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Figure 1
Goldmann tonometer intraocular pressure (IOP) readings (mean [SD]). All drugs significantly reduced IOP in comparison with the baseline except for brimonidine tartrate at midnight, 3 AM, and 6 AM. Latanoprost was more effective than brimonidine at 3 and 6 AM and at 3 and 6 PM (P= .03). The fixed combination of timolol maleate and dorzolamide hydrochloride was more effective than brimonidine at 3 and 9 AM (P= .04) and at 3 and 6 PM (P= .05). It was also more effective than latanoprost at 9 AM (P= .05). Asterisks indicate the times when brimonidine and the fixed combination of timolol and dorzolamide were administered; dagger, the time when latanoprost was administered.

Goldmann tonometer intraocular pressure (IOP) readings (mean [SD]). All drugs significantly reduced IOP in comparison with the baseline except for brimonidine tartrate at midnight, 3 AM, and 6 AM. Latanoprost was more effective than brimonidine at 3 and 6 AM and at 3 and 6 PM (P= .03). The fixed combination of timolol maleate and dorzolamide hydrochloride was more effective than brimonidine at 3 and 9 AM (P= .04) and at 3 and 6 PM (P= .05). It was also more effective than latanoprost at 9 AM (P= .05). Asterisks indicate the times when brimonidine and the fixed combination of timolol and dorzolamide were administered; dagger, the time when latanoprost was administered.

Figure 2
Supine position tonometric readings(mean [SD]). All drugs significantly reduced intraocular pressure (IOP) in comparison with the baseline except for brimonidine tartrate at midnight, 3 AM, 3 PM, and 6 PM. Latanoprost was more effective than brimonidine at midnight, 3 AM (P= .02), and 6 AM (P=.04) and at 3 and 6 PM (P= .03). Latanoprost was more effective than the fixed combination of timolol maleate and dorzolamide hydrochloride at 6 AM (P= .05), which was more effective than brimonidine at 3 AM (P= .05), 3 PM, and 6 PM and more effective than latanoprost at 9 AM (P= .05). Asterisks indicate the times when brimonidine and the fixed combination of timolol and dorzolamide were administered; dagger, the time when latanoprost was administered.

Supine position tonometric readings(mean [SD]). All drugs significantly reduced intraocular pressure (IOP) in comparison with the baseline except for brimonidine tartrate at midnight, 3 AM, 3 PM, and 6 PM. Latanoprost was more effective than brimonidine at midnight, 3 AM (P= .02), and 6 AM (P=.04) and at 3 and 6 PM (P= .03). Latanoprost was more effective than the fixed combination of timolol maleate and dorzolamide hydrochloride at 6 AM (P= .05), which was more effective than brimonidine at 3 AM (P= .05), 3 PM, and 6 PM and more effective than latanoprost at 9 AM (P= .05). Asterisks indicate the times when brimonidine and the fixed combination of timolol and dorzolamide were administered; dagger, the time when latanoprost was administered.

Figure 3
Sitting position tonometric readings(mean [SD]). All drugs significantly reduced intraocular pressure (IOP) in comparison with the baseline except for brimonidine tartrate at 3 AM, 6 AM, and 6 PM. Latanoprost was more effective than brimonidine at 3 and 6 AM (P= .02) and at noon (P= .03). It was more effective than the fixed combination of timolol maleate and dorzolamide hydrochloride at 6 AM (P= .01), which was more effective than brimonidine at 3 AM (P= .04), 9 AM (P= .05), and 6 PM (P= .01) and more effective than latanoprost at 6 PM (P= .03). Asterisks indicate the times when brimonidine and the fixed combination of timolol and dorzolamide were administered; dagger, the time when latanoprost was administered.

