HEALTH SCIENCES LIBR~RY
`SEP 22 1989
`
`Micro Labs Exhibit 1019
`
`

`

`The objective of the American Academy of Ophthalmology in publishing its journal, Ophthalmology,
`is to provide opportunities for the free exchange of ideas and information. The Academy accepts
`no responsibility for any statements published in Ophthalmology. These statements are to be
`attributed solely to their authors and are not, by the fact of their publication in Ophthalmology or
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`Academy views or policy or editorial concurrence.
`
`EDITOR-IN-CHIEF
`*PAUL R. LICHTER
`Ann Arbor, Ml
`
`EDITORIAL BOARD
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`Houston, TX
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`Ann Arbor, Ml
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`Oklahoma City, OK
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`
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`Iowa City, IA
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`Philadelphia, PA
`
`• Member. Editorial
`Advisory Committee
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`Boston, MA
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`Clayton, MO
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`Richmond, VA
`
`FREDERICK T.
`FRAUNFELDER
`Portland, OR
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`Toronto, Canada
`
`EDITORIAL STAFF
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`
`Ophthalmology (ISSN O 161-6420) is published 13 times a year (monthly except August, in which two issues are published)
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`
`2A
`
`Micro Labs Exhibit 1019-2
`
`

`

`Maintained Reduction of
`lntraocular Pressure by
`Prostaglandin F 2a-1-Isopropyl
`Ester Applied in Multiple
`Doses in Ocular Hypertensive
`and Glaucoma Patients
`
`CARL B. CAMRAS, MD, 1 EARLENE C. SIEBOLD, MD, 1
`JACQUELINE S. LUSTGARTEN, MD,1 JANET B. SERLE, MD,1
`SANDFORD C. FRISCH, MD, 1 STEVEN M . PO DOS, MD, 1 LASZLO Z. BITO, PhD2
`
`Abstract: In a randomized, double-masked, placebo-controlled study, 0.25 µg
`(n = 11) or 0.5 µg (n = 13) of prostaglandin F2a-1-isopropyl ester (PGF2a-1E)
`was applied topically twice daily for 8 days to one eye of ocular hypertensive
`or chronic open-angle glaucoma patients. Compared with contralateral , vehicle(cid:173)
`treated eyes, PGF2a-1E significantly (P < 0.05) reduced intraocular pressure
`(IOP), beginning 4 hours after the first 0.5-µg dose and lasting at least 12 hours
`after the fourteenth dose, with a significant (P < 0.005) mean reduction of 4 to
`6 mmHg maintained throughout the last day of therapy with either dose. A
`contralateral effect was not observed. Mean tonographic outflow facility was
`significantly (P < 0.05) higher in PG-treated compared with vehicle-treated eyes
`(0.17 ± 0.02 versus 0.12 ± O.Q1 µljminute/mmHg , respectively; ± standard
`error of the mean) for the 0.5-µg dose. Conjunctiva! hyperemia reached a max(cid:173)
`imum at 30 to 60 minutes after PGF2a-1E application. Some patients reported
`mild irritation lasting several minutes after some doses. Visual acuity, accom(cid:173)
`modative amplitude, pupillary diameter, aqueous humor flare, anterior chamber
`cellular response, Schirmer's test, pulse rate, and blood pressure were not
`significantly altered. Our findings show that PGF2a-1E is a potent ocular hypo(cid:173)
`tensive agent and a promising drug for glaucoma therapy. Ophthalmology 96:
`1329-1337, 1989
`
`Originally received: October 9, 1988.
`Revision accepted: March 10, 1989.
`
`1 Department of Ophthalmology, Mount Sinai School of Medicine, New
`York.
`2 Department of Ophthalmology, Columbia University, College of Physicians
`and Surgeons, New York.
`
`Presented in part at the American Academy of Ophthalmology Annual
`Meeting, Las Vegas, October 1988.
`
`Supported in part by grants EY07865, EY05852, EY01867, EY06657, and
`EY00333 from the National Eye Institute, Bethesda, Maryland; an unre(cid:173)
`stricted grant from Research to Prevent Blindness Inc, New York, New
`York; a grant-in-aid from the National Society to Prevent Blindness, Inc,
`
`New York, New York; and a contribution from Pharmacia Ophthalmics,
`Uppsala, Sweden.
`
`Dr. Bito has a proprietary interest in the development of prostaglandins
`or other eicosanoids and their derivatives for the treatment of ocular hy(cid:173)
`pertension and glaucoma through relevant patents and patent applications
`that were developed, in part, under research grant EY00333 from the
`National Eye Institute, and were assigned, according to the National In(cid:173)
`stitutes of Health directives, to the Trustees of Columbia University, New
`York, New York.
`
`Reprint requests to Carl B. Camras, MD, Department of Ophthalmology,
`Box 1183, Mount Sinai Medical Center, One Gustave L. Levy Pl, New
`York, NY 10029.
`
`1329
`
`Micro Labs Exhibit 1019-3
`
`

