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`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`420
`
`PGF2,l administered as isopropylester in eye drops.
`Six subjects participated. The eye to be treated was
`randomly selected and a 25 ul eye drop was applied
`in the conjunctival sac at 8 am (T=0). Randomisation
`was carried out only once and the same eye was used
`for all four doses. The other eye was treated with the
`vehicle. The IOP was determined before treatment
`and at T=0‘5, 1, 2, 4, 8, 12, and 24 hours. At each
`examination the eyes were evaluated for conjunctival
`hyperaemia and aqueous flare and cells. Corneal
`sensitivity was estimated with an aesthaesiometer
`(Luneau and Coffignon, Paris) 90 minutes after
`application of the eye drops, and the diameter of the
`pupils was determined on a Goldmann perimeter
`under standard light conditions (31-5 apostilbs) 30
`minutes later. The treatment schedule started with
`the lowest dose, and then successively higher concen-
`trations were tested with a washout period of at least
`48 hours between doses.
`B. Six subjects were treated with 10 [lg PGan-
`isopropylester at 8 am (T=0) for Six days in one
`randomly selected eye. The other eye was treated
`with vehicle. Corneal sensitivity and pupil diameters
`were not examined in this study, but the eyes were
`examined and IOP determined before treatment and
`at T=0-5, 2, 4, 8, 12, and 24 hours on days 1, 3,
`and 5. On the sixth day the blood-aqueous barrier
`permeability was estimated by fluorophotometry.
`C. Ten subjects were treated according to the same
`protocol as in study B with the exception that the
`dose was divided into two doses of 05 pg PGFZa-
`isopropylester given at 8 am (T=0) and 8 pm (T: 12),
`and given for 16 days. The IOP was determined and
`the eyes were examined before application of the
`morning dose and at T=4, 8, 12, and 24 hours on days
`1, 8, and 15. On day 10 the aqueous humour
`production was determined in both eyes. Blood-
`aqueous barrier permeability was determined on day
`16 and about two months later.
`‘
`D. Sixteen subjects were given 10 [Lg PGFZO, in
`one randomly selected eye and vehicle in the other
`eye. Five hours later the IOP and outflow facility
`were determined.
`
`AQUEOUS HUMOUR DYNAMICS
`The IOP was determined with a Goldmann tono-
`meter. Five consecutive readings were done in each
`eye, the right eye being taken first. The scale of the
`tonometer was masked to the examiner. The highest
`and lowest values were discarded, and the mean Of
`the remaining three values was accepted as the true
`IOP. The tonometer prism was cleaned between
`readings in the right and left eye to avoid drug
`contamination.
`
`Aqueous flow was determined by fluorophoto-
`metry (Fluorotron Master). Three drops Of 2%
`
`JO’rgen Villumsen and AlbertAlm
`
`sodium fluorescein was applied at 5-minute intervals.
`Measurements were done hourly 5 to 10 hours later,
`and from these data the aqueous flow was cal-
`culated.13 The outflow facility was calculated from
`4—minute tonograms performed with a pneumatono-
`meter (Alcon, Fort Worth) with the 10 g weight.
`
`SID E EFFECTS
`
`Hyperaemia was evaluated from photdgraphs of the
`exterior of the two eyes. Pictures of the temporal
`conjunctiva were projected on to a screen with an
`overall magnification of approximately X25. On the
`screen a square of 14x 14 dots, 1-5 mm in diameter,
`was placed, with an interval of 1 cm between dots. All
`dots having some contact with a vessel were counted
`(Fig. 1). The evaluation of the photographs was
`masked. The difference between counts in the PGFZu
`treated eye and the vehicle treated eye was used as an
`estimate of the drug induced hyperaemia. Fluoro-
`photometry was used to estimate the blood-aqueous
`barrier permeability.
`Corneal and aqueous fluorescein concentrations
`were determined in the two eyes 2, 4, 6, and 8 hours
`after an oral dose of 400—500 mg sodium-fluorescein
`diluted in orange juice. Subjective side effects were
`registered after each dose in A and after each day of
`IOP measurements in B and C. Visual disturbances,
`foreign body sensation, itching, pain, photophobia or
`any systemic symptom were asked for. The side
`effects were graded absent, slight, moderate, or
`severe and the duration was recorded.