Sitting position tonometric readings(mean [SD]). All drugs significantly reduced intraocular pressure (IOP) in comparison with the baseline except for brimonidine tartrate at 3 AM, 6 AM, and 6 PM. Latanoprost was more effective than brimonidine at 3 and 6 AM (P= .02) and at noon (P= .03). It was more effective than the fixed combination of timolol maleate and dorzolamide hydrochloride at 6 AM (P= .01), which was more effective than brimonidine at 3 AM (P= .04), 9 AM (P= .05), and 6 PM (P= .01) and more effective than latanoprost at 6 PM (P= .03). Asterisks indicate the times when brimonidine and the fixed combination of timolol and dorzolamide were administered; dagger, the time when latanoprost was administered.

Figure 4
Baseline (mean [SD]) supine position tonometric intraocular pressure (IOP) and blood pressure (BP) readings in patients with primary open-angle glaucoma or ocular hypertension. No nocturnal IOP peak in correspondence with a nocturnal BP dip was observed.

Baseline (mean [SD]) supine position tonometric intraocular pressure (IOP) and blood pressure (BP) readings in patients with primary open-angle glaucoma or ocular hypertension. No nocturnal IOP peak in correspondence with a nocturnal BP dip was observed.

Table 1 
Patient Characteristics*
Patient Characteristics*
Table 2 
Change in Intraocular Pressure (IOP)*
Change in Intraocular Pressure (IOP)*
1.
Racz  PRuzsonyi  MRNagy  ZT  et al.  Around-the-clock (circadian) intraocular pressure reduction with once-daily application of 0.005% latanoprost by itself or in combination with timolol. Arch Ophthalmol. 1996;114268- 273Article
2.
Bito  LZRacz  PRuzsony  MR  et al.  The prostaglandin analogue, Ph XA41, significantly reduces daytime and nighttime intraocular pressure (IOP) by itself, and in timolol-treated glaucomatous eyes [ARVO abstract]. Invest Ophthalmol Vis Sci. 1994;352178
3.
Kiuchi  YTakamatsu  MMishima  HK Ph XA41, a prostaglandin F 2a analogue, reduces the intraocular pressure(IOP) in human volunteers during day and night [ARVO abstract]. Invest Ophthalmol Vis Sci. 1994;352178
4.
Orzalesi  NRossetti  LInvernizzi  TBottoli  A The effect of timolol, latanoprost, and dorzolamide on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Invest Ophthalmol Vis Sci. 2000;412566- 2573
5.
Larsson  LI Intraocular pressure over 24 hours at repeated administration of latanoprost 0.005% or timolol gel-forming solution 0.5% in patients with ocular hypertension. Ophthalmology. 2001;1081439- 1444Article
6.
Larsson  LI Effect of intraocular pressure during 24 hours after repeated administration of the fixed combination of latanoprost 0.005% and timolol 0.5% in patients with ocular hypertension. J Glaucoma. 2001;10109- 114Article
7.
Asrani  SZeimer  RWilensky  J  et al.  Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma. 2000;9134- 142Article
8.
Weinreb  RN A rationale for lowering intraocular pressure in glaucoma. Surv Ophthalmol. 2001;45 ((4 suppl)) S335- S336Article
9.
Konstas  AGMaltezos  ACGandi  SHudgins  ACStewart  WC Comparison of 24-hour intraocular pressure reduction with two dosing regimens of latanoprost and timolol maleate in patients with primary open-angle glaucoma. Am J Ophthalmol. 1999;12815- 20Article
