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`British Journal of Ophthalmology, 1989, 73, 975-979
`
`Prostaglandin F2 -isopropylester eye
`drops: effect on intraocular pressure in open-angle
`glaucoma
`
`JORGEN VILLUMSEN,' ALBERT ALM,' AND MATS SODERSTROM2
`From the 'Department of Ophthalmology, University Hospital, Umea, Sweden, and the 2Department of
`Ophthalmology, Huddinge Hospital, Sweden
`
`SUMMARY In 30 patients with previously untreated open-angle glaucoma an intraocular pressure
`(TOP) curve was taken before and during treatment with PGF2,-isopropylester (PGF20-IE) eye
`drops in one eye. Compared with the pretreatment TOP, the PGF20-IE induced a slowly increasing
`reduction in TOP. Just before the first dose the IOP was 31-4 (SEM 1-6) mm Hg. When corrected
`for the fall in pressure observed in the fellow eye the largest reduction, 5 8 (SEM 0-7) mm Hg
`(p<0-001), was obtained 24 hours later, that is, 12 hours after the second dose. In a subgroup of 10
`patients the treatment was continued for one week. In this group the final pretreatment IOP was
`25*9 (SEM 1-3) mm Hg. The reduction 24 hours later was 4*5 (SEM 0.6) mm Hg (p<0-001). The
`effect was maintained and even slightly increased during the week, and on the seventh day of
`treatment the IOP reduction ranged between 4*8 and 7*6 mm Hg compared with the pretreatment
`TOP. No serious subjective or objective side effects were observed.
`
`During the last decade the effect of prostaglandin eye
`drops on intraocular pressure (1OP) has been the
`subject of many studies. In low doses they are potent
`ocular hypotensives in rabbits, cats, and monkeys.'
`The drug most thoroughly tested in primates is
`prostaglandin F20 (PGF20). Its pressure lowering
`effect seems to be due to a different mechanism from
`that of conventional glaucoma drugs. Thus, at least in
`cats and primates, changes neither in outflow
`facility4"7 nor in aqueous humour production' I
`large enough to explain the effect on IOP have been
`found. Studies in monkeys indicate that increased
`uveoscleral outflow may be the major reason for the
`reduced TOP.9-"
`In studies on the human eye 62*5-250 [ig of the
`trometamol salt of PGF20 reduces IOP 2-4 mm Hg in
`normotensive eyes, but with unacceptable side
`effects. 12-13 The lipid solubility of the trometamol salt
`is low, and esterification of PGF2, markedly increases
`the lipid solubility.'4 Thus an ester such as PGF2a-
`isopropylester (PGF20-IE) penetrates the cornea
`much easier than the parent drug and becomes de-
`esterified during its passage through the cornea.5 As
`to Jorgen
`Correspondence
`Villumsen, MD, Department of
`Ophthalmology, University Hospital, S-901 85 Umea, Sweden.
`
`a consequence 0*5-2*0 [tg PGF20-IE is enough to
`reduce IOP in man.'6 This effect is not due to reduced
`aqueous humour flow,""7 and an effect on outflow
`facility large enough to explain the effect on IOP was
`not found in normal eyes.'6 Thus an increased uveo-
`scleral outflow possibly takes place also in the human
`eye.
`Little
`is known about uveoscleral outflow in
`humans. In monkeys it is thought to be responsible
`for 30-45% of the total outflow,'8 but in humans it
`may be only about 10% . '9Furthermore, it is not clear
`to what extent results obtained in young healthy
`volunteers are valid also for glaucomatous eyes of
`elderly people. Thus the purpose of the present study
`is to determine whether the effect of PGF20-IE on
`IOP in normal eyes can be verified also in eyes with
`previously untreated open-angle glaucoma. Some of
`the results have been briefly reported previously."
`
`Subjects and methods
`
`DESIGN
`The study was designed as an unmasked, open-label
`study of the effect on IOP of PGF2A-IE. The drug
`produces some foreign body sensation and conjunc-
`
`975
`
`Micro Labs Exhibit 1034
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`
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`Br J Ophthalmol: first published as 10.1136/bjo.73.12.975 on 1 December 1989. Downloaded from
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`976
`
`tival hyperaemia even in low doses, and a reliable
`masking is not possible. Determination of IOP,
`however, was made in a masked fashion (see below).
