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Original Paper
Ophthalmic Res 2002;34:90–93
Received: June 7, 2001
Accepted: September 26, 2001
Effects of Isopropyl Unoprostone, Latanoprost,
and Prostaglandin E2 on Acute Rise
of Aqueous Flare in Pigmented Rabbits
Xue-Yun Zhang Seiji Hayasaka Yoriko Hayasaka Shuichiro Yanagisawa
Yasunori Nagaki
Department of Ophthalmology, Toyama Medical and Pharmaceutical University, Toyama, Japan
Abstract
Purpose: To evaluate the effect of isopropyl unoprostone, latanoprost, and prostaglandin E2 (PGE2) on
aqueous flare elevation. Methods: Isopropyl unoprostone (0.12%) or latanoprost (0.005%) was topically instilled. Transcorneal diffusion of PGE2, 25 Ìg/ml, using a
glass cylinder, was achieved in pigmented rabbits.
Aqueous flare was measured with a laser flare cell meter.
Results: Topical instillation of isopropyl unoprostone
induced aqueous flare elevation in rabbit eyes. Also, topical isopropyl unoprostone additionally induced aqueous flare elevation in eyes with transcorneal diffusion of
PGE2. Latanoprost did not induce flare elevation. Conclusion: Isopropyl unoprostone induced aqueous flare elevation in rabbits, and latanoprost did not produce
aqueous flare elevation.
Copyright © 2002 S. Karger AG, Basel
Studies from our laboratory previously reported that
transcorneal diffusion of prostaglandin E2 (PGE2) using a
glass cylinder induced aqueous flare elevation in pigmented rabbits, and that the elevation was reproducible
ABC
© 2002 S. Karger AG, Basel
0030–3747/02/0342–0090$18.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
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when PGE2 was applied at an interval of more than 1
week [1, 2]. We also reported that topical instillation of
betaxolol, an antiglaucoma agent, inhibited PGE2-induced aqueous flare elevation in pigmented rabbits [3].
PGF2· analogues such as isopropyl unoprostone and latanoprost are commercially available as antiglaucoma
agents. Some investigators compared the effects of these
compounds in human subjects [4–6]. Linder et al. [7] and
Widergard et al. [8] have reported that latanoprost had no
clinically significant effect on the permeability of the
blood-aqueous barrier in humans. Others have described
anterior uveitis or disruption of the blood-aqueous barrier
associated with latanoprost [9–12]. In the present study,
we examined the effects of isopropyl unoprostone, latanoprost, and PGE2 on aqueous flare elevation in pigmented
rabbits.
Materials and Methods
Animals
A total of 32 pigmented male rabbits (Japanese mongrel) that
weighed 2.5–3.5 kg each were used. The animals were housed and
treated according to the Association for Research in Vision and Ophthalmology (USA) Resolution on Use of Animals in Research. One
eye of each animal was used for the experiment.
Chemicals
PGE2 was obtained from Funakoshi Chemicals (Tokyo, Japan).
PGE2 was dissolved in 100% ethanol and stocked at –70 ° C. PGE2
Xue-Yun Zhang, PhD
Department of Ophthalmology
Toyama Medical and Pharmaceutical University
2630 Sugitani, Toyama 930-0194 (Japan)
Tel. +81 76 434 7363, Fax +81 76 436 0146
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Key Words
Aqueous flare W Isopropyl unoprostone W Latanoprost W
Prostaglandin E2 W Rabbit
Fig. 1. Changes in flare intensity following topical instillation of isopropyl unoprostone. $ = Two instillations (–30 and 0 min) of 0.12%
isopropyl unoprostone; ) = one instillation. The mean B standard
deviation (n = 4) is shown.
Fig. 2. Changes in flare intensity following transcorneal diffusion of
PGE2 with or without topical instillation of isopropyl unoprostone.
P = Transcorneal application of PGE2, 7.09 ! 10 –2 mmol/l, for
4 min (black arrow); [ = 0.12% isopropyl unoprostone was topically
instilled 60 and 30 min before PGE2 application (white arrows). The
mean value B standard deviation (n = 4) is shown.
solution was diluted to 5% ethanol with 0.9% NaCl just before use.
Isopropyl unoprostone, 0.12%, ophthalmic solution (Rescula) was
obtained from Fujisawa Pharmaceutical Company (Osaka, Japan).
Latanoprost, 0.005%, ophthalmic solution (Xalatan) was purchased
from Pharmacia Upjohn Company (Tokyo, Japan).
Statistics
Statistical analysis was performed using Scheffe’s procedure for
multiple comparisons of means. A probability (p) value less than 0.05
was considered significant.
Results
Aqueous Flare Measurement
Aqueous flare was measured with a laser flare cell meter (FC
1000, Kowa, Tokyo, Japan), according to the method described by
Sawa et al. [13]. A laser flare cell meter measured intracameral proteins. Five measurements were taken at each time point to obtain the
mean value. The measurement was taken in the midportion of the
anterior chamber. The sampling area was 0.075 mm2. Aqueous flare
elevation was expressed as the area under the curve (AUC) in arbitrary units. The person taking the measurements had no knowledge of
the treatment.
