The Effect of Adding Prostaglandin F2\g=a\-Isopropylester to Timolol in Patients With Open Angle Glaucoma J\l=o"\rgenVillumsen, MD, Albert Alm, MD \s=b\ Prostaglandin F2\g=a\-isopr hylest r (PGF2\g=a\-IE) (0.5 \g=m\g) or placebo


added twice daily for 1 week to one eye in each of 30 patients with open angle glaucoma not adequately controlled with timolol treatment. Compared with placebo, PGF2\g=a\-IE reduced the intraocular pressure of these timolol-treated eyes significantly. The absolute difference in mean change between PGF2\g=a\-IE and placebo groups was 4.5 mm Hg with a 95% confidence interval of 3.1 to 6.6 mm Hg, corresponding to a mean reduction of initial intraocular pressure of 17.4% in eyes treated with PGF2\g=a\-IE. Conjunctival or episcleral hyperemia was seen in all eyes treated with PGF2\g=a\-IE for up to 4 hours but not in eyes treated with timolol and placebo, and aqueous flare was not observed in any eye. Thirteen of 15 patients treated with PGF2\g=a\-IE, compared with only 3 of 15 who received placebo, reported mild to moderate subjective discomfort in the treated eye in the form of a foreign-body sensation that lasted for up to 2 hours. These results demonstrate that PGF2\g=a\-IE, in a dose that has previously been shown to reduce intraocular pressure in normotensive volunteers or in patients with glaucoma who are taking no other medications, also significantly reduces the intraocular pressure of patients with glaucoma whose pressures are not adequately controlled on a twicedaily regimen of timolol. (Arch Ophthalmol. 1990 ;108:1102-


Accepted for publication March 15, 1990. From the Department of Ophthalmology, University Hospital, Ume\l=a%o\, Sweden. Reprint requests to Department of Ophthalmology, University Hospital, S-901 85 Ume\l=a%o\,Sweden (Dr Alm).

Qeveral studies have demonstrated that topical application of prosta-

glandin preparations reduces

the in¬ traocular pressure (IOP) in normal and glaucomatous human eyes. The tromethamine salt of prostaglandin F2ii (PGF2J has been shown to be effective in the dose range of 62.5 to 250 pg, but such side effects as local irritation and hyperemia prevent its use for the treatment of glaucoma.12 A lipid-soluble ester, such as PGF2„-isopropylester (PGF2l>-IE),3 can be used in much lower doses and still reduce IOP in normal4"' and glaucomatous1'* eyes. Unfortunate¬ ly, the dose reduction has not resulted in an adequate separation between ef¬ fect and side effects. Local side effects were found to be unacceptable at doses of PGF2u-IE in the 2.5- to 10-pg range, which were required to obtain maximal or near-maximal IOP reduction.4 At doses of 0.5 pg, however, such side effects were usually mild and shortlasting but this dose still produced a significant reduction in IOP in previ¬ ously untreated patients with



Combination treatment is often nec¬ cases of glaucoma to obtain adequate pressure control. An additive effect of PGF2(I-IE to pilocarpine can¬ not be expected because pilocarpine has been shown to antagonize PGF2ainduced ocular hypotension in mon¬ keys." Because PGF2„-IE has no de¬ monstrable effect on aqueous flow,3,4 one would expect an additive effect of the combination PGF2a-IE and, for ex¬ ample, timolol maléate. We therefore chose to evaluate the IOP-lowering efficacy of 0.5 pg of PGF2„-IE in essary in

randomized, masked, placebo-con¬ study involving the eyes of patients with glaucoma whose prèsa


sures were not adequately controlled with twice-daily applications of 0.5% timolol alone. The results indicate that the combination of a low dose of PGF2aIE and timolol is at least as effective as the combination of timolol and


Design designed performed a random¬ ized, masked, placebo-controlled study to We


assess the effect of 0.5 µg of PGF2ll-IE or placebo applied twice daily to one eye in patients with chronic open angle glaucoma previously treated with timolol alone. In this parallel study, after 1 day's baseline observation, patients treated with timolol

randomized to receive treatment with combination of timolol and placebo or timolol and PGF2a-IE. One eye of each patient was selected for treatment at the start of the study. In patients with bilateral glaucoma (in whom both eyes fulfilled the inclusion criteria), the eye in which the IOP was higher was chosen. The drug PGF2n-IE produces some for¬ eign-body sensation and conjunctival or episcleral hyperemia for 1 to 2 hours even at low doses, and reliable masking is not possible. Possible examiner bias was pre¬ vented by masking the IOP measurements by concealing the scale of the Goldmann tonometer. The scale was read by an assis¬ tant who was unaware of the treatment that had been administered. The study pro¬ tocol was reviewed and approved by The National Board of Health and Welfare in Sweden and by the Ethics Committee of the Medical Faculty at the University of Umeá were a


Patient Selection

Patients with unilateral or bilateral chronic open angle glaucoma were recruited from two climes. Patients with an IOP of at least 22 mm Hg in one eye despite ongoing twice-daily treatment with 0.5% timolol were included. The diagnosis of glaucoma

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based on a glaucomatous visual field defect and/or a glaucomatous excavation of the optic nerve. The patient group included 11 men and 19 women ranging in age from 58 to 81 years. Patients were assigned randomly to treatment with either PGF2(lIE or placebo. Table 1 shows the results of the randomization. No important differ¬ ences were found between the two groups, and all patients completed the study.

in the two treatment groups. The results are described using the 95% confidence interval for the difference in mean change from baseline between the PGF2n-IE- and placebo-treated groups. A possible transient ocular hypertension at 8:30 AM in PGF2„-IE-treated patients was evaluated by comparing the change in IOP (8 to 8:30 AM) between the PGF2lv-IEand placebo-treated groups.

