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Increased Intraocular Pressure Induced by Corticosteroids
INCREASED INTRAOCULAR PRESSURE I N D U C E D BY CORTICOSTEROIDS YOSHIAKI KlTAZAWA, M . D . Chiba-shi,
The ability of glucocorticoids to induce a marked increase in intraocular pressure (IOP) in susceptible individuals limits the usefulness of these potent anti-in flammatory agents in clinical ophthalmol ogy. Certain compounds such as fnedrysone, fluorometholone, and tetrahydrotriamcinolone that have little effect on I O P , 1 - 3 have been made available for clinical use. Little has been known, how ever, of the potential of these newer prep arations to induce elevated IOP as com pared with corticosteroids such as betamethasone or dexamethasone, and the results of a few accessible studies are divergent. 3 ' 4 This lack of understanding has occurred for two reasons. First, the susceptibility of IOP to corticosteroids is genetically determined and the magni tude of IOP elevations caused by cortico steroids varies markedly from one indi vidual to the other. 5,6 Secondly, the mag nitude of elevated IOP depends on the frequency and duration of topical admin istration. 7 - 9 To evaluate different cortico steroids and their effects on IOP, it is mandatory to apply corticosteroids to the same individual in the same manner with regard to both the frequency and the duration of administration. It is essential to use a subject whose IOP is highly responsive to topical betamethasone or dexamethasone. I designed the present study to evaluate the IOP elevating po tentials of newer corticosteroids as com pared with betamethasone, a conventionFrom the Glaucoma Service, Department of Oph thalmology, Chiba University School of Medicine, Chiba-shi, Japan. Presented in part at the Sixth Afro-Asian Congress of Ophthalmology in Madras, India, Jan. 6, 1976. Reprint requests to Yoshiaki Kitazawa, M.D., De partment of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Japan
al corticosteroid, by using the same high ly responsive subjects. M A T E R I A L AND M E T H O D S
Twelve patients (24 eyes) from the Glaucoma Service who developed in creased IOP by applanation tonometry (greater than 16 mm Hg) in both eyes after topical administration of betamethasone sodium phosphate 0.1%, four times daily for four weeks, were used for the present study. Each patient was tested in both eyes with betamethasone sodium phos phate 0.05, 0.02, and 0.01%; medrysone 1.0%; tetrahydrotriamcinolone acetonide dipotassium phosphate 0.05, 0.25, and 1.25%; and fluorometholone 0.01, 0.05, and 0.1%. Intraocular pressure was measured with a Goldmann applanation tonometer mounted on a slit lamp (HaagStreit, model 900). Tonography lasting four minutes was taken by using an elec tric Schi0tz tonometer coupled with a recorder. Both applanation tonometry and tonography were carried out before and after four weeks of drug administration. Return of baseline IOP and outflow facil ity were confirmed before we initiated a new agent. All the results were expressed statistically as the arithmetic mean ± standard error of the mean (S.E.M.). RESULTS
The mean IOP by applanation tonome try before and after administration of dif ferent concentrations of betamethasone is shown in Table 1. All the concentrations caused a statistically significant increase in IOP. The response of IOP to beta methasone was dose-related and a doseresponse relationship demonstrated an excellent correlation (r= .99865, P<.001) between concentrations of topically ap-
492
VOL. 82, NO. 3
INCREASED INTRAOCULAR PRESSURE TABLE 1
I O P RESPONSE TO BETAMETHASONE*
IOP at 4 weeks, mm Hg
Baseline IOP, mm Hg 0.01% 0.02% 0.05% 0.1%
17.8 19.6 17.7 18.7
± ± ± ±
0.56 0.63 0.67 0.52
20.2 27.7 34.7 42.4
± ± ± ±
1.10 2.04 2.38 1.82
Difference, mm Hg 2.4 8.1 17.0 23.7
± ± ± ±
0.62 1.50 2.28 1.76
*n = 24, mean ± SEM.