`'
`
`STATISTICAL EVALUATION
`
`The two-tailed Student’s t-test of paired data was
`used to calculate observed differences. The results
`are presented as mean (with SEM). Drug effects
`were based on the difference in IOP between the two
`eyes. We assume that a possible, centrally mediated
`effect on IOP, induced by the experimental proce—
`dures, would affect the two eyes similarly. Further-
`more, prostaglandins are rapidly inactivated in the
`lungs,” and an effect on the contralateral eye induced
`by systemically absorbed PGFZQ seems unlikely.
`
`Results
`
`AQUEOUS HUMOUR DYNAMICS
`
`The effects on the IOP are presented in Tables 1—3.
`These tables include only the initial IOPs and values
`obtained at times where a significant effect was seen
`with at least one dose (study A) or On some day
`(studies B and C). Remaining non-significant differ-
`ences are included in Fig. 2, which provides a
`summary of the Observed differences between the
`two eyes for the three studies A-C. In the dose-
`response study (A) 01 rig and 0-5 pig PGFZa had no
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`Prostaglandin F2a-isopropylester eye drops: effects in normal human eyes
`
`421
`
`
`
`Fig. 1 To quantitate conjunctiva] hyperaemia, photographs of the conjunctiva were projected on a screen with a dot pattern.
`The numbers of dots in contact with a conjunctival or episcleral vessel were counted in the two eyes. The difference in counts
`ofdots between the treated eye and the control eye was used as an estimate ofthe hyperaemic response for each eye. Thefigure
`shows a medium responding eye 30 min after application of2-5 pg PGan.
`
`
`
`significant effect on IOP, while the higher doses
`produced a dose dependent reduction with a similar
`pattern — a tendency towards an increase in IOP after
`30 minutes, and then a slow decrease that reached a
`maximum 8 to 12 hours after application of the drug.
`The maximal mean difference between treated and
`non-treated eyes was 57 mmHg observed eight hours
`after application of 10 pg PGFZa. An effect that
`lasted 24 hours was observed only with the 10 pg
`dose.
`
`With 1-0 pg given once daily for six days (study B)
`a significant IOP reduction of 2—3 mmHg was ob-
`served four to eight hours after application of the
`drug throughout the study. No 24-hour effect was
`obtained, and there was no tendency to an increase
`or decrease of the response. With repeated doses of
`0-5 pg twice daily for 16 days (study C) a significant
`reduction in IOP of about 2 mmHg was obtained.
`The IOP was measured after conclusion of the study
`every twelfth hour, and 36 hours after the last drug
`
`application there was no longer any significant differ-
`ence in IOP between the two eyes.
`05 pg PGFZG twice daily for ten days had no effect
`on aqueous flow (study C). Flow was 3-05 (SEM,
`0-20) pllmin in the PGFZG treated eyes and 2-97
`(0-35) pl/min in the vehicle treated eyes. IOP and
`outflow facility (study D) are presented in Table 4.
`There was a significant reduction in IOP in the eyes
`treated with 1-0 pg PGFZa when compared with the
`vehicle treated eyes, but no significant change in
`outflow facility.
`
`SIDE EFFECTS
`
`The hyperaemic response for the dose response study
`is presented in Fig. 3. A dose dependent hyperaemia
`was seen about 10 minutes after application of the
`drug. 01 and 05 pg PGan produced a slight
`hyperaemia for about one hour. The hyperaemia
`after 25 or 10 pg was equally pronounced but more
`prolonged with 10 pg. The hyperaemia involved
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`JO’rgen Villumsen and AlbertAlm
`
`lntraocular pressures in treated and untreated eyes
`Table 1
`at various times after application of0-1, 0-5, 2-5, or 10 ug
`PGFZa-isopropylester in study A. The values are mean with
`SEM (n=6). Statistical significances were calculatedfor the
`paired differences
`
`Intraocular pressures in treated and untreated
`Table 3
`eyes at various times after application of0-5 ug
`PGFZa-isopropylester twice daily for 16 days in study C.
