Effect of Timolol, Latanoprost, and Dorzolamide on

Circadian IOP in Glaucoma or Ocular Hypertension

Nicola Orzalesi, Luca Rossetti, Tommaso Invernizzi, Andrea Bottoli, and
Alessandro Autelitano
PURPOSE. To compare the around-the-clock intraocular pressure (IOP) reduction induced by timolol
0.5%, latanoprost 0.005%, and dorzolamide in patients with primary open-angle glaucoma (POAG)
or ocular hypertension (OHT).
METHODS. In this crossover trial, 20 patients with POAG (n 10) or OHT (n 10) were treated
with timolol, latanoprost, and dorzolamide for 1 month. The treatment sequence was randomized. All patients underwent measurements for four 24-hour tonometric curves: at baseline and
after each 1-month period of treatment. The patients were admitted to the hospital, and IOP
was measured by two well-trained evaluators masked to treatment assignment. Measurements
were taken at 3, 6, and 9 AM and noon and at 3, 6, and 9 PM and midnight by handheld
electronic tonometer (TonoPen XL; Bio-Rad, Glendale, CA) with the patient supine and sitting,
and a Goldmann applanation tonometer (Haag-Streit, Bern, Switzerland) with the patient sitting
at the slit lamp. Systemic blood pressure was recorded at the same times. The between-group
differences were tested for significance by means of parametric analysis of variance. The
circadian IOP curve of a small group of untreated healthy young subjects was also recorded
using the same procedures. To compare the circadian IOP rhythms in the POAG-OHT and
control groups, the acrophases for each subject were calculated.
RESULTS. When Goldmann sitting values were considered, all the drugs significantly reduced IOP in
comparison with baseline at all times, except for timolol at 3 AM. Latanoprost was more effective
in lowering IOP than timolol at 3, 6, and 9 AM (P 0.03), noon (P 0.01), 9 PM, and midnight
(P 0.05) and was more effective than dorzolamide at 9 AM, noon (P 0.03), and 3 and 6 PM (P
0.04). Timolol was more effective than dorzolamide at 3 PM (P 0.05), whereas dorzolamide
performed better than timolol at midnight and 3 AM (P 0.05). An ancillary finding of this study
was that in the group of healthy subjects, the pattern of IOP curve was different that in patients
with eye disease.
CONCLUSIONS. Latanoprost seemed to lead to a fairly uniform circadian reduction in IOP, whereas
timolol seemed to be less effective during the nighttime hours. Dorzolamide was less effective than
latanoprost but led to a significant reduction in nocturnal IOP. The reason for the difference in the
pattern of the IOP curve of healthy subjects is currently unknown and deserves further
investigation. (Invest Ophthalmol Vis Sci. 2000;41:2566 2573)

igh intraocular pressure (IOP) is considered to be the

most important risk factor for development of primary
open-angle glaucoma (POAG), and its reduction continues to be the only reasonable way of treating the disease.1
Surprisingly enough, the vigorous efforts dedicated to finding
new drugs for ocular hypotension (OHT) have rarely been
accompanied by a careful examination of their circadian effects. With very few exceptions,2 4 reports on the efficacy of
ocular hypotensive drugs are limited to the diurnal curve of
IOP, usually from 9 AM to 5 PM. However, it is clear that such
an evaluation is not sufficient to indicate the real value of an
From the Eye Clinic, Institute of Biomedical Sciences, San Paolo
Hospital, University of Milan, Italy.
Submitted for publication November 8, 1999; revised March 6,
2000; accepted March 17, 2000.
Commercial relationships policy: N.
Corresponding author: Nicola Orzalesi, University of Milan, Institute of Biomedical Sciences, San Paolo Hospital, Via di Rudin` 8, 20142
Milano, Italy. orzalesi@mailserver.unimi.it