plied betamethasone and the magnitude of IOP response (Figure). The IOP re sponse to tetrahydrotriamcinolone and fluorometholone was also dose-related. The mean IOP before and after adminis tration of different concentrations of these corticosteroids is shown in Tables 2 and 3. A statistically significant increase in IOP was demonstrated with tetrahydro
493
triamcinolone 1.25% (P<.01) and fluoro metholone 0.1% (P<.001). Medrysone 1.0%, the only concentration studied, caused a small but statistically significant increase of IOP (P<.05, Table 4). The elevation of IOP after administration of various concentrations of different corti costeroids was classified according to Armaly's criteria for grouping (Table 5). 5 The incidence of high response decreased with the dilution of corticosteroids and high response of IOP was not elicited by betamethasone 0.01%, medrysone 1.0%, tetrahydrotriamcinolone 0.05 and 0.25%, and fluorometholone 0.05 and 0.01%. The ability of each preparation to increase IOP was expressed as the ratio of an increase in IOP after the treatment with each preparation to that after betameth asone 0.1% treatment in each eye (Table
100
Figure (Kitazawa). Dose-response relationship of intraocular pressure (IOP) to betamethasone. The re sponse of IOP to 0.1% is taken for 100%. Each dot represents the mean of IOP response of 24 eyes of 12 patients and vertical bars in dicate standard error of the mean. Linear regression is Y = 82.9 log 10 x + 187.55.
V (A
£ 50 01
0.01
0.02
0.05
Log Concentration of Betamethasone
0 1 (%)
494
AMERICAN JOURNAL OF OPHTHALMOLOGY
SEPTEMBER, 1976
TABLE 2
TABLE 4
IOP RESPONSE TO TETRAHYDROTRIAMICINOLONE*
IOP RESPONSE TO MEDRYSONE*
IOP at 4 weeks, mm Hg
Baseline IOP, mm Hg 0.05% 0.25% 1.25%
18.4 ± 1.24 18.3 ± 0.89 18.8 ± 1.27
Difference, mm Hg
19.1 ± 1.03 0.7 ± 0.33 18.3 ± 0.93 0 ± 0.93 30.7 ± 2.61 11.9 ± 3.09
1.0%
Baseline IOP, mm Hg
IOP at 4 weeks, mm Hg
Difference, mm Hg
19.9 ± 1.24
23.1 ± 2.02
3.2 ± 1.24
*n = 24, mean ± SEM.
*n = 24, mean ± SEM.
6). The order of potential of corticosteroids to elevate IOP was betamethasone 0.1%, betamethasone 0.05%, tetrahydrotriamcinolone 1.25%, betamethasone 0.02%, fluorometholone 0.1%, medrysone 1.0%, and betamethasone 0.01%. Tetrahydrotriamcinolone 0.25 and 0.05%, and fluorometholone 0.05 and 0.01%, failed to elevate IOP significantly. DISCUSSION
Although the IOP response to topically administered corticosteroids is dosedependent, the exact dose-response rela tionship of IOP to topical corticosteroid concentrations available for clinical use 3 has not been fully elucidated. By testing the same highly responsive patients with different concentrations of betameth asone for the same period of time with the same frequency, one may determine the dose-response relationship showing an excellent correlation between the ad ministered dose and the increase in IOP. By plotting the IOP response to a certain compound on the dose-response curve to betamethasone one can not only quantitaTABLE 3 IOP RESPONSE TO FLUOROMETHOLONE*
0.01% 0.05% 0.1%
Baseline IOP, m m Hg
IOP at 4 weeks, mm H g
Difference, mm Hg
19.8 ± 0.62 19.1 ± 0.74 18.4 ± 0.98
19.7 ± 0.54 20.7 ± 1.76 25.3 ± 1.52
- 0 . 1 ± 0.83 1.6 ± 1.17 6.9 ± 1.85
n = 24, mean ± SEM.
