Effects of topical 0.5% levobunolol alone or in association with 2% dorzolamide compared with a fixed combination of 0.5% timolol and 2% dorzolamide on intraocular pressure and heart rate in dogs without glaucoma.

The goal of glaucoma management is to reduce intraocular pressure (IOP) and maintain it at a level compatible with the health of the optic nerve. New therapies are constantly being sought. Topical instillation of levobunolol 0.5%, alone or with dorzolamide 2%, has a hypotensive effect on the IOP in healthy dogs, and levobunolol combined with dorzolamide produces a stronger hypotensive effect than the combination of timolol and dorzolamide. All animals tolerate these topical medications well with no signs of discomfort, and no ocular side effects have been observed. Levobunolol, alone or in combination with dorzolamide, induces bradycardia, as does timolol with dorzolamide.

Poly (epsilon-caprolactone) microparticles containing Levobunolol HCl prepared by a multiple emulsion (W/O/W) solvent evaporation technique: effects of some formulation parameters on microparticle characteristics.

The aim of this study was to prepare poly (epsilon-caprolactone) (PCL) microparticles of Levobunolol HC1 (L-HC1) for use as an anti-glaucomatous drug to the eye. The double emulsion (W/O/W) solvent evaporation technique was used for encapsulating L-HC1 as a hydrophilic drug. The study examined the impact of different factors including the pH and volume of the external aqueous phase, the concentration of polyvinylalcohol (PVA) and Pluronic F68 (PF68) used as stabilizers and drug/polymer ratios on the characteristics of the microparticles. Scanning electron microscopy (SEM) and differential scanning calorimetry (DSC) were used to identify the physical state of the drug and polymer. The zeta potential of the particles was also identified. Entrapment efficiency was found to be highest with a 0.5% PVA concentration and 100 mL volume of external aqueous phase at pH 12. The high efficiency was due to a reduction in the degree of drug ionization. The microparticles were spherical and appropriately sized for ophthalmic application. Drug release from the microparticles appears to consist of two components, with an initial rapid release followed by a slower stage. Drug release was slower when the microparticle was incorporated into the thermally reversible gel (Pluronic F127) in comparison to drug release from the free drug incorporated into the gel and drug release from the free microparticle.

Correlates of acute exercise-induced ocular hypotension.

PURPOSE: To understand those factors that determine the decrease in intraocular pressure (IOP) that occurs during acute dynamic exercise. METHODS: Three aspects of the exercise-IOP relationship were studied. These included graded exercise, with and without CO2 addition for isocapnia; comparison of the IOP response of trained and sedentary subjects to a fixed external work load; and exercise after ocular beta-adrenoceptor blockade. Graded exercise consisted of 7 minutes each at 30 and 90 watts on a cycle ergometer, then progressive work to exhaustion. Trained and sedentary subjects were defined on the basis of the blood lactate response to fixed external work (10 minutes at 90 watts). Selective beta 1-adrenoceptor blockade (betaxolol) and nonselective beta-adrenoceptor blockade (levobunolol) were superimposed on graded exercise. Intraocular pressure was measured using applanation tonometry. RESULTS: Graded exercise: Intraocular pressure decreased in proportion to exercise intensity. Hypocapnia developed in the last minutes of exhausting work, but preventing hypocapnia with CO2 addition failed to lessen the decrease in IOP. Response to fixed external work load: Intraocular pressure decreased significantly more in sedentary than in trained subjects; this decline was correlated with elevations in blood lactate but not with changes in metabolic rate or plasma osmolarity. Selective and nonselective beta-adrenoceptor blockade: Both drugs lowered IOP at baseline and throughout graded exercise; the drugs and exercise had apparently additive ocular hypotensive effects. CONCLUSIONS: Acute dynamic exercise lowers IOP in a graded fashion proportional to relative, not absolute, work load. The IOP decline is correlated with blood lactate but not with PCO2 or plasma osmolarity changes, and exercise potentiates the ocular hypotensive effects of beta-adrenoceptor blockade.

Ocular levobunolol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Levobunolol is a potent non-selective beta-adrenoceptor blocking agent used for the topical treatment of increased intraocular pressure in patients with chronic open angle glaucoma or ocular hypertension. In comparative studies of up to 2 years' duration levobunolol 0.5 to 1% reduced intraocular pressures by about 30% and adequately controlled intraocular hypertension in 50 to 85% of those treated. These results were significantly superior to those produced by placebo and comparable to the responses achieved with ocular timolol in double-blind controlled trials. Levobunolol has been well tolerated, producing only minor changes in objective and subjective ophthalmic and systemic parameters. Adverse reactions resulted in approximately 5% of patients withdrawing from treatment with levobunolol which was equivalent to that observed with timolol. Thus, ocular levobunolol is a well-tolerated and effective therapy for the management of raised intraocular pressure, and is a suitable alternative to ocular timolol in patients with chronic open angle glaucoma or ocular hypertension.

