Volume 1 Number 4 1981
`
`Reduction of intraocular pressure in normal and glaucomatous primate (Aotus
`trivirgatus) eyes by topically applied prostaglandin F,
`
`C.B.Camras, and L.Z.Bito
`
`Department of Ophthalmology, Research Division, College of Physicians and-Surgeons, Columbia
`University, New York, NY 10032, USA
`
`-
`Current
`hYe Research
`
`Received 24 June 1981; accepted 24 July 1981
`
`ABSTRACT
`Topical a p p l i c a t i o n o f a s i n g l e dose o f 1.0 mg
`(PGF,a) o n t o t h e cornea of f i v e
`prostaglandin F,a
`t r a i n e d owl monkeys ( Aotus
`t r i v i r g a t u s ) caused a
`prolonged and h i g h l y s i g n i f i c a n t o c u l a r hypotony.
`The i n t r a o c u l a r pressure ( I O P ) o f t h e t r e a t e d eye
`was 4.7 f 0.9 mn Hg below t h a t o f t h e c o n t r o l e y e
`t o 7 4 h r a f t e r PGF,a a p p l i c a t i o n and remained
`1A
`for over 72 h r . Miosis,
`s i g n i f i c a n t l y
`reduced
`aqueous f l a r e , and accunulation o f c e l l s i n
`t h e
`a n t e r i o r chamber were minimal
`i n e x t e n t .
`The
`e v e n more
`h y p o t e n s i v e e f f e c t o f PGF,a was
`pronounced when a p p l i e d t o a g l a u c o m a t o u s owl
`monkey eye with angle r e c e s s i o n , which had
`IOPs
`t o 55 mn Hg
`c o n s i s t e n t l y
`i n
`t h e 45
`range (mean:
`47.2 f 0 . 7 ) a s measured p e r i o d i c a l l y o v e r a
`one-year period. The a p p l i c a t i o n o f a s i n g l e dose
`t o t h i s hypertensive eye reduced
`of 1.0 mg o f PGF,a
`IOP by over 25 mn Hg w i t h i n 4 h r , with a r e l a t i v e
`l e a s t 6 days.
`These
`hypotony
`l a s t i n g
`f o r a t
`results show
`t h a t t o p i c a l a p p l i c a t i o n o f c e r t a i n
`PGs
`t o normotensive o r hypertensive pr imate eyes
`can cause a
`long
`l a s t i n g and h i g h l y s i g n i f i c a n t
`decrease i n IOP. and suggest t h a t p r o s t a g l a n d i n s o r
`t h e i r analogues may a i d i n t h e t h e r a p e u t i c c o n t r o l
`of o c u l a r hypertension and glaucoma.
`
`INTRODUCTION
`t h e o c u l a r e f f e c t s o f
`E a r l i e r s t u d i e s on
`i n
`prostaglandins
`(PGs) d e s c r i b i n g changes
`IOP,
`p u p i l l a r y d i a n e t e r , and p - o t e i n c o n c e n t r a t i o n i n
`t h e aqueous hunor were m o s t l y l i m i t e d t o observa-
`t i o n s du-ing t h e f i r s t few hou-s a f t e r rrlministra-
`t i o n o f r e l a t i v e l y high doses o f t h e s e autacoids.
`01 t h e b a s i s o f such s t u d i e s . it w s c o n c l d e d t h a t
`s e v e r e o c u l a r
`inflamnatory response
`PGs cause a
`c h a r a c t e r i z e d by marked o c u l a r h y p e r t e n s i o n ,
`p u p i l l a r y m i o s i s , and a breakdown o f t h e blood-
`aqueous b a r r i e r ( 1 ) . b r e r e c e n t l y , it w s shorn
`t h a t low doses o f PGF
`applied t o p i c a l l y t o r a b b i t
`2a
`eyes cause a h i g h l y s i g n i f i c a n t and
`long
`l a s t i n g
`reduction in IOP which is a s s o c i a t e d with increased
`o u t f l o w f a c i l i t y , b u t i s n o t m e d i a t e d by
`t h e
`s y n p a t h e t i c nervous
`system o r b y endcgemus PG
`s y n t h e s i s ( 2 ) .