tively evaluate the IOP effect in compari son with that of betamethasone but can also make a comparison between the ef fects of various compounds other than betamethasone on IOP. In the dose-response relationship ob tained in this study, betamethasone 0.01% has no clinically significant effect on increasing IOP. However, the doseresponse relationship I obtained is valid for the topical testing of four weeks' dura tion. With more prolonged administra tion, diluted betamethasone or dexamethasone in a concentration such as 0.005% can provoke a marked increase in IOP. 3 , 9 The frequency of administration alters the degree of IOP response. Intraocular pressure was significantly higher after four weeks of topical administration of betamethasone 0.1% when it was given TABLE 5 INCREASED IOP AFTER TOPICAL ADMINISTRATION OF VARIOUS CORTICOSTEROIDS No. of Eyes 5 mm Hg 6-15 mm Hg 16 mm Hg Betamethasone 0.1% 0.05% 0.02% 0.01%
0 3 7 20
0 10 12 4
24 11 5 0
Medrysone 1.0%
18
6
0
Tetrahydrotriamcinolone 1.25% 0.25% 0.05%
10 24 24
5 0 0
9 0 0
Fluorometholone 0.1% 0.05% 0.01%
10 17 24
12 7 0
2 0 0
VOL. 82, NO. 3
INCREASED INTRAOCULAR PRESSURE TABLE 6
RELATIVE POTENTIAL O F CORTICOSTEROIDS
TO ELEVATE IOP*
Betamethasone 0.1 0.05 0.02 0.01
1.00 0.70 0.34 0.11
Medrysone 1.0
0.15 ± 0.037
Tetrahydrotriamcinolone 1.25 0.25 0.05
0.42 ± 0.071 0.02 ± 0.013 0.05 ± 0.013
Fluorometholone 0.1 0.05 0.01
0.25 ± 0.048 0.06 ± 0.045 0.01 ± 0.028
± ± ± ±
0.000 0.059 0.053 0.028
*n = 24, mean ± SEM.
eight times daily rather than four times daily. 10 When used in commercially available concentrations (tetrahydrotriamcinolone 0.25%, fluorometholone 0.1%, and me drysone 1.0%), these newer compounds induce lower pressure elevations as com pared with betamethasone on the equimolar basis, even in highly susceptible individuals. However, my results indicate that although the newer compounds are less potent, commercially available con centrations still may increase the IOP when the duration of treatment becomes prolonged. It seems particularly true for fluorometholone 0.1%. SUMMARY
Twelve patients who were highly re sponsive to topically administered be tamethasone were subjected to various corticosteroid preparations (four times daily for four weeks). Each patient was tested in the same eye with fluorometh olone, tetrahydrotriamcinolone, med rysone, and betamethasone and the po
495
tential to elevate intraocular pressure was determined. The response of intraocular pressure to all the corticosteroids was dose-related and a highly significant cor relation was demonstrated between the concentration of betamethasone and the magnitude of intraocular pressure response. The order of potential of corti costeroids to elevate IOP was betameth asone 0.1%, betamethasone 0.05%, 1.25%, beta tetrahydrotriamcinolone methasone 0.02%, fluorometholone 0.1%, medrysone 1.0%, and betamethasone 0.01%. Tetrahydrotriamcinolone 0.25% and fluorometholone 0.05 and 0.01% failed to elevate intraocular pressure sig nificantly. REFERENCES 1. Spaeth, G. L.: Hydroxymethylprogestesone. An anti-inflammatory steroid without apparent effect on IOP. Arch. Ophthalmol. 75:783, 1966. 2. Fairbairn, M. D., and Thorson, J. C : Fluoro metholone, anti-inflammatory and I O P effects. Arch. Ophthalmol. 86:138, 1971. 3. Podos, S. M., Kolker, A. E., and Becker, B.: Topical corticosteroids. Dissociation of effects. In Kaufman H. E. (ed.): Symposium on Ocular Antiinflammatory Therapy. Springfield, Illinois, Charles C Thomas, 1970, p . 106. 4. Nelson, E. L.: Ophthalmic steroids. In Kauf man, H. E. (ed.): Symposium on Ocular Antiinflammatory Therapy. Springfield, Illinois, Charles C Thomas, 1970, p . 217. 5. Armaly, M. F.: Topical dexamethasone and IOP. In Glaucoma Symposium, Tutzing Castle, 1966. Basel, Karger, 1967, p . 73. 6. Becker, B.: Topical corticosteroids and intra ocular pressure. In Becker, B., and Drews, R. C. (eds.): Current Concepts in Ophthalmology. St. Louis, C. V. Mosby, 1967, p . 132. 7. Podos, S. M., Krupin, T., Asseff, C , and Beck er, B.: Topically administered corticosteroid prepa rations. Arch. Ophthalmol. 86:251, 1971. 8. Kitazawa, Y., Kawanishi, K., and Nakamura, Y.: Steroid responsiveness of IOP in normal popula tion. Jap. J. Clin. Ophthalmol. 22:793, 1968. 9. Armaly, M. F.: Factors affecting the doseresponse relationship in steroid-induced ocular hy pertension. In Kaufman, H. E. (ed.): Ocular Antiinflammatory Therapy. Springfield, Illinois, Charles C Thomas, 1970, p . 88. 10. Kitazawa, Y.: An ocular hypertensive effect of betamethasone, with the special reference to the frequency of administration. Acta Soc. Ophthalmol. Jap. In press.
