Investigative Ophthalmology & Visual Science, Vol. 29, No. 10, October 1988
`Copyright © Association for Research in Vision and Ophthalmology
`
`The Effect of Prostaglandin F2a on Intraocular Pressure
`in Normotensive Human Subjects
`
`Ping-Yu Lee, Hui Shoo, Liang Xu, and Chan-Kuei Qu
`
`Hypotensive and other ocular effects were studied for 24 hr after topical application of prostaglandin
`F2a as the tromethamine salt (PGF2a) in 45 normotensive human subjects. After baseline intraocular
`pressure (IOP) measurements, 62.5 ng, 125 /xg and 250 fig of PGF2a dissolved in 50 nl of saline was
`applied to one eye of 15 subjects for each dose tested. Contralateral control eyes received 50 jtil of
`saline. As compared with the IOP of the contralateral control eyes, topical application of 62.5 ng
`PGF2a caused a significant IOP reduction at 1-12 hr, with a maximal IOP reduction of 2.2 mm Hg at 2
`hr. Treatment with 125 ng of PGF2a lowered IOP significantly at 1-21 hr, with a maximal reduction of
`3.1 mm Hg at 9 hr. Administration of 250 ng PGF^ produced a significant reduction of IOP, which
`lasted for at least 24 hr. A maximal IOP reduction of 2.9 mm Hg occurred at 7 hr. Pupillary diameter
`was not altered. Aqueous flare and anterior chamber cellular response were not seen in any of the eyes
`of the subjects at any time after topical application of 62.5-250 ng PGF2a. The drug caused side
`effects consisting of reddened skin of lower lid, ocular irritation, conjunctival hyperemia and headache.
`Invest Ophthalmol Vis Sci 29:1474-1477,1988
`
`Single-dose studies have shown that a highly signif-
`icant and prolonged reduction of intraocular pressure
`(IOP) occurred following topical application of sev-
`eral prostaglandins (PGs) in normotensive rabbit,1"3
`cat,24'5 and monkey24'6 eyes with no adverse effect, or
`with only minimal inflammation. Also, a single dose
`of topically applied PGF2a significantly reduced IOP
`in glaucomatous eyes of monkeys.6-7
`Multiple-dose studies have demonstrated that topi-
`cal application of PGE2 once or twice daily in cats
`produced a maintained reduction of IOP for at least 9
`months.8 Topical application of PGF2a twice daily in
`normal monkeys showed no evidence of tolerance or
`tachyphylaxis developing to the hypotensive response
`for several days to weeks.8"10 Twice daily dosing with
`PGF2a for 2 weeks reduced IOP as much as 13 mm
`Hg in the glaucomatous monkey eyes. There was no
`evidence of tolerance or tachyphylaxis during the
`course of treatment.''
`A single topical application of 200 ng of PGF2a
`tromethamine salt produced a significant reduction
`of IOP for at least 24 hr in 18 nonglaucomatous
`human subjects.12 Topical application of PGF2a-iso-
`
`From the Beijing Institute of Ophthalmology, Tong Ren Hospi-
`tal, Capital School of Medicine, Beijing, People's Republic of
`China.
`Supported by grants from the Beijing Health Bureau.
`Submitted for publication: November 17, 1987; accepted April
`26, 1988.
`Reprint requests: Dr. Ping-Yu Lee, Beijing Institute of Ophthal-
`mology, Tong Ren Hospital, Beijing, People's Republic of China.
`
`propylester 0.5 fig at 8 AM and 8 PM for 1 day pro-
`duced significant reduction of IOP in 12 patients with
`chronic open angle or exfoliative glaucoma.13
`The purpose of the current study was to investigate
`the hypotensive and other ocular effects of PGF2a on
`normotensive human subjects.