`Ihe few reported s t u d i e s on o c u l a r e f f e c t s o f
`
`PGs i n monkeys o r hunans i n d i c a t e t h a t t h e primate
`eye is c o n s i d e r a b l y less s e n s i t i v e than t h e r a b b i t
`e y e t o t h e inflamnatory e f f e c t s of PGs ( 3 , 4 , 5 , 5 ) .
`I-bwver, no s t u d i e s have been reported on p - h a t e
`e y e s which follow I O P changes p a s t t h e f i r s t 9Q min
`a f t e r t o p i c a l a p p l i c a t i o n o f pcIs.
`In t h e p r e s e n t experiments, t h e f l o a t i n g t i p
`p e u n a t i c t o n a n e t e r w s used on t r a i n e d , conscious
`owl monkeys so
`t h a t c h a n g e s
`i n
`I O P c o u l d be
`measured p e r i o d i c a l l y f o r s e v e r a l d a y s a f t e r
`t o p i c a l a p p l i c a t i o n o f PCF
`This s t d y included
`2a'
`one owl monkey which had a long-standing u n i l a t e r a l
`angle r e c e s s i o n glaucana o f mknom o r i g i n .
`
`MATERIALS AND METHODS
`F i v e normal owl monkeys (Aotus t r i v i r g a t u s : 3
`males and 2 f a n a l e s ; 0.8 t o 1.0 kg) and one f e n a l e
`w i t h u n i l a t e r a l a n g l e r e c e s s i o n glaucoma were
`conditioned, a s previously described ( 7 ) . t o a c c e p t
`h a n d l i n g , r e s t r a i n t , and tonometry without anesthe-
`s i a . The I O P o f both eyes was measured over a one-
`year period a t random i n t e r v a l s , b u t a t l e a s t once
`each month.
`(Xle d r o p o f 0.5% proparacaine hydro-
`c h l o r i d e ( A l c a i n e ; Alcon b r p . . F o r t Worth, TX) w s
`applied t o t h e eye b e f o r e TOP was measured with a
`f l o a t i n g t i p pneunatic tonometer probe ( 8 ) attached
`t o a p r e s s u r e
`t r a n s d u c e r and a
`r e c o r d e r a s
`d e s c r i b e d b e f o r e (7). Each animal was placed
`i n
`t h e supine p o s i t i o n on t h e l a p of t h e i n v e s t i g a t o r
`and 2 or 3
`I O P measurements, each s e v e r a l seconds
`i n d u r a t i o n , were
`taken.
`The b e s t s t e a d y - s t a t e
`s e g m e n t s o f
`t r a c i n g s were
`r e a d and
`t h e
`I O P
`a v e r a g e d .
`P u p i l l a r y d i a m e t e r was measured
`i n
`normal room
`l i g h t with a pupil gauge.
`Anterior
`chamber f l a r e and c e l l u l a r invasion were determined
`by s l i t l a n p exanination and r a t e d a s p r e v i o u s l y
`described ( 9 ) .
`
`@ IRL Press Limited, 1 Falconberg Court, London W1V 5FG, England
`
`205
`
`Micro Labs Exhibit 1009
`
`

`

`( a g i f t from
`tromethamine s a l t o f R;F
`The
`2a
`IT. John E. p i h , me Upjohn 01.. Kalanazoo, Flich.)
`was dissolved
`i n p h y s i o l o g i c a l s a l i n e
`t o y i e l d
`c o n c e n t r a t i o n s of 20, 40, 90 or 200 mg/ml.
`PCF2a
`In each experiment 5 ,,1 o f one o f t h e s e s o l u t i o n s
`was applied t o one eye o f each monkey.