10.
Mishima  HKKiuchi  YTakamatsu  M  et al.  Circadian intraocular pressure management with latanoprost: diurnal and nocturnal intraocular pressure reduction and increased uveoscleral outflow. Surv Ophthalmol. 1997;41 ((suppl 2)) S139- S144Article
11.
Konstas  AGMantziris  DAMaltezos  ACate  EAStewart  WC Comparison of 24-hour control with timoptic 0.5% and timoptic-XE 0.5% in exfoliation and primary open-angle glaucoma. Acta Ophthalmol Scand. 1999;77541- 543Article
12.
Konstas  AGMaltezos  ABufidis  THudgins  AGStewart  WC Twenty-four hour control of intraocular pressure with dorzolamide and timolol maleate in exfoliation and primary open-angle glaucoma. Eye. 2000;1473- 77Article
13.
Krag  SAndersen  HBSorensen  T Circadian intraocular pressure variation with β-blockers. Acta Ophthalmol Scand. 1999;77500- 503Article
14.
Konstas  AGLake  SMaltezos  ACHolmes  KTStewart  WC Twenty-four hour intraocular pressure reduction with latanoprost compared with pilocarpine as third-line therapy in exfoliation glaucoma. Eye. 2001;1559- 62Article
15.
Follmann  PPalotas  CSuveges  IPetrovits  A Nocturnal blood pressure and intraocular pressure measurement in glaucoma patients and healthy controls. Int Ophthalmol. 1996;2083- 87
16.
Graham  SLDrance  SMWijsman  KDouglas  GRMikelberg  FS Ambulatory blood pressure monitoring in glaucoma: the nocturnal dip. Ophthalmology. 1995;10261- 69Article
17.
Hayreh  SSZimmerman  MBPodhajsky  PAlward  WLM Nocturnal arterial hypotension and its role in optic nerve head ischaemic disorders. Am J Ophthalmol. 1994;117603- 624
18.
Zeimer  RC Circadian variations in intraocular pressure. In:Ritch  RShields  MBKrupin  Teds.The Glaucomas St Louis, Mo Mosby1996;429- 445
19.
Liu  JHKKripke  DFHoffman  RE  et al.  Nocturnal elevation of intraocular pressure in young adults. Invest Ophthalmol Vis Sci. 1998;392707- 2712
20.
Frampton  PDa Rin  DBrown  B Diurnal variations of intraocular pressure and the overriding effects of sleep. Am J Optom Physiol Opt. 1987;6454- 61Article
21.
Brown  BMorris  PMuller  CBrady  ASwann  PG Fluctuations in intra-ocular pressure with sleep, I: time course of IOP increase after the onset of sleep. Ophthalmic Physiol Opt. 1988;8246- 248
22.
Brown  BBurton  PMann  SParisi  A Fluctuations in intra-ocular pressure with sleep, II: time course of IOP decrease after waking from sleep. Ophthalmic Physiol Opt. 1988;8249- 252
23.
Wildsoet  CBrown  BSwann  PG Darkness and sleep as contributing factors to diurnal variation in intraocular pressure. Glaucoma. 1990;12140- 147
24.
Wilensky  JT Diurnal variations in intraocular pressure. Trans Am Ophthalmol Soc. 1991;89757- 790
25.
Wildsoet  CEyeson-Annan  MBrown  BSwann  PGFletcher  T Investigation of parameters influencing intraocular pressure increases during sleep. Ophthalmic Physiol Opt. 1993;13357- 365Article
26.
Buguet  APy  PRomanet  JP 24-Hour (nyctohemeral) and sleep-related variations of intraocular pressure in healthy white individuals. Am J Ophthalmol. 1994;117342- 347
27.
