Absence of metabolic effects of the topical carbonic anhydrase inhibitors MK-927 and sezolamide during two-week ocular administration to normal subjects.

Potential systemic effects of the racemic carbonic anhydrase inhibitor MK-927 and its S-enantiomer, sezolamide hydrochloride, after topical ocular administration were investigated in a double-masked, randomized, placebo-controlled study in 16 healthy volunteers. A controlled diet was started 4 days before initiation of treatment and continued throughout the study. For 14 days six volunteers received bilaterally one drop of 2% MK-927 (1.2 mg) q.i.d., six received one drop of 1.8% sezolamide (1.1 mg) q.i.d., and four received the common vehicle q.i.d. Blood and urine electrolytes and acid-base profiles were measured before and on days 1, 7, and 14 of treatment, and 24-hour urine samples were collected daily. All values were compared with those on the pretreatment day. Taking the circadian variations of the parameters into account, no significant treatment effect was observed in either the daily profiles or the 14-day cumulative sodium, potassium, and citrate excretions. Because the usual variability of the measured biologic parameters has been reduced markedly by the stringent requirements of this study, it can be concluded that the induction of clinically significant metabolic changes by topically administered MK-927 or sezolamide is unlikely.

Changing therapy from timolol to betaxolol. Effect on intraocular pressure in selected patients with glaucoma. Timolol-Betaxolol Study Group.

Three hundred fifty-three patients whose intraocular pressure was controlled with a timolol maleate ophthalmic solution were studied. Following a baseline period, half were switched (masked and randomized) to treatment with a betaxolol hydrochloride ophthalmic solution and were followed up for 12 weeks. Intraocular pressure, signs, and symptoms were recorded at weeks 1, 4, 8, and 12. Those patients switched to the betaxolol ophthalmic solution had a significant increase in both ocular side effects (burning/stinging and tearing) and intraocular pressure at weeks 4, 8, and 12 when compared with those patients who continued to receive timolol.

Multiple-dose efficacy comparison of the two topical carbonic anhydrase inhibitors sezolamide and MK-927.

The multiple-dose twice-daily efficacy of the topical carbonic anhydrase inhibitor MK-927, a racemic compound, was compared with that of its pharmacologically more active S-enantiomer in a four-center, double-masked, randomized, placebo-controlled, parallel study of 1.8% sezolamide hydrochloride (MK-417), 2% MK-927, and placebo, given twice daily to 48 patients with bilateral primary open angle glaucoma or ocular hypertension and morning intraocular pressure greater than 24 mm Hg in both eyes following washout of ocular hypotensive medications. Parallel 10-hour modified diurnal curves were performed before the study and on day 14, with 4-hour curves on days 1 and 4. Both compounds demonstrated significant lowering of intraocular pressure at 8 AM, 12 hours following the evening dose, and through 10 and 6 hours following the 8 AM dose for sezolamide and MK-927, respectively. Morning trough (evening) activity as measured by mean percent change in intraocular pressure from prestudy was -9.2% for sezolamide and -11.1% for MK-927 (-13.5% and -9.6%); peak effect occurred 2 hours after dose administration and was -19.4% and -19.2% for sezolamide and MK-927, respectively. From 2 hours after dose administration, sezolamide consistently demonstrated a slightly greater decrease in intraocular pressure than MK-927; however, these differences were not statistically significant.

The efficacy and safety of dorzolamide as adjunctive therapy to timolol maleate gellan solution in patients with elevated intraocular pressure. Additivity Study Group.

PURPOSE: Two parallel, randomized, double-masked, placebo-controlled studies were conducted to assess the efficacy and safety of 2% dorzolamide hydrochloride as adjunctive therapy to 0.5% timolol maleate ophthalmic gellan (gel-forming) solution in patients with elevated intraocular pressure (IOP) that was inadequately controlled with 0.5% timolol maleate gellan solution alone. METHODS: Both studies began with an open-label 2-week run-in period on 0.5% timolol maleate gellan solution once a day. The only variation in method between the two studies was the dosage of 2% dorzolamide. In one study, 202 patients received 0.5% timolol maleate gellan solution once daily plus either 2% dorzolamide or placebo three times daily. In the other study, 181 patients received 0.5% timolol maleate gellan solution once daily plus either 2% dorzolamide or placebo twice daily. RESULTS: After 85 days, additional mean percent reductions in IOP from baseline at morning trough for the groups receiving 2% dorzolamide three times daily and placebo three times daily were 12.5% and 8.4%, respectively. Mean percent reductions for the groups receiving 2% dorzolamide twice daily and placebo twice daily were 13.1% and 6.5%, respectively. Burning and/or stinging on instillation were the only adverse experiences that affected significantly more of the patients receiving 2% dorzolamide twice or three times daily than those receiving placebo. CONCLUSION: When administered concomitantly with 0.5% timolol maleate gellan solution, 2% dorzolamide three times daily or twice daily produced a statistically significant reduction in IOP at morning trough and peak and was generally well tolerated.

