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`

`

`Volume 4 number 7 1985
`
`Current
`Eye
`Research
`
`rr
`
`Pharmacological testing in the laser-induced monkey glaucoma model
`innnee
`
`Ping-Yu Lee, Steven M. Podos, Julia R. Howard-Williams, Colette H. Severin, Aron D. Rose and Mare
`J. Siegela
`Department of Ophthalmology, Mount Sinai School of Medicine of the City University of New York,
`NY 10029, USAenneEEEUEUEnEIEda
`
`Received on 26 March 1985; accepted on 1] June 1985
`
`ABSTRACT
`Glaucoma was induced in cynomolgus monkeys by
`photocoagulating the trabecular meshwork with the
`argon laser. Repeat treatments were often
`necessary and wide intraocular pressure f luctua-
`tions were characteristic.
`Baseline intraocular pressure was measured
`with a calibrated pneumatonometer hourly for six
`hours.
`On a succeeding day a baseline measure-
`ment was made, 50 a] of the drug to be tested
`applied, and six hourly measurements of
`intraocular pressure repeated.
`The effects on
`intraocular pressure of timolol, epinephrine,
`pilocarpine, vanadate, prostaglandin Foa
`(PGFox), forskolin, and corynanthine were
`(p <
`tested in at
`least eight eyes. Significant
`0.05) reductions of
`intraocular pressure were
`produced by 0.5% timolol,
`2% epinephrine,
`4%
`pilocarpine, 1% vanadate, 500 pg of PGFoa and
`1% forskolin.
`Five per cent corynanthine
`produced no significant lowering of
`intraocular
`pressure.
`Tonography revealed an increased outflow
`facility associated with the reduction of
`intraocular pressure 2 hours after the admin-
`istration of 4% pilocarpine.
`This glaucoma animal model may be useful
`investigating agents that
`lower intraocular
`pressure by a variety of mechanisms.
`
`in
`
`INTRODUCTION
`
`The search for animals with different types of
`spontaneous glaucoma has revealed a few models in
`rabbits, dogs, chickens, and primates (1).
`The
`general disadvantage of most animal models, with
`the exception of primates,
`is that the irido-
`corneal angle anatomy is different
`from that of
`the human. Although all species seem to have a
`continuous endothelial
`lining of the aqueous
`outflow channels,
`there are major differences in
`the presence of pectinate ligaments,
`a limited
`ciliary body musculature, and a scleral venous
`plexus instead of Schlemm's canal
`(2).
`Historically,
`investigators have tried to
`create animal models of glaucoma since as early
`as 1870.
`Some methods have failed and others
`
`produced transient or prolonged elevations of
`intraocular pressure. Glaucoma has been produced
`in rabbits by the injection of 1% kaolin into the
`anterior chamber, and by encircling the globe
`with cotton threads or rubber bands (1,3).
`Kupfer (4), by inserting a polyethylene tubing
`into the angle of the anterior chamber of the
`rabbit eye, produced an elevated intraocular
`pressure within 24 hours which remained elevated
`for at
`least 3 months.
`Samis (5) and Kazdan (6)
`created glaucoma in rabbits by blocking the angle
`of the anterior chamber with methyl cel lulose.
`Hamasaki and Ellerman (7) found that injection of
`alpha-chymotrypsin directly into ow] monkey eyes
`caused an elevation in intraocular pressure.
`This technique has also been used successfully in
`rhesus monkeys (8) and rabbits (9).
`Intraocular
`pressure elevations lasting from 2 to 42 days
`have been produced in squirrel and cynomolgus
`monkey eyes by anterior chamber injections of
`autologous, fixed red blood cells (10).
`Gaasterland and Kupfer
`(11) described a new
`method for the production of sustained, elevated
`intraocular pressure in the rhesus monkey by
`repeated, circumferential argon laser photocoagu-
`lation of the mid-trabecular meshwork. This
`
`intra-
`technique caused a sustained elevation of
`ocular pressure, reduction of outflow facility,
`and retinal
`and optic nerve changes similar to
`those seen in human chronic, open-angle glaucoma.
`This model has been available for studies for 11
`
`years. Quigley and Hohman (12) treated the
`trabecular meshwork of cynomolgus monkey eyes
`with the argon laser by a variety of protocols in
`an attempt
`to cause moderate, consistent
`intraocular pressure elevation. This was
`achieved most satisfactorily with deliveries of
`
`i ©
`
`IRL Press Limited, Oxford, England.
