Jess T. Whitson

Management of Glaucoma: Focus on Pharmacological Therapy

Glaucoma represents a major cause of vision loss throughout the world. Primary open-angle glaucoma, the most common form of glaucoma, is a chronic, progressive disease often, though not always, accompanied by elevated intraocular pressure (IOP). In this disorder, retinal ganglion cell loss and excavation of the optic nerve head produce characteristic peripheral visual field deficits. Patients with normal-tension glaucoma present with typical visual field and optic nerve head changes, without a documented history of elevated IOP. A variety of secondary causes, such as pigment dispersion syndrome and ocular trauma, can result in glaucoma as well. Treatment of all forms of glaucoma consists of reducing IOP. With proper treatment, progression of this disease can often be delayed or prevented.Treatment options for glaucoma include medications, laser therapy and incisional surgery. Laser techniques for the reduction of IOP include argon laser trabeculoplasty and selective laser trabeculoplasty. Both techniques work by increasing outflow of aqueous humour through the trabecular meshwork. Surgical options for glaucoma treatment include trabeculectomy, glaucoma drainage tube implantation and ciliary body cyclodestruction. While each of these types of procedures is effective at lowering IOP, therapy usually begins with medications. Medications lower IOP either by reducing the production or by increasing the rate of outflow of aqueous humour within the eye.Currently, there are five major classes of drugs used for the treatment of glaucoma: (i) cholinergics (acetylcholine receptor agonists); (ii) adrenoceptor agonists; (iii) carbonic anhydrase inhibitors (CAIs); (iv) β-adrenoceptor antagonists; and (v) prostaglandin analogues (PGAs). Treatment typically begins with the selection of an agent for IOP reduction. Although β-adrenoceptor antagonists are still commonly used by many clinicians, the PGAs are playing an increasingly important role in the first-line therapy of glaucoma. Adjunctive agents, such as α-adrenoceptor agonists and CAIs are often effective at providing additional reduction in IOP for patients not controlled on monotherapy. As with any chronic disease, effective treatment depends on minimising the adverse effects of therapy and maximising patient compliance. The introduction of a variety of well tolerated and potent medications over the past few years now allows the clinician to choose a treatment regimen on an individual patient basis and thereby treat this disorder more effectively.

Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: A 6-month, masked, multicenter trial

OBJECTIVE To compare the safety and intraocular pressure (IOP)-lowering efficacy of once-daily travoprost (0.0015% and 0.004%) to twice-daily timolol 0.5%. DESIGN Prospective, 6-month, randomized, controlled, multicenter, double-masked, phase III study. PARTICIPANTS Six hundred five patients with open-angle glaucoma or ocular hypertension. METHODS Patients with an 8 AM IOP between 24 to 36 mmHg in at least one eye (the same eye) at two eligibility visits received either travoprost 0.0015%, travoprost 0.004% (dosed every day), or timolol 0.5% (dosed twice daily). MAIN OUTCOME MEASURES Mean IOP at 8 AM, 10 AM, and 4 PM in the patients eye with the higher baseline IOP. RESULTS The mean IOP was significantly lower for both concentrations of travoprost compared with timolol. Travoprost was statistically superior to timolol at 9 of 13 visits, with differences in IOP reductions ranging from 0.9 to 1.8 mmHg (0.0015%) and 10 of 13 visits with differences in IOP reductions from 0.9 to 2.4 mmHg (0.004%). Mean IOP changes from baseline ranged from -6.0 to -7.5 mmHg (0.0015%), -6.5 to -8.0 mmHg (0.004%), and -5.2 to -7.0 mmHg for timolol. Hyperemia was experienced at rates of 29.2% (59 of 202) for travoprost 0.0015%, 42.8% (86 of 201) for travoprost 0.004%, and 8.9% (18 of 202) for timolol. Iris pigmentation changes were observed in 1.0% (2 of 200) of patients receiving travoprost 0.004% with no changes noted in the travoprost 0.0015% group or the timolol group. A decrease in pulse and systolic blood pressure was observed in the timolol group. There were no other clinically relevant or statistically significant changes from baseline in ocular signs or laboratory values, and no serious, related, unexpected adverse events were reported for any group. CONCLUSIONS Travoprost (0.0015% and 0.004%), dosed once daily in the evening, is statistically superior or equal to timolol 0.5% dosed twice daily at all treatment visits during this 6-month study. IOP reductions of up to 2.0 mmHg greater than timolol were found in the travoprost 0.004% pooled data group. Travoprost is safe and well tolerated in patients with open-angle glaucoma or ocular hypertension.