Wilensky  JTGieser  DKDietsche  ML  et al.  Individual variability in the diurnal intraocular pressure curve. Ophthalmology. 1993;100940- 944Article
28.
Korenfeld  MSDueker  DK Occult intraocular pressure elevations and optic cup asymmetry: sleep posture may be a risk factor [ARVO abstract]. Invest Ophthalmol Vis Sci. 1993;34 ((suppl)) 994
29.
Wilensky  JT The role of brimonidine in the treatment of open-angle glaucoma. Surv Ophthalmol. 1996;41 ((suppl 1)) S3- S7Article
30.
Bill  A Uveoscleral drainage of aqueous humor: physiology and pharmacology. Prog Clin Biol Res. 1989;312417- 429
31.
Brubaker  RF Flow of aqueous humor in humans. Invest Ophthalmol Vis Sci. 1991;323145- 3165
32.
Reiss  GRLee  DATopper  JEBrubaker  RF Aqueous humor flow during sleep. Invest Ophthalmol Vis Sci. 1984;25776- 778
33.
Topper  JEBrubaker  RF Effects of timolol, epinephrine, and acetazolamide on aqueous flow during sleep. Invest Ophthalmol Vis Sci. 1985;261315- 1319
34.
McCannel  CAHeinrich  SRBrubaker  RF Acetazolamide but not timolol lowers aqueous humor flow in sleeping humans [ARVO abstract]. Invest Ophthalmol Vis Sci. 1991;32 ((suppl)) 1256
35.
Brubaker  RFCarlson  KHKullerstrand  LJMcLaren  JW Topical forskolin (Colforsin) and aqueous flow in humans. Arch Ophthalmol. 1987;105637- 641Article
36.
Koskela  TBrubaker  RF The nocturnal suppression of aqueous humor flow in humans is not blocked by bright light. Invest Ophthalmol Vis Sci. 1991;322504- 2506
37.
Maus  TLMcLaren  JWShepard  JW  JrBrubaker  RF The effects of sleep on circulating catecholamines and aqueous flow in human subjects. Exp Eye Res. 1996;62351- 358Article
38.
Larson  RSBrubaker  RF Isoprotenerol stimulates aqueous flow in humans with Horner's syndrome. Invest Ophthalmol Vis Sci. 1988;29621- 625
39.
Gharagozloo  NZLarson  RSKullerstrand  LJBrubaker  RF Terbutaline stimulates aqueous humor flow in humans during sleep. Arch Ophthalmol. 1988;1061218- 1220Article
40.
Neufeld  ABartels  SP Receptor mechanisms for epinephrine and timolol. In:Lutjen-Drecoll  Eed.Basis Aspects of Glaucoma Research Stuttgart, Germany Shattauer1982;113- 122
41.
Rushton  A Cyclic AMP and intraocular pressure [letter]. Lancet. 1983;2737Article
42.
Serle  Jand the Brimonidine Study Group III, A comparison of the safety and efficacy of twice daily brimonidine 0.2% vs betaxolol 0.25% in subjects with elevated intraocular pressure. Surv Ophthalmol. 1996;41 ((suppl 1)) S39- S47Article
43.
Schuman  JS Clinical experience with brimonidine 0.2% and timolol 0.5% in glaucoma and ocular hypertension. Surv Ophthalmol. 1996;41 ((suppl 1)) S27- S37Article
44.
Konstas  AGStewart  WCTopouzis  F  et al.  Brimonidine 0.2% given 2 or 3 times daily vs timolol maleate 0.5% in primary open-angle glaucoma. Am J Ophthalmol. 2001;131 ((6)) 729- 733Article
45.
Koskela  TBrubaker  RF Apraclonidine and timolol: combined effects in previously untreated normal subjects. Arch Ophthalmol. 1991;109804- 806Article
46.
Bergea  BBodin  LSvedberg  B Impact of intraocular pressure regulation on visual fields in open-angle glaucoma. Ophthalmology. 1999;106997- 1005Article
Clinical Sciences
April 2003

