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ABSTRACT _PURPOSE_ To compare the efficacy and safety of brimonidine 0.2% _vs_ unoprostone 0.15%, both added to timolol maleate 0.5% each given twice daily. _METHODS_ In this prospective,

multi-centred, double-masked, crossover comparison, patients were randomized to one treatment group for a 6-week treatment period, and then crossed over to the opposite treatment.

Measurements were performed at 0800, 1000, 1600, 1800, and 2000 h at baseline and at the end of each treatment period. _RESULTS_ In all, 33 patients entered this trial and 29 completed. The

baseline trough intraocular pressure (IOP) was 23.3±2.4 and the diurnal curve IOP was 22.0±1.3 mmHg. For the brimonidine and timolol maleate treatment group, the trough IOP was 21.6±3.3 and

the diurnal curve IOP was 19.8±2.1 mmHg, while the timolol and unoprostone treatment showed a trough IOP of 20.9±3.8 and a diurnal curve IOP of 19.3±2.4 mmHg. There was no significant

difference between treatment groups at any time point for the diurnal curve, or in the reduction from baseline (_P_>0.05). Both treatments failed to statistically reduce the IOP from

baseline at 1800 h. There was no difference between treatment groups regarding ocular and systemic unsolicited adverse events, but patients admitted to more dryness (_P_=0.02) and burning

upon instillation (_P_<0.0001) with unoprostone by survey. _CONCLUSION_ Brimonidine 0.2% or unoprostone 0.15% added to timolol maleate 0.5% provide similar efficacy and safety throughout

the daytime diurnal curve. SIMILAR CONTENT BEING VIEWED BY OTHERS COMPARISONS OF EFFICACY AND SAFETY BETWEEN PRESERVED AND PRESERVATIVE-FREE BRIMONIDINE TARTRATE IN GLAUCOMA AND OCULAR

HYPERTENSION: A PARALLEL-GROUPED, RANDOMIZED TRIAL Article Open access 07 April 2023 A PHASE III STUDY COMPARING PRESERVATIVE-FREE LATANOPROST EYE DROP EMULSION WITH PRESERVED LATANOPROST IN

OPEN-ANGLE GLAUCOMA OR OCULAR HYPERTENSION Article Open access 25 February 2025 CHANGING FROM PRESERVED, TO PRESERVATIVE-FREE CYCLOSPORINE 0.1% ENHANCED TRIPLE GLAUCOMA THERAPY: IMPACT ON

OCULAR SURFACE DISEASE—A RANDOMIZED CONTROLLED TRIAL Article 23 May 2023 INTRODUCTION Patients with primary open-angle glaucoma or ocular hypertension are typically treated with medication

to reduce the intraocular pressure (IOP) to prevent the onset or progression of optic nerve damage. Over the past several decades, timolol maleate has been the most commonly used primary

therapy to lower the IOP.1, 2 However, many patients need a second medication to help further reduce the IOP. Over the past several years, brimonidine 0.2% (Alphagan®, Allergan, Irvine, CA,

USA) has been an important adjunctive medication added to timolol maleate. Another medication, unoprostone 0.15% (Rescula®, Novartis Ophthalmics, Basal, Switzerland), was released recently

into the worldwide market and may also be used as adjunctive therapy to timolol maleate.3 Unfortunately, data are still limited that evaluate the diurnal curve efficacy of brimonidine _vs_

unoprostone each added to timolol maleate. Stewart and associates recently evaluated brimonidine 0.2% _vs_ unoprostone 0.15%, both given twice daily, over the diurnal curve as monotherapy.4

This study showed that, although brimonidine was more effective at peak, it lost its ocular hypertensive efficacy at the end of the daytime dosing cycle at 1800 and 2000 h.4 In contrast,

unoprostone statistically maintained the mean pressure reduction throughout the dosing cycle, and was more effective than brimonidine at 1800 and 2000 h.4 The purpose of this study was to

evaluate the daytime diurnal safety and efficacy with a larger number of measurements for the intraocular pressure and greater statistical power to detect a statistical difference between

brimonidine 0.2% and unoprostone 0.15%, both added to timolol maleate 0.5%, each given twice daily in patients with primary open-angle glaucoma or ocular hypertension. MATERIALS AND METHODS