`Tne e y e s
`l a t e r with 2 t o 4 m l of
`were r i n s e d 3
`t o 5 min
`o f s a l i n e was
`(5 $)
`s a l i n e .
`~n e q u a l volune
`s i m i l a r l y applied t o t h e c o n t r a l a t e r a l c o n t r o l eyes
`r i n s i n g . Measurements o f
`f o l l o w e d b y
`I O P ,
`p u p i l l a r y d i a m e t e r , and slit l a n p e v a l u a t i o n o f
`aqueous f l a r e and c e l l u l a r c o n t e n t o f t h e a n t e r i o r
`chamber were made a t v a r i o u s i n t e r v a l s a f t e r FGF 2 a
`a p p l i c a t i o n .
`
`RESULTS
`S t u d i e s on normal owl monkey eyes
`Topical a p p l i c a t i o n o f 0.2 mg of PGF
`t o one
`2a
`eye ( l e f t eye i n 2 and r i g h t eye i n 3 animals) o f
`t h e 5 normal owl monkeys d i d not result i n s i g n i f i -
`c a n t e f f e c t s on t h e IOP a s canpared t o t h e b a s e l i n e
`I O P o f t h e t r e a t e d e y e o r t h e simultaneously mea-
`sured IOP i n t h e c o n t r a l a t e r a l eye (Table l ) . How-
`e v e r , t o p i c a l a p p l i c a t i o n of l mg of PGF
`t o t h e
`2a
`l e f t eye o f t h e s e animals 4 t o 14 days a f t e r t h e
`f i r s t t r i a l r e s u l t e d i n a prolonged hypotony i n t h e
`t h e c o n t r a l a t e r a l eye
`t r e a t e d eye canpared with
`In 3 o f t h e 5 e y e s t h i s hypotony was
`( F i g . 1 ) .
`preceded by a 2-3 mm I-g rise i n I O P o c c u r r i n g 15
`min a f t e r treatment and s b w i n g b o r d e r l i n e s i g n i f i -
`t h e c o n t r a l a t e r a l eye ( T a b l e
`cance canpared with
`A prolonged hypotony was a l s o observed when
`1 ) .
`t h e sane dose o f PGF was applied 6 days l a t e r t o
`2a
`t h e c o n t r a l a t e r a l ( r i g h t ) e y e s o f t h e s e monkeys, o r
`Men it was applied 18 days later t o t h e o r i g i n a l l y
`t r e a t e d eyes (Table 1 ) . A l t b L g h t h e extent o f
`i n t h e t r e a t e d eye was about t h e
`o c u l a r hypotension
`sane a f t e r each a p p l i c a t i o n o f 1.0 mg of PGF
`t h e
`2a'
`s i g n i f i c a n c e o f t h e TOP d i f f e r e n c e s b e t w e n t r e a t e d
`and c o n t r a l a t e r a l e y e s was reduced on subsequent PC
`a p p l i c a t i o n because o f an apparent c o n t r a l a t e r a l
`hypotensive e f f e c t . These
`I O P e f f e c t s on t h e un-
`t r e a t e d c o n t r a l a t e r a l eyes =re not due t o d i u r n a l
`v a r i a t i o n s s i n c e tonanetry done over a 24-hr period
`t h e eyes o f t h e s e sane animals a f t e r b i l a t e r a l
`on
`
`206
`
`TABLE 1. The e f f e c t s o f t o p i c a l l y applied PGF
`2a
`t h e TOP o f f i v e normal owl monkeys
`TOP (mm kg; mean f Sm)
`B
`A
`Treated
`Control
`Eye
`Eye
`
`on
`
`P**
`A v s A
`
`PGF, a
`Treatment Time
`(dose/eye) ( i n h r s ) *
`Date
`-0.25
`0.2 mg
`+O. 25
`O.D. o r
`0. s.