`
`Materials and Methods
`Forty-five normotensive human subjects, 36 fe-
`males and nine males, were studied. Their ages
`ranged from 20 to 59 years (average age of 37). The
`subjects' informed consent was obtained. An ocular
`examination was performed to confirm that no ocu-
`lar disease was present and that the two eyes had
`similar IOPs (within 3 mm Hg) which were less than
`or equal to 21 mm Hg.
`IOP was measured with a calibrated7 pneumatono-
`meter (Model 30R; Digilab, Inc., Cambridge, MA)
`following topical application of one drop of oxybu-
`procaine hydrochloride 0.4% (Dispersa Ltd., Hettlin-
`gen, Switzerland). Horizontal pupil diameter was
`measured in 0.5 mm increments with a millimeter
`ruler under standard room illumination. The
`aqueous humor flare and cellular response in the an-
`terior chamber were assessed by slit-lamp examina-
`tion.
`Each milliliter of the stock solution (Upjohn Co.,
`Kalamazoo, MI) contained PGF2a tromethamine salt
`equivalent to 5 mg PGF2a, and benzyl alcohol, 9.45
`mg, added as a preservative. The stock solution was
`diluted with normal saline to yield concentration
`
`1474
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`No. 10
`
`EFFECT OF PGF2a ON IOP IN HUMANS / Lee er ol
`
`1475
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`
`containing 62.5 ng, 125 ^g or 250 /*g PGF2a in 50 /*1.
`For all subjects, the study began between 8:30 AM
`and 9:30 AM. After baseline measurements of IOP,
`pupil diameter, and slit-lamp examination, 50 /x\ of
`the PGF2a solution was applied to one eye of 15 sub-
`jects for each dose tested. Contralateral control eyes
`received 50 n\ normal saline. Repeat measurements
`were made at 0.5, 1,2,3,5,7,9, 12, 15, 21 and24hr
`after the drug administration.
`Statistical significance of results was determined by
`use of two-tailed, paired t-test. Discrimination of
`levels of probability were made at P > 0.05, P < 0.05,
`P<0.01 and P< 0.001.
`
`Results
`Topical administration of 62.5 ng, 125 JX% or 250 /tg
`of PGF2a to one eye of normotensive human subjects
`resulted in reduction of IOP (Table 1). The difference
`in IOP between the treated eyes and the contralateral
`control eyes is shown in Figure 1.
`As compared with the IOP of the contralateral
`control eyes, topical application of 62.5 ixg of PGF2a
`produced a significant reduction of IOP at 1 hr (P
`< 0.05), 2 hr (P< 0.01), 3-7 hr (P< 0.001), and 9-12
`hr (P < 0.05) after the drug administration, with a
`maximal IOP reduction of 2.2 ± 0.6 mm Hg (mean
`± SEM) at 2 hr. As compared with the baseline
`values, the mean IOP was reduced significantly at 2
`hr (P < 0.001), 3 hr (P < 0.01), and 5-15 hr (P
`< 0.001), with a maximal IOP reduction of 3.4 ± 0.6
`mm Hg at 7 hr.
`As compared with contralateral control values,
`treatment with 125 /xg of PGF2o lowered IOP signifi-
`cantly at 1 hr (P < 0.05), 2 hr (P < 0.01), 3-12 hr (P
`< 0.001), 15 hr (P < 0.01), and 21 hr (P < 0.05) in the
`treated eyes, with a maximal IOP reduction of 3.1
`± 0.4 mm Hg at 9 hr. As compared with the baseline
`values, a significant reduction in IOP was present at
`1-15 hr and 24 hr (P < 0.001), with a maximal IOP
`reduction of 5.1 ± 0.5 mm Hg at 12 hr.
`As compared with the contralateral control eyes,
`administration of 250 ixg PGF2a resulted in a signifi-
`cant reduction of IOP in treated eyes at 1 hr (P
`< 0.01), 2 hr (P < 0.001), 3 hr (P < 0.01), 5-12 hr (P
`< 0.001), 15 hr (P < 0.05), and 24 hr (P < 0.001),
`with a maximal IOP reduction of 2.9 ± 0.7 mm Hg at
`7 hr. As compared with the baseline values, the IOP
`was reduced significantly at 1-24 hr (P < 0.001), with
`a maximal reduction of 5.4 ± 0.7 mm Hg at 12 hr.
