied in a randomized order and in a double-blind fashion. All studies were carried out in a room monitored for temperature and humidity and with no discernible air currents. Baseline BUT values were measured at each visit; one 50 /<l drop of artificial tear was instilled in an eye and BUT was determined at 5, 10, 15, and at approximately 15 minute intervals thereafter until three successive measurements returned to baseline values. Return to baseline values was interpreted as meaning the solution was no longer present in significant quantity. BUT measurements were performed without anesthesia or holding the eye lids as previously described.7 No more than one solution was instilled on any single day. Statistical methods. The maximum time of duration (length of time an observable effect on the BUT was noted) was defined as the time until the last BUT value was greater than the baseline BUT (if the BUT was greater than baseline) or until the last BUT value was less than baseline BUT (if the observable effect was to decrease BUT). This duration time was analyzed to determine if there were any significant differences due to vehicle used, sex, age, or baseline BUT. The observations for each eye were analyzed separately. Left eye. There was a significant dillerence (p 0.01) (\y\t to vehicle but no significant ilillerences due to sex or age. Since there was a significant difference due to the stinting baseline BUT, the means for vehicles were adjusted lor these initial differences. Right ci/c. There was a significant difference (p 0.01) due to vehicle but neither the sex, age, nor baseline values differed significantly. Results. Two quantitative measurements could be determined. The first of these was the magnitude of the effect of the solution on BUT. Fig. 1 shows the average change from baseline BUT noted alter instillation of solution. All solutions significantly lengthened BUT with the exception of one. A lengthened BUT is interpreted as a reflection of enhanced tear film stability. The second measurement was that of duration of effect noted. Fig. 2 shows this in graphic form. Interestingly, BUT values were altered after Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933293/ on 05/03/2017 Reports Volume \4 Number 3 U UKA I IU N 01 257 I ON B U I 0 1 I I A R S U B S I I I IJI ( S 100 80 60 40 ?0 Fig. 2. This graph illustrates the duration over which the effect of solution instillation on BUT was seen. instillation of solution and remained altered lor a given time, reverting to baseline values without an intermediate period permitting accurate assessment of duration. In general, two groupings of duration are discernible: those lorinulations employing cellulose ethers or polyvinyl alcohol tended to last about 35 to 6'0 minutes. The lorinulations employing B1J polymer and the newly developed tear substitute (Alcon 0413) were noted to last about 90 minutes. Discussion. Attempts to measure duration ot tear substitute/vehicles have been hampered by the difficulty in finding a suitable way of marking and measuring the solution without inducing reIlex tearing. While currently available tear substitutes are limited by their short retention time, clinical experience suggests they last much longer than the few minutes reported in previous studies. The rationale for using polymers in solutions has been one primarily of increasing viscosity. Hecent studies show that viscosity seems to have little ellect on retention time*; it has been stated that the rate of tear secretion is the primary determinant. If this is true, then solutions should show longer retention time in dry eyes than in normal eyes. An alternative approach in the development of tear substitutes would lie the use of watersoluble macromolecular compounds with an adsorptive affinity for the ocular surface. In this way an ellective stitching action could be effected, promoting retention. Such an approach was used in developing the new tear substitutes tested here (Alcon 0413), using methods de- scribed elsewhere." Evidence has been presented showing that the solutions containing B1J polymer (Adapt, Adapette, and Adsoibotear) display some absorptive, properties. These solutions, therefore, might be expected to show longer retention times. The instillation of a drop of solution into the tear system results, however, in a complex series of interactions involving tear miicin, lipid, and inorganic salts with the constituents of the instilled solution. It is interesting that all but one solution resulted in prolonging BUT, indicating an enhancement of tear film stability. The one solution (Tearisol) that decreased BUT employs