`+ 4
`+ a
`a/ii/-ra
`o r 8/21/78 +24
`
`i9.u 5 n.2
`0.4
`19.2
`20.0 t 0.8
`20.8 f 0.6
`17.8 f 1.7 10.3 f 1.7
`19.0 f 2.0
`21.0 f 2.0
`18.4 f 1.2
`i9.n f 1.1
`
`NS
`NS
`NS
`NS
`NS
`
`1.0 mg
`0. s.
`8/25/78
`
`1.0 mg
`0. D.
`m i r r a
`
`1.0 mg
`0. s.
`911 2/78
`
`-
`None
`( S a l i n e )
`0. u.
`9/26/78
`
`-0.25
`+O. 25
`+ 4
`+ 8
`+12
`+2 4
`
`-0.25
`+O. 25
`+ 4
`+ a
`+12
`+24
`
`-0.25
`+O. 5
`+ 4
`+12
`+2 4
`
`-0.25
`+0.25
`+ 4
`+ a
`+12
`+2 4
`
`19.0 f n.4
`18.8 f 0.7
`NS
`21.8
`1.0 20.4 f 1.6
`(0.1
`17.4 f 0.8 a . o i
`15.4 f 0.7
`12.0 f 1.0
`16.2 f 1.2 <0.001
`11.6 f 0.7
`a . m i
`1 5 . ~ f 0.8
`14.2 f 0.4 19.0 f 0.6
`(0.001
`
`NS
`19.0 f 0.8
`19.0 f O.A
`21.2 f 0.6 19.4 f 0.9
`(0.05
`17.6 f 1.1 17.6 f 1.3
`NS
`13.2 f 1.0
`16.0 f 1.7 (0.05
`11.6 f 0.8
`14.6 f 1.2
`(0.05
`14.2 f 1.4
`16.8 f 1.0
`(0.05
`
`16.6 f 0.8 16.4 f 0.7
`19.6
`1.5 18.8 f 1.2
`14.6 f 1.7 14.6 f 1.8
`12.6
`0.9
`16.0
`1.5
`18.6 f 1.7 21.4 f 1.8
`O.S. - -
`0.n.
`19.8 2 0.4
`19.6 f 0.6
`21.7 2 0.5
`0 . 6
`20.8
`20.6 f 0.9 20.4 f 0.9
`71.4 f 1.2 21.6 f 1.7
`19.8 f 0.9
`19.6 f 1.2
`20.0 f 0.8
`20.2 f 0.q
`
`NS
`NS
`NS
`(0.05
`NS
`
`NS
`NS
`NS
`NS
`NS
`N::
`
`*time i n h r s b e f o r e ( n e g a t i v e value) or a f t e r t h e
`t o p i c a l a p p l i c a t i o n of PGF,a
`t o one e y e and an
`equal volune (5 ,,1) o f s a l i n e to t h e c o n t r a l a t e r a l
`e y e o f each animal.
`In t h e l a s t experiment:
`h r s
`b e f o r e o r a f t e r a p p l i c a t i o n o f 5 ,,l s a l i n e t o b o t h
`e y e s ( 0 . U . ) .
`
`**2-tailed paired R u d e n t ' s t-test; NS: p>0.1.
`
`saline-treatment o r a f t e r u n i l a t e r a l treatment w i t h
`a low d o s e o f ( 0 . 2 mg) PGF2a did n o t show s i g n i f i -
`IOP (Table 1 ) .
`c a n t lowering of
`m e h a l f hour a f t e r t o p i c a l a p p l i c a t i o n o f 1.0
`mg PGF2a,
`t h e r e was an average of 2.0 5 0.3 w p-
`p i l l a r y miosis canpared t o t h e c o n t r a l a t e r a l con-
`A gradual return t o normal pupil s i z e
`trol eyes.
`(4.8 5 0.2 m) occurred over
`t h e n e x t 18 h r .