PATIENTS Individuals were included in this four-centre prospective trial if they demonstrated the following criteria: 18 years of age or older; new or previous clinical diagnosis of primary

open-angle glaucoma or ocular hypertension; at baseline on timolol maleate 0.5% twice daily the IOP was between 22 and 34 mmHg, inclusive in at least one eye at 0800, and the average of all

baseline pressure measures (diurnal curve) was ⩾20 mmHg in the same eye (visit 2); and visual acuity was 20/200 or better in the study eye(s). Patients were excluded from this study for any

of the following exclusions: any abnormality preventing reliable applanation tonometry in study eye(s); any opacity or patient uncooperativeness that restricted adequate ocular examination

in the study eye; infectious/noninfectious conjunctivitis, keratitis or uveitis in either eye; any history of allergic hypersensitivity or poor tolerance to any components of the

preparations used in this trial; females of childbearing potential not using reliable means of birth control; pregnant or lactating females; any serious medical or psychiatric condition;

participation in any investigational drug or device trial within the previous 30 days prior to visit 1; intraocular conventional or laser surgery within the 3 months prior to visit 1;

according to the investigator's best judgement risk of visual field or visual acuity worsening as a consequence of participation in the trial; inability to understand the trial

procedures; any anticipated change in systemic hypotensive therapy during the active treatment portion of the trial (visits 2–6); and history of monoamine oxidase use; and bronchial asthma,

history of bronchial asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrioventricular block, or overt cardiac failure. PROCEDURES Before any

procedures were performed, the patients signed an Institutional Review Board approved informed consent form. At the screening visit (visit 1, day −28), and, at each subsequent visit,

patients had slit-lamp biomicroscopy, Early Diabetic Treatment Retinopathy Study (ETDRS) visual acuity, and Goldmann applanation tonometry performed. At visit 1, patients had the inclusion

and exclusion criteria reviewed, medical history obtained, and gonioscopy, dilated funduscopy, and a visual field (Program 24-2, Humphrey Visual Field Analyzer, Humphrey Instruments, Dublin,

CA, USA) performed. Qualified patients were placed on timolol 0.5% solution twice daily for 28 days and asked to return for the baseline visit (visit 2, day 0). At this visit and at each

subsequent visit, unsolicited adverse events were recorded. Also, at visit 2, as well at the other efficacy visits (visits 4 and 6), an ocular symptom query (dry eye, pain in or around eyes,

blurred vision, tearing, stinging or burning, crusting, itching, sandy or gritty feeling, or irritation), a systemic symptom survey (fatigue, dizziness, despondency, depression, or dry

mouth), and a diurnal curve of the intraocular pressure at 0800, 1000, 1600, 1800, and 2000 h were performed. Following the trough pressure at the baseline and efficacy visits, patients had

study medicines instilled by an unmasked dosing coordinator (who performed no other procedures) before the remainder of the diurnal curve was completed. Patients who met the intraocular

pressure requirements described above were randomized into the trial. Patients received either the brimonidine 0.2% and timolol maleate 0.5% to be instilled twice daily at 0800 and 2000 h,

or timolol maleate 0.5% and unoprostone 0.15% to be instilled twice daily at 0800 and 2000 h with 5 min separating drop instillations. The patient, physician, and study personnel (apart from

the unmasked dosing coordinator) were masked to the medicines. Patients returned for the Period 1 safety check (visit 3, week 2) and then returned for the Period 1 efficacy visit (visit 4,

week 6). Patients were then placed on the opposite treatment and returned for the Period 2 safety check (visit 5, week 8) and for the Period 2 efficacy visit (visit 6, week 12) performed the

same way as visit 4. STATISTICS Data analyses were two-sided and a 0.05 alpha level was used. The primary efficacy variable was the IOP difference at Hour 0 between visits 4 and 6. This was

analysed by a paired _t_-test for intragroup analysis.5 The standard deviation used to determine the power was 2.8 mmHg.6, 7, 8, 9 This study provided with 27 patients at least an 80% power

that a 1.5 mmHg difference could be excluded between groups. The secondary efficacy variable, intraocular pressure at each time point as well as diurnal IOP (the average of the five

individual time points), was also analysed by a paired _t_-test.5 Safety parameters for intragroup analysis were evaluated with the Wilcoxon sign rank test including the ocular and systemic

symptom queries.5 Visual acuity was analysed by a paired _t_-test.5 Adverse events were evaluated with a McNemar test.10 RESULTS PATIENTS In all, 33 patients were enrolled, who met the

inclusion and exclusion criteria. Of these, 29 patients completed the study. The average age was 61.0±11.0 years. Of these patients, 21 were Caucasian and eight were African American; 13

were male and 16 were female. A total of 20 patients had primary open-angle glaucoma and nine had ocular hypertension. INTRAOCULAR PRESSURE The individual IOP and diurnal curves are shown in