`

`OPHTHALMOLOGY • SEPTEMBER 1989
`
`• VOLUME 96
`
`• NUMBER 9
`
`coma or ocular hypertension that was not associated with
`exfoliation syndrome.
`
`PATIENTS AND METHODS
`
`PATIENT SELECTION
`Subjects were recruited from the private practice of two
`of us (CBC and SMP) and from the clinic population at
`the Mount Sinai Medical Center. All subjects met the
`following criteria: (I) they had an established diagnosis
`of either early chronic open-angle glaucoma or ocular hy(cid:173)
`pertension; (2) their mean IOP was 23 mmHg or higher
`without treatment or 17 mmHg or higher with treatment,
`based on the last three IOP values available in each pa(cid:173)
`tient's record; (3) their mean IOP on diurnal testing on
`baseline day was at least 21 mmHg; (4) the mean difference
`in IOP between contralateral eyes was 4 mmHg or less;
`(5) there was no worse than 20/60 best-corrected visual
`acuity in either eye; (6) they had nonoccludable anterior
`chamber angles; (7) their cup-to-disc was 0.8 or less; (8)
`they had full visual fields or loss no greater than two para(cid:173)
`central defects at least I 0° from fixation; and (9) they
`were 21 years of age or older.
`Patients with moderate or advanced glaucoma were ex(cid:173)
`cluded because of the possible risks of discontinuing their
`usual glaucoma therapy during the course of this study.
`If the subjects had been receiving glaucoma therapy, use
`of all of their medications was discontinued 3 weeks before
`the study. Patients were excluded from the study for any
`one of the following reasons: (I) currently pregnant, con(cid:173)
`sidering pregnancy, or nursing an infant; (2) current use
`of any ocular medications other than for glaucoma; (3)
`an established diagnosis of exfoliation syndrome, pig(cid:173)
`mentary dispersion syndrome, or any other type of sec(cid:173)
`ondary glaucoma or angle-closure glaucoma; ( 4) prior
`treatment with any ocular surgery or laser therapy; (5) a
`history of medical noncompliance or unreliability; or (6)
`known intolerance or allergy to any drugs used in the
`study.
`
`PROTOCOL
`
`After proper informed consent and approval by the In(cid:173)
`stitutional Review Board had been obtained, a thorough
`medical history, including a detailed account of all current
`use of systemic medications, was taken from each subject.
`In addition, each patient had a general physical exami(cid:173)
`nation, including pulse and blood pressure measurements.
`A complete ophthalmologic history was taken, and ocular
`examinations were done on each patient within 3 weeks
`of the onset of the study. The baseline ophthalmologic
`examination included: best-corrected Snellen visual acu(cid:173)
`ity, Goldmann visual fields, determination of IOP by use
`of a calibrated Goldmann tonometer after topical appli(cid:173)
`cation of proparacaine 0.5%, pupillary diameter mea(cid:173)
`surement under standard room illumination, gonioscopy,
`direct and indirect ophthalmoscopic examination of the
`optic nerve head and fundus, and motility, external, and
`slit-lamp biomicroscopic examination.
`
`Based on early studies in which prostagtanddins (PGs)
`d .
`t
`abbit an cat eyes
`. .
`11
`were adm1mstere mtracamera Y o r
`PG
`in high doses it was generally concluded that
`ds were
`d cause
`.
`'.
`· fl
`·
`large
`mediators of mtraocular 10 ammat10n an
`.