`
`775
`
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`Current
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`
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`
`
`least
`0.5 to 1.0 seconds and a total energy of at
`50 joules.
`8y light and electron microscopy,
`the
`trabecular beams were blunted, and scattered
`
`The disc changes in
`synechiae were present.
`these experimental eyes have been similar to
`
`those previously described in human eyes with
`glaucoma (13,14),
`A satisfactory animal model has not been
`available for the investigation of the effect of
`a number of commonly used clinical and
`
`experimental drugs for the treatment of glaucoma.
`The experimental model of glaucoma in rabbit
`induced by the posterior chamber injection of
`alpha-chymotrypsin has been studied as to the
`effects of timolol, epinephrine, norepinephrine,
`isoprotereno] and propranolol! on intraocular
`pressure (15).
`The effect of topical pilocarpine
`on intraocular pressure has been studied in
`
`normotensive and glaucomatous beagles (16). We
`carried out a study of the effect of topically
`
`applied timolol, epinephrine, pilocarpine,
`vanadate, prostaglandin Foa, forskolin and
`corynanthine on intraocular pressure in the
`laser-induced monkey glaucoma model.
`
`MATERIALS AND METHODS
`
`Eight cynomolgus monkeys weighing 3 to 4 kg,
`were used. Baseline examination showed eyes with
`normal anterior chamber angles, normal
`intra-
`ocular pressure, normal outflow facility, clear
`ocular media, and normal optic nerveheads.
`
`Following baseline examination, 13 eyes
`in 3
`(bilateral
`in 5 monkeys and unilateral
`monkeys) were treated using the argon laser
`(Coherent Radiation Model 9900, U.S.A.).
`Ketamine hydrochloride was
`injected intra-
`muscularly (5-10 mg/kg) for sedation during laser
`therapy.
`The eyes were treated with topical
`proparacaine 0.5% and photocoagulated using a
`single mirror goniolens specially made to
`cynomolgus monkey specifications (Ocular
`Instruments, Bellevue, Washington, U.5.A.).
`Between 50 and 130 50-micron spots of 1000-1500
`mW power and 0.5 seconds exposure time were
`applied to the mid-portion of the trabecular
`
`meshwork for 360°,
`
`Fundus examinations and
`
`intraocular pressure measurements were repeated
`every seven days. Retreatment of the trabecular
`meshwork with laser was done if the intraocular
`
`the
`
`pressure remained normal.
`For the intraocular pressure measurements,
`monkeys were kept
`in a sitting position in
`specially designed chairs throughout each experi-
`ment,
`The intraocular pressure was measured with
`a Model 30R pneumatonometer (Digilab, Inc.,
`Cambridge, Massachusetts, U.S.A.) in animals
`lightly anesthetized with ketamine hydrochloride,
`3-5 mg/kg given intramuscularly, about
`5 minutes
`before each measurement.
`The instrument was
`
`calibrated by the manufacturer for humans and the
`verifier was used to check the tonometer
`
`calibration. Topical 0.5% proparacaine
`anesthesia was instilled prior to all
`intraocular
`pressure measurements.
`
`The drugs employed included sodium chloride
`0.9%,
`timolol maleate 0.5% (Merck Sharp & Dohme,
`West Point, Pa., U.S.A.), L-epinephrine HC]
`2%
`(Alcon Laboratories, Inc., Fort Worth, Texas,
`U.S.A.), pilocarpine HC] 4% (Alcon, Humacao,
`Puerto Rico, U.S.A.), prostaglandin Foo
`(PGFox),
`5 mg/m)
`(The Upjohn Co., Kalamazoo,
`Michigan, U.S.A.), vanadate (NaV03)
`(E, Merck,
`Darmstadt, Germany) prepared as a 1% solution in
`distilled water,
`10% DMSO, and 5% Tween 80,
`forskolin (Calbiochem Behring Co., La Jolla,
`Calif., U.S.A.) prepared as a 1% suspension in
`isotonic buffered saline containing 0.5%
`methylcellulose, and corynanthine (Sigma Co., St.
`Louis, Mo., U.S.A.) prepared as a 5% solution in
`distilled water.
`The vanadate, forskolin, and
`corynanthine were prepared fresh daily prior to
`topical ocular delivery.
`We did not use vehicles
`in the control measurements for vanadate and
`forskolin because the vehicles had no effects on
`
`intraocular pressure in normal cynomolgus monkey
`eyes in our previous studies.