The Effect of Latanoprost, Brimonidine, and a Fixed Combination of Timolol and Dorzolamide on Circadian Intraocular Pressure in Patients With Glaucoma or Ocular Hypertension

Author Affiliations

From the Eye Clinic, Institute of Biomedical Sciences, University of Milan, San Paolo Hospital, Milan, Italy. The authors have no relevant financial interest in this article.

Arch Ophthalmol. 2003;121(4):453-457. doi:10.1001/archopht.121.4.453
Abstract

Objective  To compare the circadian intraocular pressure (IOP) reductions induced by latanoprost, brimonidine tartrate, and a fixed combination of timolol maleate and dorzolamide hydrochloride in patients with primary open-angle glaucoma(POAG) or ocular hypertension (OHT).

Methods  In this crossover study, 10 patients with POAG and 10 with OHT were treated with latanoprost once a day, brimonidine twice a day, and a fixed combination of timolol and dorzolamide twice a day for 1 month. Four 24-hour tonometric curves were obtained for each patient. Intraocular pressure (IOP) was measured at 3, 6, and 9 AM, and at noon and at 3, 6, and 9 PM, and at midnight, using a handheld electronic tonometer with the patient in supine and sitting positions and a Goldmann applanation tonometer with the patient sitting at the slitlamp.

Main Outcome Measure  Reduction of circadian IOP.

Results  All the drugs significantly reduced IOP compared with the baseline at all times, except for brimonidine at midnight, 3 AM, and 6 AM. Latanoprost was more effective than brimonidine in lowering IOP at 3 and 6 AM and at 3 PM (P = .03), and the combination of timolol and dorzolamide was more effective than brimonidine at 3 and 9 AM (P = .04) and at 3 and 6 PM (P = .05) and more effective than latanoprost at 9 AM (P = .05).

Conclusion  Latanoprost and the fixed combination of timolol and dorzolamide led to similar circadian reductions in IOP, whereas brimonidine was less effective, particularly during the night.

SEVERAL CURRENTLY available drugs reduce intraocular pressure (IOP) in patients with ocular hypertension (OHT) or primary open-angle glaucoma(POAG), but their efficacy is usually assessed on the basis of office measurements or, at best, diurnal IOP curves. Patients are rarely evaluated during the night, 114 even though this is a critical period for the control of glaucoma because of the possibility of a nocturnal decrease in systemic blood and optic nerve head perfusion pressure.1517 It has also been shown that both IOP and the rate of aqueous humor flow follow a circadian rhythm1826 and that IOP may be high immediately after awakening20,27 because of local eyelid pressure from bedclothes during the night.28 A recent study found that timolol maleate was less effective in reducing IOP during the night, whereas dorzolamide hydrochloride seemed to perform well from midnight to 9 AM.4 Other studies have found that latanoprost reduces IOP to a similar extent during the night and day, 16,9,10,14 and the α2-agonist brimonidine tartrate has been found to have a hypotensive effect, at least during the day, similar to that of a β-blocker.29 It is hypothesized that a fixed combination of timolol and dorzolamide could provide 24-hour coverage as a result of the ocular hypotensive effect of timolol during the day and the good performance of dorzolamide during the night.4,12

The aim of this study was to compare the 24-hour effects of latanoprost, brimonidine, and a fixed combination of timolol and dorzolamide on the circadian rhythm of IOP in patients with POAG or OHT, a subject that has recently aroused some debate in the literature.16,814

METHODS

The method used to evaluate 24-hour IOP curves has been described in more detail elsewhere.4 The present study included 20 patients with POAG or OHT. Glaucoma was defined as an untreated IOP of more than 21 mmHg in at least 1 eye measured on 2 consecutive occasions separated by an interval of at least 2 hours but not more than 12 weeks, glaucomatous changes in the visual field or optic disc, or defects in the retinal nerve fiber layer. Ocular hypertension was defined as an untreated IOP of more than 21 mmHg (measured as for glaucoma) with a normal visual field, optic disc, and retinal nerve fiber layer. All treated cases were controlled by medical therapy, and IOP levels during treatment were not considered as criteria for inclusion.

Exclusion criteria included a baseline untreated IOP of more than 30mmHg confirmed on 2 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 patient's ability to participate in the trial; secondary causes of high IOP, such as the use of corticosteroids, iridocyclitis, or ocular trauma; conditions for which the trial drugs are contraindicated; having only 1 eye; or pregnancy. Significant wake-sleep rhythm disturbances and the regular use of hypnotic drugs as reported by the patients were also considered reasons for exclusion.

The trial had a crossover design, and patients already on medical treatment(all POAG cases and 5 OHT cases) underwent a 4-week washout period before their baseline circadian tonometric curves were recorded. The nature and purpose of the trial were explained in detail to all participants, who gave their informed consent before entering the washout phase. The study was carried out in accordance to the Declaration of Helsinki and was approved by the Ethical Committee of the University of Milan, Milan, Italy.