`Mean with SEM (n=10). Statistical significances were
`calculatedfor the paired differences
`
`Th
`
`Vehicle
`
`PGFZ,z
`
`Difi'erence
`
`p<
`
`Th
`
`Vehicle
`
`PGFZ‘,
`
`Diflerence
`
`p<
`
`0] ug
`0
`4
`8
`12
`24
`0-5 ug
`0
`4
`8
`12
`24
`2-5 pg
`0
`4
`8
`12
`24
`IOag
`0
`4
`8
`12
`24
`
`15-7(1-1)
`13-9 (0-7)
`15-4(1-0)
`14-6 (1-0)
`13-0 (1-1)
`
`14-4 (1-1)
`14-8 (1-2)
`14-4 (1-2)
`13-6 (1-5)
`14-9 (1-5)
`
`14-1(1-4)
`13-2 (1-3)
`15-0 (1-8)
`14-8 (1-5)
`13-7 (1-4)
`
`14-0(1-2)
`13-5 (1-7)
`16-1 (1-1)
`13-9 (1-3)
`14-5 (1-3)
`
`15-4(l-1)
`12-7 (1-1)
`13-5 (1-3)
`14-3 (1-4)
`12-2 (1-3)
`
`12-8 (1-2)
`12-9 (1-5)
`13-5 (1-4)
`11-9 (1-5)
`14-2 (1-4)
`
`12-3 (1-3)
`11-4 (1-0)
`11-8 (1-1)
`11-5 (1-1)
`12-8 (1-5)
`
`13-2 (1-1)
`11-2 (1-3)
`10-4 (1-4)
`9-6 (0-9)
`12-2 (1-3)
`
`0-3 (1-0)
`1-2 (0-9)
`1-9(1-1)
`0-3 (1-0)
`0-7 (0-5)
`
`1-6 (0-9)
`1-9 (0-9)
`0-9 (0-8)
`1-7 (0-9)
`0-7 (0-5)
`
`1-8 (0-8)
`1-8 (0-6)
`3-3 (0-9)
`3-3 (1-2)
`0-8 (0-7)
`
`0-8 (0-5)
`2-3 (0-8)
`5-7 (14)
`4-3 (0-9)
`2-3 (0-3)
`
`0-05
`0-025
`0-05
`
`0-05
`0-025
`0-005
`0005
`
`Intraocular pressures in treated and untreated
`Table 2
`eyes at various times after application of I -0 ug
`PGFZa-isopropylester once daily for six days in study B.
`Mean with SEM (n=6). Statistical significances were
`calculatedfor the paired differences
`
`Th
`
`Vehicle
`
`PGFZa
`
`Difference
`
`p<
`
`Day I
`0
`2
`4
`8
`12
`24
`Day3
`0
`2
`4
`8
`12
`24
`Day5
`0-2 (0-4)
`13-7(1-3)
`13-8(1-2)
`0
`1-3 (0-3)
`13-2 (0-8)
`14-5 (1-1)
`2
`2-4 (0-8)
`12-5 (1-0)
`14-9 (1-6)
`4
`2-9 (0-9)
`11-0(l-0)
`13-9(1-6)
`8
`1-0 (0-8)
`12-2(1-1)
`13-2(1~1)
`12
`
`
`
`11-8 (1-4)12-2 (1-4)24 0-3 (0-5)
`
`0-2 (0-8)
`1-5 (0-9)
`2-9 (0-6)
`3-0 (0-8)
`2-3 (1-2)
`1-2 (0-8)
`
`0-7 (0-7)
`1-6 (05)
`2-4 (1-0)
`3-2 (1-2)
`3-2 (1-0)
`—0-2 (0-8)
`
`0-01
`0-025
`
`0-025
`
`0-05
`0-05
`
`0-025
`0-05
`0-025
`
`15-6 (1-7)
`15-1(1-1)
`14-7 (0-8)
`15-5 (1-4)
`15-3 (1-3)
`14-3 (1-4)
`
`13-4 (1-3)
`14-9 (0-9)
`15-2 (1-3)
`15-6 (1-4)
`15-5 (1-5)
`13-0 (1-3)
`
`15-4 (1-6)
`13-6(1-1)
`11-8 (1-2)
`12-5 (1-6)
`13-0(1-3)
`13-1(1-5)
`
`12-7 (1-6)
`13-3 (1-2)
`12-7 (1-3)
`124 (1-3)
`12-3 (0-9)
`13-2 (1-5)
`
`IPR Page 4/8
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`~
`
`DayI
`0
`4
`8
`12
`24
`Day8
`0
`2
`4
`8
`12
`24
`
`Day I5
`0
`4
`8
`12
`24
`
`15-2 (1-0)
`15-3 (0-9)
`14-8 (0-9)
`14-8 (0-8)
`13-2 (0-9)
`
`13-7 (0-8)
`14-3 (0-7)
`14-0 (0-6)
`13-6 (0-7)
`13-5 (0-9)
`
`13-7 (0-8)
`14-1 (0-8)
`13-6 (0-8)
`13-4 (0-7)
`13-7 (0-8)
`
`14-9 (0-7)
`13-1 (0-6)
`13-3 (0-8)
`13-1(0-8)
`12-2 (0-7)
`
`12-0 (0-7)
`11-8 (0-6)
`11-5 (0-5)
`11-8 (0-6)
`11-4 (0-8)
`
`12-7 (0-6)
`11-9 (0-5)
`12-0 (0-6)
`12-1(0-7)
`12-3 (0-8)
`
`0-3 (0-4)
`2-2 (0-9)
`1-6 (0-8)
`1-6 (0-7)
`1-0 (0-5)
`
`1-7 (0-6)
`2-5 (0-5)
`2-5 (0-4)
`1-8 (0-3)
`2-1(0-4)
`
`1-0 (0-4)
`2-1 (0-5)
`1-6 (04)
`1-3 (06)
`1-3 (05)
`
`0-05
`