`For all
`
`One drop
`experiments a 50 pl drop size was used.
`(50 1) was used of sodium chloride,
`timolol,
`L-epinephrine, pilocarpine, vanadate, forskolin,
`and corynanthine, and two drops were used of
`
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`Current
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`PGFog three to five minutes apart.
`The glaucomatous monkeys underwent baseline
`(control day) and drug treated (treated day)
`6-hour diurnal curves, the intraocular pressure
`being recorded at 9:30 a.m., 10 a.m., 10:30 a.m.,
`11:30 a.m., 12:30 p.m., 1:30 p.m., 2:30 p.m., and
`3:30 p.m,
`The baseline diurnal curve served as a
`control and was made 1 or 2 days before the
`experimental (treated) diurnal curve.
`On the
`experimental day baseline intraocular pressure
`was measured at 9:30 a.m,
`Each drug was admin-
`istered to both eyes of the monkey immediately
`after the 9:30 a.m, measurement
`(0 hour).
`
`Included in this study were those monkey eyes in
`which the intraocular pressure was 22 mm Hg or
`more in both the baseline diurnal curve and the
`
`drug treated baseline intraocular pressure
`measurements.
`A two-week washout period was
`
`employed between testing each drug on the same
`monkey. Occasionally the same eye was used twice
`to test the same drug.
`Tonography was performed after using 4%
`pilocarpine with an EDT-103 tonography unit
`(Alcon). Baseline outflow facility was
`determined between 9 a.m. and 10 a.m., 2 hours
`before administration of 4% pilocarpine.
`
`Tonography was repeated 2 hours after drug
`administration. Outflow facility values were
`
`approximated from the 1955 Friedenwald tables.
`We employed two methods to analyze the changes
`intraocular pressure after drug administra-
`of
`tion, because of
`the wide intraocular pressure
`fluctuations in the glaucomatous monkey mode).
`Method 1: The intraocular pressures on the
`treated day were compared to that on the control
`day. Method 2:
`The differences in intraocular
`pressures at
`intervals after therapy between the
`treated and control day measurements were
`compared to the initial
`(0 hour) differences
`between the treated and control day values.
`
`RESULTS
`
`meshwork and caused immediate blanching, bubble
`formation, and pigment scatter. Occasionally,
`small hyphema was noted.
`The intraocular
`pressure often fell the week following treatment
`and rose on the subsequent week or fell
`if the
`
`a
`
`treatment had been inadequate. Three eyes
`maintained a raised intraocular pressure after
`only one treatment session of 56-72 joules but
`most eyes needed 2-5 treatment sessions. Wide
`pressure fluctuations were noted in all monkey
`eyes as previously reported by Pederson and
`Gaasterland (13). Optic disc cupping was
`ultimately noted in 8 out of the 13 eyes during
`the course of this study. All eyes showed fixed
`mydriasis which may be due to laser-induced
`damage of ciliary nerves that pass through the
`ciliary body and innervate the iris sphincter
`(13).
`The effects of sodium chloride,
`
`timolol,
`
`epinephrine, pilocarpine, vanadate, PGFo4,
`forskolin, and corynanthine on the intraocular
`pressure in this glaucomatous monkey model are
`shown in Table l.
`
`Intraocular pressures before a single
`instillation of these drugs (0 hour) were similar
`in treated and contro) day measurements in all
`
`Sodium chloride 0.9% instillations had
`groups.
`no significant effect on intraocular pressure,
`comparing control and drug treated 6-hour diurnal
`curves.
`
`The 0.5% timolol significantly (p < 0.05)
`lowered intraocular pressure from 3 to 6 hours
`after instillation.
`The maximum effect occurred
`
`5 hours after drug administration, and persisted
`at this level for an additional
`1 hour, at which
`time the experiments were terminated.
`Topical application of 2% epinephrine to the
`monkey eyes produced a significant (p < 0.05)
`decrease in intraocular pressure occurring
`between 0.5 and 6 hours after drug administra-
`tion.
`The maximum reduction in intraocular
`
`pressure, occurred 1 hour after drug applica-
`tion.