`(IOP) 1 .Jowever more
`.
`.
`fi '. 1 b'
`10creases 10 10traocular pressure
`· r> be
`d e ne c1a
`1-
`recently, PGs have been s own to pro uc 2 . 1 ct·
`h
`h
`s inc u mg t e
`.
`.
`.
`.
`d
`h' h .
`olog1c effects 10 vanous tissues an organ
`eye. 3·4 It is now known that leukotriene 134, i; 1
`is. a
`':
`product of the lipoxygenase pathway of ar
`fhh o~icdacid
`·
`t · t at m uces
`k
`.
`metabolism, is a potent chemotact1c agen .
`.
`1
`the most profound sign of ocular inflammatt00
`· e~Jcytic
`s ~r~
`infiltration of the anterior chamber. In co11trahst,
`d ce c emotax1s.
`h d
`cyclooxygenase products t at o not pro u
`.
`In fact, PGs reduce IOP and cause few or no 1~traocular
`side effects when topically applied in appropnte doses
`to normotensive or glaucomatous eyes of catsf p~s, and
`monkeys. 1- 14 Although topical applicatioI1 °
`s al~o
`significantly reduces IOP in rabbits, there isa_sm~ll margm
`of safety between effective ocular hypote11s1~; Moses and
`those producing a large initial increase in JOP, b oreover,
`even low doses in rabbits seem to cause some
`r~akdown
`1
`of the blood-aqueous barrier, and tachyphY axis t~ the
`ocular hypotensive effect rapidly develops. r eventt~g a
`maintained IOP reduction for more than a ew days. Of
`all commonly used experimental animals in eye rese_arch,
`the rabbit eye may be the one which is m~t dramatically
`different from the primate eye in its sens1tIV1
`to break(cid:173)
`~
`1
`down of the blood-aqueous barrier, proba Y due to
`marked anatomic differences. 16' 17
`In the first published report on the eff ts of a PG _on
`human eyes, a single high dose of PGF2., ~omethamme
`salt caused an IOP reduction in n?rmoteJl iv,~ v~lunteers
`without significant intraocular side effi ts.
`_owever,
`other side effects, such as conjunctiva! h)-peremia, local
`irritation, ocular pain, and headaches, ,,tre ~ppa~ently
`severe enough to conclude that PGs ma)' oot. e suitable
`for the treatment of chronic glaucoma. 18 IO this.study, an
`extremely high dose (200 µ,g) of the trometha~me s~lt of
`PGF2a was used presumably because, like the ree acid of
`PGF2a, 19 it does not readily penetrate the ~o.rnea. The
`PGF2a-1-isopropyl ester (PGF2a-IE), a lipOPhtl~c prod_rug
`of PGF2a, greatly enhances delivery of the PG 2a moi~ty
`into the eye, 19 resulting in increased ocular hypotensive
`potency in animals.20-23 Of all experimental models of
`glaucoma, the laser-induced model in rn nkeys seems to
`predict most accurately the response ofth;,f.2~u~o?1ato~s
`human eye to ocular hypotensive agents. _
`smg this
`model, PGF2a-IE was foun_d to be appro~una~ely 50-fold
`greater in ocular hypotens1ve potency tb30 ! e trometh(cid:173)
`amine salt.23 When PGF2a-IE was applied m two ~oses
`12 hours apart to the eyes of ocular hypertensive pa~1e~ts
`of Scandinavian descent, most of wholil ha~ exfohattve
`glaucoma, it reduced IOP by 6 to 8 m rnJ-!g.
`Although exfoliation syndrome may ~the most com(cid:173)
`mon cause of ocular hypertension and gllucoma among
`Scandinavians,26 primary open-angle glaueoma predom(cid:173)
`inates in most other parts of the world. There~ore, ~e
`studied the IOP and potential side effect> ~f tw1<:e-da1ly
`topical application of PGF2a-IE for 8 dal m patients of
`diverse ethnic background with primary n-angle glau-
`
`5a
`
`1330
`
`Micro Labs Exhibit 1019-4
`
`