Using a list of random numbers, patients were randomized to receive 1 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; or (6) C, B, A; where A = 0.005% latanoprost(Xalatan; Pharmacia, Peapack, NJ), B = fixed combination of 0.5% timolol maleate and 2% dorzolamide hydrochloride (Cosopt; Merck, Whitehouse Station, NJ), and C = 0.2% brimonidine tartrate (Alphagan; Allergan, Irvine, Calif). Participants were given masked bottles and instructed to instill the eyedrops according to the study protocol, once daily for drug A (9 PM) and twice daily for drugs B and C (8 AM and 8 PM). Each trial drug was administered for 1 month, after which a circadian tonometric curve was recorded. Patients were washed out for about 4 weeks between each regimen of medications. A total of 4 circadian tonometric curves were therefore obtained for each patient, 1 baseline and 3 different treatment curves.

Patients entered the hospital at 8 AM and stayed for 24 hours. During the periods of hospitalization, patients were allowed to follow a regular lifestyle, including reading, watching television, and playing cards, and received normal hospital meals without any beverage restrictions, including small amounts of beer or wine and coffee or tea. No measurements were taken during known periods of increased or decreased consumption of drinks that could potentially alter IOP. Patients were also given an ad hoc questionnaire designed to assess their reaction to hospitalization, anxiety due to measurements, quality of sleep, etc. The waking period lasted from approximately 6:30 AM to 11 PM. A complete ophthalmological examination (including corneal pachymetry) was performed, and any information about systemic and local drug tolerability was recorded. Intraocular pressure was measured at 3, 6, and 9 AM, at noon, at 3, 6, and 9 PM, and at midnight. During hospitalization, drugs were administered by study personnel according to the protocol: latanoprost at 9 PM, just before the tonometric reading, and the twice-daily drugs 1 hour before the IOP evaluation. In the case of the daytime measurements (9 AM to 9 PM), patients were asked to go to bed and relax for about 15 minutes, after which supine IOP was measured in both eyes. Subsequently, their blood pressure was measured, and they were then asked to sit on the bed for further ocular pressure measurements. The interval between the supine and sitting IOP measurements did not exceed 5 minutes. After walking approximately 10 meters, patients reached the nearest examination room, where a third IOP value was measured at the slitlamp. During the night (midnight to 6 AM), patients were awakened about 10 minutes before their IOP and blood pressure were measured following the same procedure. The IOP measurements were made using a handheld electronic tonometer (Tono Pen XL; Bio-Rad Laboratories, Hercules, Calif) with the patient in supine and sitting positions and a Goldmann applanation tonometer with the patient sitting at the slitlamp. All measurements were taken by 2 well-trained evaluators(A.B. and P.F.), who were masked to the treatment assignment, and tested for measurement consistency and agreement before starting the study (κ = 0.82); κ values were calculated for a ± 2 mmHg difference and for the supine position evaluation.

The study outcome was the difference in IOP values between the groups. If both eyes were eligible, only 1 (chosen at random) was used for analytical purposes.

The sample size was calculated assuming that a difference in mean IOP of 2.5 mmHg was clinically relevant. With α = .05, 1 − β= 0.90, and an SD of 2 mmHg, approximately 20 patients were needed. Between-group differences were tested for significance by means of parametric analysis of variance, and the Bonferroni method was used to adjust P values. All analyses were performed using SPSS statistical software, version 6.0 (SPSS Inc, Chicago, Ill), for Macintosh.

