This single-center, investigator-masked, crossover study is designed to investigate the circadian rhythms of aqueous humor dynamics in human subjects with ocular hypertension (OHT) before and after intervention with a commonly used ocular hypotensive medication, brimonidine for six weeks.

Currently, the only effective treatment to prevent disease progression is lowering of the intraocular pressure (IOP).2 Usually, clinical IOP measurements are performed during the day with little information collected on nocturnal IOP. A recent surge of interest in nocturnal IOPs stems from the hypothesis that significant glaucomatous damage may occur at night.4,5 In response, some investigators have advocated particular classes of glaucoma medications based on their nocturnal IOP effects.6-8 The most efficacious drug on the market may not be the preferred treatment if it is ineffective at night. Therefore, the understanding of nighttime IOP and the aqueous humor dynamics that control it has important scientific, clinical, and commercial implications.

Previous research on glaucoma medications has been limited to the effects of ocular hypotensive drugs on 24-hour IOP or daytime aqueous humor dynamics. Few studies have evaluated nocturnal aqueous humor dynamics. The investigators recently completed studies of day and night differences in aqueous humor dynamics in patients treated with drugs from three different classes that include a prostaglandin analog, a beta blocker and a carbonic anhydrase inhibitor. The current study is designed to elucidate the physiological mechanisms driving the efficacy of brimonidine, an alpha 2 adrenergic agonist, throughout the 24-hour period, i.e. circadian rhythms in aqueous humor dynamics. Based on what the investigators know of 24 hour IOPs this drug is expected to work well at night potentially by enhancing uveoscleral outflow. This study will test this hypothesis.

This single-center, investigator-masked, crossover study is designed to investigate the circadian rhythms of aqueous humor dynamics in human subjects with ocular hypertension (OHT) before and after intervention with a commonly used ocular hypotensive medication, brimonidine. Thirty participants with ocular hypertension (intraocular pressure greater than 20mmHg) will be enrolled.

The subjects will undergo a baseline phase and medication phase using brimonidine. At both phases, they will attend a daytime and a nighttime study visit in which fluorophotometry will be used to calculate aqueous flow (production), trabecular outflow facility, and uveoscleral outflow. At the completion of the study, subjects will return to their previous ophthalmic clinic.

Inclusion Criteria:

• Subjects must be 19 years of age or older
• Subjects must exhibit a history of untreated IOPs between 21 and 35 mmHg (inclusive)

Exclusion Criteria:

• Age less than nineteen years old
• Women who are pregnant, lactating or of childbearing potential who are not using birth control measures.
• Aphakia or pseudophakia
• Best corrected visual acuity worse than 20/60 in either eye
• Chronic or recurrent severe ocular inflammatory disease
• Ocular infection or inflammation within (3) months of screening visit.
• History of clinically significant or progressive retinal disease such as retinal degeneration, diabetic retinopathy or retinal detachment.
• Any abnormality preventing reliable tonometry of either eye.
• Previous exposure to: beta-adrenergic antagonists, topical prostaglandin analogues within six (6) weeks of the baseline visit; α-adrenergic agonists within two (2) weeks of the baseline visit; and cholinergic agonists and carbonic anhydrase inhibitors within five (5) days of the treatment initiation visit.
• History of any severe ocular pathology (including severe dry eye) that would prelude the administration of a topical beta blocker, carbonic anhydrase inhibitor, or a topical prostaglandin.
• Any eye with a cup-to-disc ratio greater than 0.8.
• History of intraocular surgery
• History of ocular laser surgery
• History of severe or serious hypersensitivity to brimonidine or its vehicle.
• History of severe, unstable, or uncontrolled cardiovascular, hepatic or renal disease.
• History of bronchial asthma or chronic obstructive pulmonary disease (COPD).
• Less than one month (prior to baseline) stable dosing regimen of any non-glaucoma medication that would affect IOP.
• Gonioscopy angle < 2.
• Inability to be dosed with treatment medication
• Inability to discontinue contact lens wear.
• Therapy with any investigational agent within 30 days of screening.
• Use of any additional topical or systemic adjunctive ocular hypotensive medications during the study.
• History of open angle glaucoma (either primary open angle glaucoma or other cause of open angle glaucoma) or narrow angle glaucoma.

Intraocular pressure, episcleral venous pressure, and aqueous flow were calculated using data from 29 participants. However, tonography/outflow facility data on 2 participants were not reliable, therefore uveosleral outflow and outflow facility analysis were performed on 27 participants.