No remarkable changes in the systemic conditions
were noted following topical instillation of isopropyl unoprostone or latanoprost, or transcorneal diffusion of
PGE2. Topical instillation of 0.9% NaCl or 0.005% latanoprost had no effect on aqueous flare. After topical
instillation of isopropyl unoprostone, aqueous flare increased, peaked at 1.5–2 h, and returned to the baseline
level at 7–8 h (fig. 1). Two instillations of 0.12% isopropyl
unoprostone showed higher elevation than one instillation.
Transcorneal diffusion of 0.5% ethanol had almost no
effect on aqueous flare. After transcorneal diffusion of
PGE2, aqueous flare increased, reached its maximum at
60–120 min, and then gradually decreased and returned
to the baseline level at 8 h (fig. 2). Topical isopropyl unoprostone induced additional aqueous flare elevation.
Effects of topical instillation of isopropyl unoprostone
or latanoprost and transcorneal diffusion of PGE2 are
PGF2· Analogues and Aqueous Flare
Ophthalmic Res 2002;34:90–93
Transcorneal Diffusion of PGE2 or 5% Ethanol
For transcorneal diffusion, a glass cylinder (11 mm in diameter)
was attached to one eye, as described previously [1]. A total of 600 Ìl
of PGE2 solution, 25 Ìg/ml, or 5% ethanol was delivered into the
cylinder and pipetted out 4 min later. The cylinder was removed, and
the corneal surface and conjunctival sac were rinsed with 20 ml of
0.9% NaCl.
91
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Topical Instillation of NaCl, Isopropyl Unoprostone, or
Latanoprost
50 Ìl of 0.9% NaCl, 0.12% isopropyl unoprostone, or 0.005%
latanoprost was topically instilled in one eye. The instillation took
place twice (60 and 30 min before 0.5% ethanol or PGE2), or once
(30 min before 0.5% ethanol or PGE2).
latanoprost, and PGE2 on aqueous flare
elevation in pigmented rabbits
Topical instillation
Times1 Transcorneal
diffusion
Eyes
NaCl, 0.9%
Isopropyl unoprostone, 0.12%
2
2
1
2
ethanol, 5%
ethanol, 5%
ethanol, 5%
ethanol, 5%
4
4
4
4
18B15
670B81
307B32
17B11
2
2
1
2
PGE2, 25 Ìg/ml
PGE2, 25 Ìg/ml
PGE2, 25 Ìg/ml
PGE2, 25 Ìg/ml
4
4
4
4
1,325B201
1,947B260
1,612B215
1,240B170
Latanoprost, 0.005%
NaCl, 0.9%
Isopropyl unoprostone, 0.12%
Latanoprost, 0.005%
1
2
**
**
**
NS
**
**
**
NS
** p ! 0.01; NS, p 1 0.05.
Once, 60 min before ethanol or PGE2; twice, 60 and 30 min before ethanol or PGE2.
AUC (arbitrary units), means B SD.
shown in table 1. Topical instillation of isopropyl unoprostone induced aqueous flare elevation that was dependent on the number of instillations. The AUC (1,974
units) following two instillations of isopropyl unoprostone
and transcorneal PGE2 was quite similar to the summation of the AUC (670 units) following two instillations of
isopropyl unoprostone and the AUC (1,325 units) following transcorneal PGE2. Latanoprost had no effect on
PGE2-induced aqueous flare elevation.
Discussion
Aqueous flare elevation, mean B standard deviation,
following transcorneal PGE2 using a glass cylinder in the
present study was similar to that observed in our previous
study [2]. In the present study, isopropyl unoprostone
induced aqueous flare elevation in the rabbit eye. Sakurai
et al. [14] previously showed that the rabbit bloodaqueous barrier was disrupted after instillation of isopropyl unoprostone, using fluorescein isothiocyanate-labeled
rabbit albumin. Our data obtained using a laser flare cell
meter were quite similar to the findings of Sakurai et al.
[14]. Isopropyl unoprostone induced additional aqueous
flare elevation in eyes with transcorneal diffusion of
PGE2.
Some investigators have reported that latanoprost induced anterior uveitis or flare elevation in humans [9–
12]: Fechtner et al. [9], Warwar et al. [10] and Smith et al.
[12] contributed case reports, whereas Miyake et al. [11]
described an experimental situation following cataract
surgery. However, controlled clinical studies showed that
92
Flare elevation2 p
value
Ophthalmic Res 2002;34:90–93
inflammation was not associated with latanoprost in humans [7, 8]. Yousufzai et al. [15] reported that exogenous
latanoprost stimulated the formation of PGE2, PGD2,
and PGF2· in iris and ciliary body muscles isolated from
cats, cattle, rabbits, dogs, rhesus monkeys and humans. In
the present study, however, latanoprost did not induce
flare elevation in rabbit eyes with or without transcorneal
diffusion of PGE2. This discordance may possibly be due
to differences between in vitro (isolated tissue) versus in
vivo experiments and measurements (PGs versus flare
intensities).
Species differences in the response of the eye to irritation and trauma have been demonstrated [16]. The bloodaqueous barrier in rabbits has unique sensitivity to PGs
[17]. The blood-aqueous barrier may be more labile in
rabbits than in humans. Isopropyl unoprostone induced
aqueous flare elevation in rabbits.
Zhang/Hayasaka/Hayasaka/Yanagisawa/
Nagaki
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Table 1. Effect of isopropyl unoprostone,
References
PGF2· Analogues and Aqueous Flare
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Ophthalmic Res 2002;34:90–93
93
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