The ability of glucocorticoids to induce a marked increase in intraocular pressure (IOP) in susceptible individuals limits the usefulness of these potent anti-in flammatory agents in clinical ophthalmol ogy. Certain compounds such as fnedrysone, fluorometholone, and tetrahydrotriamcinolone that have little effect on I O P , 1 - 3 have been made available for clinical use. Little has been known, how ever, of the potential of these newer prep arations to induce elevated IOP as com pared with corticosteroids such as betamethasone or dexamethasone, and the results of a few accessible studies are divergent. 3 ' 4 This lack of understanding has occurred for two reasons. First, the susceptibility of IOP to corticosteroids is genetically determined and the magni tude of IOP elevations caused by cortico steroids varies markedly from one indi vidual to the other. 5,6 Secondly, the mag nitude of elevated IOP depends on the frequency and duration of topical admin istration. 7 - 9 To evaluate different cortico steroids and their effects on IOP, it is mandatory to apply corticosteroids to the same individual in the same manner with regard to both the frequency and the duration of administration. It is essential to use a subject whose IOP is highly responsive to topical betamethasone or dexamethasone. I designed the present study to evaluate the IOP elevating po tentials of newer corticosteroids as com pared with betamethasone, a conventionFrom the Glaucoma Service, Department of Oph thalmology, Chiba University School of Medicine, Chiba-shi, Japan. Presented in part at the Sixth Afro-Asian Congress of Ophthalmology in Madras, India, Jan. 6, 1976. Reprint requests to Yoshiaki Kitazawa, M.D., De partment of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Japan
al corticosteroid, by using the same high ly responsive subjects. M A T E R I A L AND M E T H O D S
Twelve patients (24 eyes) from the Glaucoma Service who developed in creased IOP by applanation tonometry (greater than 16 mm Hg) in both eyes after topical administration of betamethasone sodium phosphate 0.1%, four times daily for four weeks, were used for the present study. Each patient was tested in both eyes with betamethasone sodium phos phate 0.05, 0.02, and 0.01%; medrysone 1.0%; tetrahydrotriamcinolone acetonide dipotassium phosphate 0.05, 0.25, and 1.25%; and fluorometholone 0.01, 0.05, and 0.1%. Intraocular pressure was measured with a Goldmann applanation tonometer mounted on a slit lamp (HaagStreit, model 900). Tonography lasting four minutes was taken by using an elec tric Schi0tz tonometer coupled with a recorder. Both applanation tonometry and tonography were carried out before and after four weeks of drug administration. Return of baseline IOP and outflow facil ity were confirmed before we initiated a new agent. All the results were expressed statistically as the arithmetic mean ± standard error of the mean (S.E.M.). RESULTS
The mean IOP by applanation tonome try before and after administration of dif ferent concentrations of betamethasone is shown in Table 1. All the concentrations caused a statistically significant increase in IOP. The response of IOP to beta methasone was dose-related and a doseresponse relationship demonstrated an excellent correlation (r= .99865, P<.001) between concentrations of topically ap-
492
VOL. 82, NO. 3
INCREASED INTRAOCULAR PRESSURE TABLE 1
I O P RESPONSE TO BETAMETHASONE*
IOP at 4 weeks, mm Hg
Baseline IOP, mm Hg 0.01% 0.02% 0.05% 0.1%
17.8 19.6 17.7 18.7
± ± ± ±
0.56 0.63 0.67 0.52
20.2 27.7 34.7 42.4
± ± ± ±
1.10 2.04 2.38 1.82
Difference, mm Hg 2.4 8.1 17.0 23.7
± ± ± ±
0.62 1.50 2.28 1.76
*n = 24, mean ± SEM.