`0-05
`
`0025
`0001
`0-001
`0001
`0-001
`
`0-05
`0-005
`0-005
`0-005
`0-025
`
`episcleral vessels as well as conjunctiva] vessels. The
`response to 10 ug once daily (study B) was more
`pronounced than previously found for 05 ug, but
`clearly less than the 2-5 ug response. It was the same
`on day 5 as on day 1. Even 0-5 [1ng (study C)
`produced a slight hyperaemia, but it had vanished at
`the time of ocular examination four hours later.
`No cells or flare were found in any of the studies.
`Fluorescein concentrations
`in the cornea and
`aqueous ranged between 42 and 328 ng/ml and 7 and
`112 ng/ml respectively, two to eight hours after an
`oral dose of 400—500 g sodium fluorescein in studies B
`and C. The concentrations in the cornea were, as a
`rule two to three times that in the aqueous. The ratio
`of treated eye to untreated eye was calculated for
`both cornea and aqueous, and the results are pre-
`sented in Table 5. Generally the fluorescein concen-
`trations in the treated eyes tended to be lower than in
`the untreated eyes in study B while the opposite was
`true for study C. The participants in study C were re-
`examined two months later. At that time no differ—
`ence was observed between the two eyes for either
`cornea or aqueous.
`No effect on the pupil diameter could be shown for
`doses up to 25 ug PGFZa. 10 ug produced a miosis of
`1 mm in three of six participants. No change in
`corneal sensitivity was observed. The subjective
`adverse effects showed a marked dose dependence.
`No discomfort was noted for 0-1 ug. 0-5 ug produced
`a minor foreign body sensation in the treated eye in
`three of the seven participants for about one hour.
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`Prostaglandin F2a-isopropylester eye drops: effects in normal human eyes
`
`423
`
`DIFFERENCE IN IOP
`TREATED EYE - CONTROL EYE
`
`mmHg
`
`mmHg
`
`Intraocular pressures in mmHg and outflow
`Table 4
`facilities in pl/min/mmI-Ig in treated and untreated eyes five
`hours after [-0 pg [’0le1 (study D). Mean with SEM
`(n =16). Statistical significances were calculated for the
`paired differences
`
`Control eye
`Treated eye
`Difference
`p<
`
`IOP
`
`17-0 (06)
`15-3 (07)
`1-7 (0-4)
`0005
`
`Facility
`
`0-311 (0-029)
`0-334 (0-033)
`0024 (0-029)
`NS
`
`daily for six days were regarded as mild by everyone
`and remained unchanged during the study. A foreign
`body sensation was noted about 15 minutes after
`application of the drug and lasted about two hours.
`With 05 ug twice daily a slight discomfort for about
`one hour was experienced by only two of 10 persons
`on the first day of treatment. On days 8 and 15,
`however, discomfort was felt for one to two hours in
`the PGFZa treated eyes of nine of 10 participants. No
`discomfort was recorded from the vehicle treated
`
`eyes in any of the studies.
