Gary D. Novack

Ophthalmic beta-blockers since timolol

In the twenty years since beta-blockers were proposed for treatment of glaucoma, use of topical timolol has increased to account for 70% of all glaucoma medications used. The objective of this article is to review the newer beta-blockers, and to address the generalization that all ophthalmic beta-blockers are the same. The review concentrates on agents that have been studied as topical treatments for patients with elevated intraocular pressure. Sections on pharmacology and design of clinical trials are included to aid the ophthalmologist in evaluating the new drugs and published clinical reports. The major questions to consider in evaluating the therapeutic potential of a new beta-blocker for the treatment of glaucoma involve efficacy and safety: Is the drug as effective as timolol? Does it have a duration of action at least as long as timolol? Does it have ocular toxicity? Is it comfortable? What are its systemic effects?

Memory-enhancing effects of post-training dipivefrin and epinephrine : involvement of peripheral and central adrenergic receptors

These experiments examined the effects, in mice, of post-training i.p. injections of dipivefrin (DPE), a lipophilic prodrug of epinephrine, and epinephrine (EPI) on 48-h retention assessed in inhibitory avoidance and Y-maze discrimination tasks. DPE, in doses of 0.3-10 micrograms/kg significantly facilitated retention: the effects were approximately 10-fold more potent than those of EPI obtained with similar experimental conditions. The alpha-adrenergic antagonists prazosin (alpha 1; 3.0 mg/kg; i.p.), yohimbine (alpha 2; 3.0 mg/kg; i.p.) and phentolamine (alpha 1 and alpha 2; 3.0 mg/kg; i.p.) did not block the enhancement of retention induced by either DPE (10.0 micrograms/kg; i.p.) or EPI (0.1 mg/kg; i.p.). However, the beta-adrenergic antagonist propranolol (2.0 mg/kg; i.p.) attenuated the effects of both DPE and EPI. Sotalol (2.0 mg/kg; i.p.), a peripherally-acting beta-adrenergic antagonist, attenuated the effects of EPI but not those of DPE. These findings suggest the DPE-induced enhancement of memory involves central beta- but not alpha-adrenergic mechanisms while EPIs effects are initiated by activation of peripheral beta-adrenergic systems.

Glaucoma treatment with once-daily levobunolol.

Although twice-daily instillation of topical beta-blockers is the standard regimen for treatment of increased intraocular pressure, once-daily therapy might improve patient compliance and provide greater safety. In a three-month, double-masked clinical trial, 92 patients with open-angle glaucoma or ocular hypertension received levobunolol 0.5% or 1% or timolol 0.5% once daily, in both eyes. Overall mean decreases in intraocular pressure were significantly greater in the groups treated with levobunolol than in the group treated with timolol. Intraocular pressure decreases averaged 7.0 mm Hg with levobunolol 0.5%, 6.5 mm Hg with levobunolol 1%, and 4.5 mm Hg with timolol. The intraocular pressures of 72% (18 of 25 patients) of those treated with levobunolol 0.5%, 79% (22 of 28 patients) of those treated with levobunolol 1%, and 64% (16 of 25 patients) of those treated with timolol were successfully controlled during the study. Heart rate and blood pressure decreases were minimal with both levobunolol and timolol. Study results indicated that once-daily treatment with levobunolol and, to a lesser extent, timolol is sufficient to control intraocular pressure successfully and safely.

Levobunolol: A Beta-adrenoceptor Antagonist Effective in the Long-term Treatment of Glaucoma

We compared the ocular-hypotensive efficacy and systemic and ocular safety of an ophthalmic solution of levobunolol (0.5% and 1%) twice daily, with timolol (0.5%) twice daily in a long-term double-masked study of 391 patients with open-angle glaucoma or ocular hypertension. Patients received the test medication in both eyes for up to two years. Over the two-year period, both concentrations of levobunolol reduced mean IOP by 27% (range, -6 to -8 mmHg). This ocular-hypotensive effect was sustained throughout the study and was similar to that produced by timolol. Slight decreases in mean heart rate and blood pressure were observed. No unexpected adverse ocular or systemic reactions were reported. The results of these studies indicate that levobunolol is an effective therapy for the long-term treatment of glaucoma.

Epinephrine-induced memory facilitation: attenuation by adrenoceptor antagonists

The present study examined the relative importance of alpha- and beta-adrenoceptors in the memory modulatory effects of epinephrine. Posttraining epinephrine administration enhanced retention performance of a one-trial inhibitory avoidance response. Further pretraining injections of a variety of adrenoceptor antagonists, including selective alpha 1-, alpha 2-, beta 1- and/or beta 2-adrenoceptor antagonists, attenuated the retention enhancing effects of posttraining epinephrine. These results suggest that alpha- and beta-adrenoceptors of both subtypes are involved in the memory-modulating effects of epinephrine.