The use of dorzolamide and pilocarpine as adjunctive therapy to timolol in patients with elevated intraocular pressure. The Dorzolamide Additivity Study Group.

PURPOSE: To report the results of two studies on the use of dorzolamide as adjunctive therapy to timolol in patients with elevated intraocular pressure (IOP). In the larger study, the additive effect of dorzolamide administered twice daily also was compared with 2% pilocarpine. METHODS: Both studies were parallel, randomized, double-masked, placebo-controlled comparisons. In the pilot study, 32 patients received 0.5% timolol twice daily plus either 2% dorzolamide twice daily or placebo twice daily for 8 days. In the Pilocarpine Comparison Study, 261 patients received 0.5% timolol twice daily plus 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, 2% pilocarpine four times daily, or placebo (twice daily or 4 times daily) for 2 weeks. Patients then entered a 6-month extension period and received 0.5% timolol twice daily plus either 0.7% dorzolamide twice daily, 2% dorzolamide twice daily, or 2% pilocarpine four times daily. RESULTS: In the pilot study, after 8 days, additional mean percent reductions in IOP for 2% dorzolamide and placebo were 17% and 3% at morning trough and 19% and 2% at peak, respectively. In the Pilocarpine Comparison Study, after 6 months, additional mean percent reductions in IOP (morning trough) were 9%, 13%, and 10% for 0.7% dorzolamide, 2% dorzolamide, and 2% pilocarpine, respectively. Patients receiving 2% pilocarpine had the highest rate of discontinuation due to a clinical adverse experience, and the use of dorzolamide was not associated with systemic side effects commonly observed with the use of oral carbonic anhydrase inhibitors. CONCLUSION: Dorzolamide twice daily was effective and well tolerated by the patients in these studies as adjunctive therapy to timolol. The larger study demonstrated that both concentrations of dorzolamide produce similar IOP-lowering effects to 2% pilocarpine.

A randomized trial in patients inadequately controlled with timolol alone comparing the dorzolamide-timolol combination to monotherapy with timolol or dorzolamide. Dorzolamide-Timolol Combination Study Group.

OBJECTIVE: To compare the dorzolamide-timolol fixed combination twice daily to its components, timolol maleate and dorzolamide hydrochloride, given in their usual monotherapy regimens in patients whose intraocular pressure (IOP) was not controlled on timolol twice daily alone. DESIGN: Parallel, randomized, double-masked, and active-controlled study. PARTICIPANTS: Enrolled were 253 patients from 22 sites throughout the United States. INTERVENTION: After a 3-week run-in of timolol (TIMOPTIC; Merck & Co., Inc., Whitehouse Station, NJ) twice daily, eligible patients received either the combination (COSOPT; Merck & Co., Inc., Whitehouse Station, NJ) twice daily (plus placebo to ensure masking), timolol twice daily (plus placebo to ensure masking), or dorzolamide (TRUSOPT; Merck & Co. Inc., Whitehouse Station, NJ) three times daily for 3 months. MAIN OUTCOME MEASURES: Intraocular pressure taken at hours 0 (trough) and 2 (peak) after week 2 and months 1, 2, and 3 was compared to baseline within each treatment group and between the combination and each component group. The safety profile of the combination was compared to each component. RESULTS: The combination was numerically superior at all study timepoints and was statistically superior at all timepoints except for month 2, hour 0 for timolol, and month 2, hour 2 for dorzolamide. The safety profile of the combination reflected those of its two components. The number of patients reporting ocular or local adverse experiences was greater for the combination (45%) and dorzolamide (45%) than for timolol (27%), with burning and/or stinging eye being the most frequently reported. CONCLUSION: The dorzolamide-timolol combination provides additional IOP lowering compared to either of its individual components and generally is well-tolerated.