`

`CAMRAS et al • REDUCED IOP BY PGF2.-IE IN GLAUCOMA
`
`Table 1. Protocol on Baseline Day and on Days 1 and 8 of Treatment*
`
`Time of Day
`
`Measurement
`
`8:30 AM
`
`9:30 AM
`
`10:00 AM
`
`11 :00 AM
`
`1 :00 PM
`
`3:00 PM
`
`5:00 PM
`
`njunctival hyperemia
`photographst
`mptomatologyt
`ual acuity
`commodative amplitude
`pillary diameter
`junctival hyperemiat
`-lamp examination
`ueous flaret
`terior chamber cellular responset
`ocular pressure
`lse rate
`d pressure
`hirmer's test 11
`
`X
`x §
`X
`X
`X
`x §
`x §
`X §
`x §
`X §
`X
`X
`
`X
`X
`
`X
`X
`
`X
`
`X
`
`X
`X
`
`X
`X
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`X
`X
`X
`
`X
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`
`X
`
`* Treatment administered twice daily at 9:00 AM and 9:00 PM (15 doses) beginning 1 or 2 days after baseline day.
`t Evaluated on a relative scale of O to 3 as follows: 0, no reaction; 0.5, barely detectable; 1, mild; 2, moderate; 3, severe.
`
`* Including burning, stinging, irritation, foreign body sensation, pain, photophobia, tearing, and headache.
`§ These parameters were also evaluated at 9:00 AM on days 9 and 10, 24 and 48 hours, respectively, after the last dose.
`n After topical application of proparacaine 0.5%, with strips measured at 5 minutes.
`
`On the baseline day, all of the parameters indicated in
`able 1 were determined. One or 2 days later, one drop
`ntaining 0.25 or 0.5 µg of PGF2a-IE (free acid equiva(cid:173)
`t) in approximately 30 µI of vehicle solution containing
`droxypropyl methylcellulose and polysorbate (Phar(cid:173)
`·a Ophthalmics, Uppsala, Sweden) was applied to one
`of each subject, and the vehicle solution was applied
`the contralateral eye in a randomized, double-masked
`ion at 9:00 AM and 9:00 PM each day for 8 days ( 15
`). Pairs of coded bottles specifically labeled for use
`right or left eyes were supplied by the manufacturer
`armacia). Neither the examiners nor the subjects were
`onned as to which eye was receiving the active agent
`ring the course of the study. Upon completion of the
`dy, the code was broken by the manufacturer. As in-
`. ted in Table I , on the first and eighth day of treatment
`d 24 and 48 hours after the last dose, the specified pa(cid:173)
`eters were recorded at the same time of day as had
`n done on the baseline day.
`tonography
`Electronic, Schi0tz-type,
`indentation
`ode! 720, Berkeley Tonometer Co, Berkeley, CA) was
`to measure outflow facility at I :00 PM within a week
`ore beginning treatment. Tonography was repeated at
`PM on either day 2, 5, or 7 of treatment (approxi(cid:173)
`tely 4 hours after the previous dose). Outflow facility
`determined using calculations derived from standard
`ography tables27 based on work by Friedenwald.
`Compliance was monitored by careful patient ques(cid:173)
`Oning and observation of the amount of solution re(cid:173)
`· ning. Patients were asked to record the date and time
`t each dose was administered and any symptoms on
`SJ>ecially designed card that listed the specific symptoms
`llllder consideration.
`~Wo-tailed, paired t tests were used for statistical eval(cid:173)
`tion of differences between PG-treated and contralateral
`
`vehicle-treated eyes and differences between baseline and
`treatment values. The tonography tracings were evaluated
`independently by an experienced, masked observer. All
`tracings were used in the overall analyses. In addition to
`comparing absolute values for experimental and contra(cid:173)
`lateral control eyes, outflow facility was also analyzed by
`comparing the ratio of these values before and after treat(cid:173)
`ment. External photographs were evaluated independently
`by masked observers who did not take part in any clinical
`examinations. To determine relative conjunctiva! hyper(cid:173)
`emia, photographs were compared with predetermined
`standard ratings of 0, 0.5, 1, 2, and 3 for the severity of
`conjunctiva! hyperemia (Table 1).
`
`RESULTS
`
`DEMOGRAPHICS
`
`Nine women and eight men participated in the study:
`four received the 0 .25-µg dose only, six received the 0.5-
`µg dose only, and seven received both doses, separated
`by a washout period of2 weeks. Eight patients were black,
`five Hispanic, and four white. They ranged in age from
`51 to 79 years (mean, 64 ± 2). Twelve patients had full
`visual fields in both eyes, three had early glaucomatous
`loss in one eye, and two had early loss in both eyes. Five
`had been treated previously with a /3-adrenergic blocker
`alone; four with a combination of a /3-blocker and an
`adrenergic agonist; three with a /3-blocker combined with
`one or two agents other than an adrenergic agonist; and
`five had not been treated. The mean cup-to-disc ratio was
`0.44 ± 0.04 (range, 0-0.8). Fourteen patients had brown
`irides, two blue, and one green. No significant differences
`in any of these parameters existed between PG-treated
`
`1331
`
`Micro Labs Exhibit 1019-5
`
`

