Brimonidine in the Prevention of Intraocular
`Pressure Elevation Following Argon
`Laser Trabeculoplasty
`
`Robert David, MD; George L. Spaeth, MD; Charles E. Clevenger, MD; Howard F. Pcrell, MD; Les I. Siegel, MD;
`]. Charles Hcmy, MD; Michael C. Stiles, MD; MichaelS. Passo, MD; Robert L Stamper, MD; john G. Walt, MBA;
`Elaine P. Kelley; Kuankuan S. Chen, MS
`
`Olliective: To evaluate the efficacy of 0.5% brimonidine
`tartrate, an aradrenergic agonist, in preventing intraocu(cid:173)
`lar pressure (lOP) elevation following argon laser trabecu(cid:173)
`!oplasty.
`
`Design: Ina multicenter, double-mao:;ked, randomized study,
`248 patients (248 eyes) who underwent argon laser tra(cid:173)
`beculoplasty were allocated to four treatment groups: (l)
`brimonidine administered before and after the procedure;
`(2) brimonidine administered before the procedure; (3) bri(cid:173)
`monidine administered after the procedure; and (4) ave(cid:173)
`hicle administered before and after the procedure.
`
`Results: In the first 3 hours after argon laser trabeculoplasty,
`only one (0.54%) of the 183 brimonidine-treated patients
`had a postlaser lOP increase of 10 mm Hg or more, while
`
`increases of this magnitude occurred in 13 (23%) of the 56
`patients who received only the vehicle (P<.OOl). The three
`brimonidine-treatment groups demonstrated significant mean
`reductions in lOP from the pretrabeculoplasty level ( -4 to
`-8 mm Hg), whereas the vehicle-treated group showed an
`increase in mean lOP ( 4 mm I Ig). Side effects associated with
`brimonicline treaunent included conjunctival blanching( 40.9%),
`lid retraction (7.6%), and a slight lowering of the systolic
`blood pressure.
`
`Conclu5ions: One drop of 0.5% brimonidine adminis(cid:173)
`tered either before or after surgery was found to be effi(cid:173)
`cacious and safe in preventing posttrabeculoplasty eleva(cid:173)
`tions in lOP.
`
`(Arch Ophthalmol. 1993;111:1387-1390)
`
`From the Department of Oph(cid:173)
`thalmology, Soroka University
`Hospital , Bcer-Shcva, Israel (Dr
`David); Glaucoma Service, Wills
`Ey~ Hospital, Philadelphia, Pa
`(Dr Spaeth); Medical Center
`Clinic, Pensacola, Fla (Dr
`Clevenger); Department of Oph(cid:173)
`thalmology, University of Mary(cid:173)
`land at Baltimore (Dr Perell);
`Glaucoma Center of Michigan,
`Southfield (Dr Siegel); Little
`Rock (Ark) Eye Clinic (Dr
`Henry); Hunkler Eye Clinic,
`Kansas City, Mo (Dr Stiles);
`Department of Ophthalmology,
`Oregon Health Sciences Univer(cid:173)
`sity, Portland (Dr Passo); De(cid:173)
`partment of Ophthalmology,
`California Pacific Medical Cen(cid:173)
`ter, San Francisco (Dr Stamper);
`and Department of Ophthalmol(cid:173)
`ogy Clinical Research, Allergan
`Inc, Irvine, Calif (Mr Walt and
`Mss Kelley and Chen) . Mr Walt,
`Ms Kelley, and Ms Chen are
`employees of Allcrgan Inc. Tite
`other authors have no propri(cid:173)
`etary interest in either- Allergan
`Inc or its products.
`
`A RGON LASER trabeculoplasty
`
`(ALT) is a procedure widely
`used for lowering intraocu(cid:173)
`larpressure (lOP) in patients
`-w'ith glaucoma whose lOP
`remains unsatisfactorily high despite receiv(cid:173)
`ing maximalLolerated medical therapy. For
`such patients, ALT is a useful option prior
`to filtration surgery. A major complication
`with the use of ALT is the immediate lOP
`elevation that often follows the procedure.