hvdroxypropylmethyl cellulose as do a number of other solutions. Complete formulations, however, are complex mixtures of polymers, preservatives, and salts. Laboratory experience has demonstrated that seemingly small changes in inorganic salts can profoundly influence polymer behavior. Therefore, adverse efleets on tear film stability might be the result of formulation dillerences in salt content. It has also been suggested that drop size is an important determinant of retention time 1 "; in tin's connection, all drops were of the same size to eliminate a possible source of error. An interesting finding in this study concerns the baseline BUT values. Because of the study design we were able to determine serial BUT's in a given subject over a several week period. Results indicate that this value is remarkably constant in an individual. Table I shows the mean BUT determined for each of the 12 participating subjects with standard deviations. Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933293/ on 05/03/2017 258 Reports C Ophthalmology March 1975 Table I. Serial hascline B i n ' s on ten subjects taken on twelve dillerent days. Tlie mean BUT's are listed with one standard deviation (S.D.). OD Subject ID number Mean BUT 01 02 03 04 05 06 07 08 09 010 23.66 17.83 27.50 24.91 23.00 29.16 18.50 22.50 25.00 25.85 .S.D. ±4 ±3 ±5 ±6 ±5 ±6 ±5 ±4 ±3 ±7 OS Mean BUT 22.16 20.16 28.00 25.66 24.00 29.58 17.75 23.25 23.33 28.50 S.D. i3 ±5 ±6 ±8 ±3 ±8 ±4 ±4 i3 i8 The results ol the study indieate that the instillation of a drop ol an artificial tear solution into the eonjunetival sae a Meets the BUT in such a way that a definite, reproducible alteration in BUT occurs over a certain period of time. While the mechanism by which this change is ellected is unknown, the measurement of serial BUT's alter instillation ol a tear substitute seems to provide an efficient convenient nonirritative method of assessing retention time. This assumes that the observable eMects of the solution or the BUT are an indication of the remaining piesence in the conjuctival sac. Values reported are much longer than those reported with previous methods and are consistent with clinical experience. This method seems to be sufficiently discriminatory to define significant dillerences in duration and indeed elficacy (positive effect on tear film stability) between different tear substitutes. The results demonstrate greater retention times for tour products: these results are consistent with laboratory data suggesting greater absorptive properties for their constituents. 1 ' It would seem that this method oilers an excellent means of assessing new tear substitute/vehicle solutions. in part by United States Public Health Seivice Grants 5R01 EY00988-02, and a grant from Alcon Laboratories, Inc. Submitted for publication Oct. 1, 1974. Heprint requests: Dr. M. A. Lemp, Director, Cornea Service Georgetown University Medical Center, 3800 Reservoir Rd., N.W., Washington, D. C. 20007. Key words: tear film break up time, retention time, tear substitutes, ophthalmic polymers. REFERENCES 1. Lemp, M. A.: Artificial tear solutions, in: The Preocular Tear Film and Dry Eye Syndromes, Holly, F. |., and Lemp, M. A., editors. Inteniat. Ohpthalmol. Clin. l.'J: 221, 1973. 2. Krishna, N., and Brow, F.: Polyvinyl alcohol as an ophthalmic vehicle, Am. |. Ophthalmol. 57: 99, 1964. 3. Linn, M. L., and Jones, L. T.: Rale of lacrimal excretion of ophthalmic vehicles, Am. |. Ophthalmol. (15: 76, 1968. 4. Waltman, S. R., and Patiowicz, T. C : Ellects of hydroxypropyl.methylcelliilo.se and polyvinyl alcohol on intraocular penetration ol topical fluorescein 5. 6. 7. 8. 9. 10. in man, INVEST. OIMITIIALMOL. 9: 966, 1970. Lemp, M. A., Dohlman, C. II., and Holly, F. (.: Corneal desiccation despite normal tear volume, Ann. Ophthalmol. 2: 258, 1970. Lemp, M. A., Dohlman, C. H., Kuwabara, T., et al.: Dry eye secondary to mucus deficiency, Trans. Am. Acacl. Ophthalmol. Otolaryngol. 75: 1223, 1971. Lemp, M. A., and Hamill, |.: Factors allecting tear film breakup in normals, Arch. Ophthalmol. 89: 103, 1973. Acller, C. A., Marnier, D. M., and Peterson, M. E.: The el feet of viscosity on the penetration of lluorescein into the human eye, Exp. Eye Res. 11: 34, 1971. Lemp, M. A., and Szyman.ski, E. S.: Adsorption at the ocular surface, Arch. Ophthalmol. In press. Chrai, S. S., Patton, T. F., Mehla, A., et al.: Lacrimal and instilled Huid dynamics in rabbit eves, I. Pharm. Sci. f>2: 1112, 1973. From the Georgetown University Medical Center, Washington, D. C. This study was supported Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933293/ on 05/03/2017