`

`8 26
`_§.
`Oil
`<>:
`::,
`Cl)
`Cl)
`Oil
`<>:
`0..
`
`28
`
`24
`
`22
`
`20
`
`OPHTHALMOLOGY
`
`• SEPTEMBER 1989
`
`• VOLUME 96
`
`• NUMBER 9
`
`DAY 1
`
`..... PGF2<>-IE 0.25µg
`--<>- VEHICLE
`
`PG OR VEHICLE
`
`.. :,:
`
`28
`
`26
`
`24
`
`22
`
`8
`_§.
`Oil
`<>:
`::,
`Cl)
`Cl)
`Oil
`<>:
`0..
`<>:
`...,
`< 20
`::,
`<.l
`0
`< 18
`<>:
`E-<
`2::
`
`DAY 8-10
`
`.... PGF2 a-IE 0.50µg
`
`,, ,
`!'',,,
`t-+- t ------J
`r-------+---
`
`- ,o, - VEHICLE
`
`____ I __ _
`r ~---f-1r··f
`r11
`
`PG OR VEHICLE
`
`.. :,:
`
`<>: < ...,
`
`::,
`<.l
`
`0 < 18
`
`<>:
`E-<
`~
`
`0800 0900 1000 1100 1200 1300 1400 1500 1600 1700 1800
`
`TIME OF DAY
`
`Fig I. Effects on !OP of the first 0.25-µg dose of PGF20-IE (e ) to one
`eye and its vehicle (0) to the contralateral control eye of 11 ocular hy(cid:173)
`pertensive or glaucoma patients. Points represent means, and the limits
`± standard error of the mean.
`
`0800 0900 1000 1100 1200 1300 1400 1500 1600 1700
`DAY 8
`TIME OF DAY
`
`0900 0900
`DAY 9 DAY 10
`
`Fig 4. Effects on !OP before and after the fifteenth consecutive 0.5-µg
`dose of PGF20-IE ( • ) or its vehicle (0) in 13 patients.
`
`.. :,:
`
`28
`
`8 26
`_§.
`Oil
`<>: 24
`::,
`Cl)
`Cl)
`Oil 22
`<>:
`0..
`<>:
`..,,
`5
`<.l
`0
`< 18
`<>:
`E-<
`2::
`
`20
`
`PG OR VEHICLE
`
`........... -1 .~
`~ ..... --.-......-- - . -- - - -....... -
`0800 0900 1000 1100 1200 1300 1400 1500 1600 1700
`0900
`0900
`DAY 8
`DAY 9 DAY 10
`TIM E OF DAY
`
`Fig 2. Effects on !OP before and after the last (fifteenth consecutive)
`0.25-µg dose of PGF20-I E (e ) or its vehicle (0) given twice daily for 8
`days in 11 ocular hypertensive or glaucoma patients. The 8:30 AM values
`on day 8 were taken 11 112 hours after the previous dose. Day 9 and 10
`measurements were obtained 24 and 48 hours, respectively, after the last
`dose. Points represent means, and the limits ± standard error of the
`mean. • indicates measurements significantly (P < 0.05) different from
`contralateral controls using two-tailed, paired t test.
`
`DAY 1
`
`..... PGF2 a-IE 0.50µg
`- -<> - VEHICLE
`
`..
`Oil ~ ---~-------!
`----l---'
`1
`,o OR'"'""~•
`
`28
`
`:,:
`8 26
`_§.
`
`22
`
`<>: 24
`::,
`Cl)
`Cl)
`Oil
`<>:
`0..
`<>:
`< ..., 20
`::,
`<.l
`0 < 18
`<>:
`E-<
`2::
`
`I
`I