RESULTS

The main characteristics of the 20 patients (10 with POAG and 10 with OHT) are shown in Table 1. All patients completed the 3 crossover phases, and no important adverse events were recorded. Figure 1 shows Goldmann tonometer IOP values measured at baseline and after each treatment period. All the drugs significantly reduced IOP in comparison with the baseline at all points, except for brimonidine at midnight, 3 AM, and 6 AM. The mean (SD) IOP values were 22.6 (2.7) mmHg at baseline, 16.7 (0.6) mmHg after latanoprost, 16.9 (1.4) mmHg after the combination of timolol and dorzolamide, and 18.7 (1.9) mmHg after brimonidine. The differences in mean IOP values were statistically significant between latanoprost and brimonidine (P = .005) and between the combination of timolol and dorzolamide and brimonidine (P = .01). There was no statistically significant difference in the mean IOP values between the latanoprost group and the combination of timolol and dorzolamide group.

Latanoprost was more effective in lowering IOP than was brimonidine at 3 AM, 6 AM, and 3 PM (P = .03). The fixed combination of timolol and dorzolamide was more effective than brimonidine at 3 and 9 AM (P = .04) and at 3 and 6 PM (P = .05). It was also more effective than latanoprost at 9 AM (P = .05). In comparison with the baseline, mean (SD) diurnal(9 AM to 9 PM) vs nocturnal (midnight to 6 AM) reductions in IOP were −5.8(1.2) mmHg vs −4.1 (0.8) mmHg for latanoprost (P = .09), −6.1 (2.2) mmHg vs −3.2 (1.5) mmHg for the fixed combination (P = .03), and −4.4 (1.8)mmHg vs −0.8 (1.0) mmHg for brimonidine (P =.01). Table 2 shows the change in IOP from baseline for each study drug.

Figure 2 and Figure 3 show supine and sitting electronic tonometer measurements; the shape of the curves was consistent with those obtained using the Goldmann tonometer, and the differences in drug efficacy were similar. The statistical significance of between-drug comparisons is also shown. As was previously reported, 4 Goldmann tonometer readings agreed well with electronic tonometer readings in the sitting position (r = 0.8), whereas electronic tonometer values measured with patients in a supine position were higher. The mean (SD) supine vs sitting IOP values were 23.2 (1.9) mmHg vs 22.3 (1.7) mmHg at baseline, 17.6 (1.1) mmHg vs 16.6 (1.0) mmHg after latanoprost, 17.8 (1.8)mmHg vs 16.7 (1.4) mmHg after the combination of timolol and dorzolamide, and 19.3 (2.1) mmHg vs 18.5 (1.9) mmHg after brimonidine.

Blood pressure measurements and the corresponding supine IOP values at baseline are shown in Figure 4.

Responses to the questionnaire indicated that the overall quality of the days and nights spent in the hospital for the measurements of circadian IOP was "normal."