`Thirty patients were selected for treatment during
`one day (two doses), with the possibility of extending
`the treatment period to one week in 10 patients if the
`IOP was adequately controlled during the first day of
`treatment. Two centres were involved in the study.
`The study protocol was reviewed and approved by
`the National Board of Health and Welfare and by the
`Medical Faculty, University of Umea.
`
`PATIENT SELECTION
`Only patients with previously untreated open angle
`glaucoma were included in the study. The diagnosis
`was based on an IOP of more than 21 mm Hg on at
`least three of five measurements during one day,
`open angle by gonioscopy, glaucomatous excavation
`of the optic nerve, and/or glaucomatous visual field
`defect. Only one eye in each patient was included in
`the study. In seven patients with suspected bilateral
`glaucoma the eye with the highest IOP was chosen.
`The other eye was not treated with any drug during
`the study. Patients with severe active or chronic
`systemic disease, a previous history of angle closure
`or secondary glaucoma, or any concomitant ocular
`disease were excluded. Eleven men and 19 women
`between 57 and 79 years of age were included. The
`diagnosis was glaucoma capsulare in 20 eyes and
`glaucoma simplex in 10 eyes.
`
`EXAMINATION SCHEDULE
`Day 0. A routine ocular examination was performed,
`including evaluation of the optic disc, the chamber
`angle, and the visual field (automatic perimetry,
`Competer). Repeated IOP measurements were made
`to confirm the diagnosis. The tOP was determined
`with a Goldmann tonometer, the right eye first. Five
`consecutive readings were done in each eye with the
`scale of the tonometer masked to the examiner. The
`highest and lowest values were discarded, and the
`mean of the remaining three values was accepted as
`the true lOP. Before each IOP reading both eyes
`were examined with a slit-lamp for conjunctival
`hyperaemia, cells, and flare.
`Day 1. No treatment was given, but a pressure
`curve was taken for both eyes every four hours
`between 0800 and 200() and then at 0800 the next
`morning.
`Day 2. After measuring the final pretreatment lOP
`a 30 tl eye drop containing 0-5 ig PGF2(c-IE was
`applied to one eye of each patient at 0800. A new
`pressure curve was taken for both eyes. Previous
`studies with PGF9,(-IE have shown a tendency
`to an initial increase in IOP. For that reason a first
`measurement was made 30 min after the first dose.
`
`Jorgen Villumsen, Albert Alm, and Mats Soderstrom
`
`Mean IOP and lOP reductions (Wit/i SEM) in 30
`Table 1
`patients before (day 1) and during (day 2) treatment wit/i
`PGF2,-lE in one eye. (The final 0800 value on day I is the
`same as the first 0800 value on day 2). 0-5 Ftg PGF2(I-IE was
`administered after the IOP measurements at 0800 and 2000
`on day 2. For definition of IOP reductions and drug related
`IOP reductions see text
`
`Time
`
`Treated eyes
`
`Untreated eves
`
`loP day I
`
`loP day 2
`
`lOP day I
`
`32-3(17)
`
`311 (1 6)
`31-2 (1*7)
`29 7 (1.5)
`314 (1-6)
`
`31*4(16)
`32.1 (17)
`27-2(1-6)
`26-7 (1-7)
`243 (1-4)
`248 (1-3)
`
`21-0 (1-1)
`
`19-8X(0)9)
`19.6(1-0)
`19*5 (1.0)
`20(4 (1-0)
`
`loP day 2
`20-4(1(0)
`19.6 (1 2)
`186(0(0-9)
`188 (1 2)
`18X0 (1(0)
`197 (1 2)
`
`080()
`0830
`12(X)
`16(X)
`200()
`080(X
`
`Time
`
`Reduction i'n inltraocular pressure
`
`Treated eyes
`
`09+±07
`3.8+0.7***
`4.5±0.6***
`5.6±0.8***
`65± I).0***
`
`Nontreated eyes
`0-6+04
`1 -2+0 4**
`0(8±+04
`1 +(50.4***
`0(7±0(6
`
`Drug related
`
`2.7+)0.7***
`3.6+0-6***
`4.0+0.5***
`5.8±0.7***
`
`08()(
`12(X)
`16()(
`2(X)
`()8X()
`
`Asterisks indicate significance levels; *p<0.05, **p<0.01.
`***p<000l.
