Bradyarrhythmias secondary to topical levobunolol hydrochloride solution.

An 88-year-old man was admitted with fatigue, dizziness, and heart palpitations. Both the electrocardiogram and Holter confirmed the existence of sinus bradycardia and sinus arrest. One hour prior to the onset of symptoms, he received levobunolol hydrochloride solution topically. The levobunolol hydrochloride solution was discontinued and the bradycardia resolved. He was diagnosed as having intermittent sinus bradycardia and sinus arrest, induced by topical ß-blocker therapy. Levobunolol hydrochloride solution is an effective therapy for ocular hypertension, probably by reducing aqueous fluid production. However, it can induce cardiac side effects such as bradyarrhythmia and should be used with caution in elderly patients or patients with cardiac disease.

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.

Deposits in artificial corneas: risk factors and prevention.

PURPOSE: To identify risk factors for calcium deposition and pigmented staining within AlphaCor artificial corneas. METHODS: Retrospective analysis of data from 72 AlphaCor implantations was conducted. Histological analysis of explants was performed. RESULTS: Eight cases of either intraoptic calcium or pigment deposition occurred in AlphaCor patients between 2.5 and 21 months after implantation. Four cases had diffuse white deposits, confirmed to be calcium and associated with prior coadministration of topical steroids and beta-blockers. The other four cases had brown deposits, associated with cigarette smoking and topical levobunolol. CONCLUSION: These findings led to changes in patient management protocols, surgeon training and patient information so as to minimize the risk of further occurrences. No further cases of white deposition have occurred after warning surgeons of the risk associated with certain topical therapy combinations. The risk of brown staining may be difficult to remove completely as it appears that environmental exposure to chemicals may cause deposition in addition to personal smoking habits and topical medications.

Comparison of the effects of topical levobunolol and timolol solution on the human ocular surface.

PURPOSE: To compare the effects of levobunolol hydrochloride and timolol maleate on tear volume, precorneal tear film stability, and corneal epithelial barrier function in normal human eyes. SUBJECTS AND METHODS: The study population consisted of 14 healthy volunteers. To obtain pretreatment baseline values, we determined the radius of the tear meniscus (RTM) by meniscometry; the noninvasive breakup time (NIBUT) of the precorneal tear film with a tear specular microscope; and corneal fluorescein uptake with a fluorophotometer. Levobunolol hydrochloride (0.5%) or timolol maleate solution (0.5%) was instilled twice daily for 4 weeks into 1 eye; the contralateral eye was treated with the other topical drug twice daily for the same period. At the end of the study period, the same tests were performed, and the pre- and posttreatment results were compared. RESULTS: Timolol solution did, and levobunolol did not, significantly reduce NIBUT from the baseline values. RTM was significantly decreased by treatment with either timolol or levobunolol solution. Corneal fluorescein uptake was not significantly changed, although it was higher after treatment with both topical drugs. CONCLUSIONS: Four-week treatment with timolol solution resulted in significant instability of the precorneal tear film. Both timolol and levobunolol solution significantly decreased tear volume on the ocular surface. These results indicate that levobunolol solution applied twice daily has equal effects on the tear volume and corneal epithelial barrier function as does timolol solution applied twice daily and that it affects precorneal tear film stability less than timolol solution.

Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension: focus on beta-adrenergic blockade.

Glaucoma and ocular hypertension are highly prevalent conditions in individuals over the age of 40 and are commonly seen together in patients with cardiovascular disease. Many of the antiglaucoma medications, when systemically absorbed, affect the sympathetic and parasympathetic nervous systems of patients and can cause cardiovascular toxicity. Such adverse effects are frequently associated with the long-term use of potentially toxic agents in elderly people, who are most prone to chronic eye disease. Moreover, patients may not associate their symptoms with the topical eye medications, and consequently may not report adverse drug effects. Drug-drug interactions can also occur when patients are taking medications for both cardiovascular disease and glaucoma. This review focuses on beta-adrenergic blockers as topical antiglaucoma medications and other topical antiglaucoma drugs. The systemic toxicity of these agents is reviewed, along with the possible drug interactions. Brief mention is also made of other antiglaucoma medications used alone and in combination with topical beta-blockers.

[Effect of topical levobunolol on retinal, optic nerve head, and choroidal circulation in normal volunteers].

