This study is designed to identify physiological, pharmacological and pathological circadian fluctuations in aqueous humor inflow and outflow, systemic blood pressure and ocular blood flow in humans.

Glaucoma is a progressive optic neuropathy and a leading cause of blindness in the United States. In glaucoma, vision is lost through apoptosis (programmed cell death) of retinal ganglion cells, a type of cell in the retina that transmits visual information to the brain. Diagnosis of glaucoma is usually based on a combination of progressive, characteristic vision loss (measured using visual field testing) and progressive optic nerve head damage (as detected through dilated fundus examinations or disc photography). While a high pressure inside the eye (ocular hypertension, OHT) is not sufficient for a diagnosis of glaucoma, it is the greatest single risk factor for disease onset.

Currently, the only effective treatment to prevent disease progression is lowering of the intraocular pressure (IOP). IOP is determined by the balance between aqueous production (flow) and aqueous outflow through either the trabecular meshwork or uveoscleral pathway. Diurnal rhythms in aqueous humor dynamics and nocturnal fluctuations in IOP and aqueous flow have been studied in some detail9 but little is known about the nocturnal rhythms of aqueous humor outflow.

Usually, clinical IOP measurement is performed during the day; little is known about nocturnal IOP fluctuations in relation to glaucoma management . A recent surge of interest in nocturnal IOPs stems from the hypothesis that significant glaucomatous damage may occur at night. In response, some investigators have advocated particular classes of glaucoma medications based on their nocturnal IOP effects. 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.

Additionally, previous research on glaucoma medications has been limited to the effects ocular hypotensive drugs on 24-hour IOP or daytime aqueous humor dynamics; few studies have addressed their effect on nocturnal aqueous humor dynamics. Beta-blockers have been proven effective in lowering IOP during the day by decreasing aqueous flow. However, limitations have been found in their IOP-lowering effect overnight. Prostaglandins, which increase uveoscleral outflow, seem to possess a hypotensive effect that is constant throughout the 24-hour period. Dorzolamide reduces aqueous flow to lower IOP but few studies have addressed its effect at night. This study is designed to elucidate the physiological mechanisms driving the efficacy of these drugs throughout the 24-hour period, i.e. circadian rhythms in aqueous humor dynamics.

In studies of new glaucoma medications the preferred study population includes ocular hypertensive subjects. These people have high IOP but no optic nerve damage and no glaucoma. They may be taking prescribed IOP lowering drugs for this condition or they may not. Those taking ocular drugs are asked to stop taking them. Since each of the glaucoma drugs affects aqueous humor dynamics in different ways, it is essential that no residual medical effect remains from these drugs. Standard washout periods of 6-weeks will be utilized in between drug assessments. This period of time is based on the methods of other published studies which determined a necessary period of 4-8 weeks for ocular washout of prostaglandins. A concern for patient safety exists when OHT patients are taken off of glaucoma medications, as IOP may rise during the washout. In order to monitor IOP in these patients, most study methods utilize a biweekly check of the IOP. If pressure rises above the ophthalmologist's preset "target pressure" at any point, then the patient is removed from the study and returned to their previous medical regimen.

Inclusion Criteria:

• Subjects must be nineteen (19) years of age or older. Subjects must be able and willing to give written informed consent [i.e., each subject will be given ample time to read (or have read to them) the consent form, ask any questions they may have regarding the study, and have a clear understanding of the study as well as the procedures involved, prior to signing the consent form].
• Subjects must exhibit a willingness to comply with the protocol and investigator's instructions.
• Subjects must have been previously diagnosed with unilateral or bilateral ocular hypertension at least six months prior to the screening visit.
• Subjects must exhibit baseline IOPs between 21 and 35 mmHg (inclusive); the average IOP between eyes must be ≤ 5 mmHg
• Subjects will be age matched to ocular hypotensive subjects
• Subjects must exhibit baseline IOPs between 12 and 20 mmHg (inclusive); the average IOP between eyes must be ≤ 5 mmHg

Exclusion Criteria:

• Age less than nineteen years old.
• Women who are pregnant, lactating or of childbearing potential who are not using highly effective 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 three (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 (including latanoprost, unoprostone, travoprost and bimatoprost) 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 preclude 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 topical or systemic beta blockers, prostaglandins, or sulfa drugs.
• 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.