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0-
`C)
`
`a)
`
`(a
`C-
`4-3
`4U)En
`
`C3-
`
`L
`
`50
`
`20
`40
`30
`10
`Pre-treatment IOP
`The effect oftwo doses of0.5 tg PGFt-lE on IOP.
`Fig. 1
`Pretreatment values, in mm Hg, are plotted on the abscissa,
`post-treatment on thle ordinate. The value just before
`application oft/iefirst dose was chosen as pretreatment value,
`that is IOP at 0800 on day 2. Post-treatment IOP is the value
`24 /iours later, 12 hours after the second dose. The solid line
`indicates no effect. Points below the dotted line repesent esees
`where the reduction in IOP exceeds 5 mm Hg. Closed circles:
`glaucoma capsulare. Open circles: glaucoma simple.
`
`Micro Labs Exhibit 1034-2
`
`
`
`Br J Ophthalmol: first published as 10.1136/bjo.73.12.975 on 1 December 1989. Downloaded from
`
`http://bjo.bmj.com/
`
` on 29 May 2018 by guest. Protected by copyright.
`
`Prostaglandin PGF2,-isopropylester eye drops: effect on intraocular pressure in open-angle glaucoma
`
`977
`
`Apart from that the same time schedule was followed
`as on day 1. A second dose of 0 5 ptg PGF2,,-IE was
`applied after the 2000 IOP determination, and a final
`IOP was determined 12 hours later, at 0800 on day 3.
`The participants were questioned about local and
`systemic symptoms.
`Days 3-8. For 10 patients treatment was continued
`for one week. Inclusion criteria for this second part of
`the study were no IOP readings above 30 mm Hg
`after treatment had been initiated and an IOP below
`22 mm Hg on at least three of the five IOP measure-
`ments during treatment. Fourteen patients fulfilled
`these criteria; 10 of these were included in the second
`part of the study. They were treated with two daily
`doses of 0 5 [g in the glaucomatous eye for another
`six days. This subgroup consisted of one man and
`nine women, four of them with glaucoma capsulare
`and six with glaucoma simplex. On days 3 to 7 they
`were examined daily at 0800 and 2000 with slit-lamp
`biomicroscopy and IOP determinations. The drug
`was applied after the IOP determination. On day 8
`the procedures for day 2 were followed, with a final
`IOP determination at 0800 on day 9, that is, 12 hours
`after the last dose.
`
`EVALUATION OF EFFECT
`The pretreatment IOP curve on day 1 was used as
`control, and the IOP reduction was defined as the
`change from baseline, that is, the difference (pre-
`treatment IOP minus post-treatment IOP). Prosta-
`glandins are rapidly inactivated in the lungs,2' and a
`contralateral effect induced by systemically absorbed
`PGF2a seems unlikely. However, a consensual IOP
`reduction has been described for several topical
`
`ocular hypotensive drugs.2 To avoid including a
`possible general effect on IOP we also calculated the
`'corrected', drug-related IOP reduction in the treated
`eye, defined as the difference in change from baseline
`between treated and untreated eye, that is, (the IOP
`reduction in the treated eye) minus (the IOP reduc-
`tion in the untreated eye). The two-tailed Student's
`t test was used to find statistically significant differ-
`ences. The results are presented as mean with SEM.
`
`Results
`
`Table 1 presents the IOP on days 1 and 2, the IOP
`reduction observed in treated and untreated eyes on
`day 2, and the corrected drug-related IOP reduction
`in the treated eye, as defined in the 'Methods'
`section. Four hours after the first dose a highly
`significant pressure reduction was observed in the
`treated
`eye, which remained significant when
`corrected for the fall in IOP observed in the untreated
`eyes. The effect slowly increased, and the largest
`effect was observed 12 hours after the second dose.
`Fig. I presents the IOP just before treatment (0800
`on day 2) and 24 hours later, that is 12 hours after the
`second dose. All but one eye responded with a
`reduction in pressure. The reduction was more than 5
`mm Hg in 18 eyes.