`0800 0900 1000 1100 1200 1300 1400 1500 1600 1700 1800
`
`TIME OF DAY
`
`Fig 3. Effects on !OP of the first 0.5-µg dose of PGF20-IE (e ) or vehicle
`(0) to 13 ocular hypertensive or glaucoma patients.
`
`1332
`
`and contralateral vehicle-treated eyes or between those
`patients receiving the 0.25-µg versus the 0.5-µg dose.
`
`COMPLIANCE
`
`Patient compliance with the 1-week, twice-daily treat(cid:173)
`ment did not appear to be a problem throughout the
`course of the study. Upon specific questioning about
`missed or improper dosing, no patients reported missing
`any drug application during the 0.25-µg dose trial, and
`only one patient reported missing a single application (at
`9:00 PM on day 1 of treatment) during the 0.5-µ g dose
`trial. During each trial, one patient inadvertently applied
`the PG dose to both eyes at a single treatment time (at
`9:00 PM on day 2 of treatment with 0.25 µg and at 9:00
`PM on day 4 of treatment with 0.5 µg). Most patients
`reported a consistent degree of redness in the same eye
`that peaked 30 to 60 minutes after each dose, confirming
`compliance with the protocol. All patients properly re(cid:173)
`corded administration of the drops at the appropriate
`times. All patients initially enrolled successfully completed
`the study without problems with compliance or adverse
`reactions that would have necessitated their withdrawal.
`
`INTRAOCULAR PRESSURE
`The PGF2,,-IE caused a significant, dose-dependent re(cid:173)
`duction in IOP that became more pronounced with re(cid:173)
`peated dosing (Figs 1-4). It significantly reduced IOP (P
`< 0.005) by a mean of 4 to 6 mmHg throughout the
`eighth day of twice-daily treatment with either dose (Figs
`2, 4). A significant (P < 0.05) reduction ofIOP occurred
`4 hours after the first dose of 0.5 µg (Fig 3), and this re(cid:173)
`duction was maintained for the duration of the treatment
`(Fig 4). A significant (P < 0.01) 5-mmHg reduction of
`IOP persisted 12 hours after the fourteenth consecutive
`twice daily dose with either 0.25 or 0.5 µg (Figs 2, 4). No
`significant contralateral reduction ofIOP was noted when
`comparing values of the contralateral vehicle-treated eyes
`during the baseline day and during the course of treat(cid:173)
`ment.
`
`Micro Labs Exhibit 1019-6
`
`