`Pupillary diameter was not altered significantly.
`Neither aqueous humor flare nor anterior chamber
`cellular response were seen in any of the eyes of the
`subjects at any time.
`All doses of PGF2a tested produced ocular irrita-
`tion and a foreign body sensation immediately after
`
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`1476
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`INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / Ocrober 1988
`
`Vol. 29
`
`persisted as long as 24 hr after a single application.
`No miosis was noted. There was no evidence of
`breakdown of the blood-aqueous barrier as deter-
`mined by slit-lamp examination for aqueous flare.
`The mechanism of the ocular hypotensive effect of
`the PGs in general is not known. Suggestions include:
`(1) increased outflow facility12; (2) reduced aqueous
`production10; and (3) increased uveoscleral out-
`flow.14"16 Further studies are necessary with PGs in
`the hope of clearly defining their mechanism of ac-
`tion.
`In our studies, there are unfavorable side effects of
`ocular irritation, conjunctival hyperemia and
`headche. These findings are consistent with previous
`observations.1213
`PGs reduce IOP in single and/or multiple dose
`testing without evidence of tolerance or tachyphy-
`laxis in experimental animala. Significant IOP reduc-
`tions have been observed in PG-treated human eyes
`without the induction of flare, cellular response or
`miosis. They seem to show potential as new ocular
`hypotensive agents. The task remains, however, to
`conduct tests with various PG analogues to deter-
`mine which is most effective with the least local and
`systemic side effects.
`
`Key words: prostaglandin F2a, intraocular pressure, ocular
`hypotension
`
`Acknowledgments
`The authors are very grateful to Drs. Steven M. Podos
`and Carl B. Camras for their encouragement and critical
`discussions during this study. We also thank Dr. Steven M.
`Podos and Digilab, Inc. for their donation of the pneuma-
`tonometer used in this study to our Institute.
`
`References
`1. Camras CB, Bito LZ, and Eakins KE: Reduction of intraocular
`pressure by prostaglandins applied topically to the eyes of con-
`scious rabbits. Invest Ophthalmol 16:1125, 1977.
`2. Lee P-Y, Podos SM, and Severin C: Effect of prostaglandin F2a
`on aqueous humor dynamics of rabbit, cat, and monkey. In-
`vest Ophthalmol Vis Sci 25:1087, 1984.
`3. Kulkarni PS and Strinivasan BD: Prostaglandin E3 and D3
`lower intraocular pressure. Invest Ophthalmol Vis Sci 26:1178,
`1985.
`4. Stern FA and Bito LZ: Comparison of the hypotensive and
`other ocular effects of prostaglandin E2 and F2a on cat and
`rhesus monkey eyes. Invest Ophthalmol Vis Sci 22:588, 1982.
`5. Bito LZ: Comparison of the ocular hypotensive efficacy of
`eicosanoids and related compounds. Exp Eye Res 38:181,
`1984.
`6. Camras CB and Bito LZ: Reduction of intraocular pressure in
`normal and glaucomatous primate (Aotus trivirgatus) eyes by
`topically applied prostaglandin F2a. Curr Eye Res 1:205, 1981.
`7. Lee P-Y, Podos SM, Howard-Williams JR, Severin CH, Rose
`
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`i
`0 12 3
`
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`
`i
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`21
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`24
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`
`i
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`i
`i
`i
`9
`7
`5
`12
`15
`HOURS AFTER TREATMENT
`
`Fig. 1. Differences of IOP between the PG-treated eyes and the
`contralateral control eyes of 15 subjects for each dose tested (A:
`62.5 Mg/eye; B: 125 Mg/eye; C: 250 /xg/eye). Points represent the
`mean differences and the limits ± 1 SEM.