Examination Schedule



Day 1.—The




on an

outpatient basis. Each patient underwent a complete ocular examination, including vi¬ sual acuity determination, tonometry, gon¬ ioscopy, biomicroscopic evaluation of the optic disc, determination of visual fields, and a slit-lamp evaluation of the degree of conjunctival hyperemia and of the presence of flare and cells in the anterior chamber. Conjunctival hyperemia, flare, and the

presence of cells in the anterior chamber were graded as absent (0), slight ( + ), mod¬ erate ( + + ), or marked (+ + +). To estab¬ lish a pretreatment diurnal IOP curve for each subject, IOP measurements were made at 8 AM, 8:30 AM, noon, 2 PM, 6 PM, and at 8 AM the following morning. Day 2.—After the last baseline IOP mea¬ surement was obtained on the morning of day 2, one drop of PGF2l_-IE or placebo was applied to the study eye at 8 am and again at 8 PM, on both occasions 5 minutes after the application of timolol. The pressure curve was reestablished with the same time schedule as on day 1. Days 3 Through 7.—The patients ap¬ plied one drop of 0.5% timolol to the study eye at 8 AM and 8 PM at home; 5 minutes later, one drop from a masked bottle that contained either placebo or PGF2u-IE was applied. The patients were also asked to record any subjective side effects. If side

The IOP in the experimental group was gradually reduced during the first day of PGF2tl-IE treatment and an even lower level of IOP was main¬ tained in these eyes on day 8, while there was no similar IOP reduction in the placebo-treated group (Table 2). The absolute difference between the treatment groups in mean change from baseline to day 8 was 4.5 mm Hg with a 95% confidence interval of 3.1 to 6.6 mm Hg. Corresponding values for the reduction were 17.4% with a 95% confi¬ dence interval of 12.2% to 22.6%. After administration of PGF2r„ IOP increased. Thus, on day 8, when com¬ pared with placebo, the increase in IOP between the 8 am and 8:30 am measurements was significant in PGF2u-IE-treated eyes, with a mean difference of 1.46 mm Hg and a 95% confidence interval of 0.05 to 2.87 mm



between the two sexes in re¬ sponse to treatment with PGF2u-IE and no difference between the two clinics involved in the study. During enee

the study, IOP was also determined in the untreated eye. The IOP in the contralateral eyes that received nei¬ ther PGF2a-IE nor placebo applications was not significantly affected com¬ pared with IOP before the initiation of the new treatment regimen.

Objective Side Effects Flare was not the



in any eye


were seen on

Table 1.—Baseline Characteristics of the Two Treatment Groups*

Group PGF2-IE



Sex F M

16 14


Simplex Capsulare Eye

3 12

3 12


Age, IOP,

6 24 15 15


Mean SD mm





68.7 8.0








Mean SD *

analysis showed


study. A few cells

PGF2lï-IE indicates prostaglandin F2l -isopropyl-

ester; IOP, intraocular pressure.


were present, the participants were required to describe their nature, duration, and severity. Day 8.—On day 8, the patients arrived at the outpatient department at 7:30 AM with¬ out having applied their morning dose of PGF,„-IE. Their IOPs were determined be¬

fore the 8 AM dose and then with the same time schedule as on days 1 and 2, with a final dose at 8 PM and the last IOP measure¬ ment 12 hours later. Evaluation of Effect To evaluate the treatment effect, the two groups were compared with respect to change from baseline (day 1) to day 8. The six IOP values for days 1 and 8 were averaged for each subject and the differ¬ ence (mean IOPr,aj. , minus mean IOP(l.,v J was used as a measure of the effect. The treatment effect is related to the initial IOP with greater effects at high initial IOPs (Fig 1). Because percent change from base¬ line was approximately constant over the entire range of baseline IOPs (Fig 2), the statistical analysis was also performed us¬ ing this measure. The distribution of indi¬

vidual changes from baseline was compared

Fig 1. —The relationship between initial intraocular pressure (IOP) and mean IOP reduction in 15 eyes treated with 0.5 µg of prostaglandin F2u-isopropylester twice daily for 1 week. For each eye, the mean IOP of six measurements before and after 1 week's treatment was calculated, and the difference between these two mean values was used as an estimate of the mean reduction in that eye. The dashed line represents the regression line.

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to be moderate after 30


Subjective Side Effects In the placebo group, 3 of 15 patients reported some subjective discomfort; 2 reported slight discomfort for several hours in both eyes, and 1 reported slight pain in the treated eye for 5

minutes after instillation of the eye

drop on treatment day 7. In the PGF2

The effect of adding prostaglandin F2 alpha-isopropylester to timolol in patients with open angle glaucoma.

Prostaglandin F2 alpha-isopropylester (PGF2 alpha-IE) (0.5 microgram) or placebo was added twice daily for 1 week to one eye in each of 30 patients wi...
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