Assessment of Corneal Epithelial Integrity After Acute Exposure to Ocular Hypotensive Agents Preserved With and Without Benzalkonium Chloride

The corneal toxicity of 2 intraocular pressure-lowering agents was compared in a rabbit cornea model with New Zealand White rabbits. Corneal epithelial morphology and cell size were assessed by in vivo confocal microscopy. Baseline microscopic examinations were performed on 1 eye of each animal. Two weeks later, the eyes were bathed for 3 min in travoprost 0.004% preserved without benzalkonium chloride (BAK) or latanoprost 0.005% preserved with 0.02% BAK; the eyes were then rinsed with balanced salt solution, and the corneas were again examined by confocal microscopy (n=4/group). A second group of animals was exposed to the medications through a dosing regimen of 1 drop/min (3 drops total) (n=4/group). In eyes treated with travoprost without BAK (3-min bath), superficial epithelial cells were similar to baseline, as indicated by their visible cell borders and bright nuclei. In contrast, the surface cells in eyes treated with latanoprost were significantly smaller and brighter and had less distinct borders. Surface cell size was significantly smaller as compared with baseline size and as compared with rabbits treated with travoprost without BAK for 3 min. Similar effects on corneal epithelial cell morphology were observed with the 1-drop/min dosing regimen. In this rabbit model, travoprost 0.004% preserved without BAK did not cause corneal epithelial toxicity; latanoprost 0.005% induced superficial cell loss, most likely caused by the presence of a relatively high concentration of BAK (0.02%).

Von Hippel-Lindau disease: Case report of a patient with spontaneous regression of a retinal angioma

We report clinicopathologic features of a case of von Hippel-Lindau disease in a patient who had been clinically followed for bilateral retinal and cerebellar involvement. Two of the patients retinal hemangiomas appeared to show evidence of spontaneous regression.

Progression of glaucoma associated with the Sirsasana (headstand) yoga posture.

This article reports a case of progressive glaucomatous optic neuropathy and visual field loss that occurred in a patient who practiced the Sirsasana (headstand) yoga posture on a daily basis for many years. Visual field analysis was performed through standard automated perimetry. Intraocular pressure (IOP) was measured through pneumotonometry in the sitting position and in the head-down position. Stereo-optic disc photographs were obtained. IOP increased significantly in the head-down position. Optic disc evaluation revealed a new disc hemorrhage in the left eye. Visual field analysis over a period of 2 y showed progression of a superior arcuate defect in the left eye. Transient increases in IOP associated with the yoga headstand posture may lead to progressive glaucomatous optic nerve damage and visual field loss.

Aqueous Humor Concentrations of Bimatoprost Free Acid, Bimatoprost and Travoprost Free Acid in Cataract Surgical Patients Administered Multiple Topical Ocular Doses of LUMIGAN® or TRAVATAN®