`
`Discussion
`
`The purpose of study A was to find a suitable dose for
`further tests. Without previous knowledge of the
`effects on the eye we chose to use increasing concen—
`trations of PGan in the same eye. The study served
`its purpose, but an unexpected observation was the
`difference in IOP between the two eyes observed
`even before application of the three higher doses
`(Table 1). A similar difference in pretreatment IOP
`was not observed before 0-1 pg PGFZQ or before any
`of the other studies. 01 ug PGFZC, had no effect on
`IOP for the first 24 hours, and the likelihood that it
`caused a slow and almost significant (p<0-1) reduc-
`tion 48 hours later seems remote. Thus we have to
`assume that this is due to random variation. The
`information obtained from study A enabled us to
`choose a dose for further studies, but the magnitude
`of the effect with higher doses of PGan-isopropy-
`lester may be exaggerated by the unexplained differ-
`ence in pretreatment IOP between the two eyes.
`Moreover the IOP of the vehicle treated eyes tended
`to become lower during studies A—C. Obviously we
`cannot rule out a contralateral effect, but a likely
`alternative is that
`the participants become more
`relaxed as they become more familiar with the
`examination procedures. We could find no tendency
`to a reduction in IOP due to the five rapid measure-
`ments on each examination.
`The IOP response in the human eye seems to
`follow the pattern seen in primate eyes, where a
`
`20
`
`24
`
`0
`
`4
`
`16
`12
`8
`Time in hours
`Fig. 2 The mean difference (IOP in control eye minus IOP
`in treated eye) at various times after application of drugs.
`Top: Single doses offour different doses ofPGF20, (study A).
`Middle: Repeated doses of I '0 ug PGan once daily for 6
`days (study B). Bottom: Repeated doses of05 pg PGFZa
`twice daily for I6 days (study C).
`
`After 25 pg discomfort was noted by all participants
`for two to three hours. In the treated eye a marked
`foreign body sensation was felt by three subjects, and
`the remaining three had an experience of pain for
`about the same time. 10 pg produced photophobia
`and pain in the treated eyes of all six participants, one
`having a foreign body sensation for 12 hours. The
`side effects noted by the participants receiving 10 pg
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`Jorgen Villumsen and AlbertAlm
`
`
`
`0
`
`4
`
`B
`
`12
`
`16
`
`20
`
`24 0
`Time in hours
`
`4
`
`B
`
`12
`
`16
`
`20
`
`24
`
`Fig. 3 Difference in hyperaemia: treated eye minus control eye. The hyperaemic response (see Fig. I) at various times after
`application of0-1, 0-5, 2 ‘5, or 10 ug PGFZC. (study A). Since no difference could be observed between the two eyes after eight
`hours with 01 and 05 ug, no more photographs were taken. The values are mean with SEM. p Values are indicated by
`asterisks: *p<0-05. **p<0‘01. ***p<0'001.
`
`Table 5 The ratio (treated eye/untreated eye) forfluorescein
`concentration in cornea and aqueous 2—8 hours after an oral
`dose of400—500 mg sodium fluorescein. In study B six
`subjects had been treated with I -0 ug PGFZa-isopropylester
`once daily for six days in one eye, and in study C 10 subjects »
`had been treated with 05 ug PGFZa-isopropylester twice
`daily for 16 days in one eye. Values are mean with SEM.
`Significance levels indicate the probability that the true
`ratio is I .0
`
`
`biphasic IOP response is found}-5 The initial increase
`in IOP observed in the dose-finding study (Fig. 2) was
`not statistically significant but occurred with all four
`doses. The reduction in IOP is slow in comparison
`with that from commonly used glaucoma drugs.
`There is no difference between the tromethamine
`salt, as reported by Guiffré,‘o and the isopropylester
`of PGFZa with regard to time of onset. Both have an
`effect from about four hours, with a maximum 8-12
`hours after application. The doses of the isopropyl-
`ester of PGFZu used here are all less than 5% of the
`- dose of trometharnine salt previously used in human
`eyes."J
`Increased lipid solubility of PGFZQ thus
`reduces the total dose needed for IOP reduction.
`Our results did not clarify the mechanism behind
`the IOP reduction. No change in aqueous humour
`production was found, and a recent study reported a
`similar lack of effect of PGFZQ on aqueous flow in
`humans.” No increase in outflow facility was found in
`study D. There is, however, a possibility that PGFZa
`
`p<
`
`NS
`NS
`NS
`NS
`
`
`
`
`
`
`
` Th Cornea p< Aqueous
`
`Study B
`2
`4
`6
`8
`Study C
`0025
`1-08 (0-03)
`0-05
`129 (0- 12)
`2
`0025
`1-08 (0-03)
`0025
`1-17 (0-06)
`4
`NS
`1-02 (003)
`NS
`1-13 (006)
`6
`NS
`1-06 (004)
`8
`
`1-03 (005) NS
`
`001
`0025
`0‘01
`005
`
`0-95 (003)
`0-92 (004)
`091 (004)
`0-97 (007)
`
`0-78 (005)
`084 (0-05)
`0-86 (004)
`0-86 (0.05)
`
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`Prostaglandin FZa-isopropylester eye drops: effects in normal human eyes
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`425
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`affects neither aqueous flow nor outflow facility.