`

`CAMRAS et al
`
`• REDUCED IOP BY PGF20-IE IN GLAUCOMA
`
`line measurements of outflow facility in the ex(cid:173)
`ental versus contralateral control eyes were not sig(cid:173)
`tly (P > 0.20) different before treatment. During
`py with the 0.25-µg dose, mean outflow facility was
`significantly (P > 0.30) different between the PG(cid:173)
`and contralateral vehicle-treated eyes (0.16 ± 0.02
`0.14 ± 0.02 µl/minute/mmHg, respectively).
`ver, during therapy with the 0.5-µg dose, mean out(cid:173)
`facility was significantly (P < 0.05) higher in PG(cid:173)
`than in contralateral vehicle-treated eyes (0.17
`.02 versus 0.12 ± 0.01 µl/minute/mmHg, respectively).
`
`ny patients reported mild, dose-dependent local
`ptoms, such as irritation or foreign-body sensation,
`·ng several minutes after the PG applications (Table
`A mild, transient headache was noted by two patients
`me time during the week of therapy with 0.5-µg dose.
`patient had severe symptoms or requested discontin(cid:173)
`n of the medication or withdrawal from the study.
`
`JUNCTIV AL HYPEREMIA
`
`dose-dependent conjunctival hyperemic response
`ed 30 to 60 minutes after each dose of PGF2a-IE.
`· mal mean hyperemia was graded 1 to 2 after the
`-µ,g dose and almost 2 after the 0.5-µg dose (Fig 5).
`ough the extent of the conjunctival hyperemia did
`appear to increase with multiple dosing, the duration
`conjunctiva! hyperemia seemed to be longer on day 8
`5) versus day 1 of treatment. Photographs taken be(cid:173)
`and at 30 to 60 minutes after treatment were eval(cid:173)
`independently by masked observers and correlated
`with grading by the examiners during the study. There
`a wide range of variation of the conjunctiva! hyper(cid:173)
`·c response among individual subjects (Fig 6). There
`no significant correlation between the severity of the
`~unctival hyperemia and the extent of the IOP reduc(cid:173)
`for individual subjects.
`
`ER PARAMETERS EVALUATED
`No significant difference occurred between the PG-
`ted and contralateral vehicle-treated eyes or between
`line and treatment values of any of the following:
`acuity; accommodative amplitude; pupillary di(cid:173)
`r; slit-lamp biomicroscopic evaluation of the cornea,
`lens, aqueous flare, or anterior chamber cellular re(cid:173)
`nse; Schirmer's test; pulse rate; or blood pressure.
`
`Twice-daily topical application of PGF2a-IE caused a
`-dependent and statistically significant reduction of
`P, without tachyphylaxis or tolerance, in ocular hy-
`
`Table 2. Symptomatology(% of patients)*
`
`Dose of PGF2a-1E
`
`0.25 /Lg
`(n = 11)
`
`0.5 /Lg
`(n = 13)
`
`Irritation
`Foreign body sensation
`Discomfort
`Burning
`Stinging
`
`45
`27
`0
`18
`9
`
`46
`38
`23
`15
`15
`
`PGF2• -IE = prostaglandin F2.,-1-isopropyl ester.
`* All symptoms reported were graded "mild" in severity. Numbers rep(cid:173)
`resent percentage of patients reporting more symptoms in the prosta(cid:173)
`glandin-treated versus the vehicle-treated eye at anytime during the 8
`days of therapy.
`
`3 ~ - - - - - - - - - - - - - - - - -~
`
`2
`
`1
`
`2
`-~
`" -~ ;;;
`1
`<
`Sil
`"' a:
`"' ~
`1;;
`...,
`<
`>
`~
`0
`~ 0
`...,
`z
`0
`0
`
`DAY 8-10
`
`-+- PGF2 a-IE 0.50 ,g
`- -o-- VEHICLE
`
`2- - - -?--£----~- - - -- - --§-- - - - - - - - - - --- - --t----H(cid:173)
`
`I PG OR VEHICLE
`
`'---r---...-----,,---r---...--............ -~
`0800 0900 1000 llOO 1200 1300 1400 1500 1600 1700
`0900 0900
`DAY 8
`DAY 9 DAY 10
`TIME OF DAY
`
`Fig S. Effects on conjunctiva) hyperemia before and after the 15th con(cid:173)
`secutive 0.5-µg dose of PGF2. -IE (e ) or its vehicle (0) in 13 patients.
`
`pertensive and glaucoma patients. This is in sharp contrast
`to the rapid development of tolerance to the ocular hy(cid:173)
`potensive effects of PGF2a in rabbits. 9 In fact, we observed
`progressive enhancement of the IOP reduction with re(cid:173)
`peated dosing in glaucoma patients. The extended dura(cid:173)
`tion of action was apparent in the persistence of significant
`IOP reduction at least 12 hours after the 14th consecutive
`dose, and the tendency toward maintenance of the re(cid:173)
`duction even 24 and 48 hours after the last dose. Although
`the higher dose (0.5 µg) produced a significant reduction
`of IOP beginning 4 hours after the first dose, the lower
`dose (0.25 µg) required multiple dosing before a significant
`reduction was achieved. These results correlate well with
`the pronounced ocular hypotensive effect and the ex(cid:173)
`tended action of topically applied PGs or their derivatives
`4
`7
`14
`20
`24
`in cats, dogs, and nonhuman primates. 3•
`,
`-
`•
`-
`Further studies will be required to determine the dose
`of PGF2a-IE that yields optimal IOP reduction with ac(cid:173)
`ceptable side effects in humans. It is possible that a further
`reduction of IOP can be achieved with dosing for longer
`than 1 week. Contrary to the findings in previous studies
`on nonhuman primates,7· 11
`12 unilaterally administered
`•
`
`1333
`
`Micro Labs Exhibit 1019-7
`
`