`i n 4 of 5 e y e s
`S l i g h t aqueous f l a r e was p r e s e n t
`between 2 and 12 h r a f t e r t h e t o p i c a l a p p l i c a t i o n
`
`Micro Labs Exhibit 1009-2
`
`

`

`Current
`Eye
`Research
`
`I
`
`
`
`i
`0
`
`I
`20
`
`I
`40
`
`I
`60
`H O U R S
`
`I
`80
`
`I
`100
`
`1
`120
`
`lhe e f f e c t s o f t o p i c a l l y applied PGFzF,a
`F i g v e 1.
`(1.0 m u e y e ) on the IOP o f normal owl mmkey e y e s
`r e l a t i v e to t h e Iop o f t h e c o n t r a l a t e r a l
`( s a l i n e
`t r e a t e d ) c o n t r o l eye.
`The p o i n t s r e p r e s e n t t h e
`
`i n
`( t r e a t e d - c o n t r o l
`t h e d i f f e r e n c e s
`mean o f
`IOP
`t h e limits
`e y e ) o b t a i n e d on f i v e a n i m a l s and
`r e p r e s e n t t 1 S M .
`
`A t 48 hr, a few cells were ob-
`of 1.0 mg of PGF2a.
`i n 3 o f t h e 5 t r e a t e d , b u t i n none o f t h e
`served
`There was no apparent c o r r e l a t i o n
`control eyes.
`between IOP r e d u c t i o n and t h e p-esence o f f l a r e and
`cells i n
`t h e a n t e r i o r chamber,
`t h e o c u l a r
`i.e.
`h y p o t e n s i o n was n o t a s s o c i a t e d w i t h a n o t a b l e
`i n f l a m a t o r y response.
`S t u d i e s on a glaucomatous owl monkey eye
`When purchased, one female monkey had e y e s ex-
`h i b i t i n g a marked a n i s o c o r i a with t h e r i g h t pupil
`being a c o n s i s t e n t 2 mn
`t h e l e f t .
`l a r g e r
`than
`Gonioscopic exanination of t h e r i g h t eye revealed
`a n g l e recessim. Ophthalmoscopic e x a n i n a t i o n b y a
`
`p a c t i c i n g ophthalmologist (Dr . E. D. Srinivasan)
`
`r a t i o s with deep
`revealed asymnetric c u p t o - d i s c
`excavation o f t h e c u p and temporal d i s c p a l l o r i n
`t h e r i g h t e y e , me cornea o f t h i s eye showed d i f -
`f u s e s t r u n a l haze and moderate e d m a w i t h micro-
`cystic changes, b u t t h e r e was no evidence o f en-
`d o t h e l i a l cell l o s s , c o r n e a l scars or r e c e n t i n j v y
`to t h e eye. U l t r a s o n i c measurenents by m. Jackson
`C o l a a n ' s l a b o r a t o r y showed a n t e r i o r chamber d e p t h s
`o f 4.4 and 3.7 mn and axial
`l e n g t h s of 14.6 and
`12.7 nun for t h e r i g h t and l e f t e y e s , r e s p e c t i v e l y .
`
`period p i o r
`Repeated exanination over a one-year
`t o t h e time PGF was applied showed t h a t t h e pl-
`20
`p i l l a r y diameter o f t h e r i g h t eye (9 mn) mas con-
`s i s t e n t l y l a r g e r than t h a t of t h e l e f t e y e (7 mm),
`b u t both p u p i l s c o n s t r i c t e d to 1 mn 20 min a f t e r
`t h e t o p i c a l a p p l i c a t i o n o f 0.5% p i l o c a r p i n e .
`The
`mean o f 46 IOP measurements taken over a period of
`0.7 and 24.5 5 0.6 mn Hg f o r
`one year was 47.2
`t h e r i g h t and
`l e f t e y e s r e s p e c t i v e l y .
`Fleven
`months b e f o r e t h i s s t u d y on t h e e f f e c t s of PGF
`20 *
`t o p i c a l a p p l i c a t i o n of 1% p i l o c a r p i n e reduced
`t h e
`IOp by 4 mn Hg i n t h e l e f t eye, b u t r a i s e d the IOP
`of t h e r i g h t eye by 16 mn lg. Cutotremorine (0.05%)
`also increased t h e IOp o f t h e r i g h t eye.