2566

ocular hypotensive treatment for at least three reasons. First,

both IOP and the rate of aqueous humor flow have a circadian
rhythm,5 and higher IOP may be recorded during the night.513
Second, nighttime may be considered a critical period for the
control of glaucoma (particularly low-tension glaucoma) because the nocturnal decrease in systemic blood pressure may
make the nocturnal IOP even more critical.14 16 Finally, the
effect of ocular hypotensive drugs may not be the same during
the night and day. Some investigators have suggested that
-blockers do not decrease the production of aqueous humor
during sleep,1719 whereas both acetazolamide and apraclonidine also have been found to suppress the rate of aqueous
flow in the sleeping eye.17 Moreover, administered once a day,
the recently introduced latanoprost leads to a reduction in IOP
throughout the night that is comparable to its daytime effect.2 4
The purpose of this study was to compare the effect of
three of the most widely used ocular hypotensive drugs on the
circadian rhythm of IOP in patients with POAG or OHT.
Investigative Ophthalmology & Visual Science, August 2000, Vol. 41, No. 9
Copyright Association for Research in Vision and Ophthalmology

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IOVS, August 2000, Vol. 41, No. 9

Circadian IOP Reduction by Ocular Hypotensive Drugs

METHODS
The trial involved 20 patients with diagnosed POAG or OHT.
Glaucoma was defined as IOP higher than 21 mm Hg without
medication (in at least one eye and measured on two consecutive occasions separated by an interval of at least 2 hours but
not more than 12 weeks), glaucomatous field or optic disc
changes, or retinal nerve fiber layer defects. OHT was defined
as IOP higher than 21 mm Hg without medication (measured as
in POAG), and a normal visual field, optic disc, and retinal
nerve fiber layer.
Visual fields were considered normal on the basis of normal global mean defect (MD) and corrected pattern SD (CPSD)
field indices confirmed by at least two consecutive tests (Humphrey perimeter, 30-2 central threshold program; Humphrey
Instruments, San Leandro, CA). To be deemed normal, the
optic disc had to have intact rims with no disc hemorrhages,
notches, localized pallor, or asymmetry of more than 0.3 in the
cup-to-disc ratios (vertical or horizontal) of the two eyes. The
retinal nerve fiber layer (evaluated with the Scanning Laser
Ophthalmoscope 101; Rodenstock, Ottobrunn, Germany) was
considered normal if a normal striation pattern was visible in all
the peripapillary sectors, giving rise to a uniform lightsilver
reflex.
Glaucomatous visual fields had abnormal MD and CPSD
field indices. For ethical reasons, patients with visual field
defects within the central 10 were not included. Glaucomatous optic discs had a cup-to-disc ratio of more than 0.7. Nerve
fiber layer defects included wedge defects (i.e., darker focal
areas in which the visibility of the normal striation pattern was
reduced or lost) that were wider than a first-order branch vein,
which originated at the disc border and arched from the disc to
the periphery, and diffuse defects (i.e., a diffuse and generalized rarefaction of the normal striation pattern that seemed to
blur into a uniform, dull, granular whitish gray; in these areas,
the walls of the denuded blood vessels stood out sharply
instead of being buried in the retinal nerve fiber).
The exclusion criteria included baseline untreated IOP
higher than 30 mm Hg confirmed on two occasions within 1
week; angle-closure glaucoma; corneal abnormalities preventing reliable IOP measurement, including photorefractive keratectomy; previous filtration surgery; a life-threatening or debilitating disease limiting the patients ability to participate in the
trial; secondary causes of elevated IOP, such as the use of
corticosteroids, iridocyclitis, or ocular trauma; conditions for
which the trial drugs are contraindicated; absence of vision in
one eye; and pregnancy. Significant disturbances of wake
sleep rhythms and/or the regular consumption of hypnotic
drugs reported by the patients were also considered reasons
for exclusion.
The trial had a crossover design with the patients in
medical treatment undergoing a 4-week wash-out before the
baseline circadian tonometric curve was recorded. The nature
and purpose of the trial was explained in detail to all participants, and their informed consent was obtained before drug
wash-out was initiated. The study protocol adhered to the
tenets of the Declaration of Helsinki.
The patients were randomized to receive one of the following treatment sequences: 1) A, B, C; 2) A, C, B; 3) B, A, C;
4) B, C, A; 5) C, A, B; 6) C, B, A, where A was timolol 0.5%
(Timoptic; Merck, Darmstadt, Germany), B was latanoprost