`
`Elevated intraocular pressure (10P) was
`achieved in all 13 eyes treated with the argon
`Four percent pilocarpine produced a
`laser. Treatment was to the mid-trabecular
`significant
`(p < 0.05) reduction of intraocular
`
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`Current
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`Table 1: Effect of Sodium Chloride, Timolol, Epinephrine, Pilocarpine, Vanadate, PGFoa, Forskolin, and
`Corynanthine, Topically Administered, on the Intraocular Pressure in Glaucomatous Cynomolgus Monkey Eyes
`
`Groupst
`
`Eye
`No.
`
`QO Hr¥
`
`0.5 hr
`
`1 hr
`
`2 hrs
`
`3 hrs
`
`4 hrs
`
`5 hrs
`
`6 hrs
`
`Mean intraocular pressure (mm Hg + S.E.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Control 32.942.8©33.743.312 36,0+3.4 35,843.6 35,443.49 34.743,2 35.543.2 35,043.09
`
`Sodium
`
`chloride 0.9% 33.1H4.2©32,444.312 34,0+3.6 33,7+3.8 33.44+3.8 33.543.8 33.043.8 32.94.09
`
`Control
`Timo1ol, 0.5%
`
`Control
`Epinephrine,
`
`2%
`
`8
`8
`
`8
`8
`
`35.944.4
`36.874.6
`
`38.343.3
` 34,673,5
`
`34.144.4
`34.664.3
`
`32.5+4.4
`29.974.4
`
`28,943.8
`25.443.7
`
` 29,643.9
` 22,974.1§
`
`29,3+3.8
`21.474.5§
`
`27,8+3.9
`19.843.7§
`
`28.0+4.0
`20.973.7§
`
` 39.543.5
`28.493.6§
`
`40.043.3
`28.874.2§
`
`39.543.8
`29.574.6§
`
`39.843.9
`30.344.6§
`
`39.044.0
`29.874.8§
`
` 38.0+4.3
`28.074.9§
`
` 35.644.5
`26, 374.6*
`
`31.9+3.1
`32.742.9
`33.6+2.9
`33,6+3.0
`34.14+2.9
`34.143.2
`34,4+3,3
`35.0+3.4
`14
`Control
`
`
`
`
`
`
`
`
`Pilocarpine, 24.273.2§©24.03.4*4% 14 33,773.2 25.443.2§ 23,143.36 23,573.26 24.473.3§ 23.973.3§
`
`
`
`Control 41.143.7—39.443.78 39,143,8 40,143.9 41,043.7 42.143.4 42.943.4 42,543.69
`
`
`
`
`
`
`
`
`Vanadate,
`1%
`8
`37.344,1
`36,343,8*
`37,643.9* 35,644,4
`34,374.7*
`34,944.8
`34,644.4
`35,644.3
`
`
`
`Control 29.74+3.4=28.643.3 32.144,0=30.4+3.89 32.243.9 28.7+4,1 27,3+3.4 26.4+3.0
`
`
`
`
`
`
`
`
`
`
`PGFoa, 0.005% 28.473.5927.1F73.7§9 -32.772.8 32,173.0 25.943.9§ 23.8F3.7§ 24.773.6 24. 773.4
`
`
`
`
`Control 32.443.8©29.843.69 33.043.8 32.3+3.9 31.943.6 33.943.7 34.143.9 —-28.743.2
`
`
`
`
`
`
`
`
`Forskolin,
`1%
`5
`33.643.2
` 29.144.0
`27,844.18 30.144.4
`30, 044.3
`29.444.4
`29.244.3
`28.7+4.5
`
`33,04+3.6
`32.943.5
`32,0+3,4
`31,9+3.0
`31.6+2.9
`33.04+2.7
`33.842.9
`34.643.0
`14
`Control
`
`
`
`
`
`
`Corynanthine,5% 14 31.143.2929.343.5929.343.6©29.143.732.143.1t . 133. 30. 5+3 8F 30. 445.5 31.644.1
`
`
`
`(sodium chloride, timolol, epinephrine,
`tBoth eyes of the drug-treated group were treated with 50 yl
`pilocarpine, vanadate,
`forskolin, and corynanthine) or 100 1 (PGF2a) of the indicated concentration.
`Time after administration
`
`*Significantly different (p < 0.05) from the control day measurements at corresponding intervals, paired t-test.
`
`(p < 0.05) from the control day measurements at corresponding intervals and the
`$Significantly different
`differences between the treated and control day measurements significantly different
`(p < 0.05) from the initia
`(O hr) differences between the treated and control day measurements, paired t-test.
`
`pressure at 0,5 to 6 hours after the drug
`administration.
