This study was designed to compare the 24-hour efficacy on intra ocular pressure (IOP) of drugs acting either on aqueous humor production ("inflow drugs") or on aqueous humor outflow ("outflow drugs") in human eyes affected by ocular hypertension and virgin to treatment. The enrolled patients will be exposed, in a cross-over design, to n = 2 aqueous suppressants and n= 3 uveoscleral outflow enhancers, and 24 hr IOP will be measured. It is hypothesised that outflow drugs may offer a better and more stable control of IOP through the 24 hours.

(a) study design: Prospective, open label, investigator-masked clinical trial, with cross-over design, both eyes treated, OD chosen for analysis; (b) study population: patients, showing ocular hypertension, who were never exposed to hypotensive treatment (see inclusion and exclusion criteria for details). (c) study drugs: Timolol and dorzolamide will be chosen as inflow drugs. The three prostaglandin analogues (PGA) Latanoprost, travoprost and bimatoprost will be chosen as outflow drugs. (d) study flow-chart: upon enrollment, patients will be initiated to the following schedule: 60 days timolol 0.5% bid, 60 days washout, 60 days timolol 0.5%-dorzolamide 2% fixed combination bid, 60 days washout, 60 days PGA1, 60 days washout, 60 days PGA2, 60 days washout, 60 days PGA3. Patients were assigned to the PGAs according to a sequence (L-T-B) randomly generated. Data will be collected at baseline and at the and of each study phase (i.e. active treatment and washout)(e) main efficacy outcome: change in the mean IOP (with respect to baseline) at the end of each study phase and change of IOP (with respect to baseline) at the different time points of the 24-hour phasing. IOP will be measured at 8 a.m., 11 a.m., 3 p.m., 6 p.m. and 9 p.m. by means of Goldmann applanation tonometry at the slit lamp. At midnight, 2 a.m. and 6 a.m. the Tonopen in supine position will be used. (f) statistics: the analysis of co-variance (ANCOVA) for paired samples with Bonferroni correction will be adopted. A minimum sample size of 51 patients is needed for a minimal expected difference in mean IOP between inflow and outflow drugs = 2.5 mmHg, with an estimated pooled variance = 4 , a power = 90% and an alpha probability = 5%.

Inclusion Criteria:

• IOP > 22 mmHg and < 30 mmHg on at least three readings on separate days ,
• Open angle on gonioscopy,
• CCT > 550 m,
• optic disk classified as "within normal limits" by Moorfields Regression analysis, HRTII,
• normal visual field (standard achromatic perimetry, Humphrey Field Analyzer, 24/2 SITA standard),
• Age > 40 and < 70 years,
• refraction between - 5 and + 2 dyopters,
• best corrected visual acuity better than 0.2 LogMAR,

Exclusion Criteria:

• PEX
• PDS
• ocular comorbidiities other than refractive problems and/or mild dry eye
• history of diabetes
• treatment with systemic beta blockers and steroids
• previous treatment with ocular hypotensive drugs