2567

0.005% (Xalatan; Pharmacia Upjohn, Kalamazoo, MI), and C

was dorzolamide 2% (Trusopt, Merck). Randomization was
obtained using a list of random numbers. The patients were
given the masked bottles and instructed to instill the eyedrops
according to the study protocol: twice daily for drug A (8 AM
and 8 PM), once daily for drug B (9 PM), and three times daily
for drug C (8 AM, 2 PM, and 8 PM). The duration of treatment
with each trial drug was 1 month, after which a circadian
tonometric curve was recorded. Four circadian tonometric
curves were therefore obtained for each patient: one baseline
and three different treatment curves.
For recording of the circadian tonometric curves, the
patients were admitted to the hospital in the morning (at 7 AM)
and stayed for the following 24 hours. During hospital stays,
they were allowed a normal lifestyle, including reading, watching television, and playing cards. They had normal hospital
meals without any beverage restrictions, including small
amounts of beer or wine and coffee or tea. The patients were
also given an ad hoc questionnaire designed to assess their
reactions to the hospital stay, anxiety due to measurements,
and quality of sleep. The awake period lasted from approximately 6:30 AM to 11:00 PM. A complete ophthalmic examination (including corneal pachymetry) was performed, and any
information about systemic and local tolerance of the drug was
recorded. IOP was measured at 3, 6, and 9 AM and noon and at
3, 6, and 9 PM and midnight. While patients were in the
hospital, drugs were administered by the study personnel according to the protocol. For the daytime measurements (9 AM
to 9 PM), the patients were asked to relax in bed for approximately 15 minutes, after which supine IOP was measured in
both eyes. Subsequently, the omeral blood pressure was assessed, and patients were then asked to sit on the bed for
another measurement of IOP. The interval between IOP measurements in the supine and sitting positions did not exceed 5
minutes. After walking approximately 10 m, the patients
reached the nearest examination room where a third IOP value
was measured at the slit lamp. During the night (midnight to 6
AM), the patients were awakened approximately 10 minutes
before IOP and blood pressure were measured by the same
procedure at midnight and 3 and 6 AM. The IOP measurements
were made using a handheld electronic tonometer (TonoPen
XL; Bio-Rad, Glendale, CA) with the patient in supine and
sitting positions, and a Goldmann applanation tonometer with
the patient sitting at the slit lamp. All the measurements were
performed by two well-trained evaluators who were masked to
the treatment assignments, and measurements were tested for
consistency and agreement ( 0.82) before beginning the
study.
The study outcome was the difference in IOP between the
groups. If both eyes were eligible, only one eye (chosen at
random) was used for analytical purposes.
The sample size calculation was based on the assumption
that a difference in mean IOP of 2.5 mm Hg is clinically
relevant. Approximately 2O patients were needed, given an
0.05, 1- 0.90, and an SD 2 mm Hg. The betweengroup differences were tested for significance by means of
parametric analysis of variance (ANOVA) with Bonferronis
method used to adjust P. The normality of the data distribution
was checked by means of the ShapiroFrancia W test in all
cases. Correlation was used to test the possible association
between continuous variables.

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Orzalesi et al.

IOVS, August 2000, Vol. 41, No. 9

TABLE 1. Patients Main Characteristics

n
POAG (n)
OHT (n)
Age (mean SD)
Sex
IOP (mean at enrollment)
Corneal thickness
Prestudy therapy (n)
None
-Blockers
Dorzolamide
Association*
Systemic hypertension (n)
Treated with -blockers (n)
Other treatments (n)

20
10
10
67 11.5
13 F, 7 M
23.9 4.7 mmHg
550 20 mm
6
8
1
5
13
7
6

* Combination of a -blocker and pilocarpine (three patients),

-blocker and dorzolamide (one patient), and -blocker and dipivalylepinephrine (one patient).

As a preliminary step, to evaluate the normal circadian IOP

curve without treatment, a group of seven healthy young
volunteers (aged 2326 years) was recruited from among the
medical students attending the Eye Clinic of San Paolo Hospital
and underwent the same evaluation procedures as the POAGOHT group.
To compare the circadian IOP rhythms in the POAG-OHT
and control groups, the acrophases (timing of the fitted peak)
for each subject were calculated as the best fitting 24-hour
cosine for the eight IOP averages of both eyes.6 The supine
values of the patients with POAG-OHT at baseline were com-

pared with those of the young volunteers. Differences in the

median values of the acrophases were tested using the twotailed MannWhitney test. All analyses were performed by
computer (SPSS ver. 6.0 for Macintosh; SPSS, Chicago, IL).

