Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

6th International Symposium on Ocular Pharmacology and Therapeutics

Berlin, Germany / March 30-April 2, 2006

There is abundant evidence that the long-term use of topical agents containing commonly-used preservatives can induce ocular surface changes leading to discomfort, tear film instability, conjunctival inflammation, subconjunctival fibrosis, epithelial apoptosis and corneal surface impairment, with a heightened risk of failure for further glaucoma surgery. According to Dr. Christophe Baudouin, Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France, “You can observe subclinical inflammation in about 80% of patients on long-term topical treatment, especially among the 40% of patients who take a combination of two, three or maybe four drugs. And the preservative is the cause of the problem in 90% of cases.”

After two to three years of treatment, almost all patients will experience dry eyes or alterations of tear film. A few will develop scarring and fibrosis of the conjunctiva and cornea, which is impossible to treat even surgically because of the presence of inflammation. It is especially dangerous in such a potentially blinding disease as glaucoma. Such adverse effects obviously have a negative impact on compliance; almost 40% to 50% of glaucoma patients are poorly compliant with therapy, Dr. Baudouin commented. “We must try to use unpreserved drugs as much as possible,” he suggested.

Attributing those adverse effects to an allergy to the active compound is a mistake, according to Dr. Baudouin. In most cases, it is a direct toxic effect of a commonly used preservative. The most frequently used preservative, benzalkonium chloride (BAK) applied in concentrations of 0.015% to 0.05%, has consistently demonstrated toxic effects in experimental and clinical studies. A quaternary ammonium, BAK causes tear film instability, loss of goblet cells, squamous metaplasia, epithelial apoptosis, corneal epithelium barrier disruption, loss of endothelial cells if introduced into the anterior chamber, and even blood-aqueous barrier disruption in the early phase of pseudophakia. BAK-containing eye drops have been implicated in pseudo-ocular cicatricial pemphigoid, conjunctival keratinization and anterior uveitis. A sensitization rate to BAK of approximately 6% has been reported among patients with conjunctivitis or contact dermatitis of the eyelids. “The quaternary ammoniums are extremely toxic because they are lipophilic and destroy everything lipidic, including membranes of the eye and lipidic tear film,” Dr. Baudouin told delegates.

The carbonic anhydrase inhibitor (CAI) dorzolamide and the fixed combination of dorzolamide/timolol are the only preservative-free glaucoma topical medications obtainable in Canada. In fact, Canada is the only country worldwide in which both preservative-free formulations of the CAI are available for use in ophthalmology to avoid the potentially toxic, allergic and inflammatory reactions associated with preservative agents.

Ocular Blood Flow

“To be sure, intraocular pressure [IOP] is a risk factor for glaucoma, but some clinical cases are not well explained by elevated pressure alone,” reported Dr. Peter Netland, Hamilton Eye Institute, University of Tennessee, Memphis. “In low-tension glaucoma, progression often occurs despite low IOP. On the other hand, many patients with ocular hypertension do not progress, even with high IOP. This has raised the concept of non-pressure-dependent risk factors, one of which is ocular blood flow.”

In an evidence-based review of 606 articles examining ocular blood flow, Dr. Netland found strong support for the premise that blood flow abnormalities are common in glaucoma patients, and that glaucoma medication can improve ocular blood flow. He noted that the American Academy of Ophthalmology preferred practice pattern now states that “elevated IOP is not necessary for the diagnosis of glaucoma,” and the European Glaucoma Society advises its members that “progression of glaucomatous optic neuropathy is dependent not only on IOP, but is also related to the vascular supply to the optic nerve head.”

There is interplay between increased IOP and ischemia that appears to be relevant to the pathogenesis of the disease. Vascular dysfunction and ischemia may trigger glutamate release and start a cascade of events leading to apoptosis of retinal ganglion cells, all of which are independent of IOP, he explained. These events may include abnormalities of perfusion pressure and autoregulation, vasospasm and anomalies in the circulation. Autoregulation maintains constant blood flow despite variations in perfusion pressure in the eye, Dr. Netland elaborated. It has become evident that autoregulation is atypical in glaucoma patients. Researchers in Germany have recently demonstrated that dorzolamide improves vascular autoregulation in glaucoma patients (Nagel et al. Curr Eye Res 2005;30(2):129-37).