Table 1 and in diagrammatical form in Figure 1. The baseline trough pressure was 23.3±2.4 and the baseline diurnal curve was 22.0±1.3 mmHg on timolol alone. This study found that both study

treatments caused a significant reduction for the diurnal curve, from baseline and at each time point (_P_>0.05), except at 1800 h following dosing (_P_>0.05). The brimonidine and

timolol maleate therapy showed a trough IOP of 21.6±3.3 mmHg and a diurnal curve of 19.8±2.1 mmHg. In contrast, timolol maleate and unoprostone showed a trough IOP of 20.9±3.8 mmHg

(_P_=0.49) and a diurnal curve pressure of 19.3±2.4 mmHg (_P_=0.45). There was no difference between treatment groups at any time point in the absolute pressure value or in the reduction of

the IOP from baseline (_P_>0.05) (Table 1). ADVERSE EVENTS Ocular adverse events are shown in Table 2 and systemic adverse events in Table 3 . There was no significant difference for any

individual adverse event between the two treatments evaluated in this trial. The most frequent ocular adverse events were burning and conjunctival hyperaemia. There were no significant

differences in systemic adverse events between the two treatment groups (_P_>0.05). There were no serious adverse events. On the systemic query, no significant difference existed between

groups for any solicited systemic adverse event. However, on the ocular symptom survey, more patients reported dryness (_n_=7) with unoprostone than brimonidine (_n_=1, _P_=0.02). Also, a

greater number of patients indicated more stinging upon instillation with unoprostone (_n_=26) than brimonidine (_n_=8, _P_<0.001). No difference in visual acuity was observed between

treatment periods (_P_=0.93). DISCONTINUED PATIENTS In all, 29 patients completed both the trough time points of the study. Two patients were excluded from data analysis because of a site

administrative error. One patient was not used due to incorrect dosing and one patient was exited early from a treatment period because of dermatitis of the eyelid while on brimonidine.

DISCUSSION Brimonidine 0.2% was commercially released by Allergan in late 1996. It is a highly selective _α_2-adrenergic agonist, and reduces the IOP primarily by decreasing aqueous

production. It has become a popular adjunctive agent for glaucoma and, when prescribed, it is frequently given as monotherapy. It reduces the IOP at the 0800 trough level approximately

15–16% from baseline.11, 12, 13, 14 It is labelled three times a day, but is most frequently dosed twice daily. Brimonidine may cause side effects, including ocular allergy with an incidence

approximately 10% presenting 3 months or later after initiation of therapy.15 Also, systemic side effects of dry mouth, fatigue, and blood pressure changes may occur.16, 17 Unoprostone

0.15% was released onto the commercial market in October 2000. This medicine demonstrates the structural characteristics of an F2_α_ prostaglandin, but may not be active at the FP-receptor

in humans (internal data, Novartis Ophthalmics). It is labelled as a docosanoid by the United States regulatory agency. Unoprostone reduces the IOP by increasing outflow.17 However, the

exact pathway by which it acts, uveoscleral or conventional, has not yet been clarified. Regulatory trials in the United States and Europe have shown that unoprostone reduces the IOP from

baseline between 14 and 19%, with a consistent pressure reduction maintained over the 12-h daytime diurnal curve (internal data, Novartis Ophthalmics).18 However, in these studies,

unoprostone was not as effective statistically in reducing the IOP as timolol maleate. In addition, several reports have recently shown that latanoprost reduces the IOP statistically more

than unoprostone.19, 20 Ocular stinging upon instillation is the most common side effect.21 This current report evaluated brimonidine 0.2% and timolol maleate 0.5% therapy given twice daily