plied betamethasone and the magnitude of IOP response (Figure). The IOP re sponse to tetrahydrotriamcinolone and fluorometholone was also dose-related. The mean IOP before and after adminis tration of different concentrations of these corticosteroids is shown in Tables 2 and 3. A statistically significant increase in IOP was demonstrated with tetrahydro
493
triamcinolone 1.25% (P<.01) and fluoro metholone 0.1% (P<.001). Medrysone 1.0%, the only concentration studied, caused a small but statistically significant increase of IOP (P<.05, Table 4). The elevation of IOP after administration of various concentrations of different corti costeroids was classified according to Armaly's criteria for grouping (Table 5). 5 The incidence of high response decreased with the dilution of corticosteroids and high response of IOP was not elicited by betamethasone 0.01%, medrysone 1.0%, tetrahydrotriamcinolone 0.05 and 0.25%, and fluorometholone 0.05 and 0.01%. The ability of each preparation to increase IOP was expressed as the ratio of an increase in IOP after the treatment with each preparation to that after betameth asone 0.1% treatment in each eye (Table
100
Figure (Kitazawa). Dose-response relationship of intraocular pressure (IOP) to betamethasone. The re sponse of IOP to 0.1% is taken for 100%. Each dot represents the mean of IOP response of 24 eyes of 12 patients and vertical bars in dicate standard error of the mean. Linear regression is Y = 82.9 log 10 x + 187.55.
V (A
£ 50 01
0.01
0.02
0.05
Log Concentration of Betamethasone
0 1 (%)
494
AMERICAN JOURNAL OF OPHTHALMOLOGY
SEPTEMBER, 1976
TABLE 2
TABLE 4
IOP RESPONSE TO TETRAHYDROTRIAMICINOLONE*
IOP RESPONSE TO MEDRYSONE*
IOP at 4 weeks, mm Hg
Baseline IOP, mm Hg 0.05% 0.25% 1.25%
18.4 ± 1.24 18.3 ± 0.89 18.8 ± 1.27
Difference, mm Hg
19.1 ± 1.03 0.7 ± 0.33 18.3 ± 0.93 0 ± 0.93 30.7 ± 2.61 11.9 ± 3.09
1.0%
Baseline IOP, mm Hg
IOP at 4 weeks, mm Hg
Difference, mm Hg
19.9 ± 1.24
23.1 ± 2.02
3.2 ± 1.24
*n = 24, mean ± SEM.
*n = 24, mean ± SEM.
6). The order of potential of corticosteroids to elevate IOP was betamethasone 0.1%, betamethasone 0.05%, tetrahydrotriamcinolone 1.25%, betamethasone 0.02%, fluorometholone 0.1%, medrysone 1.0%, and betamethasone 0.01%. Tetrahydrotriamcinolone 0.25 and 0.05%, and fluorometholone 0.05 and 0.01%, failed to elevate IOP significantly. DISCUSSION
Although the IOP response to topically administered corticosteroids is dosedependent, the exact dose-response rela tionship of IOP to topical corticosteroid concentrations available for clinical use 3 has not been fully elucidated. By testing the same highly responsive patients with different concentrations of betameth asone for the same period of time with the same frequency, one may determine the dose-response relationship showing an excellent correlation between the ad ministered dose and the increase in IOP. By plotting the IOP response to a certain compound on the dose-response curve to betamethasone one can not only quantitaTABLE 3 IOP RESPONSE TO FLUOROMETHOLONE*
0.01% 0.05% 0.1%
Baseline IOP, m m Hg
IOP at 4 weeks, mm H g
Difference, mm Hg
19.8 ± 0.62 19.1 ± 0.74 18.4 ± 0.98
19.7 ± 0.54 20.7 ± 1.76 25.3 ± 1.52
- 0 . 1 ± 0.83 1.6 ± 1.17 6.9 ± 1.85
n = 24, mean ± SEM.
tively evaluate the IOP effect in compari son with that of betamethasone but can also make a comparison between the ef fects of various compounds other than betamethasone on IOP. In the dose-response relationship ob tained in this study, betamethasone 0.01% has no clinically significant effect on increasing IOP. However, the doseresponse relationship I obtained is valid for the topical testing of four weeks' dura tion. With more prolonged administra tion, diluted betamethasone or dexamethasone in a concentration such as 0.005% can provoke a marked increase in IOP. 3 , 9 The frequency of administration alters the degree of IOP response. Intraocular pressure was significantly higher after four weeks of topical administration of betamethasone 0.1% when it was given TABLE 5 INCREASED IOP AFTER TOPICAL ADMINISTRATION OF VARIOUS CORTICOSTEROIDS No. of Eyes 5 mm Hg 6-15 mm Hg 16 mm Hg Betamethasone 0.1% 0.05% 0.02% 0.01%
0 3 7 20
0 10 12 4
24 11 5 0
Medrysone 1.0%
18
6
0
Tetrahydrotriamcinolone 1.25% 0.25% 0.05%
10 24 24
5 0 0
9 0 0
Fluorometholone 0.1% 0.05% 0.01%
10 17 24
12 7 0
2 0 0
VOL. 82, NO. 3
INCREASED INTRAOCULAR PRESSURE TABLE 6
RELATIVE POTENTIAL O F CORTICOSTEROIDS
TO ELEVATE IOP*
Betamethasone 0.1 0.05 0.02 0.01
1.00 0.70 0.34 0.11
Medrysone 1.0
0.15 ± 0.037
Tetrahydrotriamcinolone 1.25 0.25 0.05
0.42 ± 0.071 0.02 ± 0.013 0.05 ± 0.013
Fluorometholone 0.1 0.05 0.01
0.25 ± 0.048 0.06 ± 0.045 0.01 ± 0.028
± ± ± ±
0.000 0.059 0.053 0.028
*n = 24, mean ± SEM.