`This complication has been observed since
`the procedure became popular in the early
`1980s and it has been reported to occur at
`a magnitude of 10 mm Hg or more in 12%
`of the cases when ALT is performed over
`180° of the angle 1 and in 14% to 50%2.1 of
`cases when it is performed over 360° of the
`angle. This pressure increase may result from
`mechanical blockage of the trabecular mesh(cid:173)
`work by cellular debris, pigment dispersion,
`or inflammatory cells4
`; however, the exact
`mechanism by which this complication de(cid:173)
`velops is unclear. 5 This immediate lOP in(cid:173)
`crease may be of sufficient magnitude to pro-
`
`duce serious complications, including per(cid:173)
`manent loss of central field 3 ·6 In an effort
`to overcome this complication of a proce(cid:173)
`dure that is otherwise generally safe, clini(cid:173)
`cians have sought means to control the lOP
`elevations following ALT. Pressure-lowering
`drugs that are in common use are reported
`to have equivocal results. Pilocarpine (4%)
`was reported to have some effect/ but this
`has not been confirmed by others.8 Aceta(cid:173)
`zolamide was found to be ineffective in pre(cid:173)
`increases. 9 Recently, an
`lOP
`venting
`a-adrenergic agent, apraclonidine, was found
`to be effective in preventing lOP elevations
`followingALT ,10.1 1 iridotomy,5 and other an(cid:173)
`terior segment procedures. 12
`Brimonidine tartrate is a selective a 2-
`adrenergic agonist that lowers lOP in ex-
`
`Se~ Patients and Methods
`on next.. page
`
`ARCH OPHTHALMOUVOL Ill, OCT 1993
`1387
`
`Page 1 of 4
`
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`

`

`PATIENTS AND METHODS
`
`Two hundred forty-eight patients participated in a muhi(cid:173)
`center, randomized, double-masked study. To qualify, pa(cid:173)
`tients had to be at least 21 years old with useful vision in
`both eyes. Patients with prior glaucoma surgery or intraocu(cid:173)
`lar surgery were not included. Institutional review board
`approvals were obtained and all patients signed informed
`consent forms . Each patient was assigned to one of four
`treatment regimens: brimonidine administered both before
`and after ALT (B/B); brimonidine administered before and
`vehicle administered after ALT (BN); vehicle administered
`before and brimonidinc administered after ALT (VIB); and
`vehicle administered both before and after ALT (VN).
`The rationale for the selection of treatment regimens
`was based on the accepted standard clinical practice and
`recommended for apraclonidine (two instillations) which
`was to be challenged with the alternatives of treating with
`a single dose, either before or after the procedure.
`The groups were similar with regard to the type of pres(cid:173)
`sure-lowering medications that the patients were receiving
`prior to enrollment in the study. We did not collect infor(cid:173)
`mation on optic nerve appearance or visual field status to
`assess the severity of glaucomatous damage. All four groups
`received the medication 30 to 45 minutes before and im(cid:173)
`mediately after ALT.
`The study consisted of three visits The first visit usu(cid:173)
`ally took place on the clay when the AL T was performed.
`On that day, a baseline eye examination, as well as heart
`
`rate and blood pressure measurements, was performed prior
`to instillation of the first drop of study medication. Argon
`laser rrabeculoplasty was performed according to standard
`procedures, with 90±28 applications over 360° of the angle.
`The spot size was 50 J..l.m, the exposure time was 0.1 sec(cid:173)
`ond, and the intensity varied between 500 and 1500 mW
`and was aimed at the anterior portion oft he trabecular mesh(cid:173)
`work. The number of applications and the amount of power
`used were similar in all four treatment groups. Intraocular
`pressure, heart rate, and blood pressure were measured 1,
`2, and 3 hours after ALT. In addition, patients underwent
`full slit-lamp examinations at these times. If at any stage an
`unacceptable lOP elevation was observed, the patient re(cid:173)
`ceived other lOP-lowering medication(s) as needed and was
`removed from the study. At the second visit scheduled 1 to
`2 weeks after ALT treatment, and at the final visit 4 to 6
`weeks after ALT. a complete eye examination (including mea(cid:173)
`surement of lOP) was performed, and heart rate and blood
`pressure were measured.
`The data were analyzed with the two-way analysis of
`variance with Fisher's protected least significant difference
`test. Within each treatment group, mean changes from base(cid:173)
`line at each follow-up visit were analyzed using a paired t
`test. The incidence rate of lOP increases was analyzed using
`the Cochran-Mantel-Haenszel method. Of the 248 patients
`enrolled in the study, nine were disqualified from the sta(cid:173)
`tistical analysis. Two subjects had been improperly entered
`into the study and seven were excluded due to study pro(cid:173)
`tocol violations. The remaining 239 patients (239 eyes) pro(cid:173)
`vided the data for the statistical analysis.