`
`the drug administration that lasted for 0.5-1 hr in
`treated eyes in all subjects. Immediately after topical
`application of PGF2a a marked conjunctival hyper-
`emia was observed in the treated eyes in all subjects.
`The hyperemia persisted for 9-12 hr after application
`of 62.5 us or 125 Mg PGF2« and for 12-24 hr after
`application of 250 ng PGF2a. Erythema of the skin of
`the lower lid was noted in two of the 15 treated eyes
`following 125 ng or 250 ng PGF2a instillation. This
`effect was reduced after 10 hr in the 125 /xg treatment
`group and after 12 hr in the 250 ng treatment group.
`Moreover, 50% of the subjects in 125 /xg or 250 ng
`treatment group had a slight headache, which gener-
`ally resolved after 2-3 hr.
`
`Discussion
`The results presented here indicate that topical ad-
`ministration of 62.5 fig, 125 ng or 250 ng PGF2« to
`one eye of normotensive human subjects causes a
`significant IOP reduction. Topical use of this drug
`group did not significantly affect pupillary diameter,
`and did not cause aqueous humor flare or anterior
`chamber cellular response. These findings are similar
`to previous observations.12
`Giuffre12 has observed that topical application of
`200 ng PGF2« tromethamine salt produced a signifi-
`cant reduction of IOP of as much as 4 mm Hg, peak-
`ing at 7-10 hr, when compared with either contralat-
`eral control eyes or baseline values in 18 normoten-
`sive human subjects. A significant reduction of IOP
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`No. 10
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`EFFECT OF PGF2a ON IOP IN HUMANS / Lee er ol
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`1477
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`AD, and Siegel MJ: Pharmacological testing in the laser-in-
`duced monkey glaucoma model. Curr Eye Res 4:775, 1985.
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`topical application of prostaglandins to cat or rhesus monkey
`eyes. Invest Ophthalmol Vis Sci 24:312, 1983.
`9. Camras CB, Podos SM, Rosenthal JS, Lee P-Y, and Severin
`CH: Multiple dosing of prostaglandin F2a or epinephrine on
`cynomolgus monkey eyes: 1. Aqueous humor dynamics. In-
`vest Ophthalmol Vis Sci 28:463, 1987.
`10. Crawford K, Kaufman PL, and Gabelt BT: Effects of topical
`PGF2n on aqueous humor dynamics in cynomolgus monkeys.
`Curr Eye Res 6:1035, 1987.
`11. Lee P-Y, Podos SM, Serle JB, Camras CB, and Severin CH:
`Intraocular pressure effects of multiple doses of drugs applied
`to glaucomatous monkey eyes. Arch Ophthalmol 105:249,
`1987.
`
`12. Giuffre G: The effects of prostaglandin F2n in the human eye.
`Graefes Arch Clin Exp Ophthalmol 222:139, 1985.
`13. Villumsen J and Aim A: The effect of prostaglandin F2n eye
`drops in open angle glaucoma. ARVO Abstracts. Invest Oph-
`thalmol Vis Sci 28(Suppl):378, 1987.
`14. Crawford K and Kaufman PL: Pilocarpine antagonizes prosta-
`glandin F2a-induced ocular hypotension in monkeys: Evidence
`for enhancement of uveoscleral outflow by prostaglandin F2n.
`Arch Ophthalmol 105:1112, 1987.
`15. Hayashi M, Yablonski ME, and Bito LZ: Eicosanoids as a new
`class of ocular hypotensive agents: 2. Comparison of the appar-
`ent mechanism of the ocular hypotensive effects of A and F
`type prostaglandins. Invest Ophthalmol Vis Sci 28:1639, 1987.
`16. Nilsson Siv FE, Stjernschantz J, and Bill A: PGF2n increases
`uveoscleral outflow. ARVO Abstracts. Invest Ophthalmol Vis
`Sci 28(Suppl):284, 1987.
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