RESULTS
Twenty patients were enrolled in the trial (10 with POAG and
10 with OHT) Their main characteristics are shown in Table 1.
Corneal pachymetry was within normal ranges for all subjects.
All patients completed the three crossover phases, and no
important adverse event was recorded. Figure 1 shows the
Goldmann tonometer readings of baseline, timolol, latanoprost, and dorzolamide circadian curves. All the drugs significantly reduced IOP in comparison with baseline at all time
points, except for timolol at 3 AM. The mean IOPs were 22.7
1.8 mm Hg at baseline, 18.7 0.9 mm Hg with timolol, 16.3
0.6 with latanoprost, and 19.3 1.7 with dorzolamide. The
differences in mean IOP were statistically significant when
latanoprost was compared with timolol (P 0.001) and dorzolamide (P 0.001). There was no statistically significant
difference in the mean IOP between timolol and dorzolamide.
Latanoprost was more effective in lowering IOP than timolol at 3, 6, and 9 AM, at noon, at 9 PM, and at midnight. It was
also more effective than dorzolamide at 9 AM, at noon, and at
3 and 6 PM. Timolol significantly reduced IOP in comparison
with dorzolamide at 3 PM, whereas dorzolamide performed
better than timolol at midnight and 3 AM. In comparison with
baseline, the mean diurnal (9 AM to 9 PM) versus nocturnal
(midnight to 6 AM) reductions in IOP were, respectively,

FIGURE 1. Goldmann tonometer

IOP readings (mean SD). All drugs
significantly reduced IOP in comparison with baseline, except timolol at
3 AM. Latanoprost was more effective than timolol at 3, 6, and 9 AM
(P 0.03), at noon (P 0.01), and
at 9 PM and midnight (P 0.05).
Latanoprost was more effective than
dorzolamide at 9 AM and noon (P
0.03) and at 3 and 6 PM (P 0.04).
Timolol was more effective than
dorzolamide at 3 PM (P 0.05),
whereas dorzolamide performed better than timolol at midnight and 3 AM
(P 0.05).

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Circadian IOP Reduction by Ocular Hypotensive Drugs

2569

FIGURE 2. Supine tonometric readings (mean SD). All drugs significantly reduced IOP in comparison
with baseline, except timolol at 3
and 6 AM. Latanoprost was more effective than timolol at 3, 6, and 9 AM
(P 0.03) and at 3 PM (P 0.05).
Latanoprost was more effective than
dorzolamide at 9 AM and noon (P
0.03) and 3 and 6 PM (P 0.04).
Dorzolamide was more effective than
timolol at 3 and 6 AM (P 0.05).

4.1 1.2 mm Hg versus 1.9 0.5 mm Hg (P 0.04) for

timolol, 6.8 1.3 mm Hg versus 4.9 1.0 mm Hg (P
0.1) for latanoprost, and 3.5 1.2 mm Hg versus 3.4 1.0
mm Hg (P 0.8) for dorzolamide.
Figures 2 and 3 show the electronic tonometer measurements in the supine and sitting positions. The shape of the
curves was consistent with those obtained using the Goldmann
tonometer, and the differences in drug efficacy were maintained. The statistical significance of the between-drug comparisons is shown in Figures 2 and 3. As previously found,2
Goldmann tonometer readings agreed well with the electronic
tonometer readings in the sitting position (r 0.90), whereas
the IOP measured by electronic tonometer with the patients
supine were slightly higher. The mean supine versus sitting
IOPs were, respectively, 23.7 1.9 mm Hg versus 22.5 1.7
mm Hg at baseline, 19.4 1.6 mm Hg versus 18.5 1.2 mm
Hg with timolol, 17.5 1.0 mm Hg versus 16.8 0.9 with
latanoprost, and 20.0 1.1 mm Hg versus 19.1 1.6 mm Hg
with dorzolamide. When the data are considered as a whole,
the supine IOPs were significantly higher than the sitting IOPs
only at noon and at 3 PM (P 0.04). The mean diurnal versus
nocturnal difference in IOP between the supine and sitting
IOPs were 1.4 1 mm Hg and 0.9 1.1 mm Hg, respectively.
This difference was not statistically significant.
Figures 4 and 5 show the circadian curves and acrophases
of baseline IOP in the patients with POAG or OHT compared
with those observed in the group of young healthy volunteers.
The median acrophases in the two groups were compared: the
amplitude of the circadian rhythm in the POAG-OHT group
was significantly higher than in the control subjects (P 0.02,
MannWhitney test). The mean acrophase in the POAG-OHT

