Inhibition of eicosanoid release from synovial organ culture by incubation with tepoxalin and its acid metabolite.

The pharmacological profile of a novel dual inhibitor, tepoxalin and of its carboxylic acid metabolite on cyclooxygenase and lipoxygenase pathways was evaluated by in vitro incubation with synovial tissue. Tissue specimens obtained at surgery in rheumatoid arthritis (RA, n = 10) or osteoarthritis (OA, n = 11) patients were incubated. Tepoxalin (10(-7), 10(-6), 10(-5) M) decreased eicosanoid release calculated in % of tyrode control for OA: LTC4 to 71-33%, 6-keto-PGF1a to 37-20%, PGE2 to 29-6%. For RA: LTC4 to 56-22%, 6-keto-PGF1a to 43-22%, PGE2 to 57-32%. Similarly, its metabolite (10(-7), 10(-5)M) decreased release in OA: LTC4 to 99 and 60%, PGE2 to 42 and 20%, 6-keto-PGF1a to 54 and 25%. In RA:LTC4 to 81 and 45%, PGE2 to 61 and 30%, 6-keto-PGF1a to 46 and 18%. Significance (P < 0.05) was achieved for all but 1 group (LTC4 metabolite at 10(-7)M vs tyrode). In summary a marked and dose dependent decrease of LT and PG release was obtained when incubating the dual inhibitor tepoxalin and its active carboxylic acid metabolite with synovial tissue at doses expected to be reached in the joint during therapy.

Sezolamide: additivity to timolol twice daily.

Sezolamide, a potent topical carbonic anhydrase inhibitor previously known as MK-417, was studied to determine its ocular hypotensive activity in patients with elevated intraocular pressure while on continuing therapy with topical timolol. This was a three-centre, double-masked, randomised, placebo-controlled, parallel study in 36 patients with bilateral primary open angle glaucoma or ocular hypertension on therapy receiving 0.5% timolol twice daily, with a morning intraocular pressure greater than or equal to 22 mmHg in both eyes 2-4 hours following an 8 a.m. dose of timolol. Sezolamide 1.8% or placebo twice daily was added to treatment with timolol on the evening of day 1 and continued for 2 weeks. Twelve-hour diurnal curves were performed before the study on day 1 (timolol alone) and on day 15. Intraocular pressure measurements were also taken on days 2 and 8 at 8 a.m. and 9 a.m. Patients who received timolol and sezolamide showed additional intraocular pressure reductions from day 1 (timolol alone) of 8.0 to 15.5%, which were significant at all times. At hours 1, 2, 4 and 8 the reductions in intraocular pressure observed in the group receiving sezolamide and timolol were significantly greater than those in the group receiving timolol and placebo.

Comparative tolerability of topical carbonic anhydrase inhibitor MK-927 and its S-enantiomer MK-417.

A single-dose, randomised, double-masked, placebo-controlled, five-period cross-over comparative ocular tolerance study was undertaken with the topical carbonic anhydrase inhibitor (CAI) MK-927 (1% and 2% concentrations) and its S-enantiomer MK-417 (1% and 1.8% concentrations) in 20 healthy, normal volunteers. Subjects received one drop of placebo (common vehicle) or CAI in each eye on five different days that were separated by washout intervals of 1 week. The incidence of burning increased significantly after treatment with 2% MK-927 (P less than 0.01) and 1.8% MK-417 (P less than 0.05) as compared with placebo. The mean duration of burning following placebo was 16.8 s, somewhat less than that following CAI application (23-37.1 s). The duration of tearing following CAI treatment was also significantly prolonged (P less than 0.05). Pupil size was not changed by CAIs. No other side effects were observed. At 3 h after instillation, intraocular pressure (IOP) was found to be decreased following all four CAI treatments, significantly so with 1% and 1.8% MK-417. The reasonable single-dose tolerability of MK-927 and MK-417 in this sensitive normal-volunteer model supports their potential as topical glaucoma medications. This study suggests that MK-417 may possess greater IOP-lowering activity than MK-927 in man.

A single dose of the topical carbonic anhydrase inhibitor MK-927 decreases IOP in patients.

MK-927 is a novel topical carbonic anhydrase inhibitor (CAI). We present the first single-dose clinical trial of MK-927 in 24 patients with bilateral primary open-angle glaucoma or ocular hypertension. This investigation was conducted as a two-centre, double-masked, randomised, placebo controlled study. Patients received one drop of 2% MK-927 in one eye and placebo in the other eye. Modified diurnal intraocular pressure (IOP) curves were performed before the study and on one treatment day. A single dose of 2% MK-927 induced a peak mean IOP decrease of 10.5 mmHg at 4.5 hours postdose. With compensation for diurnal variation, as determined by the prestudy diurnal pressure curve, the net peak mean reduction of IOP caused by MK-927 was 7.5 mmHg versus a corresponding net change of 1.4 mmHg in the contralateral placebo treated eye. Thus a single dose of MK-927 gave a clinically significant IOP reduction in patients.

MK-927: a topically effective carbonic anhydrase inhibitor in patients.

The effects on intraocular pressure of the novel topical carbonic anhydrase inhibitor MK-927 were investigated for the first time in patients. Three drops of 2% MK-927 was administered in a two-center, double-masked, randomized, placebo-controlled, two-period crossover study in 25 patients with bilateral primary open angle glaucoma or ocular hypertension. At 4.5 hours after the dose, MK-927-treated eyes demonstrated a peak mean change of -7.7 mm Hg from a mean intraocular pressure of 27.8 mm Hg immediately before the dose; this compares with a change of -3.9 mm Hg from a mean intraocular pressure of 28.2 mm Hg when the same eyes were treated with placebo. The peak mean percent change in intraocular pressure in eyes treated with MK-927 was -26.7% at 6 hours after the dose compared with a change of -13.7% after treatment with placebo. No contralateral effect on intraocular pressure due to MK-927 was observed.

Local tolerance and activity of MK-927, a novel topical carbonic anhydrase inhibitor.

A three-dose, randomized, double-masked, parallel, placebo-controlled ocular tolerance study was undertaken in 12 healthy, normal volunteers with the water-soluble, topical carbonic anhydrase inhibitor MK-927. To our knowledge, this constitutes the first administration of MK-927 to humans. Ten subjects received three drops of 2% MK-927 ophthalmic solution and two subjects received three drops of placebo (vehicle) in one randomly selected eye. Local tolerance of 2% MK-927 was acceptable and supports further clinical trials in patients. Significant intraocular pressure (IOP)-lowering activity was noted when comparing IOP four hours after first dose with that 20 hours predose in the treated eye of subjects receiving MK-927 (mean percent change in IOP, -29.7%; mean change in IOP, -4.6 mm Hg) as opposed to the same comparison for the contralateral, untreated eye (-7.2% and -1.3 mm Hg, respectively). In the two subjects treated with placebo, IOP-lowering activity was not seen in either the placebo-treated eye (-0.4%) or the contralateral, untreated eye (+3.1%).