Long-term evaluation of 0.25% levobunolol and timolol for therapy for elevated intraocular pressure.

In a one-year, double-masked, randomized study, the ocular hypotensive efficacy of twice-daily treatment with 0.25% levobunolol hydrochloride or timolol maleate was evaluated in 78 patients with glaucoma or ocular hypertension (phase 1). If intraocular pressure (IOP) was not well controlled during the study, the concentration of medication was increased to 0.5%, and the patient was followed up for an additional three months (phase 2). During phase 1, the mean IOP was reduced by 4.6 mm Hg in the timolol treatment group and by 5.1 mm Hg in the levobunolol treatment group. Seventy-one percent (29/41) of the patients in the timolol treatment group and 70% (26/37) of the patients in the levobunolol treatment group successfully completed phase 1. Of those patients who required the higher concentration of medication, 89% (8/11) in the timolol treatment group and 75% (3/4) in the levobunolol treatment group successfully completed phase 2. Higher concentration, however, did not produce greater IOP reduction. No statistically or clinically significant differences between the groups were noted in any of the efficacy or safety variables evaluated.

Levobunolol. A three-month efficacy study in the treatment of glaucoma and ocular hypertension.

The ocular hypotensive effect and the safety of levobunolol hydrochloride (0.5% and 1%) were compared with vehicle in this double-masked study of 42 patients with chronic open-angle glaucoma or ocular hypertension. After a washout of ocular hypotensive medication, patients received one of the three test treatments in both eyes twice daily for three months. Both concentrations of levobunolol produced significant reductions in intraocular pressure, while decreases in vehicle-treated patients were minimal. Over the three-month study period, average pressure reductions were approximately 9.0 mm Hg in patients receiving either concentration of levobunolol and 0.5 mm Hg in patients receiving vehicle. Fewer patients were terminated from the study for inadequately controlled intraocular pressure in the levobunolol groups than in the vehicle group. No patients were terminated for drug-related adverse experiences.

Levobunolol compared with timolol for the long-term control of elevated intraocular pressure.

Levobunolol hydrochloride (0.5% and 1%) and timolol maleate (0.5%) are being compared in an ongoing, double-masked, randomized study of 141 patients with ocular hypertension or chronic open-angle glaucoma. Baseline intraocular pressure (IOP) in the three treatment groups ranged from 26 to 27 mm Hg. During the first 15 months of the study, the two drugs have not proved to be significantly different in ocular hypotensive efficacy, with overall mean IOP decreases of 6.8 to 7.6 mm Hg. In addition, the two concentrations of levobunolol have been equally effective in controlling IOP. Neither drug has been associated with any significant ocular side effects. Both drugs have produced significant decreases (five to ten beats per minute) in mean heart rate. The effect on mean blood pressure has been less pronounced: overall decreases have been less than 4 mm Hg for both systolic and diastolic blood pressure. The results of this ongoing study suggest that levobunolol is as effective and as safe as timolol for the long-term control of IOP.

Topical ophthalmic beta-adrenergic blockade for the treatment of glaucoma and ocular hypertension.

Since the late 1970s, topical beta-adrenergic blockers have been the drugs of choice in treating ocular hypertension and associated glaucoma. The currently available drugs are timolol, betaxolol, levobunolol, metipranolol, and carteolol. All reduce intraocular pressure by decreasing the production of aqueous humor. Although these drugs are applied locally in the eye, they may enter the general circulation and reach concentrations high enough to cause systemic effects, including alterations in heart rate and rhythm, bronchoconstriction, dyslipidemia, and central nervous system abnormalities. Interactions with other drugs may also occur. Ocular beta- blockers differ in beta 1-selectivity (betaxolol is beta 1-selective, whereas the other drugs are nonselective) and in intrinsic sympathomimetic activity (ISA) or partial agonist properties (only carteolol possesses ISA). These differences give betaxolol and carteolol potential advantages in minimizing certain side effects. The advantage of betaxolol vis-à-vis systemic side effects is more clearly established than that of carteolol. Further systematic study is needed to determine what advantages, if any, are conferred by the presence of ISA.

Efficacy and tolerability of 0.5% timolol maleate ophthalmic gel-forming solution QD compared with 0.5% levobunolol hydrochloride BID in patients with open-angle glaucoma or ocular hypertension.