COMMENT

The results of this trial suggest that the effects of the 3 treatments may vary considerably during different phases of the circadian IOP curve. All drugs led to a statistically significant decrease in IOP in comparison with the baseline, except for brimonidine during the night. As was reported in previous studies, 16,9,10,14 the effect of latanoprost administered once daily in the evening appeared to be fairly uniform throughout the circadian cycle but was slightly, although not significantly, greater during the day.4,5 This finding can be explained by the fact that latanoprost is most effective 12 to 18 hours after administration.5,9 In addition, in a recent trial, the efficacy of the fixed combination of latanoprost and timolol administered at 8 AM was found not to be significantly different from that of placebo at 3 AM, 6 when the baseline IOP measurement was lowest. A further explanation might involve the ability of prostaglandins to relax nocturnal ciliary muscle tone and thus increase uveoscleral outflow.2,30 The fixed combination of timolol and dorzolamide was effective in reducing IOP at 9 AM, and its effect was superior to that induced by latanoprost. The combination was significantly more effective during the day than during the night, and the difference reached statistical significance. This finding might be explained by the fact that timolol loses some of its effect during the night.3135 Several studies indicate that the rate of aqueous flow during sleep is much lower than during waking hours3133,36,37 and that drugs affecting aqueous flow can have different effects at different times of day.31,33,38,39 Timolol, which substantially decreases aqueous flow during the day, has been found to have no measurable effect at night3335 because of the existence of a baseline flow rate that cannot be further suppressed by any drug or the lack of timolol-blockable activity in the sleeping eye.31,40,41 On the contrary, it has been found that dorzolamide retains its good hypotensive action during the night, 4,12 a finding confirmed by our own results. When interpreting the magnitude of the response to the combination, the fact that 5 patients (25% of the sample) were already taking systemic β-blockers should be considered. The difference between the diurnal and nocturnal effects of brimonidine was statistically significant. Brimonidine is a selective α2-agonist that has been found to have a daytime hypotensive effect similar to that of timolol, 29,4244 and we also found that its mean daytime effect on IOP was good in comparison with the baseline (−4.4 mmHg; 25%). The marked decrease in efficacy during the night observed in this trial may have been due to the frequency of administration; it has been found that brimonidine is more effective in controlling diurnal IOP when administered 3 times rather than twice daily, which induces a marked and long-lasting trough period.44 However, brimonidine is currently given twice daily in clinical practice. To the best of our knowledge, relatively few studies have evaluated the nocturnal efficacy of brimonidine. In a recent trial, Konstas et al44 found that brimonidine was more effective in reducing the 24-hour IOP when given 3 times daily rather than twice daily, except for the morning measurements. On the other hand, the lack of effect of brimonidine during the night cannot be supported by studies of aqueous humor flow, indicating that α-agonists(unlike timolol) can suppress the aqueous flow at night.45

Finally, it must be noted that the administration time for latanoprost(9 PM) was different than the times for twice-daily dosing (8 AM and 8 PM), and consequently IOP measurements were at different times after administration.

The supine and sitting circadian curves recorded on the basis of the handheld electric tonometer and the Goldmann measurements were basically similar, but, as expected, sitting values were lower than the tonometric supine values because of the increase in venous pressure in the supine position. However, the postural effect on IOP was less than may have been expected, probably because we adopted a short interval between the supine and sitting measurements to limit as much as possible the measurement-related awakening time during the "sleeping period."

This study was designed to detect a 2.5–mmHg difference between treatment arms. We are aware that there may be situations in which smaller differences would be helpful, although for studies such as this one a big and clinically relevant difference in treatment effect will be much more straightforward to interpret.

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 interpreting the results. The most important biases concern the measurement of IOP in a clinical setting: hospitalization, sudden awakenings and exposure to light for nocturnal measurements, and disturbed sleeping patterns may all affect the evaluation of IOP. We tried to limit these biases as much as possible by using a randomized crossover design that assured their even distribution across all treatment periods. Furthermore, a special questionnaire was used to assess the "normality" of the time spent in the hospital. Finally, it should be mentioned that, although drug bottles were masked, patients might have distinguished latanoprost from the other 2 drugs on the basis of the frequency of dosing. Evaluators, on the other hand, were masked to treatment assignment and frequency of administration.

Despite these potential limitations, the results of this trial once again suggest the importance of assessing nocturnal IOP because considerable variations in pressure were recorded that would not have been revealed by diurnal curves or isolated office-hour measurements. It has recently been pointed out that fluctuations in IOP seem to be an important risk factor for the progression of glaucoma, 46 so efforts to detect them should be made in order to prevent the worsening of the disease. It has been widely demonstrated that, at least in some patients, different OHT drugs can have different effects on IOP during a 24-hour period, and 24-hour IOP recordings might help ensure the complete evaluation of OHT drug regimens, particularly in those patients experiencing progression of the disease. In fact, nocturnal IOP evaluation could reveal abnormal spikes that would be overlooked if only diurnal measurements are considered.

Corresponding author and reprints: Nicola Orzalesi, MD, Institute of Biomedical Sciences, University of Milan, San Paolo Hospital, Via di Rudinì, 8 20142 Milan, Italy (e-mail: lucamrossetti@libero.it).

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Submitted for publication January 24, 2002; final revision received October 24, 2002; accepted December 26, 2002.

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