`The maximum effect occurred at
`to 2 hours.
`
`1
`
`One percent vanadate significantly (p < 0.05)
`decreased intraocular pressure in the treated
`eyes at 0.5, 1, and 3 hours only comparing
`control and treated day measurements.
`The
`maximum reduction occurred 3 hours after drug
`administration.
`
`Topical application of 500 yg of PGFoato
`the monkey eyes produced a significant
`(p < 0.05)
`decrease in intraocular pressure occurring
`between 2 to 4 hours after drug administration.
`The levels of
`intraocular pressure reduction were
`Similar at 2, 3, and 4 hours.
`
`One percent forskolin significantly (p < 0.05)
`lowered intraocular pressure only at 1 hour after
`drug administration.
`There was no significant (p > 0.1) difference
`in intraocular pressure between treated and
`control eyes after 5% corynanthine
`administration.
`
`In 13 eyes of 8 qlaucomatous monkeys, 2 hours
`after a topical administration of 4% pilocarpine,
`the mean intraocular pressure was significantly
`{p < 0.001) reduced in the treated eyes as com-
`pared to the baseline value, and the mean outflow
`
`facility was significantly (p < 0.01) increased
`as compared to the baseline value (Table 2).
`Before laser photocoagulation,
`the intraocular
`
`
`778
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`Current
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`
`The Effect of 4% Pilocarpine on the
`Table 2.
`Outflow Facility of 13 Eyes of 8 Glaucomatous
`Monkeys
`
`Intraocular
`
`pressure
`mean + S.E.
`mm_Hg)
`35.7 FS
`226+ 2.5%
`
`Out fT ow
`
`facility
`mean + S.E£.
`(ui /min/mm Hg
`0.10 + 0.02
`0.21 + 0.03t
`
`Baseline
`Treated
`
`*Significantly different as compared to baseline
`(p < 0.001), paired t-test.
`tSignificantly different as compared to baseline
`(p < 0.01), paired t-test.
`
`pressure was 19.6 + 0.5 mm Hg (mean + S.E.) and
`the outflow facility was 0.57 + 0.05 wl/min/mm Hg
`in the 13 monkey glaucoma eyes.
`
`DISCUSSION
`
`The open anterior chamber angles and the optic
`nervehead changes in the monkey eyes with
`elevated intraocular pressure induced by laser
`treatment of the trabecular meshwork are similar
`
`to the findings in human eyes with open-angle
`glaucoma.
`The glaucomatous monkey model differs
`from human glaucoma by the presence of scattered
`anterior synechiae and wide intraocular pressure
`fluctuations.
`The weekly intraocular pressure
`fluctuation in the monkey glaucoma eyes (24 +12
`mm Hg, mean IOP fluctuation + $.0.) is greater
`than in untreated human primary open-angle
`glaucoma. This finding is in agreement with that
`of previous workers (11,13).
`The mean maximum
`diurnal
`intraocular pressure fluctuation in the
`13 monkey glaucoma eyes is 8.1 mm Hg.
`Gaasterland and Kupfer (11) report that outflow
`facility, determined in laser-induced glaucoma of
`rhesus monkeys,
`ranges from 0.02 to 0.11
`yl/min/mm Hg
`(normal values: 0.33 to 0.75
`ul/min/mm Hg).
`The mean outflow facility is 0.10
`+ 0.02 y1/min/mm Hg (mean + S.E.)
`(normal values:
`0.57 + 0.05 yl/min/mm Hg)
`in our studies in 13
`cynomolgus glaucomatous monkey eyes.
`The two
`results are similar.
`
`in
`The present study employs drops of 50 yl
`order to mimic the clinical situation with regard
`to drop volume.
`Of note, a 50 pl drop is very
`large for the small monkey conjunctival cul de
`sac.
`
`The present experiments demonstrate that
`topical application of timolol, epinephrine,
`vanadate, PGFaa, pilocarpine, and forskolin
`significantly lower intraocular pressure in the
`laser-induced monkey glaucoma model and corynan-
`thine has no significant effect.
`The intraocular pressure lowering effects of
`timolol, epinephrine, and pilocarpine in this
`
`monkey model are consistent with their actions in
`clinical use.
`It is reassuring that the latter
`two compounds which act predominantly by
`increasing outflow facility are effective in the
`glaucomatous monkey eye since laser damage to the
`outflow mechanism must be rather extensive to
`
`In the present
`create the ocular hypertension.