eight times daily rather than four times daily. 10 When used in commercially available concentrations (tetrahydrotriamcinolone 0.25%, fluorometholone 0.1%, and me drysone 1.0%), these newer compounds induce lower pressure elevations as com pared with betamethasone on the equimolar basis, even in highly susceptible individuals. However, my results indicate that although the newer compounds are less potent, commercially available con centrations still may increase the IOP when the duration of treatment becomes prolonged. It seems particularly true for fluorometholone 0.1%. SUMMARY
Twelve patients who were highly re sponsive to topically administered be tamethasone were subjected to various corticosteroid preparations (four times daily for four weeks). Each patient was tested in the same eye with fluorometh olone, tetrahydrotriamcinolone, med rysone, and betamethasone and the po
495
tential to elevate intraocular pressure was determined. The response of intraocular pressure to all the corticosteroids was dose-related and a highly significant cor relation was demonstrated between the concentration of betamethasone and the magnitude of intraocular pressure response. The order of potential of corti costeroids to elevate IOP was betameth asone 0.1%, betamethasone 0.05%, 1.25%, beta tetrahydrotriamcinolone methasone 0.02%, fluorometholone 0.1%, medrysone 1.0%, and betamethasone 0.01%. Tetrahydrotriamcinolone 0.25% and fluorometholone 0.05 and 0.01% failed to elevate intraocular pressure sig nificantly. REFERENCES 1. Spaeth, G. L.: Hydroxymethylprogestesone. An anti-inflammatory steroid without apparent effect on IOP. Arch. Ophthalmol. 75:783, 1966. 2. Fairbairn, M. D., and Thorson, J. C : Fluoro metholone, anti-inflammatory and I O P effects. Arch. Ophthalmol. 86:138, 1971. 3. Podos, S. M., Kolker, A. E., and Becker, B.: Topical corticosteroids. Dissociation of effects. In Kaufman H. E. (ed.): Symposium on Ocular Antiinflammatory Therapy. Springfield, Illinois, Charles C Thomas, 1970, p . 106. 4. Nelson, E. L.: Ophthalmic steroids. In Kauf man, H. E. (ed.): Symposium on Ocular Antiinflammatory Therapy. Springfield, Illinois, Charles C Thomas, 1970, p . 217. 5. Armaly, M. F.: Topical dexamethasone and IOP. In Glaucoma Symposium, Tutzing Castle, 1966. Basel, Karger, 1967, p . 73. 6. Becker, B.: Topical corticosteroids and intra ocular pressure. In Becker, B., and Drews, R. C. (eds.): Current Concepts in Ophthalmology. St. Louis, C. V. Mosby, 1967, p . 132. 7. Podos, S. M., Krupin, T., Asseff, C , and Beck er, B.: Topically administered corticosteroid prepa rations. Arch. Ophthalmol. 86:251, 1971. 8. Kitazawa, Y., Kawanishi, K., and Nakamura, Y.: Steroid responsiveness of IOP in normal popula tion. Jap. J. Clin. Ophthalmol. 22:793, 1968. 9. Armaly, M. F.: Factors affecting the doseresponse relationship in steroid-induced ocular hy pertension. In Kaufman, H. E. (ed.): Ocular Antiinflammatory Therapy. Springfield, Illinois, Charles C Thomas, 1970, p . 88. 10. Kitazawa, Y.: An ocular hypertensive effect of betamethasone, with the special reference to the frequency of administration. Acta Soc. Ophthalmol. Jap. In press.