`
`perimental animals 13 and in patients with open angle glau(cid:173)
`coma and ocular hypertension. 14 The mechanism by which
`brimonidine reduces lOP is most likely similar to other
`a-agonists (clonidine, apraclonidine) by decreasing aque(cid:173)
`ous humorproduction. 15 Based on a long-term dose-response
`study, 1
`" the 0.5% concentration was identified as the most
`effecLive and safe dose for acute lOP lowering and, there(cid:173)
`fore, this concentration was elected for use in this study.
`
`RESl LTS
`
`The four groups were similar with respect to demograph(cid:173)
`ics and iris color. The mean lOP before ALTon the day of
`the procedure in the four groups was 23.3 mm Hg for Lhe
`BIB group, 23.9 mm Hg for the BN group, 24.1 mm Hg
`for the VIB group, and 24.0 mm Hg for the VN group. Fol(cid:173)
`lowing ALT, lOP increases of 10 mm Hg or more occurred
`in one (0.54%) of 183 patients in the three groups treated
`with brimonidine and in l3 (23%) of 56 subjects in the
`vehicle-treated group. This difference was found to be sta(cid:173)
`tisticallysignificant (P<.001) (Table). As very few brimonidine(cid:173)
`treated patients had lOP increases of l 0 mm Hg or greater,
`post-AL T elevations greater than or equal to 5 mm Hg were
`also analyzed. Increases of 5 mm Hg or greater were ob-
`
`served in seven (4%) of 183 brimonidine-treated patients
`and in 23 ( 41 %) of 56 patients who received vehicle alone
`(P<.OOl) (Table).
`Changes in lOP after AL T were also measured
`(Figure 1 ). The mean of the maximal lOP change (least
`decrease or most increase) from baseline was -6.5 mm Hg
`in the BIB group, -4.2 mm Hg in the BN and V/B groups,
`and +4.2 mm Hg in the VN group . The differences be(cid:173)
`tween the brimonidine-treated groups and the vehicle-treated
`group were found to be statistically significant (P<.OOl).
`As expected, at the subsequent follow-up visits (l to 6 weeks
`after AL T) there were no significant differences among the
`groups. At these follow-up visits, all four groups demon(cid:173)
`strated significant mean decreases in lOP from baseline, of
`5 to 7 mm Hg, as a result of the procedure (P<.OOl).
`Mean lOP at baseline in the contralateral eye was simi(cid:173)
`lar in all four treatment groups. Within the first 3 hours
`after instillation of the medications, there were several sig(cid:173)
`nificant among-group differences in lOP in the contralat(cid:173)
`eral eye. The BIB group showed a mean decrease in lOP
`ranging from 2. 4 to 3.3 mm Hg; in comparison, the groups
`that received the vehicle only and brimonidine before and
`vehicle after laser surgery had a mean decrease in lOP be(cid:173)
`tween 0.6 and 1.4 mm Hg. These differences, too, were
`
`ARCH OPHTHALMOUVOL tt I. OCT 1993
`B88
`
`Page 2 of 4
`
`SLAYBACK EXHIBIT 1029
`
`

`

`found to be statistically significant (P::S.012)_ Heart rate was
`unaffected by brimonidine (Figure 2). There was a sta(cid:173)
`tistically signHicant decrease in systolic blood pressure in
`the BIB group 1, 2, and 3 hours following ALT (FiguN 3),
`but these decreases were not clinically significant. To rule
`out the effect of presurgical anxiety on the blood pressure
`readings recorded at baseline, we performed an alternative
`analysis, averaging the data from the second and third vis(cid:173)
`its ( 1 to 2 weeks and 4 to 6 weeks after AL T) to serve as
`an alternative baseline. In this alternative analysis, the de(cid:173)
`crease in systolic and diastolic blood pressure in the BIB
`group was less than in the original analysis and not sig(cid:173)
`nificantly different from the other three treatment groups.