PURPOSE: Using three different techniques of ocular blood flow measurement, we evaluated the effects of topical levobunolol on retinal, optic nerve head, and choroidal circulation. METHODS: Twenty normal volunteers received one drop of levobunolol in one eye and one drop of placebo in the fellow eye. Retinal venous blood flow was measured using multiple scattering laser velocimetry. Retinal capillary blood flow and optic nerve head blood flow were measured by Heidelberg Retina Flowmeter. Pulsatile ocular blood flow was measured by ocular blood flow tonography. Changes in blood pressure, heart rate, retinal venous blood flow, retinal capillary blood flow, optic nerve head blood flow, intraocular pressure and pulsatile ocular blood flow were detected from measurements taken at baseline and at 90 to 120 minutes following the instillation. RESULTS: Intraocular pressure decreased significantly in both eyes. Retinal capillary blood flow increased significantly in both eyes. Optic nerve head blood flow increased significantly in treated eyes but remained unchanged in placebo eyes. There were no significant changes in retinal venous blood flow or pulsatile ocular blood flow in either eyes. CONCLUSION: Our results suggest that one administration of levobunolol may increase the retinal and optic nerve circulation but does not decrease the choroidal circulation.

Ultrastructural effects of topical beta-adrenergic antagonists and an alpha-adrenergic agonist on the rabbit cornea.

In the present study the effects of beta-adrenergic antagonist and alpha-adrenergic agonist drugs on rabbit corneas were evaluated in vivo by using transmission electron microscopy. Twenty-four New Zealand albino rabbits were divided into six groups according to the drug applied. The rabbits to which only balanced salt solution (BSS) or BSS and benzalkonium chloride (BAC) were applied were taken as the control groups. The other four groups consisted of the rabbits to which Timoptic 0.5%, Betagan 0.5%, Betoptic 0.5% and Iopidine 1% were applied, respectively. All of drugs were instilled topically twice daily for 6 weeks. In the BSS group, all layers of the cornea were ultrastructurally normal. In the BSS and BAC group slight epithelial and endothelial changes were found. However, in the other groups, loss of microvilli, increase in glycogen particles, nuclear indentation, widening of the intercellular spaces and cytoplasmic vacuolization in epithelium were observed. No significant abnormality was found in the basal lamina, stroma and Descemet's membrane. Slight ultrastructural changes were noted in the endothelium such as vacuolization due to dilatation of the endoplasmic reticulum cisternae and focal cytoplasmic lytic areas. The results of this study indicate that various ultrastructural changes occur in groups treated with antiglaucomatous drug and that topical treatment with timolol and apraclonidine for 6 weeks is more toxic to the rabbit cornea than levobunolol and betaxolol.

The acute effect of topical beta-adrenoreceptor blocking agents on retinal and optic nerve head circulation.

PURPOSE: Topical beta-blockers are the most common treatment for ocular hypertension in glaucoma, but their ocular hemodynamic effects are not well known. We investigated the acute effects of betaxolol (beta-1 selective antagonist), levobunolol (non-selective antagonist with active polar metabolite), and timolol (non-selective antagonist) on retinal and superficial optic nerve head circulation. METHODS: Intraocular pressure (IOP), heart rate, blood pressure, and retinal circulation were evaluated in 12 healthy subjects (6F/6M; mean age=24+/-2 years) before and two hours after instillation of each drug on separate occasions at least two weeks apart. Macular capillary blood velocity (MCBV), epipapillary blood velocities (EBV), arteriovenous passage (AVP) times, and arterial and venous diameters were measured by digital image analysis of scanning laser fluorescein angiograms. RESULTS: All drugs significantly (p<0.05) reduced IOP. There was no significant effect on blood pressure or calculated ocular perfusion pressure. Only levobunolol significantly lowered heart rate (p<0.05). Each drug produced a significant (p<0.01) decrease in AVP time of approximately 25%. MCBV was significantly (p<0.01) increased by approximately 20% in all three conditions; each drug also produced significant (p<0.01) increases in EBV. Arterial and venous diameters remained unaffected. CONCLUSION: All three drugs, despite different beta-adrenergic properties, increased blood velocities in retinal and epipapillary capillaries. These changes, occurring as they do in concert with decreased retinal arteriovenous passage time at constant retinal arterial and venous diameter, may indicate improved retinal perfusion after drug treatment. Improved circulation, if it indeed occurs, in tandem with reduced IOP, might explain in part the beneficial effect of beta-adrenoreceptor blocking agents in glaucomatous patients.

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.

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.

The safety of topical beta-blockers in glaucoma treatment.

While adverse effects are uncommon in patients who are otherwise fit and well, doctors should be aware of the implications of the systemic effects of these drugs, particularly the non-selective types, and particularly in the elderly.