PURPOSE To quantify the aqueous humor (AH) concentrations of bimatoprost (amide), travoprost (isopropyl ester), and their hydrolysis products, bimatoprost free acid (BFA) and travoprost free acid (TFA), after multiple topical ocular doses of LUMIGAN and TRAVATAN, respectively, in patients awaiting cataract surgery. METHODS In 2 separate open-label, sparse-sampling trials, glaucoma patients with cataracts received LUMIGAN (bimatoprost ophthalmic solution, 0.03%) or TRAVATAN (travoprost ophthalmic solution, 0.004%) bilaterally once daily for at least 21 days prior to cataract surgery. Anterior chamber paracentesis was performed at selected times up to 5 h after the last dose and an AH sample was collected. AH samples were assayed by an independent bioanalytical laboratory using a sensitive and validated tandem LC-MS/MS method. The assay lower limits of quantitation were 0.59 nM for bimatoprost, 0.29 nM for BFA, and 0.44 nM for TFA. RESULTS AH concentrations of BFA (17-phenyl-trinor PGF(2alpha)) were quantifiable in all but one sample at 0.5 h. The maximum concentration achieved (C(max)) of BFA was 30.9 + or - 16.41 nM (n =5), observed at 2 h postdose. AH concentrations of bimatoprost amide were lower than BFA at all time points, with a C(max) of 6.81 + or - 1.36 nM (n = 7) at 1 h postdose. For TFA, measurable AH concentrations were obtained at all time points with a TFA C(max) of 3.91 + or - 2.27 nM (n = 5), which was observed at 3 h after the dose (all data are mean + or - SEM). CONCLUSIONS Once daily topical ocular administration of LUMIGAN or TRAVATAN for 3 weeks resulted in significant concentrations of BFA and TFA in the AH. Quantifiable levels of bimatoprost amide were also measured. Maximum concentrations of BFA (30.9 nM) and TFA (3.91 nM) in the anterior chamber are sufficient to fully activate the FP prostanoid receptors in the target cells of the ciliary muscle and trabecular meshwork. Both bimatoprost in LUMIGAN and travoprost in TRAVATAN are essentially prodrugs that are rapidly hydrolyzed to their respective free acids that induce the IOP-lowering effect observed with both drugs in vivo.

Glaucoma: a review of adjunctive therapy and new management strategies

Glaucoma is a major cause of vision loss throughout the world. Treatment for glaucoma consists of reducing intraocular pressure (IOP) to an acceptable target range to prevent further optic nerve damage. Typically, this involves the selection of a topical IOP-lowering agent. Five major classes of glaucoma medications are presently available for clinical use. These include α-adrenergic agonists, β-adrenergic antagonists (β-blockers), carbonic anhydrase inhibitors (CAIs), cholinergics and prostaglandin analogs (PGAs). Although β-blockers enjoyed great success as first-line glaucoma therapy for many years, recently the PGAs have gained favor as the initial treatment of choice for most patients. Although the PGAs offer robust IOP reduction as monotherapy, a significant number of patients will require an adjunctive agent for adequate IOP control. Recent studies have demonstrated that α-agonists, β-blockers and CAIs can be used safely and effectively as adjunctive therapy for patients being treated with a PGA. Comparison studies are beginning to appear in the literature to help determine which adjunctive agent is the most effective when used in combination with a PGA. Additional IOP-lowering efficacy with adjunctive therapy does have limitations, particularly with the addition of a third or fourth agent. For those patients on maximal tolerated medical therapy who still need additional IOP reduction, other available options include laser trabeculoplasty and filtration surgery.

Central corneal thickness in patients with congenital aniridia.

Purpose. To compare the mean central corneal thickness (CCT) in patients with congenital aniridia to that of a group of age-matched control subjects. The findings of specular and confocal microscopy in a patient with aniridia are discussed. Methods. The mean values of five consecutive pachymetry measurements of patients with aniridia and control subjects were used for analysis. Statistical analysis was performed with a Mann–Whitney rank sum test. Specular microscopy was performed on one patient with aniridia using a Konan Specular Microscope Noncon ROBO CA (Hyogo, Japan). Confocal microscopy through focusing was performed with the Tandem Scanning Confocal Microscope (Reston, VA). Results. Mean CCT measured 691.8 ± 75.4 μm for patients with aniridia (16 eyes of 10 patients) and 548.2 ± 21.2 μm for control subjects (P<0.001). Specular microscopy in a patient with aniridia showed normal endothelial cell counts and structure. Confocal microscopy through focusing of this patient showed normal-appearing keratocytes and a thick corneal stroma. Conclusions. Patients with congenital aniridia have significantly thicker corneas than do age-matched control subjects. This difference can have important implications for the treatment of those patients who develop secondary glaucoma. The increased CCT in patients with aniridia is not a result of endothelial dysfunction but appears to be the result of the production of a thickened but otherwise healthy cornea by the mutated PAX6 gene.