`

`OPHTHALMOLOGY
`
`• SEPTEMBER 1989
`
`• VOLUME 96
`
`• NUMBER 9
`
`Fig 6. Photographs taken during the time of maximal conjunctiva! hyperemia 30 minutes after the high (0.5-µg) dose of PGF2. -IE on the last (eighth)
`day of treatment of two patients showing the extremes of the response. Top left, the right, PG-treated eye of the first patient showing mi nimal
`hyperemia compared with: top right, the left, vehicle-treated eye of the same patient. Bottom right, the left, PG-treated eye of another patient showi ng
`severe hyperemia compared with: bottom left , the right, vehicle-treated eye of the same patient.
`
`PGs have no apparent contralateral effect in humans.
`Previous studies showed a reduction of IOP in normo(cid:173)
`tensive volunteers after a single dose of PGF2" trometh(cid:173)
`amine salt 18 or PGF2a-IE. 28 The only previous report on
`the effect of PGF2a-IE on glaucomatous human eyes stud(cid:173)
`ied primarily patients with exfoliative glaucoma who lived
`in northern Sweden. 25 Our study showed a persistent ocu(cid:173)
`lar hypotensive effect after multiple dosing in primary
`open-angle glaucoma and ocular hypertensive patients
`with diverse ethnic and racial backgrounds.
`Differences in methodology and patient selection make
`it difficult to compare the results of our study using PGF2" (cid:173)
`IE with those using the PGF2" tromethamine salt.18 How(cid:173)
`ever, PGF2"-IE appears to be many times more potent in
`humans. These results are consistent with the results of
`23 presumably because the lipid
`20-
`animal experiments, 3•
`4
`•
`soluble ester penetrates the cornea more readily, 19 allowing
`application of a lower dose which produces fewer adverse
`effects. In our study, the effective dose of0.25 µgin 30 µI
`is a concentration of approximately 0.00 I%, which is 500-
`to 4000-fold lower than the standard dose of the topically
`applied agents-timolol, epinephrine, and pilocarpine(cid:173)
`that are used clinically. Apparently, PGF2a-IE is the most
`
`potent topically applied ocular hypotensive agent ever re(cid:173)
`ported in humans.
`Previous studies on cats and monkeys that evaluated
`aqueous flow by fluorophotometry or outflow facility in(cid:173)
`dicated that the extent of IOP reduction after PG appli(cid:173)
`cation cannot be completely accounted for by either a
`decrease in aqueous flow or an increase in conventional
`29
`30 Recent studies suggest that PGs
`12
`outflow facility.10
`-
`•
`•
`act primarily by increasing uveoscleral outflow. 31
`33 In
`-
`our study, the 0.25-µg dose of PGF2"-IE significantly re(cid:173)
`duced IOP by 5 mmHg without significantly increasing
`outflow facility as determined by indentation tonography.
`These results, coupled with a previous fluorophotometric
`demonstration that PGF2"-IE has no effect on aqueous
`flow,28 are consistent with an effect of increasing uveo(cid:173)
`scleral outflow in humans. In our study, the significant
`increase in outflow facility measured with the 0.5-µg dose
`was not of sufficient magnitude to account completely for
`the observed reduction of IOP, which also suggests an
`effect on uveoscleral outflow.
`Topically applied PGF2"-IE did not alter pupillary di(cid:173)
`ameter in our study, which is consistent with previously
`reported responses in human volunteers' 8 and nonhuman
`
`1334
`
`Micro Labs Exhibit 1019-8
`
`

`

`CAMRAS et al
`
`• REDUCED IOP BY PGF20-IE IN GLAUCOMA
`
`·mates. 11 Only extremely high doses of PGF2a cause
`· d miosis in nonhuman primates.7·9
`•12 On the other
`d, PGF2a is a potent miotic agent in cats3·8-10·13·20 and
`22
`A~ in nonhuman primates,34 PGs do not produce a
`ificant anterior chamber cellular response in humans,
`shown in our study and others. 18·28 This observation is
`nsistent with the fact that PGs lack chemotactic prop(cid:173)
`· es. 6 Unlike nonhuman primates, that develop mild,
`t significant, aqueous flare 12·34 and mild elevations of
`protein concentration in the aqueous humor34 during
`ted, high dosing with PGF2a, our human subjects
`d others18·28 did not develop significant aqueous humor
`in treated versus contralateral control eyes. It is in(cid:173)
`ting that histopathologic studies have shown no in(cid:173)
`matory or other adverse effects in monkeys after
`ultiple applications of high doses of PGF2a.35 Because
`are actively removed from the circulation and me(cid:173)
`Jized by the lungs36·37 and because both PGs and their
`"tial pulmonary metabolites are actively excreted by the
`ney,38 systemic effects are not expected and were not
`rved in this study; there were no changes in pulse rate
`blood pressure.
`In our study, conjunctiva! hyperemia was the only
`· ically observable side effect of topically applied PGF2a(cid:173)
`. This effect, which is solely a cosmetic problem, is
`bably a result of the known vasodilatory effect of
`F2a. Unfortunately, conjunctiva! hyperemia may result
`poor compliance and lack of patient acceptance. Con-
`nctival hyperemia is not nec