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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
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Orzalesi et al.
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
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,
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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).
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.
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).
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
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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.
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References
1. Alward WC. Medical management of glaucoma. N Engl J Med.
1998;339:1298 1307.
2. Racz P, Ruzsonyi MR, Nagy ZT, et al. Around-the-clock (circadian)
intraocular pressure reduction with once-daily application of
25.
26. Letchinger SL, Frohlichstein D, Glieser DK, et al. Can the concentration of timolol or the frequency of its administration be reduced? Ophthalmology. 1993;100:1259 1262.
27. Strahlman E, Tipping R, Vogel R, and the International Dorzolamide Study Group. A double-masked, randomized 1-year study
comparing dorzolamide (Trusopt), timolol, and betaxolol. Arch
Ophthalmol. 1995;113:1009 1016.
28. McCannel CA, Heinrich SR, Brubaker RF. Acetazolamide but not
timolol lowers aqueous humor flow in sleeping humans [ARVO
Abstract]. Invest Ophthalmol Vis Sci. 1991;32(4):S1256. Abstract
nr 2879.
29. Brubaker RF, Carlson KH, Kullerstrand LJ, McLaren JW. Topical
forskolin (Colforsin) and aqueous flow in humans. Arch Ophthalmol. 1987;105:637 641.
30. Neufeld A, Bartels SP. Receptor mechanisms for epinephrine and
timolol. In: Lu
tjenDrecoll E, ed. Basic Aspects of Glaucoma
Research. Stuttgart, Germany: Shattauer; 1982:113122.
31. Rushton A. Cyclic AMP and intraocular pressure. Lancet. 1983;2:
737.
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