group was at 8:55 AM as opposed to 5:20 AM in the control

group. This difference was also statistically significant (P
0.04).
The blood pressure measurements in the patients with
POAG or OHT and the corresponding supine IOP at baseline
are shown in Figure 6. A significant correlation was found
between supine IOP and systolic blood pressure at baseline
(r 0.61, P 0.02).
Responses to the questionnaire indicated that although
some patients experienced some difficulty in going to sleep, in
general all judged the quality of days and nights spent at the
hospital for the assessment of the circadian IOP curves to be
normal.

DISCUSSION
The results of this trial clearly show that the effects of the three
studied drugs differed markedly in the various phases of the
circadian IOP curve.
All the drugs led to a statistically significant decrease in
IOP in comparison with baseline. Latanoprost was the most
effective ocular hypotensive agent and, as reported in previous
studies,2 4 its effect appeared to be fairly uniform throughout
the circadian cycle. However, its efficacy was slightly but not
significantly greater during the day. Similar behavior was more
marked with timolol, which had a nocturnal efficacy only
approximately half that obtained during the day. Finally, dorzolamide was less effective than both latanoprost and timolol
during the day but maintained its efficacy during the night,
when it was superior to timolol. Previous observations may

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Orzalesi et al.

IOVS, August 2000, Vol. 41, No. 9

FIGURE 3. Sitting tonometric readings (mean SD). All drugs significantly reduced IOP in comparison
with baseline, except timolol at 6
AM. Latanoprost was more effective
than timolol at 3, 6, and 9 AM (P
0.03), noon (P 0.01), and 3 PM
(P 0.04). Latanoprost was more
effective than dorzolamide at 9 AM
and noon (P 0.03) and at 3 and 6
PM (P 0.04). Dorzolamide was
more effective than timolol at 3 AM
(P 0.05).

help to explain the results of this trial. A number of studies

indicate that the rate of aqueous flow during sleep is much
lower than during waking hours,1721 and that drugs affecting
aqueous flow can have different effects at different times of
day.17,19,22,23 Timolol, which has a substantial effect when

tested during the day,1,24 27 has been found to have no measurable effect at night.19,28,29 This has been attributed to the
existence of a baseline rate of flow that cannot be further
suppressed by any drug, or to the absence of timolol-blocking
activity in the sleeping eye.17,30,31 However, acetazolamide

FIGURE 4. Baseline supine tonometric readings (mean SD) in the

POAG-OHT and healthy young volunteer groups. IOPs were significantly
different at all time points (P
0.001). Note the different shape of
the two curves.

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Circadian IOP Reduction by Ocular Hypotensive Drugs

FIGURE 5. Polar coordinates displaying the least-squares estimates of

the 24-hour rhythms in IOP. The position of the acrophase around the
circle shows its timing, whereas the radial distance from the center
shows the amplitude of IOP rhythm. (F), Patients with POAG or OHT;
(E), healthy subjects. Medians of both acrophases and amplitudes were
significantly different when the two groups were compared.

and apraclonidine both suppress the rate of aqueous flow in

the sleeping eye,28,32 and in this study dorzolamide (a derivative of acetazolamide) maintained its effect on IOP during the
night. Previous studies have shown that the effect of latanoprost (which reduces IOP by increasing uveoscleral outflow) is
present throughout the circadian cycle.2 4 In the present
crossover trial, latanoprost seemed to be more effective during