`Ocular side effects that occurred during the first 3 hours
`after instillation included conjunctival blanching and lid
`retraction; the latter was observed in 14 (7.6%) of 183 pa(cid:173)
`tients treated with brimonidine. Lid retraction was recorded
`as moderate in one case; all the others were mild. Conjunc(cid:173)
`tival blanching was noted in 75 ( 40.9%) of 183 brimonidine(cid:173)
`treated patients. Again, the majority of these cases were re(cid:173)
`ported as mild. Blanching was rated as moderate in 16 pa(cid:173)
`tients and severe in one patient in the BIB group (at the
`first post-ALT examination, 1 hour after the second drop
`of brimonidine). Three cases each of blanching of the con(cid:173)
`junctiva and lid retraction were reported (5.4%) in the ve(cid:173)
`hicle group. There were no differences between groups in
`the other ocular parameters examined (anterior chamber
`activity, corneal staining, and visual acuity).
`
`- - -----i!Mijii§i -~--------
`The acute lOP elevation that follows ALT is a major haz(cid:173)
`ard of this procedure. The sudden increase in pressure
`may have a harmful effect, especially if the optic nerve is
`already severely compromised; serious consequences have
`6 Many lOP-lowering agents have been evalu(cid:173)
`been reported. 3
`·
`ated in an effort to prevent these post-ALT lOP increases.
`The most successful of these agents has been 1% apra(cid:173)
`clonidine, an a-adrenergic agonist. It is usually instilled
`both before and after the procedure, and it has been re(cid:173)
`ported to considerably reduce the frequency of acute post(cid:173)
`ALT elevations in lOP. 10
`12
`17
`•
`-
`The present study considered the safety and efficacy
`
`Ovaralllncldanca Iii lfitraocular Pressure (lOP) Rises•
`
`ito. of Subjil:ls
`
`Treatment Group
`Brimonjdinelbdmondine (n=60)
`Brimonldine/\lehicle (n=62)
`Vehiclelbrimonidine (n=61)
`Vehicle/Vehicle (n=56)
`
`IOP<!:5 mm Hg
`2
`2
`3
`23
`
`IOP<!:10 mm Hg
`0
`
`0
`13
`
`*The overall incidence of lOP increases of 5 mm Hg or more and 10
`mm Hg or more was significantly greater in the vehicle-treated group than
`in the three brimonidine-treated groups (P<.001).
`
`28
`
`26
`
`"" 24
`:J:
`E
`E 22
`c.:
`2
`~ 20
`~
`
`18
`
`16
`
`14
`HourO
`
`Hour 1
`
`Hour 2
`
`Hour 3 Weeks 1-2 Weeks 4-6
`
`Figure 1. Mean intraocular pressure (lOP) for 3 hours following argon
`laser trabeculoplasly and at the two follow-up visits. Solid circles indicate
`eyes receiving brimonidine both before and after surgery; solid squares,
`eyes receiving brimonidine only before surgery; solid diamonds, eyes
`receiving brimonidine only after surgery; and solid triangles, eyes receiving
`the vehicle. All three brimonidine groups showed a significant reduction
`(P< .OOT) from baseline at all three hourly readings whereas the vehicle
`showed a significant (P=.001) increase at hour 1.
`
`of another a 2-agonist, brimonidine, for reducing the in(cid:173)
`cidence of! OP increases following ALT. Three different treat(cid:173)
`ment regimens were evaluated: one drop before ALT, one
`drop after ALT, or two drops (one before and one after ALT)_
`All three regimens were significantly more effective than
`the vehicle. An increase in lOP of l 0 mm Hg or more oc(cid:173)
`curred in only one of the brimonidine-treated patients (0.54%).
`whereas an increase of this magnitude was seen in 13 vehicle(cid:173)
`treated patients (23%). The only brimonidine-treated pa(cid:173)
`tient with an IOP increase arter ALI did not differ from the
`rest of the study population. She was a 64-year-old woman
`with primary open angle glaucoma. Her treated (timolol
`and pilocarpine) lOP was 19 mm Hg. One hour after ALT.
