A three-dose, randomized, double-blind parallel, placebo-controlled ocular tolerancy study was undertaken in 24 healthy, normal volunteers with two formulations of 2% MK-507 (L-671 152), a novel ...water-soluble, topical carbonic anhydrase inhibitor. In this study MK-507 was administered to humans for the first time. Subjects received 3 sequential drops of the test drug in one randomly selected eye (at 13:00, 14:00, and 14:10 o'clock): ten received 2% MK-507 formulated with 0.5% hydroxyethylcellulose (HEC); ten, 2% MK-507 with no HEC; two, vehicle with HEC; and two, vehicle without HEC. Local tolerance of 2% MK-507 was good with predominantly mild and transient local symptoms, somewhat fewer for the formulation without HEC. Significant lowering of intraocular pressure (IOP) by up to 7 mmHg was noted when comparing IOP 4 h and 5 h after the first dose with IOP 20 h and 19 h before the first dose in the treated eyes of subjects receiving MK-507. Slightly greater activity was noted when MK-507 was formulated with HEC.
A comparative ocular tolerance study was undertaken with the topical carbonic anhydrase inhibitor (CAI) MK-927 (1% and 2%) and its S-enantiomer MK-417 (1% and 1.8%) in 20 healthy normal volunteers. ...In this randomized, double-blind cross over study, placebos were used for control over five periods. The subjects received one drop of placebo (common vehicle) or CAI in each eye in successive periods separated by a washout period of 1 week. Three hours after the dose, the IOP was found to be decreased by 5.3% to 9.1%, depending on the dose, with all four CAI treatments and significantly so with MK-417. Pupil-size and central vision were unchanged by CAIs. External and anterior segment examination revealed no changes following any of the treatments. The incidence of burning was significantly increased by 2% MK-927 (p less than 0.01) and 1.8% MK-417 (p less than 0.05) compared to placebo. The mean duration of burning placebo was 16.8 s, but it was significantly longer (23 to 37.1 s) following CAI application. Duration of tearing following CAI application was also significantly prolonged (p less than 0.05).
As MK-417, the S-enantiomer of the racemic compound MK-927, is the more active enantiomer in vitro, the potential differential ocular hypotensive activity was investigated in patients. The 1% ...concentration was chosen as the basis for comparison, as preliminary data indicated that the concentration would fall relatively steeply on the dose-response curve. This was a two-center crossover study of 1% MK-417, 1% MK-927, and placebo (common vehicle) in 27 patients with bilateral, relatively symmetric primary open-angle glaucoma or ocular hypertension. Following a washout period for ocular hypertensive therapy, IOP had to be greater than or equal to 23 mmHg at 10:00 o'clock with IOP difference between eyes less than or equal to 6 mmHg. Treatment days were separated by a 1-2 week washout period. IOP was measured at 9:30. At 10:00 patients received the test drug in one designated eye and placebo in the other eye. IOP was measured at 1, 2, 4, 6, and 8 h after the dose. IOP and the percentage of change in IOP from 30 min before the dose in the active drug-treated eye shows that MK-417 is slightly more potent than MK-927 in this patient model.