`Within 20 min after a p p l i c a t i o n of 1.0 mg o f
`to
`t h e r i g h t e y e of
`t h i s owl monkey,
`pGF2a
`IOP
`dropped p a n an average p-etreatment value of 50 mn
`Hg t o 3 mn lg, followed b y a more gradual d e c l i n e
`d v i n g t h e n e x t 12 h r , u l t i m a t e l y reaching a value
`s i m i l a r t o t h a t o f t h e c o n t r o l e y e and a s low a s 14
`lhe IOP o f t h e tw, eyes then re-
`mm lg ( F l g . 2 ) .
`followed b y a
`s i m i l a r for about 3 d a y s ,
`mained
`gradual r e t u r n i n t h e r i g h t eye to p-etreatment IOP
`l e v e l s o f 50 mn lg. During t h i s period o f nonno-
`
`207
`
`Micro Labs Exhibit 1009-3
`
`

`

`Current
`Eye
`Research
`
`40
`01 I
`
`RIGHT EYE r
`
`HOURS
`
`Reduction o f TOP i n a glaucanatous owl
`Figure 2.
`monkey eye following t o p i c a l a p p l i c a t i o n o f 1.0 mg
`
`DAYS
`
`o f PGF,a.
`
`t e n s i o n , t h e r e was marked c l e a r i n g o f t h e corneal
`haze o f t h e r i g h t e y e , b u t t h i s haze reappeared a s
`t h e I O P r o s e t o i t s b a s e l i n e v a l u e s i n t h e 40-50 mn
`Hg range.
`kbwever, f o r s e v e r a l weeks t h e r e a f t e r ,
`t h e IOP o f t h i s eye appeared t o be much more l a b i l e
`than it was before t h e PGF
`a p p l i c a t i o n .
`2a
`
`DISCUSSION
`The p-esent r e s u l t s c l e a r l y show t h a t t o p i c a l -
`l y applied PGF2
`can cause a prolonged and highly
`a
`s i g n i f i c a n t IOP r e d u c t i o n i n normal and glaucana-
`A dose of 1.0 mg PGF
`t o u s owl monkey e y e s .
`i n
`20
`t h e owl monkey eye p r o d u c e s an
`IOP r e d u c t i o n
`canparable i n e x t e n t t o t h a t caused by 5 ug PGF
`2a
`lhe need for a higher dose
`i n t h e r a b b i t eye ( 2 ) .
`was a n t i c i p a t e d , s i n c e it was shown t h a t primates
`a r e less s e n s i t i v e
`than
`r a b b i t s
`t o
`t h e o c u l a r
`e f f e c t s of PGs (3). Mwever, t h e d u r a t i o n of IOP
`r e d w t i o n was much longer i n t h e o d monkeys than
`was previously observed i n r a b b i t s (2).
`This sug-
`g e s t s t h a t t h e r e i s an i n h e r e n t d i f f e r e n c e between
`t h e s e two s p e c i e s with r e s p e c t t o t h e mechanism of
`a c t i o n and/or b i o a v a i l a b i l i t y o f PGs. lhis conclu-
`sion is supported by t h e observation t h a t a l t h o t g h
`increasing t h e dose o f PGF
`increased t h e d v a t i o n
`2a
`o f hypotony i n r a b b i t s , t h i s hypotony could not be
`extended beyond 20 h r i n t h a t species without caus-
`ing a breakdown o f t h e blood-aqueous b a r r i e r and
`
`i n i t i a l i n c r e a s e i n IOp ( 2 ) .