According to Dr. Mark R. Lesk, Department of Ophthalmology, Université de Montréal, Quebec, the most comprehensive literature on eye drops for glaucoma relates to dorzolamide, which appears to be the only topical agent to consistently improve blood flow to the choroid, retina, retinal rim, cuff and most likely to the retrobulbar compartment. The CAI appears to work by increasing the partial pressure of oxygen in the optic nerve head and this effect appears to be independent of IOP. “In one of the largest and best studies in the ocular blood flow literature, dorzolamide and timolol given to 140 glaucoma patients had similar impacts on IOP reduction at two weeks, three months and six months, but only dorzolamide had a positive impact on neuroretinal rim blood flow, cuff blood flow and choroidal blood flow in the eye.”

Clinical Trials

Examining the effect of dorzolamide and timolol on variations in both IOP and ocular blood flow in glaucoma patients, investigators found that the CAI significantly improved retinal blood flow. Dr. Francesco Parmeggiani, Ferrara University Department of Ophthalmology, Italy, reported co-administration of the two agents lowered IOP from 18.6 to 16.4 mm Hg, which was a statistically significant improvement compared to timolol monotherapy (P<0.001); mean retinal blood flow increased from 285 arbitrary units (AU) to 330 AU (P<0.001). Administration of the two compounds as a single, fixed combination further increased mean retinal blood flow from 330 AU to 353 AU (P<0.05). No visual field variations occurred, he added. Researchers indicated that their data support the beneficial effect of the CAI on optic nerve head hemodynamics. “Given that vascular dysregulation appears to be an early manifestation in glaucoma, dorzolamide may benefit optic nerve head preservation by increasing ocular perfusion,” they concluded.

Dr. Oczan Kayikcioglu, Celal Bayar University, Manisa, Turkey, addressed the issue of treating glaucoma patients who have very high IOP and serious optic nerve damage. Noting that surgery in such advanced glaucoma carries significant risk and single-agent medical therapy might reduce IOP by only 20% to 35% at best, his group undertook a three-month trial of the fixed dorzolamide/timolol combination co-administered with the prostaglandin analog latanoprost in 21 previously untreated advanced glaucoma patients with very high cup:disc ratios, low visual acuity and IOP >30 mm Hg in at least one eye. “We started with a mean IOP of 38.7 mm Hg and achieved a surprising 16.1 mm Hg after the first month and 18.5 mm Hg after month 3, which we considered satisfactory,” Dr. Kayikcioglu reported. “This cohort consisted of 10 patients with primary open-angle glaucoma [POAG], seven with pseudoexfoliation syndrome, three with chronic angle closure and one case of angle recession. We had similar results among the subgroup with POAG, lowering IOP from 39.1 mm Hg to 15.8 mm Hg after one month and to 18.6mm Hg after three months with the prostaglandin analog added to the CAI and timolol fixed combination.”

Regarding side effects, he said five had moderate hyperemia and two complained of metallic taste, but none were serious events. “However, we had 10 individuals who were unresponsive to treatment, defined as having IOP remaining higher than 22 mm Hg, or found it too hard to comply with the regimen at three months,” he told delegates. “They were mainly exfoliative and chronic narrow-angle glaucoma patients and were offered surgery. We had nice short-term results, but were worried that this particular group might not adhere well to the regimen. These were difficult cases because they had high pressures and advanced glaucoma, but slightly more than half of them were able to avoid surgery with this therapy.”

According to Dr. Kayikcioglu, dorzolamide, timolol and latanoprost is the best maximum therapy that could have been offered to such advanced-disease patients and he feels they achieved a very satisfactory and well-tolerated response to this novel treatment strategy.

Summary

Dr. Alon Harris, Director, Glaucoma Research and Diagnostic Center, Indiana University School of Medicine, Indianapolis, indicated the importance of looking at vascular risk factors in glaucoma emerged from the same evidence-based population studies that only in the last decade actually confirmed the role of IOP. The studies demonstrate numerous ocular hemodynamic deficits in POAG, whether or not the patients have elevated IOP, and that optic nerve head blood flow is impaired early in the glaucomatous process, suggesting a role in the pathogenic process.