`the lOP increased to 30 mm Hg but consequently decreased
`without any treatment to 26 mm Hg at hour 2 and to 24
`mm Hg at hour 3. The incidence of increases that occurred
`in the vehicle-treated group was similar to that seen in pre(cid:173)
`2
`vious reports in the literature. 1
`.1
`The effect ofbrimonidine as measured during the first
`3 hours following the procedure is most apparent. During
`this period, the mean lOP in the three brimonidine groups
`decreased by at least 5 to 8 mm Hg from the baseline mean,
`while the pressure increased by a mean of 4 mm Hg in the
`vehicle-treated group. Decreases in TOP from the pre-ALT
`level of 15 to 23 mm Hg were seen among brimonidine(cid:173)
`treated patients several times in the 3 hours after ALT.
`There was a slight lOP decrease from baseline in the
`contralateral eye of patients in the BIB group, but not in
`the other two brimonidine-treatment groups. This contralat(cid:173)
`eral effect ofbrimonidine has been reported in monkeys"
`and is known to also occur with apraclonidine. 17 The find(cid:173)
`ing in our study, that only patients from the BIB group had
`a contralateral effect, may indicate that this is most likely
`due to the double-dosing within a 45-minute period.
`As expected from an a-adrenergic agonist, some lid
`
`ARCH OPHTHALMOLJVOL. ll l, OCT I Y9 l
`1389
`
`Page 3 of 4
`
`SLAYBACK EXHIBIT 1029
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`

`

`90
`
`85
`
`£
`~
`80
`~
`"' c.
`"' 75
`-:;; .,
`~ 70
`a:
`t::
`ill
`I
`
`65
`
`CD
`
`60
`Hour 0
`
`Hour 1
`
`Hour 2
`
`Hour 3 Weeks 1-2 Weeks 4-6
`
`Figure 2. Mean heart rate for 3 hours following argon laser
`trabeculoplasty and at the two follow-up visits. Solid circles Indicate eyes
`receiving brlmonidine both before and after surgery: solid squares, eyes
`receiving brimonidfne only before surgery; solid di3monds. eyes receiving
`brimonidine only after surgery; and solid triangles, eyes receiving the
`vehicle. There were no significant changes from baseline or significant
`differences among groups.
`
`160
`
`0> 140
`:c
`E
`E
`~ 120
`~
`~ c..
`"C 100
`0
`0
`a5
`
`sor-----,-----~-----,,-----~----~
`HourO
`Hour 1
`Hour2
`Hour 3 Weeks 1-2 Weeks 4-6
`
`Figure 3. Mean systolic and diastolic blood pressure for 3 hours following
`argon laser lrabeculoplasf1; and at the two follow-up visits. Solid circles
`indicate eyes receiving brimonidine both before and after surgery; solid
`squares, eyes receiving brimonidine only before surgery; solid diamonds,
`eyes receivmg brimonldlne only after surgery; and solid trfangles, eyes
`receiving the Vehicle. All three brimonidine groups showed a significant
`reduction (P s .O 10) from baseline at all three hourly readings and the
`vehicle-treated group showed a reduction at hour 2 in diastolic blood
`pressure only (P=.010).
`
`retraction and conjunctival blanching accompanied this treat(cid:173)
`ment. These ocular side effects were mostly mild, were noted
`1 and 2 hours after AL T, and had diminished by the 3-hour
`post -ALT examination. In some cases, the conjunctival blanch(cid:173)
`ing was the surgeon's description of what, in fact, appears
`to he a "normal-looking" eye, as opposed to the usually red,
`inflamed conjunctiva seen in patients after the manipula(cid:173)
`tions with the contact lens while performing ALT.
`The systemic side effects of hrimonidine were mild.
`The drug had no measurable impact on the heart rate. A
`decrease in systolic blood pressure was statistically sig(cid:173)
`nificant in the BIB group at the three hourly measure(cid:173)
`ments after ALT. However, this decrease in blood pres(cid:173)
`sure was clinically insignificant; no patient fainted , needed
`treatment, or was terminated from the study as a result of
`
`blood pressure changes. As mentioned before, when the
`baseline blood pressure measurements were averaged with
`their levels l to 6 weeks after the treatment, thus allow(cid:173)
`ing for the anxiety often contributing on the day of ALT .
`the decrease in the BIB treated patients was not signifi(cid:173)
`cantly different from that in the other three treatment groups.
`This suggests that 0.5% brimonidine instilled before and
`after ALT does have a mild systemic hypotensive effect
`but that the effect is not as pronounced as the original
`analysis seemed to indicate.