Levobunolol vs timolol for open-angle glaucoma and ocular hypertension.

A group of 162 patients with chronic open-angle glaucoma or ocular hypertension were treated twice daily for up to 15 months with one of the following topical ophthalmic solutions: 0.5% levobunolol, 1% levobunolol, or 0.5% timolol. Overall mean reductions in intraocular pressure were 8 mm Hg for patients receiving 0.5% levobunolol or timolol and 8.2 mm Hg for patients receiving 1% levobunolol. There were no significant differences between levobunolol and timolol in mean reductions in intraocular pressure, percent of patients with adequately controlled intraocular pressure, or life-table estimates of the probability of successful treatment.

Levobunolol and Betaxolol: A Double-masked Controlled Comparison of Efficacy and Safety in Patients with Elevated Intraocular Pressure

In a double-masked, randomized, controlled clinical trial, the authors evaluated the ocular hypotensive efficacy of twice-daily treatment with levobunolol (0.25 and 0.5%) and betaxolol (0.5%) in 85 patients with open-angle glaucoma or ocular hypertension. During the 3-month study, intraocular pressure (IOP) reductions in the two levobunolol groups were significantly greater than in the betaxolol group. From a mean baseline IOP of approximately 25 mmHg, overall mean reductions were 6.2 and 6.0 mmHg for the 0.25 and 0.5% levobunolol groups, respectively, and 3.7 mmHg for the betaxolol group. No clinically or statistically significant among-group differences were noted in the systemic safety variables evaluated. These data suggest that although all three treatments are effective, levobunolol provides a greater reduction in IOP than betaxolol.

Prophylactic treatment of intraocular pressure elevations after neodymium: YAG laser posterior capsulotomies and extracapsular cataract extractions with levobunolol.

The prophylactic effect of topical 0.5% levobunolol on intraocular pressure (IOP) elevations after neodymium:YAG (Nd:YAG) laser posterior capsulotomies and extracapsular cataract extractions (ECCEs) was investigated in two separate, double-masked, placebo-controlled studies. In study 1, 42 patients received either levobunolol or vehicle 1 hour before a unilateral Nd:YAG laser posterior capsulotomy. Elevated IOP (greater than or equal to 10 mmHg) occurred in up to 38% of those in the vehicle group and none in the levobunolol group. Mean IOP increased up to 6 mmHg in the vehicle group, whereas it decreased up to 3 mmHg in the levobunolol group. In study 2, 41 patients received either levobunolol or vehicle immediately after a unilateral ECCE involving the use of a viscoelastic preparation and the implantation of a posterior chamber intraocular lens (PC IOL). The incidence of IOP elevations (greater than or equal to 10 mmHg) was up to 40% in the vehicle group and 19% in the levobunolol group. Mean IOP increased up to 9 mmHg in the vehicle group and up to 2 mmHg in the levobunolol group. Thus, marked elevations in IOP after posterior capsulotomies or ECCEs may be minimized by prophylactic treatment with levobunolol.

A comparison of the ocular hypotensive efficacy of once-daily and twice-daily levobunolol treatment.

The authors compared the ocular hypotensive efficacy of two different treatment regimens of levobunolol 0.5% in a double-masked, randomized, controlled clinical trial. Seventy-one patients with open-angle glaucoma or ocular hypertension received levobunolol 0.5% as their sole glaucoma medication either on a once-daily or twice-daily treatment regimen for 3 months. Approximately 81% of the patients in the once-daily treatment group and 88% of subjects in the twice-daily treatment group successfully completed the 3-month study period. The overall mean decrease in intraocular pressure (IOP) was 4.5 mmHg in the once-daily group and 5.6 mmHg in the twice-daily group. These differences were not statistically different. For both treatment groups, effects on mean heart rate and blood pressure were minimal. The authors data from this population suggest that once-daily treatment with levobunolol is an effective glaucoma regimen.

Minimum Concentration of Levobunolol Required To Control Intraocular Pressure in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension

In a double-masked, randomized, comparison titration study to determine the effective dose of topically applied levobunolol, three concentrations of levobunolol (0.25%, 0.5%, and 1%) and of timolol (0.125%, 0.25%, and 0.5%) were evaluated in patients with mild open-angle glaucoma or ocular hypertension. Following a washout of ocular hypotensive medication, twice-daily treatment in both eyes was initiated with the lowest of the three doses of either drug. The concentration was increased if intraocular pressure remained uncontrolled. Intraocular pressure was controlled in 63% (15 of 24) of the patients tested with the lowest concentration of levobunolol and 69% (18 of 26) with the lowest concentration of timolol. Overall, 75% (18 of 24) of the patients in the levobunolol group and 73% (19 of 26) of the patients in the timolol group had adequately controlled intraocular pressure. At the lowest concentrations tested, mean decreases from baseline in intraocular pressure ranged from 6 to 8 mm Hg in both treatment groups.