We compared the efficacy of timolol maleate ophthalmic gel-forming solution 0.5% QD with that of levobunolol hydrochloride 0.5% BID, as measured by change in intraocular pressure (IOP), effect on heart rate, and ocular tolerability. The study had a positive-controlled, double-masked, randomized, multicenter, 12-week, two-period (6 weeks each), crossover design. One hundred fifty-two patients with open-angle glaucoma or ocular hypertension were randomized to receive either timolol maleate gel-forming solution QD or levobunolol BID for 6 weeks, followed by a crossover to the alternate treatment. IOP and heart rate were measured at morning trough and peak during weeks 3, 6, 9, and 12. Timolol maleate gel-forming solution QD was comparable to levobunolol BID in reducing IOP at peak and trough. Although the effects on peak heart rate were similar between the two medications, the effect on trough heart rate of timolol maleate gel-forming solution QD was significantly less than that of levobunolol BID (P = 0.001). The incidence of ocular burning and stinging was comparable between the two treatments. Patients experienced significantly more blurred vision when using timolol maleate gel-forming solution than when using levobunolol (P = 0.013). Overall, more patients experienced at least one adverse event when using timolol maleate gel-forming solution. Timolol maleate gel-forming solution QD is as efficacious in reducing IOP as levobunolol BID.

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.

A dose-response study of the effect of levobunolol on ocular hypertension.

We conducted a randomized, double-masked, dose-response study of the ocular hypotensive effect of the beta-adrenergic blocker, levobunolol. A single drop of placebo or levobunolol (at concentrations of 0.03%, 0.3%, 0.6%, 1%, and 2%) was administered to one eye of each of 48 patients with ocular hypertension. The 0.3% and 0.6% concentrations decreased intraocular pressure significantly from baseline levels compared to placebo at one, two, and four hours after treatment. The 1% and 2% concentrations decreased intraocular pressure significantly from baseline compared to placebo at one, two, four, six, eight, and 12 hours after administration. No objective or subjective side effects were noted, and no substantial changes in visual acuity, pupil diameter, pulse rate, or blood pressure were recorded during the study. These results appear to justify long-term studies of levobunolol for the treatment of increased intraocular pressure.

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.

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.

A clinical evaluation of the effects of topically applied levobunolol and timolol on increased intraocular pressure.

Data from two short-term double-masked studies using 24 and 16 subjects suggest that topically applied levobunolol safely and effectively treats open-angle glaucoma and ocular hypertension. The onset of effect of a single drop of 0.5% levobunolol occurred within the first hour, producing a maximal hypotensive effect of more than 8 mm Hg after two hours. An intraocular pressure deceased of greater than or equal to 2 mm Hg was still observed after 24 hours for both concentrations of levobunolol tested (0.5% and 1%). Intraocular pressure decreases of more than 9 mm Hg persisted during a one-month trial in which patients were treated twice daily, confirming the results obtained in the 24-hour study. Systemic effects of both timolol (0.5%) and levobunolol (0.5% and 1%) included a consensual intraocular pressure-decreasing effect in the untreated eye and clinically significant reductions in heart rate. Diastolic blood pressure was decreased at two and four hours after administration of 0.5% levobunolol.

Lichen planus associated with topical beta-blocker therapy.

PURPOSE: We studied two clinical cases that demonstrated an association between topical beta-blocker therapy and lichen planus. METHODS: Two patients developed skin lesions while on topical beta-blocker therapy for open-angle glaucoma. They underwent skin biopsies to determine the origin of the lesions. They were subsequently treated and followed up clinically. RESULTS: Skin biopsy specimens from each patient demonstrated infiltrates consistent with a lichenoid drug reaction. The symptoms resolved after discontinuation of the topical beta-blocker therapy. Neither patient developed a recurrence. CONCLUSION: We suggest that lichen planus is a possible side effect of topical beta-blocker therapy.

Levobunolol compared with timolol: a four-year study.

Fifty-one patients with raised intraocular pressure (IOP) were treated for up to four years with one of three ophthalmic solutions: 0.5% levobunolol, 1% levobunolol, or 0.5% timolol. The study was conducted as a double-masked, randomised trial in which medications were administered twice daily to both eyes. Levobunolol and timolol were equally effective in reducing overall mean IOP; reductions were greater than 8.8 mmHg in all three treatment groups. The study showed levobunolol to be as safe and effective as timolol in the long-term control of raised IOP.

Levobunolol and metipranolol: comparative ocular hypotensive efficacy, safety, and comfort.

Topical levobunolol 0.5% was compared with topical metipranolol 0.6% for efficacy, safety, and comfort in 46 patients with open angle glaucoma or ocular hypertension. The study was of parallel design, randomised, double-masked, and of three months' duration. After a washout interval the study medications were instilled twice daily in both eyes. The overall mean decrease in intraocular pressure (IOP) was approximately 7 mmHg in both groups. More than 90% of patients in both groups successfully completed the study. Both agents caused slight decreases in heart rate and blood pressure. More complaints of burning and stinging were reported in the metipranolol group than in the levobunolol group. This three-month, 46-patient study showed levobunolol 0.5% and metipranolol 0.6% to be similarly effective ocular hypotensive agents.