Comparison of the Safety and Efficacy of Dorzolamide 2% and Brimonidine 0.2% in Patients with Glaucoma or Ocular Hypertension

Purpose:To compare the intraocular pressure (IOP) reduction between dorzolamide 2% and brimonidine 0.2% in primary open-angle glaucoma (POAG) or ocular hypertension (OHT). Methods:This study was a prospective, double-masked, randomized, crossover comparison of dorzolamide 2% (Trusopt®) and brimonidine 0.2% (Alphagan®), three times daily during two six-week study periods. The primary endpoint was mean change from baseline in trough IOP and secondary endpoints were mean change from baseline in IOP one and three hours after dosing. T-tests and a repeated-measures ANOVA were used to statistically evaluate the data. Results:Of 43 patients enrolled, 41 completed the first treatment and 38 completed both treatments. Baseline IOP for dorzolamide was 24.3 mm Hg and brimonidine, 24.6 mm Hg (P = 0.9). Mean IOP reduction at trough was similar for both agents, 3.0 mm Hg (P = 0.96). Reductions at one and three hours were comparable (P = ns). Both agents were well tolerated with adverse events consistent with the package inserts. Dorzolamide was associated with more frequent stinging (P = 0.017) and burning (P < 0.001), while brimonidine was associated with more frequent dry eye (P = 0.04). Conclusions:Dorzolamide and brimonidine, as monotherapy, produced equivalent IOP-lowering efficacy at trough and at one and three hours after instillation, and both were well tolerated.

Travoprost – a new prostaglandin analogue for the treatment of glaucoma

Travoprost, a highly selective and potent analogue of the prostaglandin PGF2 α, has recently been approved and marketed as a topical ocular hypotensive agent for the treatment of ocular hypertension and glaucoma. Following absorption into the eye, the free acid form of travoprost interacts with the endogenous FP prostanoid receptor to enhance aqueous humor outflow and lower intraocular pressure (IOP). Travoprost is distinguished from other marketed prostaglandin analogues in that it is a full agonist at the prostaglandin receptor. It is also highly selective with little or no affinity for other prostanoid or non-prostanoid receptors in the eye. Travoprost provides robust lowering of IOP with little diurnal fluctuation and results in low target pressures in a large percentage of patients. In controlled clinical trials, travoprost 0.004% o.d. used as monotherapy produced greater IOP reduction than timolol 0.5% b.i.d. and equal or greater reduction than latanoprost 0.005% o.d. Travoprost 0.004% was also shown to be an effective adjunctive agent offering an additional 5 – 7 mmHg IOP reduction in patients inadequately controlled on timolol 0.5%. Subgroup analysis of a large Phase III trial revealed travoprost 0.004% to be significantly more effective at lowering IOP in African American patients by almost 2 mmHg compared to non-African Americans. Moreover, a higher percentage of African American patients responded to travoprost 0.004% and reached lower target pressures than with either latanoprost 0.005% or timolol 0.5%. Travoprost is a very stable compound, maintaining its efficacy following exposure to extremely low and high temperatures, repeated freezing and thawing and exposure to light. Throughout all clinical trials, travoprost was found to be safe and well-tolerated with very few (< 5%) discontinuations due to adverse events. Travoprost 0.004% represents a clinically significant advance for the treatment of glaucoma and ocular hypertension, offering superior IOP reduction and diurnal control, especially among African American patients, in a safe, well-tolerated, stable formulation.