2571

the day than during the night (6.8 1.3 mm Hg versus

4.9 1.0 mm Hg, respectively). Although not significant,
this difference may be related to nocturnal variations in ciliary
muscle tone that could affect uveoscleral outflow, as is suggested by the ability of prostaglandins to relax the ciliary
muscle and thus increase the uveoscleral outflow.2,33
The circadian curves recorded using the TonoPen and
Goldmann measurements in the sitting and supine positions
were basically similar but, as expected, the sitting values were
lower than the TonoPen supine measurements (a statistically
significant difference was found at noon and at 3 PM), probably
because of the increase in venous pressure in the supine
position. The results of this study, however, show a smaller
postural effect on IOP than was expected. This probably occurred because the interval between supine and sitting IOP
measurements did not exceed 5 minutes. The brief time between the two recordings was considered to shorten, as much
as possible, the awake time during the sleep period.
The circadian curves obtained in the patients with POAG
or OHT at baseline and under treatment followed the pattern of
the curve traditionally quoted in the literature as the day-type
curve, which is characterized by a peak in the morning (between 8 and 10 AM) and a trough at night.5 This pattern was
particularly evident in the case of the supine measurements. A
day-type curve was not observed, however, in the small control
group of healthy young subjects, who showed higher pressures during the night than during the day. This pattern is
similar to that reported by Liu et al.6 in a recent study of
healthy volunteers examined under strictly controlled experimental conditions, which showed a peak at 5:30 AM and a
trough at 9:30 PM.
The reasons for this difference can only be hypothesized.
It is possible that the different characteristics of the two groups
in age (20 versus 60 years) and health may have played a role.

FIGURE 6. Baseline supine tonometric readings (mean SD) and blood

pressure readings in patients with
POAG or OHT. No IOP nocturnal
peak in correspondence with a nocturnal blood pressure dip was observed. SSBP, supine systolic blood
pressure; SDBP, supine diastolic
blood pressure.

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Orzalesi et al.

Another explanation could reside in the experimental conditions applied by Liu et al., particularly in relation to the effect
of exposure to light during IOP assessment, although in another recent study by Liu et al.,34 environmental light at night
had no significant effect on the nocturnal IOP elevation in
healthy young adults. That our healthy subjects were examined
under the same conditions as those used for the patients with
POAG or OHT and behaved similar to those of Liu et al. seems
to indicate that more cogent reasons are involved.
An association between baseline supine IOP measurements and systolic blood pressure was found in the group of
patients with POAG or OHT. This interesting result may suggest a role of blood pressure in influencing the circadian
rhythm of supine IOP. Little is known about factors associated
with circadian variation of IOP, and a positive correlation
between IOP readings and blood pressure measurements has
been described.35 This issue, which was not within the scope
of this trial, deserves a large amount of basic and clinical
research and future investigations are needed to clarify
whether blood pressure levels are really associated with the
circadian variations of IOP.
Any trial such as ours is naturally exposed to a series of
biases that cannot be easily avoided and must be taken into
consideration when drawing conclusions. The most important
concern the measurement of IOP in a clinical setting: hospitalization, exposure to light during the measurements made at
night, disturbed sleep, and sudden awakenings can all potentially affect the evaluation of IOP. We tried to protect the study
results against these biases as much as possible, most of all with
the masked, crossover design of the study, which assured an
even distribution of biases to all treatments.
As far as the effect of ocular hypotensive drugs is concerned, the literature usually refers to the articles showing that
the effect of latanoprost is constant during the circadian cycle,2,36 whereas timolol has no effect on aqueous flow and
therefore does not decrease IOP during the night.17 To our
knowledge, there is no previously published direct comparison
in a clinical setting. Our results can therefore be considered of
value, in that they show that the current therapeutic strategies
used in the treatment of glaucoma, which are primarily based
on -blockers, may mean that the majority of patients are less
well protected during the critical nighttime period. Over the
years, a large number of studies on the medical treatment of
glaucoma have been undertaken in which differences of just a
few millimeters of mercury were considered to be a significant
result worthy of influencing clinical practice. It is therefore
surprising that similar differences occurring during the night,
not only between different treatments, but also with the same
treatment, are routinely ignored. The results of this study
underline the fact that ophthalmologists treating patients with
POAG should not continue to ignore, for practical reasons, the
nocturnal part of the circadian IOP curve. As Odberg37 has
recently, and very appropriately, pointed out, Glaucoma is
after all a 24-hour disease.

IOVS, August 2000, Vol. 41, No. 9

3.

4.

5.

6.

7.

8.

9.

10.

11.
12.

13.

14.

15.

16.
17.
18.
19.

20.

21.

22.

23.

24.

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