`The fact that a single drop of brimonidine instilled
`either before or after ALT was as effective as treatment with
`two drops (one drop before and one after ALT) leaves the
`treating ophthalmologist the option of any one of the two
`single-drop modalities and minimizes the possible unde(cid:173)
`sired side effects that a two-drop regimen might produce.
`
`Accepted for publication May 5, 1993.
`Presented in part at the Association for Research in Vision
`and Ophthalmology Annual Meeting, Sara'>ota, Fla, May 7, 1992.
`Reprint requests to Ophthalmology Clinical Research De(cid:173)
`partment, Allergan Inc, PO Box 19534, Irvine, CA 92713-
`9534 (Mr Walt).
`
`1. Glaucoma Laser Trial Research Group. The glaucoma laser trial, 1: acute effects
`of argon laser trabeculoplasty on intraocular pressure. Arch Ophthalmol.1989;
`107:1135-1142.
`2. Krupin T, Kolker AE, Kass MA, Becker B. Intraocular pressure the day of argon laser
`trabeculoplasty in primary open-angle glaucoma. Ophthalmology. 1984;91 :361-365.
`3. Weinreb RN, Ruderman J, Juster R, Zweig K. Immediate intraocular pressure
`response to argon laser trabeculoplasty. Am J Ophthalmol_ 1983;95:279-286.
`4. Meyer E, Gdai-On M. Ultra-structural study of argon laser trabeculoplasty in
`open-angle glaucoma. Glaucoma. 1990;12:84-87.
`5. Krupin T, Stank T, Feitl ME. Apraclonidine pretreatment decreases the acute
`intraocular pressure rise after laser trabeculoplasty or iridotomy. J Glaucoma.
`1992;1 :79-86.
`6. Thomas J, Simmons RJ, Belcher CD. Argon laser trabeculoplasty in the pre(cid:173)
`surgical glaucoma patient. Ophthalmology. 1982;89:187-197.
`7. Ofner S, Samples JR. Van Buskirk EM. Pilocarpine and the increase in in(cid:173)
`traocular pressure after trabeculoplasty. Am J Ophthalmol. 1984;97:647-649.
`8. Robin AL, Pollack IP, Enger C, House B. Medical therapy for acute postop(cid:173)
`erative intraocular pressure rise following argon laser trabeculoplasty. Arch
`Ophtllalmol. 1987;105:1476-1477.
`9. Hoskins HD, Hetherington J, Minckler DS, Lieberman MF, Shaffer RN. Com(cid:173)
`plications of laser trabeculoplasty. Ophthalmology. 1983;90:796-799.
`10. Robin AL, Pollack IP, House B, Enger C. Effects of ALO 2145 on intraocular pres(cid:173)
`sure following argon laser trabeculoplasty_ Arch Ophthalmol. 1987;1 05:646-650.
`11 . Holmwood PC, Chase RO, Krupin T, et al. Apraclonidine and argon laser tra(cid:173)
`beculoplasty. Am J Ophthalmol. 1992;114:19-22.
`12 Brown RH, Stewart RH, Lynch MG, et al. ALO 2145 reduces the intraocular pressure
`elevation after anterior segment laser surgery Ophthalmology. 1988;95:378-384.
`13. Burke JA. Potter OE. The ocular effects of a relatively selective alpha 2 agonist
`(UK 14,304-18) in cats, rabbits and monkeys. Curr Eye Res. 1986;5:665-667.
`14_ Walters TR, Repass RL, Sargent JP, et al. A pilot study of the efficacy and
`safety of AGN 190342-LF 0.02% and 0.08% in patients with elevated intraocu(cid:173)
`lar pressure. Invest Ophthalmol Vis Sci_ 1991 ;32(suppl):988.
`15. Serle JB, Steidl S, Wang RF, Mittaa TW, Podos SM. Selective alpha,(cid:173)
`adrenergic agonists B-HT 920 and UK14304-18 effects on aqueous humor dy(cid:173)
`namics in monkeys. Arch Ophthalmol. 1991;109:1158-1162.
`16. Derick RJ, Walters TR, Robin AL. et al. Brimonidine tartrate: a one month dose
`response study. Invest Opl!thalmol Vis Sci. 1993;34(suppl):929.
`17. Robin AL. Short-term effects of unilateral1% apraclonidine therapy. Arch Oph(cid:173)
`thalmol. 1988;106:912-915
`
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