`The IOP for the subgroup of patients treated for
`one week with 0 5 [ig PGF2,,-IE twice daily are
`presented in Fig. 2. Treatment reduced the IOP
`significantly, and the effect remained stable through-
`out the period of treatment. Before treatment the
`mean IOP ranged between 23-6 and 26-1 mm Hg,
`after treatment between 15 5 and 20-4 mm Hg. Table
`
`Fig. 2 IOP (mean with SEM) in 10
`patients treated with 0 5 [g
`PGF0,,-IE twice daily in one eye for
`7 days. The IOP was determined
`every four hours between 0800 and
`2000 on days 1, 2, and 8, and at 0800
`and 2000 on days 3-7. Treatment
`was initiated after the 0800
`measurement on day 2 (arrow). The
`last dose was given at 2000 on day 8,
`and the final measurement was
`made 12 hours later. Closed circles:
`treated eye. Open circles: untreated
`eye.
`
`cn
`
`= E
`
`-
`E-rI
`
`.,,
`
`C)
`
`1
`
`2
`
`3
`
`5
`4
`6
`Time in days
`
`7
`
`8
`
`9
`
`Micro Labs Exhibit 1034-3
`
`
`
`Br J Ophthalmol: first published as 10.1136/bjo.73.12.975 on 1 December 1989. Downloaded from
`
`http://bjo.bmj.com/
`
` on 29 May 2018 by guest. Protected by copyright.
`
`978
`
`2 presents the reductions in IOP observed on days 2
`and 8 in these patients. Also in this subgroup there is
`a significant reduction in IOP in the treated eye from
`four hours after the first dose, even when corrected
`for the fall in IOP in the fellow eye. Once again a slow
`increase in effect is observed during the first day of
`treatment, and the IOP reduction in the treated.eye is
`more marked on day 8 than on day 2.
`that PGF2,,-IE
`A separate
`analysis revealed
`seemed to have similar effects on eyes with glaucoma
`simplex and glaucoma capsulare. Thus just before
`administration of the drug the IOP was 34-4 (SEM
`2 1) mm Hg in 20 eyes with glaucoma capsulare and
`25-3 (SEM 1 1) mm Hg in 10 eyes with glaucoma
`simplex. The drug related IOP reduction observed 24
`hours later was 6-5 (SEM 1.0) mm Hg in glaucoma
`capsulare and 4-5 (SEM 0.5) mm Hg in glaucoma
`simplex, that is 19 and 18% of initial, untreated IOP
`respectively.
`A slight to moderate conjunctival hyperaemia was
`observed in most patients in the treated eyes half an
`hour after administration' of PGF2,,-IE. With few
`exceptions the hyperaemia had disappeared 3-4
`hours later. No flare or cells were observed.
`About half the patients felt some discomfort in the
`treated eye for about one hour after application of
`the drug. This discomfort, mainly in the form of a
`foreign body sensation, was judged to be slight or
`moderate, and there was no tendency towards
`increased or decreased discomfort among the 10
`patients that were treated for seven days. No systemic
`symptoms were reported.
`
`Discussion
`
`In a previous study on the effect of PGF2,,-IE on the
`human eye a dose dependent reduction in IOP was
`observed, with 0-5 [g at the lower level of the dose
`response curve.' There was a tendency to increased
`IOP after 30 minutes and then a slow reduction that
`reached a maximum 8 to 12 hours after application of
`the drug. A similar pattern was observed in the
`present study. After a transient small increase the
`reduction slowly reached its maximum, and the
`results obtained in the group treated for one week
`indicate that the maximal effect may not even be
`reached during the first day of treatment. It must be
`kept in mind, however, that this subgroup was
`selected from patients who all responded with a
`reduction in lOP, and therefore a further increase in
`effect after the first day of treatment may be a biased
`observation.