`i n d w i n g a p-onomced
`It should be noted t h a t t h e long term reduc-
`t i o n of IOP caused by twice d a i l y t o p i c a l epine-
`phrine a p p l i c a t i o n t o r a b b i t e y e s was shown t o be
`
`blocked by indanethacin r e t r e a t m e n t ( 1 n) . This
`
`s u g g e s t s t h a t t h e hypotony produced b y epinephrine
`may be dependent upon endogenous s y n t h e s i s o f cy-
`clooxygenase products and,
`i n f a c t ,
`t h e hypotony
`
`may be mediated, a t l e a s t i n part, b y PGs .
`
`There is accunulating evidence t h a t t h e r a b b i t
`eye is s i n g u l a r l y a t y p i c a l anong t h e eyes o f verte-
`b r a t e s , e s p e c i a l l y with r e s p e c t t o sane a s p e c t s o f
`t h e p-ostaglandin system (11.12).
`l h u s , much of
`t h e previous work on t h e o c u l a r e f f e c t s of PGs w i l l
`have to be repeated on o t h e r species.
`i n c l d i n g
`primates, b e f o r e t h e i r a p p l i c a b i l i t y t o t h e hunan
`eye can be e v a l u a t e d . m i l e t h e r e may be s p e c i e s
`v a r i a t i o n even among primates, preliminary experi-
`ments i n o u l a b o r a t o r y ( 1 3 ) i n d i c a t e t h a t , l i k e i n
`t h e owl monkey,
`t o p i c a l l y applied PGF2a a l s o h a s
`hypotensive e f f e c t s on eyes of
`r h e s u s monkeys.
`Furthennore, it should be noted
`t h a t PGF
`was
`2a
`t o reduce
`f o m d
`I O P when administered by
`i n t r a -
`u t e r i n e or intravenous i n j e c t i o n to pregnant wanen
`mese c o n s i d e r a t i o n s
`i n d w e a b o r t i o n s ( 6 1.
`t o
`suggest t h a t t o p i c a l l y applied PCS, or t h e i r ana-
`logues. may p-ovide a more d i r e c t approach t o t h e
`therapy o f glaucana
`than a d r e n e r g i c a g e n t s and
`
`208
`
`Micro Labs Exhibit 1009-4
`
`

`

`r e l a t e d drugs.
`
`ACKNOWLEDGMENTS
`t o thank F s . D.J. Coleman
`The a u t h o r s wish
`and h i s s t a f f
`f o r p e r f o r m i n g
`t h e u l t r a s o u n d
`Srinivasan
`f o r exanining
`t h e
`measurements, B.D.
`J.E.
`Pike of The
`o c u l a r hypertensive animal and
`Upjohn Co., Kalamazoo, M I f o r p r o v i d i n g
`t h e
`i n t h i s stucly. We m u l d a l s o
`prostaglandins used
`l i k e t o thank R.A. Baroody. S.Q. Merritt and A.
`Zaragoza f o r t h e i r a s s i s t a n c e .
`T h i s r e s e a r c h was s u p p o r t e d by 1J. S. P. H. S.
`Research Grants EY 00333 and EY 00402 fran t h e
`National Eye m s t i t u t e .
`
`Corresponding author: Laszlo Z.Bito, Ph.D., Department
`of Ophthalmology, College of P and S, Columbia University,
`630 W. 168th St., New York, NY 10032, USA
`
`prostagland i n s , -: 6 243-251.
`
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`i n t r a o c u l a r
`I. The b i p h a s i c
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` Eye ks., 2. 41-52.
`~ p
`.
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`Current
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`Z. and Klein, E. M. (1981) The r o l e
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`s p e c i f i c X-ray-induced
`inflamnation o f t h e r a b b i t
`eye.
`m v e s t . Cphthal. V i s . Sci., Accepted
`f o r
`p u b l i c a t i o n .
`13. S t e r n , F.
`( 1 9 8 1 ) A
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`r h e s u s monkey e y e s .
`Invest. Ophthal. V i s . S c i . ,
`Accepted f o r pub1 i c a t i o n .
`
`209
`
`Micro Labs Exhibit 1009-5
`
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