`In monkeys PGFZO, reduces IOP without reducing
`aqueous
`flow57 or
`increasing outflow facility.16
`Recent studies indicate that the IOP reduction in
`monkeys is due to an increased uveoscleral out-
`flow.1718 Uveoscleral outflow is present in human
`eyes,” and an increase in uveoscleral outflow could
`well be part of the mechanism in the human eye.
`
`subjective side effects. However, the results indicate
`that prostaglandins are potentially effective for IOP
`reductions and that
`the mechanism behind the
`IOP reduction may differ from commonly used
`glaucoma drugs. It seems worthwhile to evaluate
`other formulations of the drug or other prosta-
`glandins, with respect also to long-term effects on the
`IOP and the blood—aqueous barrier.
`
`5 i D E EFFECTS
`
`In doses that reduced the IOP PGFZO, also produced
`local irritation, mainly in the form of a foreign body
`sensation and,
`in higher doses, pain and photo-
`phobia. This sensation appeared first after one or two
`minutes, unlike the immediate stinging sensation
`experienced with physically irritating eye drops. We
`conclude that this is a pharmacologically mediated
`pain response. Prostaglandins produce hyperalgesia
`rather than pain and exert their effect synergistically
`with pain producing mediators such as bradykinin
`and histamine.20 When 05 pg PGFZGI was given twice
`daily for two weeks there was a tendency towards
`increasing discomfort during the study. Although the
`discomfort was mild even at the end of the study, this
`observation suggests that side effects may increase
`with repeated treatment.
`Prostaglandins are involved in various aspects of
`the inflammatory response of the eye. They seem to
`produce miosis during surgery,21 which may explain
`the slight miosis observed in three participants after
`10 ug PGFZG. They mediate inflammatory vasodila-
`tation22 and increase blood flow through the anterior
`uvea in rabbits.23 Flare and cells have been observed
`
`in the anterior chamber of experimental animals after
`topical application of PGFZQF” 7 The human eye
`seems to be less sensitive in this respect, since no cells
`or aqueous flare were observed. The fluorophoto—
`metry results indicated an increased permeability of
`the barrier in study C but not in study B. Sodium
`fluorescein is a small molecule which makes this a
`
`potentially very sensitive technique. Entrance of
`fluorescein into the anterior chamber from limbal
`
`vessels, with the cornea as a reservoir, is a possible
`source of error. This seems to be an important route
`in rabbits." If this is true also for human eyes, the
`slight
`increase in anterior chamber fluorescence
`observed in study C may only reflect a corresponding
`difference for the cornea (see Table 5), rather than
`increased penetration through the blood-aqueous
`barrier. In study B the opposite occurred; ratios
`lower than 1.0 were observed for both cornea and
`aqueous. Further studies are obviously necessary to
`resolve this question.
`-
`The use of very low doses of PGFZG, made possible
`with the increased lipid solubility of the ester, did not
`cause a sufficiently efficient separation of effect and
`
`PGFZu-isopropylester eye drops were supplied by Pharmacia
`Ophthalmics AB, Uppsala, Sweden. The authors have no com-
`mercial or proprietary interest in PGFZa eye drops.
`
`References
`
`1 Beitch BR, Eakins KE. The effects of prostaglandins on the
`intraocular pressure of the rabbit. Br J Pharmacol 1969; 37:
`158—67.
`2 Camras CB, Bito LZ, Eakins KE. Reduction of intraocular
`pressure by prostaglandins applied topically to the eyes of
`conscious rabbits. Invest Ophthalmol Vis Sci 1977; 16: 1125—34.
`3 Camras CB, Bito LZ. Reduction of intraocular pressure in
`normal and glaucomatous primate (Aotus trivirgatus) eyes by
`topically applied prostaglandin F2a. Curr Eye Res 1981; 1: 205—9.