Levobunolol 0.5% and timolol 0.5% to prevent intraocular pressure elevation after neodymium:YAG laser posterior capsulotomy.

PURPOSE: To evaluate the prophylactic effect of levobunolol 0.5%, timolol 0.5%, or vehicle in reducing the incidence of postoperative intraocular pressure (IOP) spikes of 5 and 10 mm Hg or more in patients having neodymium:YAG (Nd:YAG) laser posterior capsulotomy. SETTING: Miami Vision Center, Coral Gables, Florida; Cullen Eye Institute, Baylor College of Medicine, Houston, Texas; Cincinnati Eye Institute, Cincinnati, Ohio; South Texas Cataract and Glaucoma Center, San Antonio, Texas; Mid-South Eye Foundation, Memphis, Tennessee, USA. METHODS: This prospective, double-masked, randomized study comprised 144 patients having Nd:YAG laser posterior capsulotomy in one eye. One drop of the test medication was administered preoperatively and one drop on the evening after surgery; IOP was measured preoperatively and 1,2,3 and 24 hours postoperatively. RESULTS: Intraocular pressure elevations of 5 mm Hg or more were seen in 1 of 60 patients (2%) in the levobunolol group, 4 of 54 (7%) in the timolol group, and 10 of 28 (36%) in the vehicle group. These elevations occurred significantly more frequently in the vehicle group than in the levobunolol (P < .001) or timolol (P < .004) groups. Elevations of 10 mm Hg or more were found in 2 of 28 patients (7%) treated with vehicle but were not observed in the patients treated with levobunolol or timolol. CONCLUSIONS: Levobunolol 0.5% or timolol 0.5% administered preoperatively and again in the evening after Nd:YAG laser capsulotomy effectively blunted the IOP rise that frequently follows laser surgery.

Extracapsular cataract extraction with posterior chamber lens implantation in primary angle-closure glaucoma.

PURPOSE: To evaluate long-term intraocular pressure (IOP) control after extracapsular cataract extraction (ECCE) with posterior chamber intraocular lens (IOL) implantation in patients with primary angle-closure glaucoma. SETTING: Ophthalmology Department, Groote Schuur Hospital, Cape Town, South Africa. METHODS: This retrospective study comprised 17 patients (19 eyes) with primary angle-closure glaucoma who had ECCE and posterior chamber IOL implantation. Four presented initially with acute glaucoma, 5 with subacute angle-closure glaucoma, and 8 (10 eyes) with chronic angle-closure glaucoma. In all, less than half the circumference of the angle was permanently closed. The drainage angle was evaluated preoperatively and postoperatively to monitor changes in the amount of angle closure. Intraocular pressure was measured in the early and late postoperative periods. RESULTS: On the first postoperative day, mean IOP was 17.2 mm Hg, although 5 patients (26%) had an IOP rise above 21 mm Hg despite the use of perioperative topical pilocarpine gel. After a mean follow-up of 19 months, IOP remained below 22 mm Hg without medication in 13 eyes (68%) and with topical medication in 5 eyes (26%). Mean number of glaucoma medications was reduced from 1.5/eye preoperatively to 0.5/eye postoperatively. CONCLUSION: Cataract extraction with IOL implantation resulted in good long-term IOP control in patients with primary angle-closure glaucoma, suggesting that combined cataract and trabeculectomy surgery may not be necessary to achieve long-term IOP control in these patients.

Disposition of levobunolol after an ophthalmic dose to rabbits.

The ocular and systemic disposition of levobunolol (LBUN), an antiglaucoma agent, was studied in albino rabbits. After topical administration to eyes, LBUN was rapidly adsorbed, with 2.5% of the dose bioavailable to the intraocular tissues as intact drug and 46% to the systemic circulation. On passage across the cornea, approximately 4.7% of a topically applied LBUN dose was biotransformed to dihydrolevobunolol (DHB), and subsequently became bioavailable to intraocular tissues. The major sites of ocular metabolism were the cornea epithelium and the iris-ciliary body. Another 12% of the topical LBUN dose entered the systemic circulation as DHB after presystemic biotransformation. Our study indicated a rapid absorption of LBUN into the aqueous humor after topical dosing. The tpeak was 15 min after dosing and the Cmax was 4 micrograms/mL. Dihydrolevobunolol (DHB) was formed steadily and reached a maximum in the aqueous humor 45 min after dosing. After distribution equilibrium had been reached, the aqueous humor concentrations of both LBUN and DHB declined. Six hours after dosing, the concentration of DHB in the aqueous humor was approximately 10 times higher than that of its parent compound. Because DHB is equivalent to its parent compound in beta-blocking activity, its formation in the rabbit eye may contribute to the pharmacodynamic effects observed after topical doses of LBUN.