`0-1 itg PGF2,-IE had no effect on IOP in normal
`eyes," and thus it seems unlikely that the decrease in
`IOP observed in the second, untreated eye is due to a
`true contralateral drug effect. In fact, a large part of
`
`Jorgen Villumsen, Albert Alm, and Mats Soderstrom
`
`Table 2 Mean reductions in IOP (with SEM) in 10 patients
`on the first and seventh day of treatment (days 2 and 8) wit/
`0-5 [tg PGF2(,-IE twice daily. For definitions of IOP
`reduction and drug related IOP reduction see text
`
`Time
`
`080
`1200
`1600
`20(X)
`0800
`
`Time
`
`0800
`12(X)
`160(0
`2(X)0
`08X)
`
`Treated eyes
`Day 2
`0(2 (1 *0)
`40 (0.9)**
`4.5 (1-1)**
`5-2 (0-7)***
`6f1 (1I.0)***
`
`Treated eyes
`Day8
`
`70 (1 2)***
`7-1 (1-2)***
`66 )0.8)***
`5-7 (1-2)***
`7.8 (1
`)***
`
`Untreated eyes
`Dav 2
`
`Drug related
`Day 2
`
`0-5 (0-4)
`0(5 (1.0)
`08 (07)
`2-0 (0.5)
`18(1-0)
`
`3-5 (1 4)*
`37 (9)**
`3?3 (0.4)***
`4.3 (0-6)***
`
`Untreated eves
`Dav 8
`
`Drug related
`Dav 8
`
`08(0)9)
`0 8 (1.-2)
`1 6 (0(6)*
`0-9 (0(7)
`0-2 (0-9)
`
`6-3 (1 *0)***
`6.3 (1-4)**
`4.9 (0-6)***
`4-8 (1-2)**
`7.6 (0-7)***
`
`Asterisks indicate significance levels: *p<0.05, **p<0.01,
`***p<O-Ol
`
`that reduction was observed already before any drug
`had been applied to the eye. These patients had no
`previous experience with measurements of IOP, and
`an obvious possibility is that part of the reduction
`was due to accommodation to the examination
`techniques.
`A slight conjunctival/episcleral hyperaemia was
`the only objective side effect observed in the present
`study. Large doses of prostaglandins may break
`down the blood-aqueous barrier, and flare and cells
`have been found in the anterior chamber of experi-
`mental animals.'4 No aqueous flare or cells were
`observed in the present study, which is in accordance
`with our previous experience with PGF2(,-IE in
`human eyes. In normal eyes topical administration of
`0-5-1-0 [tg PGF2(C-IE for one week has little or no
`effect on the permeability of the blood-aqueous
`barrier, even to a small molecule such as sodium
`fluorescein. 1h
`The present study was designed to evaluate effects
`on IOP, and subjective side effects cannot be
`properly evaluated because local anaesthesia was
`given for IOP measurements before every drug
`administration. Among patients treated for one week
`about half experienced no subjective side effects,
`while the slight to moderate foreign body sensation
`reported by half of them seemed to be of the same
`order as in the previous study on healthy volunteers.'5
`In conclusion, topical PGF2(,-IE reduces IOP in
`glaucomatous eyes in elderly patients. The maximal
`IOP reduction was about 20% of untreated IOP. The
`pattern of the IOP response and side effects were
`similar to those described previously for normal eyes
`in young healthy volunteers.
`
`Micro Labs Exhibit 1034-4
`
`
`
`Br J Ophthalmol: first published as 10.1136/bjo.73.12.975 on 1 December 1989. Downloaded from
`
`http://bjo.bmj.com/
`
` on 29 May 2018 by guest. Protected by copyright.
`
`Prostaglandin PGF21,-isopropylester eye drops: effect on intraocular pressure in open-angle glaucoma
`
`979
`
`PGFr,,-isopropylester eye drops were generously supplied by
`Pharmacia Ophthalmics AB, Uppsala, Sweden. The authors have
`no commercial or proprietary interest in PGFt-IE eye drops.
`
`References
`
`I Camras CB. Bito LZ, Eakins KE. Reduction of intraocular
`pressure by prostaglandins applied topically to the eyes of
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`2 Camras CB, Bito LZ. Reduction of intraocular pressure in
`normal and glaucomatous primate (Aotus triirgatlus) eyes by
`topically applied prostaglandin F2, Curr Eve Rex 1981, 1: 205-9.
`3 Stern FA, Bito LZ. Comparison of the hypotensive and other
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`Oplithalmol Vis Sci 1987; 28: 463-9.
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`15 Bito LZ, Baroody RA. The ocular pharmacokinetics of eico-
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`16 Villumsen J, Alm A. Prostaglandin F,,,-isopropylester eye
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`17 Kerstetter JR, Brubaker RF, Wilson SE, et al. Prostaglandin F,,H-
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`19 Bill A, Phillips Cl. Useosscleral drainage of aqueous humour in
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`20) Villumsen J, Alm A. The effect of prostaglandin F2,, eye drops in
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`21 Ferreira SH, Vane JR. Prostaglandins: their disappearance from
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`22 Gibbens MV. the consensual ophthalmotonic reaction. Br J
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`
`Accepted for publication 8 June 1989.
`
`Micro Labs Exhibit 1034-5
`
`