`study,
`the ocular hypotensive effect of
`pilocarpine is associated with an increase of
`outflow facility measured tonographical ly.
`Vanadate, a potent inhibitor of the enzyme
`sodium-potassium-activated adenosine triphospha-
`tase [(Nat, Kt)ATPase],
`lowers intraocular
`pressure in rabbits (17).
`The fall
`in
`intraocular pressure is not associated with
`significant changes in outflow facility or
`episcleral venous pressure. Topical
`administration of 1% vanadate in a formulation
`
`designed to enhance penetration reduces
`intraocular pressure in normal cynomolgus monkey
`eyes associated with significant decreases in
`aqueous flow (18).
`The effects of this
`formulation of vanadate in the glaucona monkey
`model are less impressive than those of the drugs
`in clinical use.
`
`Topical application of either prostaglandin
`PGEo or PGFoa effectively reduces the
`intraocular pressure in rabbits, cats, and
`monkeys (19-21). Tonography reveals an increased
`facility of outflow but no change in aqueous flow
`simultaneous with the reduction of
`intraocular
`
`pressure in the normal eyes of cats and monkeys
`
`=
`
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`the change in outflow facility does not
`As
`(22).
`account for the total observed reduction in
`
`intraocular pressure, other mechanisms may be
`possible which may or may not be operant
`in the
`glaucomatous monkey model eye. Nevertheless, of
`the experimental drugs used in this study,
`PGFoa has the most significant effect on
`intraocular pressure.
`
`Forskolin is a unique activator of adenylate
`cyclase (23). Caprioli and Sears (24) report
`that topical ocular application of forskolin
`lowers intraocular pressure in rabbit, monkey,
`and humans and reduces aqueous flow in rabbit.
`In rabbits,
`intracameral
`injection of forskolin
`jowers intraocular pressure and increases outflow
`
`facility as measured by a constant pressure
`perfusion technique (25),
`A recent study (26)
`notes that
`topical administration of a 1%
`forskolin suspension significantly reduces
`intraocular pressure in normal cynomolgus monkey
`eyes associated with a signficant decrease in
`aqueous humor flow measured by a fluorophoto-
`metric technique and without change in
`tonographic outflow facility.
`The reductions of
`intraocular pressure induced in the present study
`are minimal.
`
`a selective oy-adrenergic
`Corynanthine,
`antagonist,
`is effective in the reduction of
`intraocular pressure when topically applied to
`the normal eyes of rabbits and monkeys (27).
`fall
`in intraocular pressure is not associated
`with significant changes in outflow facility or
`aqueous humor flow.
`The absence of an
`intraocular pressure effect
`in the glaucomatous
`monkey eye may reflect a severe reduction of
`the
`uveoscleral outflow mechanism induced by the
`laser procedure.
`
`The
`
`(1) suggests that the laser-induced
`Gelatt
`glaucoma monkey model will probably be most
`useful for the study of posterior segment changes
`as the extensive iridocorneal angle scarring
`will, for the most part, minimize many
`physiological and pharmacological alterations
`affecting aquecus outflow.
`The present study,
`however, demonstrates that the glaucoma monkey
`
`is not only suitable for investigating drug
`model
`that affect aqueous humor production (ji.e.,
`timolol, vanadate, forskolin), but also suitable
`for investigating drugs that act on outflow
`(j.e., epinephrine, pilocarpine, PGF2a).
`Drawbacks of this glaucoma model are the wide
`intraocular pressure fluctuations and the
`
`instability of the model which limits long-term
`experiments. Short-term pharmacological trials
`utilizing tonography and fluorophotometry are in
`progress.
`
`ACKNOWLEDGEMENTS
`
`The authors would like to acknowledge
`Elizabeth Wilkins for assistance in preparation
`of the manuscript,
`This work was supported in part by grants
`EY03651 and EYO1867 from the National Eye
`Institute, Bethesda, Maryland and by an
`unrestricted grant from Research to Prevent
`Blindness,
`Inc. Dr. Siegel was supported by a
`Mary and Alexander P. Hirsch award from Fight for
`Sight, Inc., N.Y¥., N.Y.
`
`CORRESPONDING AUTHOR
`
`Steven M. Podos, M.D., Department of
`Ophthalmology, Mount Sinai School of Medicine of
`the City University of New York, One Gustave L.
`Levy Place, New York, N.Y.
`10029.
`
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