`4 Stem FA, Bito LZ. Comparison of the hypotensive and other
`ocular effects of prostaglandins Em and Fm on cat and rhesus
`monkey eyes. Invest Ophthalmol Vis Sci 1982; 22: 588—98.
`5 Lee P, Podos SM, Severin C. Effects of prostaglandin F2“ on
`aqueous humour dynamics of rabbit, cat, and monkey. Invest
`Ophthalmol Vis Sci 1984; 25: 1087-93.
`6 Crawford K, Kaufman PL, True Gabelt B. Effects of topical
`PGFZG on aqueous humor dynamics in cynomolgus monkeys.
`Curr Eye Res 1987; 6: 1035—44.
`7 Camras CB, Podos SM, Rosenthal JS, Lee PY, Severin CH.
`Multiple dosing of prostaglandin F2u or epinephrine on
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`Ophthalmol Vis Sci 1987; 28: 463—9.
`8 Camras CB, Bhuyan KC, Podos SM, Bhuyan DK, Master RWP.
`Multiple dosing of prostaglandin F2,x or epinephrine on
`cynomolgus monkey eyes. I]. Slit-lamp biomicroscopy, aqueous
`humor analysis and fluorescein angiography. Invest Ophthalmol
`Vis Sci 1987; 28: 921-6.
`9 Zajacz M, Torok M, Mocsary P. Effect on human eye of
`prostaglandin analogue used to induce abortion. IRCS Med Sci
`1976; 4: 316.
`10 Guiffré G. The effects of prostaglandin F2“ in the human eye.
`Graefes Arch Clin Exp Ophthalmol 1985; 222: 139-41.
`11 Bito LZ. Comparison of the ocular hypotensive efficacy of
`eicosanoids and related compounds. Exp Eye Res 1984; 38:
`181—94.
`12 Alm A, Villumsen J. Intraocular pressure and ocular side effects
`after prostaglandin Fm eye drops. A single-dose response study
`in humans. Proc Int Soc Eye Res 1986; 4: 14.
`13 Brubaker RF. Clinical evaluation of the circulation of aqueous
`humor.
`In: Duane TD,
`ed. Clinical Ophthalmology.
`Philadelphia: Lippincott, 1986; 3: 1—11.
`14 Ferreira SH, Vane JR. Prostaglandins: their disappearance from
`and release into the circulation. Nature 1967; 216: 868—73.
`15 Kerstetter JR, Brubaker RF, Wilson SE, Kullerstrand L.
`Prostaglandin Fm-l-isopropylester lowers intraocular pressure
`without decreasing aqueous humor flow. Am J Ophthalmol
`1988; 105: 30—4.
`16 Kaufman PL. Effects of intracamerally infused prostaglandins
`on outflow facility in cynomolgus monkey eyes with intact or
`retrodisplaced ciliary muscle. Exp Eye Res 1986; 43: 819—27.
`17 Crawford C, Kaufman PL. Pilocarpine antagonizes prosta-
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`426
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`Jorgen Villumsen and Albert/11m
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`glandin FZu-induced ocular hypotension in monkeys. Evidence
`for enhancement of uveoscleral outflow by prostaglandin F2“.
`Arch Ophthalmol 1987; 105: 1112—6.
`18 Nilsson SFE, Stjemschantz J. Bill A. PGF;u increases uveo—
`scleral outflow. Invest Ophthalmol Vis Sci 1987; 28 (ARVO
`suppl): 284.
`19 Bill A, Phillips CI. Uveoscleral drainage of aqueous humour in
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`20 Ferreira SH, Nakamura M. Pathogenesis and pharmacology of
`pain. In: Weissman G, Paoletti R, Samuelsson B, eds. Advances
`in inflammation research. New York: Raven Press, 1979; 1:
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`
`21 Keates RH, McGowan KA. The effect of topical indomethacin
`ophthalmic solution in maintaining mydriasis during cataract
`surgery. Ann Ophthalmol 1984; 16: 1116—21.
`22 Williams T], Peck MJ. Role of prostaglandin-mediated vasodila-
`tation in inflammation. Nature 1977', 270: 530—2.
`23 Starr MS. Effects of prostaglandin on blood flow in the rabbit
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`24 Shiraya K, Nagataki S. Fluorescein and fluorescein-monoglucur-
`onide in the eye after intravenous administration of fluorescein.
`Invest Ophthalmol Vis Sci 1986; 27 (ARVO Suppl): 290.
`
`Accepted for publication 16 August 1988.
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