A randomized trial in patients inadequately controlled with timolol alone comparing the dorzolamide-timolol combination to monotherapy with timolol or dorzolamide.

OBJECTIVE: To compare the dorzolamide-timolol fixed combination twice daily to its components, timolol maleate and dorzolamide hydrochloride, given in their usual monotherapy regimens in patients whose intraocular pressure (IOP) was not controlled on timolol twice daily alone. DESIGN: Parallel, randomized, double-masked, and active-controlled study. PARTICIPANTS: Enrolled were 253 patients from 22 sites throughout the United States. INTERVENTION: After a 3-week run-in of timolol (TIMOPTIC; Merck & Co., Inc., Whitehouse Station, NJ) twice daily, eligible patients received either the combination (COSOPT; Merck & Co., Inc., Whitehouse Station, NJ) twice daily (plus placebo to ensure masking), timolol twice daily (plus placebo to ensure masking), or dorzolamide (TRUSOPT; Merck & Co. Inc., Whitehouse Station, NJ) three times daily for 3 months. MAIN OUTCOME MEASURES: Intraocular pressure taken at hours 0 (trough) and 2 (peak) after week 2 and months 1, 2, and 3 was compared to baseline within each treatment group and between the combination and each component group. The safety profile of the combination was compared to each component. RESULTS: The combination was numerically superior at all study timepoints and was statistically superior at all timepoints except for month 2, hour 0 for timolol, and month 2, hour 2 for dorzolamide. The safety profile of the combination reflected those of its two components. The number of patients reporting ocular or local adverse experiences was greater for the combination (45%) and dorzolamide (45%) than for timolol (27%), with burning and/or stinging eye being the most frequently reported. CONCLUSION: The dorzolamide-timolol combination provides additional IOP lowering compared to either of its individual components and generally is well-tolerated.

The effect of timolol, betaxolol, and placebo on corneal sensitivity in healthy volunteers.

This study in sixty healthy volunteers investigated the effect of a single drop of either 0.5% timolol ophthalmic solution, 0.5% betaxolol ophthalmic solution, or placebo on corneal sensitivity as measured by the Cochet-Bonnet anesthesiometer. Corneal sensitivity was measured immediately prior to the drop and then 1, 3, 6, 10, 15 and 30 minutes after drop instillation. The timolol treated eyes showed a significant decrease at one minute after instillation. An increase in sensitivity occurred in the placebo group at 15 and 30 minutes. In the eyes treated with betaxolol, a significant reduction in corneal sensitivity was seen at every time point through the 10-minute measurement.

Effect of timolol versus pilocarpine on visual field progression in patients with primary open-angle glaucoma.

BACKGROUND: Relatively few studies have been conducted linking decreasing intraocular pressure (IOP) to preservation of visual field. This investigation was conducted to determine if this link could be made and to compare the long-term effect of two ocular hypotensive agents on preservation of visual field. METHODS: In an observer-masked study, 189 patients with primary open-angle glaucoma received either timolol or pilocarpine by random allocation. The dose of antiglaucoma agent was increased from 0.25% to 0.5% twice daily for timolol or from 2% to 4% four times daily for pilocarpine if the initial IOP response was inadequate. After an on-treatment baseline, visual fields were followed every 4 months for 2 years using the Octopus program 32. RESULTS: Compared with timolol, significantly more patients receiving pilocarpine discontinued use because of inadequate IOP control (P < or = 0.01). By comparing the mean visual field scores, it can be seen that the pilocarpine group had a significantly worse score at all timepoints from month 4 to month 24. The pilocarpine group also had a greater mean number of test loci with decreased sensitivity of 5 or more decibels (dB) at all timepoints. The mean within-patient regression slope for timolol was 0.01 dB/month and for pilocarpine was -0.06 dB/month (P < 0.01). The study has shown that over a 2-year period, patients treated with pilocarpine 2% or 4% four times daily experienced a significantly greater visual field deterioration than that seen in patients receiving either 0.25% or 0.5% timolol twice daily. CONCLUSION: Although these data do not support a link between lowering of IOP and visual field preservation, treatment with timolol was associated with significantly less visual field loss than treatment with pilocarpine.

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.