_vs_ concomitant timolol maleate 0.5% and unoprostone 0.15%, each given twice daily in patients with primary open-angle glaucoma or ocular hypertension. This study found that both treatments

caused a significant reduction at each time point and for the diurnal curve from baseline, except at 1800 h after dosing. The reason why both medications did not reduce IOP at 1800 h after

dosing, but at each other time point including 2000 h after dosing, is not clear from the results. For brimonidine, the results at the end of the dosing cycle were consistent with several

past studies. In two separate diurnal curve studies, Stewart and coworkers4 showed no effect from brimonidine as monotherapy when given twice daily at 1800 and 2000 h.4 Stewart and

associates also noted, in contrast, that a small effect was shown at both time points when brimonidine was added to timolol maleate (1.0 mmHg decrease).22 Unoprostone typically demonstrates

a 12-h effect with twice daily dosing, and does not typically demonstrated a peak effect.21, 23 In a previous study (mentioned above), the effect of unoprostone monotherapy at peak was shown

to be less than that of brimonidine (1200 h after dosing).4 In contrast, unoprostone maintained a reduced pressure effect for the 12-h daytime dosing cycle. In this current study, an ocular

hypotensive effect was seen throughout the dosing cycle, except at 1800 h when unoprostone was added to timolol. The reason for the lack of effect at 1800 h in this trial is not clear. When

the two treatment groups were compared, there was no significant difference in the IOP between treatments at each time point and for the diurnal curve of the pressure. Timolol and

unoprostone showed a slight trend to be better at morning trough, whereas brimonidine and timolol showed a tendency to be better 8 h after dosing. In addition, there was no significant

difference between treatments at each time point for the amount of reduction of the IOP. Both brimonidine and unoprostone statistically reduced the IOP compared to timolol alone, but only by

approximately 2 mmHg. This is less than that observed with the addition of latanoprost compared to timolol alone, and slightly more than that observed with the dorzolamide/timolol fixed

combination compared to timolol alone (1.2 mmHg).24, 25, 26, 27 The results of this study are similar, but slightly less, to those of Hommer and associates,28 in which approximately a 3 mmHg

further reduction was found when adding brimonidine or unoprostone to timolol. The reason for the differences in the extent of the reduction between the current trial and Hommer's

study is not readily apparent. Safety results were similar between treatment results. The most common ocular adverse events were conjunctival hyperaemia and ocular stinging upon

instillation, for which there was no significant difference between treatments. Stinging has been noted previously with unoprostone.21, 23 On the solicited ocular symptom survey, stinging

upon instillation and dryness was noted more commonly with unoprostone. No differences in unsolicited or solicited systemic events were noted. There were no serious adverse events in this

trial. This study suggests that brimonidine 0.2% or unoprostone each added to timolol maleate 0.5% provide similar efficacy and safety throughout the daytime diurnal curve. This study did

not evaluate other types of glaucoma or nighttime IOPs with these medications. In addition, the study did not evaluate the efficacy of brimonidine _vs_ unoprostone dosed per label (three

times daily for brimonidine). Further research may help clarify any important medical differences between brimonidine and unoprostone as monotherapy or adjunctive therapy. REFERENCES *

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2003; 87: 592–598. Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Glaucoma Consultants and Center for Eye Research, Mt. Pleasant, SC, USA E

D Sharpe * Little Rock Eye Clinic, Little Rock, AR, USA C J Henry * Charlotte, NC, USA T K Mundorf * Omni Eye Services, Atlanta, GA, USA D G Day * Pharmaceutical Research Network, LLC,

Charleston, SC, USA J A Stewart, J N Jenkins & W C Stewart * Department of Ophthalmology at the University of South Carolina, Columbia, SC, USA W C Stewart Authors * E D Sharpe View

author publications You can also search for this author inPubMed Google Scholar * C J Henry View author publications You can also search for this author inPubMed Google Scholar * T K Mundorf

View author publications You can also search for this author inPubMed Google Scholar * D G Day View author publications You can also search for this author inPubMed Google Scholar * J A

Stewart View author publications You can also search for this author inPubMed Google Scholar * J N Jenkins View author publications You can also search for this author inPubMed Google

Scholar * W C Stewart View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to W C Stewart. ADDITIONAL INFORMATION This

study was supported by Novartis Ophthalmics, Atlanta, GA, USA. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Sharpe, E., Henry, C., Mundorf, T. _et

al._ Brimonidine 0.2% _vs_ unoprostone 0.15% both added to timolol maleate 0.5% given twice daily to patients with primary open-angle glaucoma or ocular hypertension. _Eye_ 19, 35–40 (2005).

https://doi.org/10.1038/sj.eye.6701392 Download citation * Received: 22 August 2003 * Accepted: 06 November 2003 * Published: 16 April 2004 * Issue Date: 01 January 2005 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * brimonidine * unoprostone * timolol maleate